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Posts Tagged ‘Human Genome Project’


International Award for Human Genome Project

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

The Thai royal family awarded its annual prizes in Bangkok, Thailand, in late January 2018 in recognition of advances in public health and medicine – through the Prince Mahidol Award Foundation under the Royal Patronage. This foundation was established in 1992 to honor the late Prince Mahidol of Songkla, the Royal Father of His Majesty King Bhumibol Adulyadej of Thailand and the Royal Grandfather of the present King. Prince Mahidol is celebrated worldwide as the father of modern medicine and public health in Thailand.

 

The Human Genome Project has been awarded the 2017 Prince Mahidol Award for revolutionary advances in the field of medicine. The Human Genome Project was completed in 2003. It was an international, collaborative research program aimed at the complete mapping and sequencing of the human genome. Its final goal was to provide researchers with fundamental information about the human genome and powerful tools for understanding the genetic factors in human disease, paving the way for new strategies for disease diagnosis, treatment and prevention.

 

The resulting human genome sequence has provided a foundation on which researchers and clinicians now tackle increasingly complex problems, transforming the study of human biology and disease. Particularly it is satisfying that it has given the researchers the ability to begin using genomics to improve approaches for diagnosing and treating human disease thereby beginning the era of genomic medicine.

 

National Human Genome Research Institute (NHGRI) is devoted to advancing health through genome research. The institute led National Institutes of Health’s (NIH’s) contribution to the Human Genome Project, which was successfully completed in 2003 ahead of schedule and under budget. NIH, is USA’s national medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases.

 

Building on the foundation laid by the sequencing of the human genome, NHGRI’s work now encompasses a broad range of research aimed at expanding understanding of human biology and improving human health. In addition, a critical part of NHGRI’s mission continues to be the study of the ethical, legal and social implications of genome research.

 

References:

 

https://www.nih.gov/news-events/news-releases/human-genome-project-awarded-thai-2017-prince-mahidol-award-field-medicine

 

http://www.mfa.go.th/main/en/news3/6886/83875-Announcement-of-the-Prince-Mahidol-Laureates-2017.html

 

http://www.thaiembassy.org/london/en/news/7519/83884-Announcement-of-the-Prince-Mahidol-Laureates-2017.html

 

http://englishnews.thaipbs.or.th/us-human-genome-project-influenza-researchers-win-prince-mahidol-award-2017/

 

http://genomesequencing.com/the-human-genome-project-is-awarded-the-thai-2017-prince-mahidol-award-for-the-field-of-medicine-national-institutes-of-health-press-release/

 

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The Human Genome Project

Larry H Bernstein, MD, FCAP, Curator

Leaders in Pharmaceutical Intelligence

Series E. 2; 2.12

 

Craig Venter, Francis Collins

Francis Sellers Collins (born April 14, 1950) is an American physiciangeneticist noted for his discoveries of disease genes and his leadership of the Human Genome Project. He is director of the National Institutes of Health (NIH) in Bethesda, Maryland.

Before being appointed director of the NIH, Collins led the Human Genome Project and other genomics research initiatives as director of the National Human Genome Research Institute (NHGRI), one of the 27 institutes and centers at NIH. Before joining NHGRI, he earned a reputation as a gene hunter at the University of Michigan. He has been elected to the Institute of Medicine and the National Academy of Sciences, and has received the Presidential Medal of Freedom and the National Medal of Science.

Collins also has written a number of books on science, medicine, and spirituality, including the New York Times bestseller, The Language of God: A Scientist Presents Evidence for Belief.

After leaving the helm of NHGRI and before becoming director of the NIH, he founded and served as president of The BioLogos Foundation, which promotes discourse on the relationship between science and religion and advocates the perspective that belief in Christianity can be reconciled with acceptance of evolution and science, especially through the advancement of evolutionary creation.[1] In 2009, Pope Benedict XVI appointed Collins to the Pontifical Academy of Sciences.

Collins was born in Staunton, Virginia, the youngest of four sons of Fletcher Collins and Margaret James Collins. Raised on a small farm in Virginia’s Shenandoah Valley, Collins was home schooled until the sixth grade.[2] He attended Robert E. Lee High School in Staunton, Virginia. Through most of his high school and college years he aspired to be a chemist, and he had little interest in what he then considered the “messy” field of biology. What he referred to as his “formative education” was received at the University of Virginia, where he earned a Bachelor of Science in Chemistry in 1970. He earned a Doctor of Philosophy in Physical Chemistry at Yale University in 1974. While at Yale, a course in biochemistry sparked his interest in the subject. After consulting with his mentor from the University of Virginia, Carl Trindle, he changed fields and enrolled in medical school at the University of North Carolina at Chapel Hill, earning an Doctor of Medicine there in 1977.

At Yale, Collins worked under the direction of Sherman Weissman, and in 1984 the two published a paper, “Directional Cloning of DNA Fragments at a Large distance From an Initial Probe: a Circularization Method”.[3] The method described was named chromosome jumping, to emphasize the contrast with an older and much more time-consuming method of copying DNA fragments called chromosome walking.[4]

Collins joined the University of Michigan faculty in 1984, rising to the rank of professor in internal medicine and human genetics. His gene-hunting approach, which he named “positional cloning”,[5][6] developed into a powerful[7] component of modern molecular genetics.

Several scientific teams worked in the 1970s and 1980s to identify genes and their loci as a cause of cystic fibrosis. Progress was modest until 1985, when Lap-Chee Tsui and colleagues at Toronto’s Hospital for Sick Children identified the locus for the gene.[8] It was then determined that a shortcut was needed to speed the process of identification, so Tsui contacted Collins, who agreed to collaborate with the Toronto team and share his chromosome-jumping technique. The gene was identified in June 1989,[9][10] and the results were published in the journal Science on Sept. 8, 1989.[11] This identification was followed by other genetic discoveries made by Collins and a variety of collaborators. They included isolation of the genes for Huntington’s disease,[12] neurofibromatosis,[13][14] multiple endocrine neoplasia type 1,[15] and Hutchinson-Gilford Progeria Syndrome.[16]

In 1993, National Institutes of Health Director Bernadine Healy appointed Collins to succeed James D. Watson as director of the National Center for Human Genome Research, which became National Human Genome Research Institute (NHGRI) in 1997. As director, he oversaw the International Human Genome Sequencing Consortium,[17] which was the group that successfully carried out the Human Genome Project.

In 1994, Collins founded NHGRI’s Division of Intramural Research,[18] a collection of investigator-directed laboratories that conduct genome research on the NIH campus.

In June 2000, Collins was joined by President Bill Clinton and biologist Craig Venter in making the announcement of a working draft of the human genome.[19] He stated that “It is humbling for me, and awe-inspiring to realize that we have caught the first glimpse of our own instruction book, previously known only to God.”[20][21][22] An initial analysis was published in February 2001, and scientists worked toward finishing the reference version of the human genome sequence by 2003, coinciding with the 50th anniversary of James D. Watson and Francis Crick‘s publication of the structure of DNA.

Another major activity at NHGRI during his tenure as director was the creation of the haplotype map of the human genome. This International HapMap Project produced a catalog of human genetic variations—called single-nucleotide polymorphisms—which is now being used to discover variants correlated with disease risk. Among the labs engaged in that effort is Collins’ own lab at NHGRI, which has sought to identify and understand the genetic variations that influence the risk of developing type 2 diabetes.

In addition to his basic genetic research and scientific leadership, Collins is known for his close attention to ethical and legal issues in genetics. He has been a strong advocate for protecting the privacy of genetic information and has served as a national leader in securing the passage of the federal Genetic Information and Nondiscrimination Act, which prohibits gene-based discrimination in employment and health insurance.[23] In 2013, spurred by concerns over the publication of the genome of the widely used HeLa cell line derived from the late Henrietta Lacks, Collins and other NIH leaders worked with the Lacks family to reach an agreement to protect their privacy, while giving researchers controlled access to the genomic data.[24]

Building on his own experiences as a physician volunteer in a rural missionary hospital in Nigeria,[25] Collins is also very interested in opening avenues for genome research to benefit the health of people living in developing nations. For example, in 2010, he helped establish an initiative called Human Heredity and Health in Africa (H3Africa)[26] to advance African capacity and expertise in genomic science.

Collins announced his resignation from NHGRI on May 28, 2008, but has continued to maintain an active lab there.[27]

While leading the National Human Genome Research Institute, Collins was elected to the Institute of Medicine and the National Academy of Sciences. He was a Kilby International Awards recipient in 1993, and he received the Biotechnology Heritage Award with J. Craig Venter in 2001.[45][46] He received the William Allan Award from the American Society of Human Genetics in 2005. In 2007, he was presented with thePresidential Medal of Freedom.[47] In 2008, he was awarded the Inamori Ethics Prize[48] and National Medal of Science.[49] In the same year, Collins won the Trotter Prize where he delivered a lecture called “The Language of God”.

Francis Collins: The Scientist as Believer

http://ngm.nationalgeographic.com/ngm/0702/voices.html

The often strained relationship between science and religion has become particularly combative lately. In one corner we have scientists such as Richard Dawkins and Steven Pinker who view religion as a relic of our superstitious, prescientific past that humanity should abandon. In the other corner are religious believers who charge that science is morally nihilistic and inadequate for understanding the wonders of existence. Into this breach steps Francis Collins, who offers himself as proof that science and religion can be reconciled. As leader of the Human Genome Project, Collins is among the world’s most important scientists, the head of a multibillion-dollar research program aimed at understanding human nature and healing our innate disorders. And yet in his best-selling book,The Language of God, he recounts how he accepted Christ as his savior in 1978 and has been a devout Christian ever since. “The God of the Bible is also the God of the genome,” he writes. “He can be worshiped in the cathedral or in the laboratory.” Recently Collins discussed his faith with science writer John Horgan, who has explored the boundaries between science and spirituality in his own books The End of Science and Rational Mysticism. Horgan, who has described himself as “an agnostic increasingly disturbed by religion’s influence on human affairs,” directs the Center for Science Writings at the Stevens Institute of Technology in Hoboken, New Jersey.

Interview by John Horgan

Horgan: As a scientist who looks for natural explanations of things and demands evidence, how can you also believe in miracles, like the resurrection?

Collins: I don’t have a problem with the concept that miracles might occasionally occur at moments of great significance, where there is a message being transmitted to us by God Almighty. But as a scientist I set my standards for miracles very high.

Horgan: The problem I have with miracles is not just that they violate what science tells us about how the world works. They also make God seem too capricious. For example, many people believe that if they pray hard enough God will intercede to heal them or a loved one. But does that mean that all those who don’t get better aren’t worthy?

Collins: In my own experience as a physician, I have not seen a miraculous healing, and I don’t expect to see one. Also, prayer for me is not a way to manipulate God into doing what we want him to do. Prayer for me is much more a sense of trying to get into fellowship with God. I’m trying to figure out what I should be doing rather than telling Almighty God what he should be doing. Look at the Lord’s Prayer. It says, “Thy will be done.” It wasn’t, “Our Father who art in Heaven, please get me a parking space.”

Horgan: I must admit that I’ve become more concerned lately about the harmful effects of religion because of religious terrorism like 9/11 and the growing power of the religious right in the United States.

Collins: What faith has not been used by demagogues as a club over somebody’s head? Whether it was the Inquisition or the Crusades on the one hand or the World Trade Center on the other? But we shouldn’t judge the pure truths of faith by the way they are applied any more than we should judge the pure truth of love by an abusive marriage. We as children of God have been given by God this knowledge of right and wrong, this Moral Law, which I see as a particularly compelling signpost to his existence. But we also have this thing called free will, which we exercise all the time to break that law. We shouldn’t blame faith for the ways people distort it and misuse it.

Horgan: Many people have a hard time believing in God because of the problem of evil. If God loves us, why is life filled with so much suffering?

Collins: That is the most fundamental question that all seekers have to wrestle with. First of all, if our ultimate goal is to grow, learn, and discover things about ourselves and things about God, then unfortunately a life of ease is probably not the way to get there. I know I have learned very little about myself or God when everything is going well. Also, a lot of the pain and suffering in the world we cannot lay at God’s feet. God gave us free will, and we may choose to exercise it in ways that end up hurting other people.

Horgan: Physicist Steven Weinberg, who is an atheist, asks why six million Jews, including his relatives, had to die in the Holocaust so that the Nazis could exercise their free will.

Collins: If God had to intervene miraculously every time one of us chose to do something evil, it would be a very strange, chaotic, unpredictable world. Free will leads to people doing terrible things to each other. Innocent people die as a result. You can’t blame anyone except the evildoers for that. So that’s not God’s fault. The harder question is when suffering seems to have come about through no human ill action. A child with cancer, a natural disaster, a tornado or tsunami. Why would God not prevent those things from happening?

Horgan: Some philosophers, such as Charles Hartshorne, have suggested that maybe God isn’t fully in control of his creation. The poet Annie Dillard expresses this idea in her phrase “God the semi-competent.”

Collins: That’s delightful—and probably blasphemous! An alternative is the notion of God being outside of nature and time and having a perspective of our blink-of-an-eye existence that goes both far back and far forward. In some admittedly metaphysical way, that allows me to say that the meaning of suffering may not always be apparent to me. There can be reasons for terrible things happening that I cannot know.

Horgan: I’m an agnostic, and I was bothered when in your book you called agnosticism a “cop-out.” Agnosticism doesn’t mean you’re lazy or don’t care. It means you aren’t satisfied with any answers for what after all are ultimate mysteries.

Collins: That was a put-down that should not apply to earnest agnostics who have considered the evidence and still don’t find an answer. I was reacting to the agnosticism I see in the scientific community, which has not been arrived at by a careful examination of the evidence. I went through a phase when I was a casual agnostic, and I am perhaps too quick to assume that others have no more depth than I did.

Horgan: Free will is a very important concept to me, as it is to you. It’s the basis for our morality and search for meaning. Don’t you worry that science in general and genetics in particular—and your work as head of the Genome Project—are undermining belief in free will?

Collins: You’re talking about genetic determinism, which implies that we are helpless marionettes being controlled by strings made of double helices. That is so far away from what we know scientifically! Heredity does have an influence not only over medical risks but also over certain behaviors and personality traits. But look at identical twins, who have exactly the same DNA but often don’t behave alike or think alike. They show the importance of learning and experience—and free will. I think we all, whether we are religious or not, recognize that free will is a reality. There are some fringe elements that say, “No, it’s all an illusion, we’re just pawns in some computer model.” But I don’t think that carries you very far.

Horgan: What do you think of Darwinian explanations of altruism, or what you call agape, totally selfless love and compassion for someone not directly related to you?

Collins: It’s been a little of a just-so story so far. Many would argue that altruism has been supported by evolution because it helps the group survive. But some people sacrificially give of themselves to those who are outside their group and with whom they have absolutely nothing in common. Such as Mother Teresa, Oskar Schindler, many others. That is the nobility of humankind in its purist form. That doesn’t seem like it can be explained by a Darwinian model, but I’m not hanging my faith on this.

Horgan: What do you think about the field of neurotheology, which attempts to identify the neural basis of religious experiences?

Collins: I think it’s fascinating but not particularly surprising. We humans are flesh and blood. So it wouldn’t trouble me—if I were to have some mystical experience myself—to discover that my temporal lobe was lit up. That doesn’t mean that this doesn’t have genuine spiritual significance. Those who come at this issue with the presumption that there is nothing outside the natural world will look at this data and say, “Ya see?” Whereas those who come with the presumption that we are spiritual creatures will go, “Cool! There is a natural correlate to this mystical experience! How about that!”

Horgan: Some scientists have predicted that genetic engineering may give us superhuman intelligence and greatly extended life spans, perhaps even immortality. These are possible long-term consequences of the Human Genome Project and other lines of research. If these things happen, what do you think would be the consequences for religious traditions?

Collins: That outcome would trouble me. But we’re so far away from that reality that it’s hard to spend a lot of time worrying about it, when you consider all the truly benevolent things we could do in the near term.

Horgan: I’m really asking, does religion require suffering? Could we reduce suffering to the point where we just won’t need religion?

Collins: In spite of the fact that we have achieved all these wonderful medical advances and made it possible to live longer and eradicate diseases, we will probably still figure out ways to argue with each other and sometimes to kill each other, out of our self-righteousness and our determination that we have to be on top. So the death rate will continue to be one per person, whatever the means. We may understand a lot about biology, we may understand a lot about how to prevent illness, and we may understand the life span. But I don’t think we’ll ever figure out how to stop humans from doing bad things to each other. That will always be our greatest and most distressing experience here on this planet, and that will make us long the most for something more.

Policy: NIH plans to enhance reproducibility

Francis S. Collins& Lawrence A. Tabak

A growing chorus of concern, from scientists and laypeople, contends that the complex system for ensuring the reproducibility of biomedical research is failing and is in need of restructuring12. As leaders of the US National Institutes of Health (NIH), we share this concern and here explore some of the significant interventions that we are planning.

Science has long been regarded as ‘self-correcting’, given that it is founded on the replication of earlier work. Over the long term, that principle remains true. In the shorter term, however, the checks and balances that once ensured scientific fidelity have been hobbled. This has compromised the ability of today’s researchers to reproduce others’ findings.

Let’s be clear: with rare exceptions, we have no evidence to suggest that irreproducibility is caused by scientific misconduct. In 2011, the Office of Research Integrity of the US Department of Health and Human Services pursued only 12 such cases3. Even if this represents only a fraction of the actual problem, fraudulent papers are vastly outnumbered by the hundreds of thousands published each year in good faith.

Instead, a complex array of other factors seems to have contributed to the lack of reproducibility. Factors include poor training of researchers in experimental design; increased emphasis on making provocative statements rather than presenting technical details; and publications that do not report basic elements of experimental design4. Crucial experimental design elements that are all too frequently ignored include blinding, randomization, replication, sample-size calculation and the effect of sex differences. And some scientists reputedly use a ‘secret sauce’ to make their experiments work — and withhold details from publication or describe them only vaguely to retain a competitive edge5. What hope is there that other scientists will be able to build on such work to further biomedical progress?

Exacerbating this situation are the policies and attitudes of funding agencies, academic centres and scientific publishers. Funding agencies often uncritically encourage the overvaluation of research published in high-profile journals. Some academic centres also provide incentives for publications in such journals, including promotion and tenure, and in extreme circumstances, cash rewards6.

Then there is the problem of what is not published. There are few venues for researchers to publish negative data or papers that point out scientific flaws in previously published work. Further compounding the problem is the difficulty of accessing unpublished data — and the failure of funding agencies to establish or enforce policies that insist on data access.

Nature special: Challenges in irreproducible research

Preclinical problems

Reproducibility is potentially a problem in all scientific disciplines. However, human clinical trials seem to be less at risk because they are already governed by various regulations that stipulate rigorous design and independent oversight — including randomization, blinding, power estimates, pre-registration of outcome measures in standardized, public databases such as ClinicalTrials.gov and oversight by institutional review boards and data safety monitoring boards. Furthermore, the clinical trials community has taken important steps towards adopting standard reporting elements7.

Preclinical research, especially work that uses animal models1, seems to be the area that is currently most susceptible to reproducibility issues. Many of these failures have simple and practical explanations: different animal strains, different lab environments or subtle changes in protocol. Some irreproducible reports are probably the result of coincidental findings that happen to reach statistical significance, coupled with publication bias. Another pitfall is overinterpretation of creative ‘hypothesis-generating’ experiments, which are designed to uncover new avenues of inquiry rather than to provide definitive proof for any single question. Still, there remains a troubling frequency of published reports that claim a significant result, but fail to be reproducible.

Proposed NIH actions

As a funding agency, the NIH is deeply concerned about this problem. Because poor training is probably responsible for at least some of the challenges, the NIH is developing a training module on enhancing reproducibility and transparency of research findings, with an emphasis on good experimental design. This will be incorporated into the mandatory training on responsible conduct of research for NIH intramural postdoctoral fellows later this year. Informed by this pilot, final materials will be posted on the NIH website by the end of this year for broad dissemination, adoption or adaptation, on the basis of local institutional needs.

“Efforts by the NIH alone will not be sufficient to effect real change in this unhealthy environment.”

Several of the NIH’s institutes and centres are also testing the use of a checklist to ensure a more systematic evaluation of grant applications. Reviewers are reminded to check, for example, that appropriate experimental design features have been addressed, such as an analytical plan, plans for randomization, blinding and so on. A pilot was launched last year that we plan to complete by the end of this year to assess the value of assigning at least one reviewer on each panel the specific task of evaluating the ‘scientific premise’ of the application: the key publications on which the application is based (which may or may not come from the applicant’s own research efforts). This question will be particularly important when a potentially costly human clinical trial is proposed, based on animal-model results. If the antecedent work is questionable and the trial is particularly important, key preclinical studies may first need to be validated independently.

Informed by feedback from these pilots, the NIH leadership will decide by the fourth quarter of this year which approaches to adopt agency-wide, which should remain specific to institutes and centres, and which to abandon.

The NIH is also exploring ways to provide greater transparency of the data that are the basis of published manuscripts. As part of our Big Data initiative, the NIH has requested applications to develop a Data Discovery Index (DDI) to allow investigators to locate and access unpublished, primary data (see go.nature.com/rjjfoj). Should an investigator use these data in new work, the owner of the data set could be cited, thereby creating a new metric of scientific contribution unrelated to journal publication, such as downloads of the primary data set. If sufficiently meritorious applications to develop the DDI are received, a funding award of up to three years in duration will be made by September 2014. Finally, in mid-December, the NIH launched an online forum called PubMed Commons (see go.nature.com/8m4pfp) for open discourse about published articles. Authors can join and rate or contribute comments, and the system is being evaluated and refined in the coming months. More than 2,000 authors have joined to date, contributing more than 700 comments.

Community responsibility

Clearly, reproducibility is not a problem that the NIH can tackle alone. Consequently, we are reaching out broadly to the research community, scientific publishers, universities, industry, professional organizations, patient-advocacy groups and other stakeholders to take the steps necessary to reset the self-corrective process of scientific inquiry. Journals should be encouraged to devote more space to research conducted in an exemplary manner that reports negative findings, and should make room for papers that correct earlier work.

Related stories

We are pleased to see that some of the leading journals have begun to change their review practices. For example, Nature Publishing Group, the publishers of this journal, announced8 in May 2013 the following: restrictions on the length of methods sections have been abolished to ensure the reporting of key methodological details; authors use a checklist to facilitate the verification by editors and reviewers that critical experimental design features have been incorporated into the report, and editors scrutinize the statistical treatment of the studies reported more thoroughly with the help of statisticians. Furthermore, authors are encouraged to provide more raw data to accompany their papers online.

Similar requirements have been implemented by the journals of the American Association for the Advancement of Science — Science Translational Medicine in 2013 and Science earlier this month9 — on the basis of, in part, the efforts of the NIH’s National Institute of Neurological Disorders and Stroke to increase the transparency of how work is conducted10.

Perhaps the most vexed issue is the academic incentive system. It currently over-emphasizes publishing in high-profile journals. No doubt worsened by current budgetary woes, this encourages rapid submission of research findings to the detriment of careful replication. To address this, the NIH is contemplating modifying the format of its ‘biographical sketch’ form, which grant applicants are required to complete, to emphasize the significance of advances resulting from work in which the applicant participated, and to delineate the part played by the applicant. Other organizations such as the Howard Hughes Medical Institute have used this format and found it more revealing of actual contributions to science than the traditional list of unannotated publications. The NIH is also considering providing greater stability for investigators at certain, discrete career stages, utilizing grant mechanisms that allow more flexibility and a longer period than the current average of approximately four years of support per project.

In addition, the NIH is examining ways to anonymize the peer-review process to reduce the effect of unconscious bias (see go.nature.com/g5xr3c). Currently, the identifiers and accomplishments of all research participants are known to the reviewers. The committee will report its recommendations within 18 months.

Efforts by the NIH alone will not be sufficient to effect real change in this unhealthy environment. University promotion and tenure committees must resist the temptation to use arbitrary surrogates, such as the number of publications in journals with high impact factors, when evaluating an investigator’s scientific contributions and future potential.

The recent evidence showing the irreproducibility of significant numbers of biomedical-research publications demands immediate and substantive action. The NIH is firmly committed to making systematic changes that should reduce the frequency and severity of this problem — but success will come only with the full engagement of the entire biomedical-research enterprise.

 

 

Craig Venter, PhD

  1. Craig Venter, Ph.D., is regarded as one of the leading scientists of the 21st century for his numerous invaluable contributions to genomic research. He is founder, chairman, and CEO of the J. Craig Venter Institute (JCVI), a not-for-profit, research organization with approximately 250 scientists and staff dedicated to human, microbial, plant, synthetic and environmental genomic research, and the exploration of social and ethical issues in genomics.

Dr. Venter is co-founder, executive chairman and co-chief scientist of Synthetic Genomics Inc (SGI), a privately held company focused on developing products and solutions using synthetic genomics technologies.

Dr. Venter is also a co-founder, executive chairman and CEO of Human Longevity Inc (HLI), a San Diego-based genomics and cell therapy-based diagnostic and therapeutic company focused on extending the healthy, high performance human life span.

Dr. Venter began his formal education after a tour of duty as a Navy Corpsman in Vietnam from 1967 to 1968. After earning both a Bachelor’s degree in Biochemistry and a Ph.D. in Physiology and Pharmacology from the University of California at San Diego, he was appointed professor at the State University of New York at Buffalo and the Roswell Park Cancer Institute. In 1984, he moved to the National Institutes of Health campus where he developed Expressed Sequence Tags or ESTs, a revolutionary new strategy for rapid gene discovery. In 1992 Dr. Venter founded The Institute for Genomic Research (TIGR, now part of JCVI), a not-for-profit research institute, where in 1995 he and his team decoded the genome of the first free-living organism, the bacterium Haemophilus influenzae, using his new whole genome shotgun technique.

In 1998, Dr. Venter founded Celera Genomics to sequence the human genome using new tools and techniques he and his team developed. This research culminated with the February 2001 publication of the human genome in the journal, Science. He and his team at Celera also sequenced the fruit fly, mouse and rat genomes.

Dr. Venter and his team at JCVI continue to blaze new trails in genomics. They have sequenced and analyzed hundreds of genomes, and have published numerous important papers covering such areas as environmental genomics, the first complete diploid human genome, and the groundbreaking advance in creating the first self- replicating bacterial cell constructed entirely with synthetic DNA.

Dr. Venter is one of the most frequently cited scientists, and the author of more than 280 research articles. He is also the recipient of numerous honorary degrees, public honors, and scientific awards, including the 2008 United States National Medal of Science, the 2002 Gairdner Foundation International Award, the 2001 Paul Ehrlich and Ludwig Darmstaedter Prize and the King Faisal International Award for Science. Dr. Venter is a member of numerous prestigious scientific organizations including the National Academy of Sciences, the American Academy of Arts and Sciences, and the American Society for Microbiology.

http://www.jcvi.org/cms/about/bios/jcventer/0#sthash.tojhbWtd.dpuf

In 2001, Craig Venter made headlines for sequencing the human genome. In 2003, he started mapping the ocean’s biodiversity. And now he’s created the first synthetic lifeforms — microorganisms that can produce alternative fuels.

Craig Venter, the man who led the private effort to sequence the human genome, is hard at work now on even more potentially world-changing projects.

First, there’s his mission aboard the Sorcerer II, a 92-foot yacht, which, in 2006, finished its voyage around the globe to sample, catalouge and decode the genes of the ocean’s unknown microorganisms. Quite a task, when you consider that there are tens of millions of microbes in a single drop of sea water. Then there’s the J. Craig Venter Institute, a nonprofit dedicated to researching genomics and exploring its societal implications.

In 2005, Venter founded Synthetic Genomics, a private company with a provocative mission: to engineer new life forms. Its goal is to design, synthesize and assemble synthetic microorganisms that will produce alternative fuels, such as ethanol or hydrogen. He was on Time magzine’s 2007 list of the 100 Most Influential People in the World.

https://www.ted.com/speakers/craig_venter

https://www.ted.com/talks/craig_venter_on_dna_and_the_sea

https://www.ted.com/talks/craig_venter_is_on_the_verge_of_creating_synthetic_life

https://www.ted.com/talks/craig_venter_unveils_synthetic_life

http://www.technologyreview.com/news/529601/three-questions-for-j-craig-venter/

What’s clear is that genome research and data science are coming together in new ways, and at a much larger scale than ever before. We asked Venter why.

How are we doing in genomics?

In my view there have not been a significant number of advances. One reason for that is that genomics follows a law of very big numbers. I’ve had my genome for 15 years, and there’s not much I can learn because there are not that many others to compare it to.

Why did you hire an expert in machine translation as your top data scientist?

Until now, there’s not been software for comparing my genome to your genome, much less to a million genomes. We want to get to a point where it takes a few seconds to compare your genome to all the others. It’s going to take a lot of work to do that.

Google Translate started as a slow algorithm that took hours or days to run and was not very accurate. But Franz [Och] built a machine-learning version that could go out on the Web and find every article translated from German to English or vice versa, and learn from those. And then it was optimized, so it works in milliseconds.

I convinced Franz, and he convinced himself, that understanding the human genome at the scale that we are trying to do it is going to be one of the greatest translation challenges in history.

How is discovering the connection between genes and disease like translating languages?

Everything in a cell derives from your DNA code, all the proteins, their structure, whether they last seconds or days. All that is preprogrammed in DNA language. Then it is translated into life. People are going to be very surprised about how much of a DNA software species we are.

WHAT IS LIFE? A 21st CENTURY PERSPECTIVE

On the 70th Anniversary of Schroedinger’s Lecture at Trinity College by J. Craig Venter [7.12.12]

Introduction
by John Brockman

Several weeks ago, I received the following message from Craig Venter:

“John,

“I would like to extend an invitation for you to join me in Dublin, Ireland the week of July 10 during which one of the landmark events of 20th Century science will be celebrated and reinterpreted for the 21st Century as part of the Science in the City program of Euroscience Open Forum 2012 (ESOF 2012). This unique event will connect an important episode in Ireland’s scientific heritage with the frontier of contemporary research.

“In February 1943 one of the most distinguished scientists of the 20th Century, Erwin Schrödinger, delivered a seminal lecture, entitled ‘What is Life?’, under the auspices of the Dublin Institute for Advanced Studies, in Trinity College, Dublin. The then Prime Minister, Éamon de Valera, attended the lecture and an account of it featured in the 5 April 1943, issue of Timemagazine.

“The lecture presented far-sighted ideas on how hereditary information could be encoded in a chemical structure (aperiodic crystal) in living cells. Schrödinger’s book (1944) of the same title is considered to be a scientific classic. The book was cited by Crick and Watson as one of the inspirations which ultimately led them to unravel the structure of DNA in 1953, a breakthrough which won them the Nobel prize. Recent advances in genetics and synthetic biology mean that it is now timely to reconsider the fundamental question posed by Schrödinger 70 years ago. I have been asked to revisit Schrödinger’s question and will do so in a lecture entitled “What is Life? A 21st century perspective”; on the evening of Thursday, July 12 at the Examination Hall in Trinity College Dublin.”

Never one to turn down an interesting invitation, I was able to organize an interesting week beginning with an Edge Dinner in Turin, in honor of Venter, Brian Eno and myself, where Venter, in an after-dinner talk, began to publicly present some of the new ideas he would flesh out in his Dublin talk.

Then on to Dublin, where I sat in the front row at Examination Hall next to Jim Watson and Irish Prime Minister (the “Taoiseach) Enda Kenny for Venter’s  lecture. At it’s conclusion, the two legendary scientists, Watson and Venter, shook hands on stage, as Watson congratulated Venter  for “a beautiful lecture”. Schrödinger to Watson to Venter: It was an historic moment.

WHAT IS LIFE? A 21st CENTURY PERSPECTIVE

  1. CRAIG VENTER: I was asked earlier whether the goal is to dissect what Schrödinger had spoken and written, or to present the new summary, and I always like to be forward-looking, so I won’t give you a history lesson except for very briefly. I will present our findings on first on reading the genetic code, and then learning to synthesize and write the genetic code, and as many of you know, we synthesized an entire genome, booted it up to create an entirely new synthetic cell where every protein in the cell was based on the synthetic DNA code.

As you all know, Schrödinger’s book was published in 1944 and it was based on a series of three lectures here, starting in February of 1943. And he had to repeat the lectures, I read, on the following Monday because the room on the other side of campus was too small, and I understand people were turned away tonight, but we’re grateful for Internet streaming, so I don’t have to do this twice.

Also, due clearly to his historical role, and it’s interesting to be sharing this event with Jim Watson, who I’ve known and had multiple interactions with over the last 25 years, including most recently sharing the Double Helix Prize for Human Genome Sequencing with him from Cold Spring Harbor Laboratory a few years ago.

Schrödinger started his lecture with a key question and an interesting insight on it. The question was “How can the events in space and time, which take place within the boundaries of a living organism be accounted for by physics and chemistry?” It’s a pretty straightforward, simple question. Then he   answered what he could at the time, “The obvious inability of present-day physics and chemistry to account for such events is no reason at all for doubting that they will be accounted for by those sciences.” While I only have around 40 minutes, not three lectures, I hope to convince you that there has been substantial progress in the last nearly 70 years since Schrödinger initially asked that question, to the point where the answer is at least nearly at hand, if not in hand.

I view that we’re now in what I’m calling “The Digital Age of Biology”. My teams work on synthesizing genomes based on digital code in the computer, and four bottles of chemicals illustrates the ultimate link between the computer code and the digital code.

Life is code, as you heard in the introduction, was very clearly articulated by Schrodinger as code script. Perhaps even more importantly, and something I missed on the first few readings of his book earlier in my career, was as far as I could tell, it’s the first mention that this code could be as simple as a binary code. And he used the example of how the Morse code with just dots and dashes, could be sufficient to give 34 different specifications. I’ve searched and I have not found any earlier references to the Morse code, although an historian that I know wrote Crick a letter asking about that, and Crick’s response was, “It was a metaphor that was obvious to everybody.” I don’t know if it was obvious to everybody after Schrodinger’s book, or some time before.

One of the things, though, Schrodinger was right about a lot of things, which is why, in fact, we celebrate what he talked about and what he wrote about, but some things he was clearly wrong about, like most scientists in his time, he relied on the biologist of the day. They thought that protein, not DNA was the genetic information. It’s really quite extraordinary because just in 1944 in the same year that he published his book is when the famous experiment by Oswald Avery, who was 65 and about ready to retire, along with this colleagues, Colin MacLeod and Maclyn McCarty, published their key paper demonstrating that DNA was  the substance that causes bacterial transformation, and therefore was the genetic material.

This experiment was remarkably simple, and I wonder why it wasn’t done 50 years earlier with all the wonderful genetics work going on with drosophila, and chromosomes. Avery simply used proteolytic enzymes to destroy all the proteins associated with the DNA, and showed that the DNA, the naked DNA was, in fact, a transforming factor. The impact of this paper was far from instantaneous, as has happened in this field, in part because there was so much bias against DNA and for its proteins that it took a long time for them to sink in.

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In 1949, was the first sequencing of a protein by Fred Sanger, and the protein was insulin. This work showed, in fact, that proteins consisted of linear amino acid codes. Sanger won the Nobel Prize in 1958 for his achievement. The sequence of insulin was very key in terms of leading to understanding the link between DNA and proteins. But as you heard in the introduction, obviously the discovery that changed the whole field and started us down the DNA route was the 1953 work by Watson and Crick with help from Maurice Wilkins and Rosalind Franklin showing that DNA was, in fact, a double helix which provided a clear explanation of how DNA could be self-replicated. Again, this was not, as I understand, instantly perceived as a breakthrough because of the bias of biochemists who were still hanging on to proteins as the genetic material. But soon with a few more experiments from others, the world began to change pretty dramatically.

The next big thing came from the work of Gobind Khorana and Marshall Nirenberg in 1961 where they worked out the triplet genetic code. It’s three letters of genetic code, coding for each amino acid. With this breakthrough it became clear how the linear DNA code had coded for the linear protein code. This was followed a few years later by Robert Holley’s discovery of the structure of tRNA, and tRNA is the key link between the messenger RNA and bringing in the amino acids in for  protein synthesis. Holley, Nirenberg and Khorana shared the Nobel Prize in 1968 for their work.

 

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The next decade brought us restriction enzymes from my friend and colleague, Ham Smith, who is at the Venter Institute now; in 1970 discovered the first restriction enzymes. These are the molecular scissors that cut DNA very precisely, and enabled the entire field of molecular engineering and molecular biology. Ham Smith, and Warner Arber, and Dan Nathans shared the Nobel prize in 1978 for their work. The ’70s brought not only some interesting dress codes and characters, (Laughter) but the beginning of the molecular splicing revolution, using restriction enzymes, Cohen and Boyer, and Paul Berg all published the first papers on recombinant DNA, and Cohen and Boyer at Stanford filed a patent on their work, and this was used by Genentech and Eli Lilly to produce a human insulin as the first recombinant drug.

DNA sequencing and reading the genetic code progressed much more slowly. In 1973 Maxam and Gilbert published a paper on only 24 base pairs, 24 letters of genetic code. RNA sequencing progressed a little bit faster, so the first actual genome, a viral genome, an RNA viral genome was sequenced in 1976 by Walter Fiers from Belgium. This was followed by Fred Sanger’s sequencing the first DNA virus, Phi X 174. This became the first viral DNA genome, and it was also accompanied by a new DNA sequencing technique of dideoxy DNA sequencing, now referred to as “Sanger sequencing” that Sanger introduced.

This is a picture of Sanger’s team that sequenced Phi X 174. The second guy from the left on the bottom is Clyde Hutchison, who is also a member of the Venter Institute, and joined us after retiring from the University of North Carolina, and played a key role in some of the synthetic genome work.

In 1975 I was just getting my PhD as the first genes were being sequenced. Twenty years later I led the team to sequence the first genome of living species, and Ham Smith was part of that team. This was Haemophilus influenzae. Instead of 5,000 letters of genetic code, this was 1.8 million letters of genetic code. Or about 300 times the size of the Phi X genome. Five years later, we upped the ante another 1,600 times with the first draft of the human genome using our whole genome shotgun technique.

I view DNA as an analogue coding molecule, and when we sequence the DNA, we are converting that analogue code into digital code; the 1s and 0s in the computer are very similar to the dots and dashes of Schrodinger’s metaphor. I call this process “digitizing biology”.

The human genome is about a half a million times larger the Phi X genome, so it shows how fast things were developing. Reading genomes has now progressed extremely rapidly from requiring years or decades, it now takes about two hours to sequence a human genome. Instead of genomes per day or genomes per hour, or hours per genome, we can now and have recently done a demonstration sequencing 2,000 complete microbial genomes in one machine run. The pace is changing quite substantially.

I view DNA as an analogue coding molecule, and when we sequence the DNA, we are converting that analogue code into digital code; the 1s and 0s in the computer are very similar to the dots and dashes of Schrodinger’s metaphor. I call this process “digitizing biology”.

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Numerous scientists have drawn the analogy between computers and biology. I take these even further. I describe DNA as the software of life and when we activate a synthetic genome in a recipient cell I describe it as booting up a genome, the same way we talk about booting up a software in a computer.

June 23rd of this year would have been Alan Turing’s 100th birthday. Turing described what has become to be known as Turing Machines. The machine described a set of instructions written on a tape. He also described the Universal Turing Machine, which was a machine that could take that set of instructions and rewrite them, and this was the original version of the digital computer. His ideas were carried further in the 1940s by John von Neumann, and as many people know he conceived of the self-replicating machine. Von Neumann’s machine consisted of a series of cells that uncovered a sequence of actions to be performed by the machine, and using the writing head, the machine can print out a new pattern of cells, allowing it to make a complete copy of itself on the tape. Many scientists have made the obvious analogy between Turing machines and biology. The latest was most recently in nature by Sydney Brenner who played a role in almost all the early stages of molecular biology. Brenner wrote an article about Turing and biology, and in this he argued that the best examples of Turing and von Neumann machines are from biology with the self-replicating code, the internal description of itself, and how this is the key kernel of biological theory.

While software was pouring out of sequencing machines around the world, substantial progress was going on describing the hardware of life, or proteins. In biochemistry the first two decades of the 20th century was dominated by what was called “The colloid theory”. Life itself was explained in terms of the aggregate properties of all the colloidal substances in an organism. We now know that the substances are a collection of three-dimensional protein machines. Each evolved to carry out a very specific task.

Now, these proteins have been described as nature’s robots. If you think about it for every single task in the cell, every imaginable task as described by Tanford and Reynolds, “there is a unique protein to carry out that task. It’s programmed when to go on, when to go off. It does this based on its structure. It doesn’t have consciousness; it doesn’t have a control from the mind or higher center. Everything a protein does is built into its linear code, derived from the DNA code”.

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There are multiple protein types, everything you know about your own life, and most of it is protein-derived. About a quarter of your body is collagen, it’s a matrix protein just built up of multiple layers. We have rubber-like proteins that form blood vessels as well as the lung tissue, and we have transporters that move things in and out of cells, and enzymes that copy DNA, metabolize sugars, et cetera.

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The most important breakthroughs, outside of the genetic code, was in determining the process of protein synthesis.  To show you how recent all of this is, this is the three-dimensional structure of the bacterial ribosome determined in 2005, and the three-angstrom structure of the eukaryotic chromosome, which was just determined and published in December of last year. These ribosomes are extraordinary molecules. They are the most complex machinery we have in the cell, as you can see there are numerous components to it. I try to think of this as maybe the Ferrari engine of the cell. If the engine can’t convert the messenger RNA tape into proteins, there is no life. If you interfere with that process, you kill life. It’s the major antibiotics that we all know about, the amino glycosides, tetracycline, chloramphenicol, erythromycin, et cetera, all kill bacterial cells by interfering with the function of the ribosome.

The ribosome is clearly the most unique and special structure in the cell. It has seven major RNA chains, including three tRNA chains and one messenger RNA. It has 47 different proteins going into the structure and one newly synthesized protein chain, and a size of several million Daltons. This is the heart of all biology. We would not have cells, we would not have life without this machine that converts the linear DNA code into proteins working.

The process of converting the DNA code into protein starts with the synthesis of mRNA from DNA, called “transcription”, and protein synthesis from the mRNA is called “translation”. If these processes were highly reliable, life would be very different, and perhaps we would not need the same kind of information-driven system. If you were building a factory to build automobiles that worked the way the ribosome did, you would be out of business very quickly. A significant fraction of all the proteins synthesized, are degraded shortly after synthesis, because they formed the wrong confirmations and they aggregate in the cell, or cause some other problem.

Transfer RNA brings in the final amino acid to a growing peptide chain coming out of the ribosome. The next step is truly one of the most remarkable in nature, and that’s the self-folding of the proteins. The number of potential protein confirmations is enormous: if you have 100 amino acids in a protein then there are on the order of 2 to the 100th power different conformations, and it would take about ten to the tenth years to try each conformation. But built into the linear protein code with each amino acid are the folding instructions in turn determined by the linear genetic code. As a result these processes happen very quickly.

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Here’s a movie that spreads out 6 microseconds of protein folding over several seconds, to show you folding of a small protein. This is the end folded structure that starts with a linear protein, and over 6 microseconds it goes through all the different confirmations to try and get to the final fold.

Somehow the linear amino acid code limits the number of possible folds it can take, but each protein tries a large number of different ones, and if it gets them wrong in the end, the protein has to be degraded very quickly or it will cause problems. Imagine all the evolutionary selection that went into these processes, because the protein structure determines its rate of folding, as well as the final structure and hence its function. In fact, the end terminal amino acid determines how fast a protein is degraded. This is now called “The “N” rule pathway for protein degradation”. For example, if you had the amino acid, lysine, or arginine or tryptophan as the N terminal on a protein beta-galactosidase, it results in a protein with a half-life of 120 seconds in E. coli, or 180 seconds in a eukaryotic cell, yeast. Whereas you have three different amino acids, serine, valine or methionine, you get a half-life of over ten hours of in bacteria, over 30 hours in yeast.

Because of the instability, aggregation and turnover of proteins in a cell one of the most important pathways in any cell is the proteolytic pathway.  Degradation of proteins and protein fragments is of vital importance as they can be highly toxic to the cell by forming intracellular aggregates.

A bacterial cell in an hour or less will have to remake of all its proteins. Our cells make proteins at a similar rate, but because of protein instability and the random folding and misfolding of proteins, protein aggregation is a key problem. We have to constantly synthesize new proteins, and if they fold wrong, you have to get rid of them or they clog up the cell, the same way as if you stop taking out the trash in a city everything comes to a halt. Cells work the same way. You have to degrade the proteins; you have to pump the trash out of the cell. Miss folded proteins can become toxic very quickly. There are a number of diseases known to most of you that are due to misfolding or aggregation, Alzheimer’s and mad cow disease are examples of diseases caused by the accumulation of toxic protein aggregates.

Life is a process of dynamic renewal. We’re all shedding about 500 million skin cells every day. That is the dust that accumulates in your home; that’s you.  You shed your entire outer layer of skin every two to four weeks. You have five times ten to the 11th blood cells that die every day. If you’re not constantly synthesizing new cells, you die.

Several human diseases arise from protein misfolding leaving too little of the normal protein to do its job properly. The most common hereditary disease of this type is cystic fibrosis. Recent research has clearly shown that the many, previously mysterious symptoms of this disorder all derive from lack of a protein that regulates the transport of the chloride ion across the cell membrane. More recently scientists have shown that by far the most common mutation underlying cystic fibrosis hinders the dissociation of the transport regulator protein from one of its chaperones. Thus, the final steps in normal folding cannot occur, and normal amounts of active protein are not produced.

I’m trying to leave you with a notion that life is a process of dynamic renewal. We’re all shedding about 500 million skin cells every day. That is the dust that accumulates in your home; that’s you.  You shed your entire outer layer of skin every two to four weeks. You have five times ten to the 11th blood cells that die every day. If you’re not constantly synthesizing new cells, you die.  During normal organ development about half of all of our cells die. Everything in life is constantly turning over and being renewed by rereading the DNA software and making new proteins.

Life is a process of dynamic renewal. Without our DNA, without the software of life cells die very rapidly.  Rapid protein turnover is not just an issue for bacterial cells; our 100 trillion human cells are constantly reading the genetic code and producing proteins.  A recent study assaying 100 proteins in living human cancer cells showed half-lives that ranged between 45 minutes and 22.5 hours.

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Now, as you know, all life is cellular, and the cellular theory of life is that you can only get life from preexisting cells, and all kinds of special vitalistic parameters have been attributed to cells over time. This slide shows what an artist’s view of what a cell cytoplasm might look like. It’s quite a crowded place, it’s relatively viscous, it’s not this empty bag with a few proteins floating around in it, and it’s a very unique environment. About one quarter of the proteins are in solid phase.

A key tenant of chemistry is the notion of “synthesis as proof”. This perhaps dates back to 1828 when Friedrich Wöhler synthesized urea. The Wöhler synthesis is of great historical significance because for the first time an organic compound was produced from inorganic reactants.  Wöhler synthesis of urea was heralded as the end of vitalism because vitalists thought that you could only get organic molecules from living entities. Today there are tens of thousands of scientific papers published that either have “proof by synthesis” as the starting point or as a key part of the title.

We decided to take the approach of proof by synthesis that DNA codes for everything a cell produces and does. Back in 1995 when we sequenced the first genome, we sequenced a second genome that year.  For comparative purposes we were looking for the cell with the smallest genome, and we chose mycoplasma genitalium. It has 482 protein-coding genes, and 43 RNA genes. We asked simple questions, how many of these genes are essential for life?; what’s the smallest number of cells needed for a cellular machinery? After extensive experimentation we ultimately decided that the only way to answer these questions would be to design and construct a minimal DNA genome of the cell.  As soon as we started down that route, we had new questions. Would chemistry even allow us to synthesize a bacterial chromosome? And if we could, would we just have a large piece of DNA, or could we  boot it up in the cell like a new chemical piece of software?

We decided to start where DNA history started, with Phi X 174. We chose it as a test synthesis because you can make very few changes in the genetic code of Phi X without destroying viral particles. Clyde Hutchison, who helped sequence Phi X in Sanger’s lab, Ham Smith and I developed a new series of techniques to correct the errors that take place when you synthesize DNA. The machines that synthesize DNA are not particularly accurate; the longer the piece of DNA you make, the more spelling errors. We had to find ways to correct errors.

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Starting with the digital code we synthesized DNA fragments and assembled the genome. We corrected the errors and in the end had a 5,386-basepair piece of DNA that we inserted into E. coli, and this is the actual photo of what happened. The E. coli recognized the synthetic piece of DNA as normal DNA, and the proteins, being robots, just started reading the synthetic genetic code, because that’s what they’re programmed to do. They made what the DNA code told them to do, to make the viral proteins. The virus proteins self-assembled and formed a functional virus. The virus showed its gratitude by killing the cells, which is how we effectively get these clear plaques in a lawn of bacterial cells. I call this a situation where the “software is building its own hardware”. All we did was put a piece of DNA software in the cell, and we got out a protein virus with a DNA core.

Now, our goal is not to make viruses, we wanted to make something substantially larger. We wanted to make an entire chromosome of a living cell. But we thought if we could make viral-sized chromosomes accurately, maybe we could make 100 or so of those and find a way to put them together.  That’s what we did.

The teams starting with synthetic segments the size of Phi-X, we sequentially assembled larger and larger segments.  At each stage we  sequenced  verified them before going on to the next assembly stage. We put four pieces together creating segments that were 24,000 letters long. We would clone the segments in E. coli, sequence them, and assemble three together, to get pieces that were 72,000 base pairs. This was a very laborious process that took about a year and a half to do.

We put two of the 72,000bp segments together to obtain new segments representing one quarter of the genome each at 144,000 letters in length. This was way beyond the largest piece that had ever been synthesized by other of only 30,000 base pairs. E. coli didn’t like these large pieces of synthetic DNA in them, so we switched to yeast. I found out last night this is a city that loves beer that is produced from the same brewer’s yeast.  Aside from fermentation, this little cell has remarkable properties of assembling DNA.

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All we had to do was put the four synthetic quarter molecules into yeast with a small synthetic yeast centromere, and yeast automatically assembled these pieces together. That gave us the first synthetic bacterial chromosome, and this is what we published in 2008. This was the largest chemical of a defined structure ever synthesized.

We continued to work on DNA synthesis, and somebody who started out as a young post-doc, Dan Gibson, came up with a substantial breakthrough. Instead of the hours, to days, to years, he found out that by putting three enzymes together with all the DNA fragments in one tube at 50 degrees centigrade for a little while, they would automatically assemble these pieces. DNA assembly went from days down to an hour. This was a breakthrough for a number of reasons. Most importantly, it allows us now to automate genome synthesis. Having a simple one-step method allows us to go from the digital code in the computer to the analogue code of DNA in a robotic fashion. This means scaleing up substantially. We proved this initially by just one step synthesizing the mouse mitochondrial genome.

I had two teams working, one on the chemistry and one on the biology. It turns out the biology ended up being more difficult than the chemistry. How do you boot up a synthetic chromosome in a cell? This took substantial time to work out, and this paper that we published in 2007 is one of the most important for understanding how cells work and what the future of this field brings.

This paper is where we describe genome transplantation, and how by simply changing the genetic code, the chromosome, in one cell, swapping it out for another, we converted one species into another. Because this is so important to the theme of what we’re doing, I’m going to walk you through this a little bit.  And by the way, these are two of the scientists pictured here that led this effort, Carole Lartigue and John Glass, and the team working with them.

 

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We started by isolating the chromosome from a cell called M. mycoides. Chromosomes are enshrouded with proteins, which is why there was confusion for so many years over whether the proteins or the DNA was the genetic material. We simply did what Avery did, we treated the DNA with proteolytic enzymes, removing all the proteins because if we’re making a synthetic chromosome, we need to know can naked DNA work on its own, or are there going to be some special proteins needed for transplantation? We added a couple of gene cassettes to the chromosome, one so we could select for it, and another so it turns cells bright blue if it gets activated. After considerable effort we found a way to transplant this genome into a recipient cell, a cell M. capricolum, which is about the same distance apart genetically from M. mycoides as we are from mice. So relatively close, on the order of 10 percent or more different.

Life is based on DNA software. We’re a DNA software system, you change the DNA software, and you change the species. It’s a remarkably simple concept, remarkably complex in its execution.

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Let me show you what happened with this very sophisticated movie. We inserted the M. mycoides chromosome into the recipient cell. Just as with the Phi X, as soon as we put this DNA into this cell, the protein robots started producing mRNA, started producing proteins. Some of the early proteins produced were the restriction enzymes that Ham Smith discovered in 1970, we think that they recognized the initial chromosome in the cell as foreign DNA and chewed it up.  Now we have the body and all the proteins of one species, and the genetic software of another. What happened?

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In a very short period of time we have these bright blue cells. When we interrogated the cells, they had only the transplanted genome, but more importantly, when we sequenced the proteins in these cells, there wasn’t a single protein or other molecule from the original species. Every protein in the cell came from the new DNA that we inserted into the cell. Life is based on DNA software. We’re a DNA software system, you change the DNA software, and you change the species. It’s a remarkably simple concept, remarkably complex in its execution.

Now, we had a problem, that some of you may have picked up on or have read about. We were assembling the bacterial chromosome in a eukaryotic cell. If we’re going to take the synthetic genome and do the transplantations, we had to find a way to get the genome out of yeast to transplant it back into the bacterial cell. We developed a whole new way to grow bacteria chromosomes in yeast as eukaryotic chromosomes. It was remarkably simple in the end. All we do is add a very small synthetic centromere from  yeast to the bacterial chromosome, and all of a sudden it turns into a stable eukaryotic chromosome.

 

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Now we can stabley grow bacterial chromosomes in yeast. We had the situation where we had the M. mycoides chromosome in the eukaryotic cell, we could try isolating it and doing a transplantation. The trouble is, it didn’t work. This little problem took us two and a half years to solve of why it didn’t work. It turns out when we initially did the transplantations taking the chromosome out of the M. mycoides cell, that DNA had been methylated, and that’s how cells protect their own DNA from interloping species. We proved this by isolating the six methylases, and methylating the DNA when we took it out of yeast. If we methylated the DNA, we could then do the transplantation. We proved this ultimately by in the recipient cell removing the restriction enzyme system, and in that case we can just transplant the naked unmethylated DNA because there’s nothing to destroy the DNA in the cell.

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We were now at the point where we thought we had solved all the problems. We could create the new bacterial strains from the bacterial genomes cloned in yeast. We had this new cycle, we could work our way around the circle, we could add a centromere to the bacterial chromosome and turn it into a eukaryotic chromosome. The advantages, for those of you who work with bacteria, most bacteria do not have genetic systems, which is why most scientists don’t work with them. As soon as you put that bacterial genome in yeast, we have the complete repertoire of genetic tools available in yeast such as homologous recombination. We can make rapid changes in the genome, isolate the chromosome, methylate it if necessary, and do a transplantation to create a highly modified cell.

With all the new techniques and success we decided to synthesize the much larger M. mycoides genome. Dan Gibson led the effort that started with pieces that were 1,000 letters long. We put ten of those together to make these over 10,000 letters long. We put ten of those together to make pieces now that are 100,000 letters long, and we had eleven 100,000 base pair pieces. We put them in yeast, which assembled the genome. We knew how to transplant it out of yeast and we did the transplantation and it didn’t work.

Those of you who are software engineers know that software engineers have debugging software to tell them where the problems are in their code. So we had to develop the biological version of debugging software, which was basically substituting natural pieces of DNA for the synthetic ones so we could find out what was wrong. We found out we could have 10 of the 11 synthetic pieces, and the last piece had to be the native genome DNA to get a living cell. We re-sequenced our synthetic segment and found one letter wrong in an essential gene that made the difference between life and no life. The deletion was in the DNAa gene, which is an essential gene for life. We corrected that error, the one error out of 1.1 million, and we got the first actual synthetic cell from the genome transplants.

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One of the ways that we knew that what we had was a synthetic cell was by watermarking the DNA so we could always tell our synthetic species from any naturally occurring one.  Now about the watermarks, when we watermarked the first genome we just used the single letter amino acid code to write the authors names in the DNA. We were accused of not having much of an imagination. For this new genome we went a little bit farther by adding three quotations from the literature. But first the team developed a whole new code where by we could write the English language complete with numbers and punctuation in DNA code. It was quite interesting. We sent the paper to Science for a review, and one of the reviewers sent back their review written in DNA code, much to the frustration of the Science editor, who could not decipher it. (Laughter) But the reviewer’s DNA code was based on the ASCII code, and with biology that creates a problem because you can get long stretches of new without a stop codon. We developed this new code that puts in very frequent stop codons, because the last thing you want to do is put in a quote from James Joyce and have it turn into a new toxin that kills the cell or kills you. You didn’t know poetry could do that, I guess.

We built in the names of the 46 scientists that contributed to the effort, and also there was a message with an URL. So being the first species to have the computer as a parent, we thought it was appropriate it should have its own Web addressed built into the genome. As people solved this code, they would send an e-mail to the Web address written in the genome. Once numerous people solved it, we made this available.

The three quotes are the first one, and the probably most important one to this country is James Joyce, “To live, to err, to fall, to triumph, to recreate life out of life.” Somehow that seemed highly appropriate. The second is from Oppenheimer’s biography, “American Prometheus”. “See things not as they are, but as they might be.” In the third, from Richard Feynman, “What I cannot build, I cannot understand.”

Everybody thought this was very cool until a few months after this appeared, we got a letter from James Joyce’s estate attorney saying, “Did you seek permission to use this quotation?” In the US, at least, there are fair use laws that allow you to quote up to a paragraph without seeking permission. We sort of dismissed that one, and James Joyce was dead, and we didn’t know how to ask him anyway.

Then we started getting an e-mail trail from a Caltech scientist saying we misquoted Richard Feynman. But if you look on the Internet, this is the quotation that you find everywhere. We argued back this is what we found, and this is what was in his biography. So to prove his point, he sent a picture of Feynman’s blackboard with the original quotation, and it was, “What I cannot create, I do not understand.” I think it’s a much better quotation, and we’ve gone back to correct the DNA code so that Feynman can rest much more peacefully.

[Enlarge]

All living cells that we know of on this planet are DNA software driven biological machines comprised of hundreds to thousands of protein robots coded for by the DNA software.  The protein robots carry out precise biochemical functions developed by billions of years of evolutionary software changes.

Science can go much further now, and there is an exciting paper out of Stanford with a team led by Markus Covert and that included John Glass from my institute using the work on the mycoplasma cell to do the first complete mathematical modeling of a cell. But this is coming out in Cell next week. It’s going to be an exciting paper. We can go from the digital code to the genetic code, and now modeling the entire function of the cell in a computer, going the complete digital circle. We are going even further now, by using computer software to design new DNA software to create a new synthetic life.

I hope it is becoming clear that all living cells that we know of on this planet are DNA software driven biological machines comprised of hundreds to thousands of protein robots coded for by the DNA software.  The protein robots carry out precise biochemical functions developed by billions of years of evolutionary software changes.  The software codes for the linear protein sequence, which in turn determines the rate of folding as well as the final 3-dimensional structure and function of the protein robot.  The primary sequence determines the stability of the protein and therefore its dynamic regulation in the cell.  By making a copy of the DNA software, cells have the ability to self-replicate.  All these processes require energy.  From all the genomes we have sequenced we have seen that there is a range of mechanisms for the generation of cellular energy molecules through a process we call metabolism.  Some cells are able to transport sugars across the membrane into the cell and by some now well defined enzymatic processes capture the chemical energy in the sugar molecule and to supply it to the required cellular processes.  Other cells such as the autotroph Methanococcus jannaschii use only inorganic chemicals to make every molecule in the cell while providing the cellular energy.  These cells do this by a series of proteins that convert carbon dioxide into methane to generate cellular energy molecules and to provide the carbon to make proteins. These processes are all coded for in the genetic code.

Schrödinger citing the second law of thermodynamics (entropy principal)-the natural tendency of things to go over into disorder, described his notion of “order based on order”. We have now shown using synthetic DNA genomes that when you put new DNA software into the cell the protein robots coded for are produced, changing the cellular phenotype.  When you change the DNA software you change the species. This is consistent with Schrodinger’s Code-script and “An organism’s astonishing gift of concentrating a ‘stream of order’ on itself …”

We can digitize life, and we generate life from the digital world. Just as the ribosome can convert the analogue message in mRNA into a protein robot, it’s becoming standard now in the world of science to convert digital code into protein viruses and cells. Scientists send digital code to each other instead of sending genes or proteins. There are several companies around the world that make their living by synthesizing genes for scientific labs. It’s faster and cheaper to synthesize a gene than it is to clone it, or even get it by Federal Express.

As an example BARDA in the US government sends us as a part of our synthetic genomic flu virus program with Novartis, an email with a test pandemic flu virus sequence. We convert the digital sequence into a flu virus genome in less than 12 hours. We are in the process of building a simple smaller faster converter device, “a digital to biological converter”, that in a fashion similar to the telephone where digital information is converted to sound; we can send digital DNA code at the close to the speed of light and convert the digital information into proteins, viruses and living cells. With a new flu pandemic we could digitally distribute a new vaccine in seconds around the world, perhaps even to each home in the future.

Currently all life is derived from other cellular life including our synthetic cell.  This will change in the near future with the discovery of the right cocktail of enzymes, ribosomes, and chemicals including lipids together with the synthetic genome to create new cells and life forms without a prior cellular history. Look at the tremendous progress in the 70 years since Schrodinger’s lecture on this campus.  Try to imagine 70 years from now in the year 2082 what will be happening.  With the success of private space flight, the moon and Mars will be clearly colonized.  New life forms for food or energy production or for new medicines will be sent as digital information to be converted back into life forms in the 4.3 to 21 minutes that it takes for a digital wave to go from earth to Mars.

I suggested in place of sending living humans to distant galaxies that we can send digital information together with the means to boot it up in tiny space vessels.  More importantly and as I will speak to on Saturday evening synthetic life will enable us to understand all life on this planet and to enable new industries to produce food, energy, water and medicine as we add 1 billion new humans to earth every 12 years.

Schrodinger’s “What is Life?” helped to stimulate Jim Watson and Francis Crick to help kick off this new era of DNA science.  One can only hope that the newest frontier of synthetic life will have a similar impact on the future.

REMARKS BY JAMES D. WATSON

JAMES WATSON: In 1963, which was 10 years after the Double Helix, I began putting together a book which became the Molecular Biology of the Gene. It was before we knew the complete code, it was after what Nirenberg had shown and so I thought we knew the general principles. I thought initially the title we would use for the book was This Is Life, but I thought that will be controversial because I hadn’t explained everything, so it just became The Molecular Biology of the Gene.

I want to congratulate Craig on a very beautiful lecture.

Certainly Craig’s talk is …it’s much more beautiful 60 years later. And everything. I think chemistry is a good thing. I think our finding the DNA structure was unusual in that Crick or I, neither of us knew any chemistry. Luckily there was a chemist in the room, and helped. But I think we’re in this era of beautiful high technology. Sentimentally, I hope there’s still a role for the biologist.

Time will tell, but I want to congratulate Craig on a very beautiful lecture.

 

https://pharmaceuticalintelligence.com/2014/08/30/cracking-the-code-of-human-life-the-birth-of-bioinformatics-computational-genomics/

https://pharmaceuticalintelligence.com/2014/04/21/what-comes-after-finishing-the-euchromatic-sequence-of-the-human-genome/

https://pharmaceuticalintelligence.com/2013/05/06/humane-genome-project-10th-anniversary-interview-with-kevin-davies-phd-the-1000-genome/

https://pharmaceuticalintelligence.com/2012/11/24/human-variome-project-encyclopedic-catalog-of-sequence-variants-indexed-to-the-human-genome-sequence/

https://pharmaceuticalintelligence.com/2015/01/13/university-of-california-santa-cruzs-genomics-institute-will-create-a-map-of-human-genetic-variations/

https://pharmaceuticalintelligence.com/2014/11/19/exceptional-genomes-the-process-to-find-them/

https://pharmaceuticalintelligence.com/2014/09/05/multiple-lung-cancer-genomic-projects-suggest-new-targets-research-directions-for-non-small-cell-lung-cancer/

https://pharmaceuticalintelligence.com/2014/07/14/reference-genes-in-the-human-gut-microbiome-the-bgi-catalogue/

 

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Icelandic Population Genomic Study Results by deCODE Genetics come to Fruition: Curation of Current genomic studies

Reporter/Curator: Stephen J. Williams, Ph.D.

 

UPDATED on 9/6/2017

On 9/6/2017, Aviva Lev-Ari, PhD, RN had attend a talk by Paul Nioi, PhD, Amgen, at HMS, Harvard BioTechnology Club (GSAS).

Nioi discussed his 2016 paper in NEJM, 2016, 374:2131-2141

Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease

Paul Nioi, Ph.D., Asgeir Sigurdsson, B.Sc., Gudmar Thorleifsson, Ph.D., Hannes Helgason, Ph.D., Arna B. Agustsdottir, B.Sc., Gudmundur L. Norddahl, Ph.D., Anna Helgadottir, M.D., Audur Magnusdottir, Ph.D., Aslaug Jonasdottir, M.Sc., Solveig Gretarsdottir, Ph.D., Ingileif Jonsdottir, Ph.D., Valgerdur Steinthorsdottir, Ph.D., Thorunn Rafnar, Ph.D., Dorine W. Swinkels, M.D., Ph.D., Tessel E. Galesloot, Ph.D., Niels Grarup, Ph.D., Torben Jørgensen, D.M.Sc., Henrik Vestergaard, D.M.Sc., Torben Hansen, Ph.D., Torsten Lauritzen, D.M.Sc., Allan Linneberg, Ph.D., Nele Friedrich, Ph.D., Nikolaj T. Krarup, Ph.D., Mogens Fenger, Ph.D., Ulrik Abildgaard, D.M.Sc., Peter R. Hansen, D.M.Sc., Anders M. Galløe, Ph.D., Peter S. Braund, Ph.D., Christopher P. Nelson, Ph.D., Alistair S. Hall, F.R.C.P., Michael J.A. Williams, M.D., Andre M. van Rij, M.D., Gregory T. Jones, Ph.D., Riyaz S. Patel, M.D., Allan I. Levey, M.D., Ph.D., Salim Hayek, M.D., Svati H. Shah, M.D., Muredach Reilly, M.B., B.Ch., Gudmundur I. Eyjolfsson, M.D., Olof Sigurdardottir, M.D., Ph.D., Isleifur Olafsson, M.D., Ph.D., Lambertus A. Kiemeney, Ph.D., Arshed A. Quyyumi, F.R.C.P., Daniel J. Rader, M.D., William E. Kraus, M.D., Nilesh J. Samani, F.R.C.P., Oluf Pedersen, D.M.Sc., Gudmundur Thorgeirsson, M.D., Ph.D., Gisli Masson, Ph.D., Hilma Holm, M.D., Daniel Gudbjartsson, Ph.D., Patrick Sulem, M.D., Unnur Thorsteinsdottir, Ph.D., and Kari Stefansson, M.D., Ph.D.

N Engl J Med 2016; 374:2131-2141June 2, 2016DOI: 10.1056/NEJMoa1508419

Abstract
Article
References
Citing Articles (22)
Metrics

BACKGROUND

Several sequence variants are known to have effects on serum levels of non–high-density lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease.

METHODS

We sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability.

RESULTS

We found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P=1.0×10−16), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P=4.0×10−6). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P=1.8×10−3).

CONCLUSIONS

ASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health and others.)

 

Amgen’s deCODE Genetics Publishes Largest Human Genome Population Study to Date

Mark Terry, BioSpace.com Breaking News Staff reported on results of one of the largest genome sequencing efforts to date, sequencing of the genomes of 2,636 people from Iceland by deCODE genetics, Inc., a division of Thousand Oaks, Calif.-based Amgen (AMGN).

Amgen had bought deCODE genetics Inc. in 2012, saving the company from bankruptcy.

There were a total of four studies, published on March 25, 2015 on the online version of Nature Genetics; titled “Large-scale whole-genome sequencing of the Icelandic population[1],” “Identification of a large set of rare complete human knockouts[2],” “The Y-chromosome point mutation rate in humans[3]” and “Loss-of-function variants in ABCA7 confer risk of Alzheimer’s disease[4].”

The project identified some new genetic variants which increase risk of Alzheimer’s disease and confirmed some variants known to increase risk of diabetes and atrial fibrillation. A more in-depth post will curate these findings but there was an interesting discrete geographic distribution of certain rare variants located around Iceland. The dataset offers a treasure trove of meaningful genetic information not only about the Icelandic population but offers numerous new targets for breast, ovarian cancer as well as Alzheimer’s disease.

View Mark Terry’s article here on Biospace.com.

“This work is a demonstration of the unique power sequencing gives us for learning more about the history of our species,” said Kari Stefansson, founder and chief executive officer of deCode and one of the lead authors in a statement, “and for contributing to new means of diagnosing, treating and preventing disease.”

The scale and ambition of the study is impressive, but perhaps more important, the research identified a new genetic variant that increases the risk of Alzheimer’s disease and already had identified an APP variant that is associated with decreased risk of Alzheimer’s Disease. It also confirmed variants that increase the risk of diabetes and a variant that results in atrial fibrillation.
The database of human genetic variation (dbSNP) contained over 50 million unique sequence variants yet this database only represents a small proportion of single nucleotide variants which is thought to exist. These “private” or rare variants undoubtedly contribute to important phenotypes, such as disease susceptibility. Non-SNV variants, like indels and structural variants, are also under-represented in public databases. The only way to fully elucidate the genetic basis of a trait is to consider all of these types of variants, and the only way to find them is by large-scale sequencing.

Curation of Population Genomic Sequencing Programs/Corporate Partnerships

Click on “Curation of genomic studies” below for full Table

Curation of genomic studies
Study Partners Population Enrolled Disease areas Analysis
Icelandic Genome

Project

deCODE/Amgen Icelandic 2,636 Variants related to: Alzheimer’s, cardiovascular, diabetes WES + EMR; blood samples
Genome Sequencing Study Geisinger Health System/Regeneron Northeast PA, USA 100,000 Variants related to hypercholestemia, autism, obesity, other diseases WES +EMR +MyCode;

– Blood samples

The 100,000 Genomes Project National Health Service/NHS Genome Centers/ 10 companies forming Gene Consortium including Abbvie, Alexion, AstraZeneca, Biogen, Dimension, GSK, Helomics, Roche,   Takeda, UCB Rare disorders population UK Starting to recruit 100,000 Initially rare diseases, cancer, infectious diseases WES of blood, saliva and tissue samples

Ref paper

Saudi Human Genome Program 7 centers across Saudi Arabia in conjunction with King Abdulaziz City Science & Tech., King Faisal Hospital & Research Centre/Life Technologies General population Saudi Arabia 20,000 genomes over three years First focus on rare severe early onset diseases: diabetes, deafness, cardiovascular, skeletal deformation Whole genome sequence blood samples + EMR
Genome of the Netherlands (GoNL) Consortium consortium of the UMCG,LUMCErasmus MCVU university and UMCU. Samples where contributed by LifeLinesThe Leiden Longevity StudyThe Netherlands Twin Registry (NTR), The Rotterdam studies, and The Genetic Research in Isolated Populations program. All the sequencing work is done by BGI Hong Kong. Families in Netherlands 769 Variants, SNV, indels, deletions from apparently healthy individuals, family trios Whole genome NGS of whole blood no EMR

Ref paper in Nat. Genetics

Ref paper describing project

Faroese FarGen project Privately funded Faroe Islands Faroese population 50,000 Small population allows for family analysis Combine NGS with EMR and genealogy reports
Personal Genome Project Canada $4000.00 fee from participants; collaboration with University of Toronto and SickKids Organization; technical assistance with Harvard Canadian Health System Goal: 100,000 ? just started no defined analysis goals yet Whole exome and medical records
Singapore Sequencing Malay Project (SSMP) Singapore Genome Variation Project

Singapore Pharmacogenomics Project

Malaysian 100 healthy Malays from Singapore Pop. Health Study Variant analysis Deep whole genome sequencing
GenomeDenmark four Danish universities (KU, AU, DTU and AAU), two hospitals (Herlev and Vendsyssel) and two private firms (Bavarian Nordic and BGI-Europe). 150 complete genomes; first 30 published in Nature Comm. ? See link
Neuromics Consortium University of Tübingen and 18 academic and industrial partners (see link for description) European and Australian 1,100 patients with neuro-

degenerative and neuro-

muscular disease

Moved from SNP to whole exome analysis Whole Exome, RNASeq

References

  1. Gudbjartsson DF, Helgason H, Gudjonsson SA, Zink F, Oddson A, Gylfason A, Besenbacher S, Magnusson G, Halldorsson BV, Hjartarson E et al: Large-scale whole-genome sequencing of the Icelandic population. Nature genetics 2015, advance online publication.
  2. Sulem P, Helgason H, Oddson A, Stefansson H, Gudjonsson SA, Zink F, Hjartarson E, Sigurdsson GT, Jonasdottir A, Jonasdottir A et al: Identification of a large set of rare complete human knockouts. Nature genetics 2015, advance online publication.
  3. Helgason A, Einarsson AW, Gumundsdottir VB, Sigursson A, Gunnarsdottir ED, Jagadeesan A, Ebenesersdottir SS, Kong A, Stefansson K: The Y-chromosome point mutation rate in humans. Nature genetics 2015, advance online publication.
  4. Steinberg S, Stefansson H, Jonsson T, Johannsdottir H, Ingason A, Helgason H, Sulem P, Magnusson OT, Gudjonsson SA, Unnsteinsdottir U et al: Loss-of-function variants in ABCA7 confer risk of Alzheimer’s disease. Nature genetics 2015, advance online publication.

Other post related to DECODE, population genomics, and NGS on this site include:

Illumina Says 228,000 Human Genomes Will Be Sequenced in 2014

CRACKING THE CODE OF HUMAN LIFE: The Birth of BioInformatics & Computational Genomics

CRACKING THE CODE OF HUMAN LIFE: The Birth of BioInformatics and Computational Genomics – Part IIB

Human genome: UK to become world number 1 in DNA testing

Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

Genomic Promise for Neurodegenerative Diseases, Dementias, Autism Spectrum, Schizophrenia, and Serious Depression

Sequencing the exomes of 1,100 patients with neurodegenerative and neuromuscular diseases: A consortium of 18 European and Australian institutions

University of California Santa Cruz’s Genomics Institute will create a Map of Human Genetic Variations

Three Ancestral Populations Contributed to Modern-day Europeans: Ancient Genome Analysis

Impact of evolutionary selection on functional regions: The imprint of evolutionary selection on ENCODE regulatory elements is manifested between species and within human populations

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War on Cancer Needs to Refocus to Stay Ahead of Disease Says Cancer Expert


War on Cancer Needs to Refocus to Stay Ahead of Disease Says Cancer Expert

Writer, Curator: Stephen J. Williams, Ph.D.

Is one of the world’s most prominent cancer researchers throwing in the towel on the War On Cancer? Not throwing in the towel, just reminding us that cancer is more complex than just a genetic disease, and in the process, giving kudos to those researchers who focus on non-genetic aspects of the disease (see Dr. Larry Bernstein’s article Is the Warburg Effect the Cause or the Effect of Cancer: A 21st Century View?).

 

National Public Radio (NPR) has been conducting an interview series with MIT cancer biology pioneer, founding member of the Whitehead Institute for Biomedical Research, and National Academy of Science member and National Medal of Science awardee Robert A. Weinberg, Ph.D., who co-discovered one of the first human oncogenes (Ras)[1], isolation of first tumor suppressor (Rb)[2], and first (with Dr. Bill Hahn) proved that cells could become tumorigenic after discrete genetic lesions[3].   In the latest NPR piece, Why The War On Cancer Hasn’t Been Won (seen on NPR’s blog by Richard Harris), Dr. Weinberg discusses a comment in an essay he wrote in the journal Cell[4], basically that, in recent years, cancer research may have focused too much on the genetic basis of cancer at the expense of multifaceted etiology of cancer, including the roles of metabolism, immunity, and physiology. Cancer is the second most cause of medically related deaths in the developed world. However, concerted efforts among most developed nations to eradicate the disease, such as increased government funding for cancer research and a mandated ‘war on cancer’ in the mid 70’s has translated into remarkable improvements in diagnosis, early detection, and cancer survival rates for many individual cancer. For example, survival rate for breast and colon cancer have improved dramatically over the last 40 years. In the UK, overall median survival times have improved from one year in 1972 to 5.8 years for patients diagnosed in 2007. In the US, the overall 5 year survival improved from 50% for all adult cancers and 62% for childhood cancer in 1972 to 68% and childhood cancer rate improved to 82% in 2007. However, for some cancers, including lung, brain, pancreatic and ovarian cancer, there has been little improvement in survival rates since the “war on cancer” has started.

(Other NPR interviews with Dr. Weinberg include How Does Cancer Spread Through The Body?)

As Weinberg said, in the 1950s, medical researchers saw cancer as “an extremely complicated process that needed to be described in hundreds, if not thousands of different ways,”. Then scientists tried to find a unifying principle, first focusing on viruses as the cause of cancer (for example rous sarcoma virus and read Dr. Gallo’s book on his early research on cancer, virology, and HIV in Virus Hunting: AIDS, Cancer & the Human Retrovirus: A Story of Scientific Discovery).

However (as the blog article goes on) “that idea was replaced by the notion that cancer is all about wayward genes.”

“The thought, at least in the early 1980s, was that were a small number of these mutant, cancer-causing oncogenes, and therefore that one could understand a whole disparate group of cancers simply by studying these mutant genes that seemed to be present in many of them,” Weinberg says. “And this gave the notion, the illusion over the ensuing years, that we would be able to understand the laws of cancer formation the way we understand, with some simplicity, the laws of physics, for example.”

According to Weinberg, this gene-directed unifying theory has given way as recent evidences point back once again to a multi-faceted view of cancer etiology.

But this is not a revolutionary or conflicting idea for Dr. Weinberg, being a recipient of the 2007 Otto Warburg Medal and focusing his latest research on complex systems such as angiogenesis, cell migration, and epithelial-stromal interactions.

In fact, it was both Dr. Weinberg and Dr. Bill Hanahan who formulated eight governing principles or Hallmarks of cancer:

  1. Maintaining Proliferative Signals
  2. Avoiding Immune Destruction
  3. Evading Growth Suppressors
  4. Resisting Cell Death
  5. Becoming Immortal
  6. Angiogenesis
  7. Deregulating Cellular Energy
  8. Activating Invasion and Metastasis

Taken together, these hallmarks represent the common features that tumors have, and may involve genetic or non-genetic (epigenetic) lesions … a multi-modal view of cancer that spans over time and across disciplines. As reviewed by both Dr. Larry Bernstein and me in the e-book Volume One: Cancer Biology and Genomics for Disease Diagnosis, each scientific discipline, whether the pharmacologist, toxicologist, virologist, molecular biologist, physiologist, or cell biologist has contributed greatly to our total understanding of this disease, each from their own unique perspective based on their discipline. This leads to a “multi-modal” view on cancer etiology and diagnosis, treatment. Many of the improvements in survival rates are a direct result of the massive increase in the knowledge of tumor biology obtained through ardent basic research. Breakthrough discoveries regarding oncogenes, cancer cell signaling, survival, and regulated death mechanisms, tumor immunology, genetics and molecular biology, biomarker research, and now nanotechnology and imaging, have directly led to the advances we now we in early detection, chemotherapy, personalized medicine, as well as new therapeutic modalities such as cancer vaccines and immunotherapies and combination chemotherapies. Molecular and personalized therapies such as trastuzumab and aromatase inhibitors for breast cancer, imatnib for CML and GIST related tumors, bevacizumab for advanced colorectal cancer have been a direct result of molecular discoveries into the nature of cancer. This then leads to an interesting question (one to be tackled in another post):

Would shifting focus less on cancer genome and back to cancer biology limit the progress we’ve made in personalized medicine?

 

In a 2012 post Genomics And Targets For The Treatment Of Cancer: Is Our New World Turning Into “Pharmageddon” Or Are We On The Threshold Of Great Discoveries? Dr. Leonard Lichtenfield, MD, Deputy Chief Medical Officer for the ACS, comments on issues regarding the changes which genomics and personalized strategy has on oncology drug development. As he notes, in the past, chemotherapy development was sort of ‘hit or miss’ and the dream and promise of genomics suggested an era of targeted therapy, where drug development was more ‘rational’ and targets were easily identifiable.

To quote his post

That was the dream, and there have been some successes–even apparent cures or long term control–with the used of targeted medicines with biologic drugs such as Gleevec®, Herceptin® and Avastin®. But I think it is fair to say that the progress and the impact hasn’t been quite what we thought it would be. Cancer has proven a wily foe, and every time we get answers to questions what we usually get are more questions that need more answers. The complexity of the cancer cell is enormous, and its adaptability and the genetic heterogeneity of even primary cancers (as recently reported in a research paper in the New England Journal of Medicine) has been surprising, if not (realistically) unexpected.

                                                                               ”

Indeed the complexity of a given patient’s cancer (especially solid tumors) with regard to its genetic and mutation landscape (heterogeneity) [please see post with interview with Dr. Swanton on tumor heterogeneity] has been at the forefront of many clinicians minds [see comments within the related post as well as notes from recent personalized medicine conferences which were covered live on this site including the PMWC15 and Harvard Personalized Medicine conference this past fall].

In addition, Dr. Lichtenfeld makes some interesting observations including:

  • A “pharmageddon” where drug development risks/costs exceed the reward so drug developers keep their ‘wallets shut’. For example even for targeted therapies it takes $12 billion US to develop a drug versus $2 billion years ago
  • Drugs are still drugs and failure in clinical trials is still a huge risk
  • “Eroom’s Law” (like “Moore’s Law” but opposite effect) – increasing costs with decreasing success
  • Limited market for drugs targeted to a select mutant; what he called “slice and dice”

The pros and cons of focusing solely on targeted therapeutic drug development versus using a systems biology approach was discussed at the 2013 Institute of Medicine’s national Cancer Policy Summit.

  • Andrea Califano, PhD – Precision Medicine predictions based on statistical associations where systems biology predictions based on a physical regulatory model
  • Spyro Mousses, PhD – open biomedical knowledge and private patient data should be combined to form systems oncology clearinghouse to form evolving network, linking drugs, genomic data, and evolving multiscalar models
  • Razelle Kurzrock, MD – What if every patient with metastatic disease is genomically unique? Problem with model of smaller trials (so-called N=1 studies) of genetically similar disease: drugs may not be easily acquired or re-purposed, and greater regulatory burdens

So, discoveries of oncogenes, tumor suppressors, mutant variants, high-end sequencing, and the genomics and bioinformatic era may have led to advent of targeted chemotherapies with genetically well-defined patient populations, a different focus in chemotherapy development

… but as long as we have the conversation open I have no fear of myopia within the field, and multiple viewpoints on origins and therapeutic strategies will continue to develop for years to come.

References

  1. Parada LF, Tabin CJ, Shih C, Weinberg RA: Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene. Nature 1982, 297(5866):474-478.
  2. Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, Dryja TP: A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 1986, 323(6089):643-646.
  3. Hahn WC, Counter CM, Lundberg AS, Beijersbergen RL, Brooks MW, Weinberg RA: Creation of human tumour cells with defined genetic elements. Nature 1999, 400(6743):464-468.
  4. Weinberg RA: Coming full circle-from endless complexity to simplicity and back again. Cell 2014, 157(1):267-271.

 

Other posts on this site on The War on Cancer and Origins of Cancer include:

 

2013 Perspective on “War on Cancer” on December 23, 1971

Is the Warburg Effect the Cause or the Effect of Cancer: A 21st Century View?

World facing cancer ‘tidal wave’, warns WHO

2013 American Cancer Research Association Award for Outstanding Achievement in Chemistry in Cancer Research: Professor Alexander Levitzki

Genomics and Metabolomics Advances in Cancer

The Changing Economics of Cancer Medicine: Causes for the Vanishing of Independent Oncology Groups in the US

Cancer Research Pioneer, after 71 years of Immunology Lab Research, Herman Eisen, MD, MIT Professor Emeritus of Biology, dies at 96

My Cancer Genome from Vanderbilt University: Matching Tumor Mutations to Therapies & Clinical Trials

Articles on Cancer-Related Topic in http://pharmaceuticalintelligence.com Scientific Journal

Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

Issues in Personalized Medicine: Discussions of Intratumor Heterogeneity from the Oncology Pharma forum on LinkedIn

Introduction – The Evolution of Cancer Therapy and Cancer Research: How We Got Here?

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Proteomics, Metabolomics, Signaling Pathways, and Cell Regulation: a Compilation of Articles in the Journal http://pharmaceuticalintelligence.com


Compilation of References by Leaders in Pharmaceutical Business Intelligence in the Journal http://pharmaceuticalintelligence.com about
Proteomics, Metabolomics, Signaling Pathways, and Cell Regulation

Curator: Larry H Bernstein, MD, FCAP

Proteomics

  1. The Human Proteome Map Completed

Reporter and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/08/28/the-human-proteome-map-completed/

  1. Proteomics – The Pathway to Understanding and Decision-making in Medicine

Author and Curator, Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/06/24/proteomics-the-pathway-to-
understanding-and-decision-making-in-medicine/

3. Advances in Separations Technology for the “OMICs” and Clarification of Therapeutic Targets

Author and Curator, Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/10/22/advances-in-separations-technology-for-the-omics-and-clarification-         of-therapeutic-targets/

  1. Expanding the Genetic Alphabet and Linking the Genome to the Metabolome

Author and Curator, Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/09/24/expanding-the-genetic-alphabet-and-linking-the-genome-to-the-                metabolome/

5. Genomics, Proteomics and standards

Larry H Bernstein, MD, FCAP, Author and Curator

https://pharmaceuticalintelligence.com/2014/07/06/genomics-proteomics-and-standards/

6. Proteins and cellular adaptation to stress

Larry H Bernstein, MD, FCAP, Author and Curator

https://pharmaceuticalintelligence.com/2014/07/08/proteins-and-cellular-adaptation-to-stress/

 

Metabolomics

  1. Extracellular evaluation of intracellular flux in yeast cells

Larry H. Bernstein, MD, FCAP, Reviewer and Curator

https://pharmaceuticalintelligence.com/2014/08/25/extracellular-evaluation-of-intracellular-flux-in-yeast-cells/

  1. Metabolomic analysis of two leukemia cell lines. I.

Larry H. Bernstein, MD, FCAP, Reviewer and Curator

https://pharmaceuticalintelligence.com/2014/08/23/metabolomic-analysis-of-two-leukemia-cell-lines-_i/

  1. Metabolomic analysis of two leukemia cell lines. II.

Larry H. Bernstein, MD, FCAP, Reviewer and Curator

https://pharmaceuticalintelligence.com/2014/08/24/metabolomic-analysis-of-two-leukemia-cell-lines-ii/

  1. Metabolomics, Metabonomics and Functional Nutrition: the next step in nutritional metabolism and biotherapeutics

Reviewer and Curator, Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/08/22/metabolomics-metabonomics-and-functional-nutrition-the-next-step-          in-nutritional-metabolism-and-biotherapeutics/

  1. Buffering of genetic modules involved in tricarboxylic acid cycle metabolism provides homeomeostatic regulation

Larry H. Bernstein, MD, FCAP, Reviewer and curator

https://pharmaceuticalintelligence.com/2014/08/27/buffering-of-genetic-modules-involved-in-tricarboxylic-acid-cycle-              metabolism-provides-homeomeostatic-regulation/

Metabolic Pathways

  1. Pentose Shunt, Electron Transfer, Galactose, more Lipids in brief

Reviewer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/08/21/pentose-shunt-electron-transfer-galactose-more-lipids-in-brief/

  1. Mitochondria: More than just the “powerhouse of the cell”

Ritu Saxena, PhD

https://pharmaceuticalintelligence.com/2012/07/09/mitochondria-more-than-just-the-powerhouse-of-the-cell/

  1. Mitochondrial fission and fusion: potential therapeutic targets?

Ritu saxena

https://pharmaceuticalintelligence.com/2012/10/31/mitochondrial-fission-and-fusion-potential-therapeutic-target/

4.  Mitochondrial mutation analysis might be “1-step” away

Ritu Saxena

https://pharmaceuticalintelligence.com/2012/08/14/mitochondrial-mutation-analysis-might-be-1-step-away/

  1. Selected References to Signaling and Metabolic Pathways in PharmaceuticalIntelligence.com

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/08/14/selected-references-to-signaling-and-metabolic-pathways-in-                     leaders-in-pharmaceutical-intelligence/

  1. Metabolic drivers in aggressive brain tumors

Prabodh Kandal, PhD

https://pharmaceuticalintelligence.com/2012/11/11/metabolic-drivers-in-aggressive-brain-tumors/

  1. Metabolite Identification Combining Genetic and Metabolic Information: Genetic association links unknown metabolites to functionally related genes

Writer and Curator, Aviva Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/2012/10/22/metabolite-identification-combining-genetic-and-metabolic-                        information-genetic-association-links-unknown-metabolites-to-functionally-related-genes/

  1. Mitochondria: Origin from oxygen free environment, role in aerobic glycolysis, metabolic adaptation

Larry H Bernstein, MD, FCAP, author and curator

https://pharmaceuticalintelligence.com/2012/09/26/mitochondria-origin-from-oxygen-free-environment-role-in-aerobic-            glycolysis-metabolic-adaptation/

  1. Therapeutic Targets for Diabetes and Related Metabolic Disorders

Reporter, Aviva Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/2012/08/20/therapeutic-targets-for-diabetes-and-related-metabolic-disorders/

10.  Buffering of genetic modules involved in tricarboxylic acid cycle metabolism provides homeomeostatic regulation

Larry H. Bernstein, MD, FCAP, Reviewer and curator

https://pharmaceuticalintelligence.com/2014/08/27/buffering-of-genetic-modules-involved-in-tricarboxylic-acid-cycle-              metabolism-provides-homeomeostatic-regulation/

11. The multi-step transfer of phosphate bond and hydrogen exchange energy

Larry H. Bernstein, MD, FCAP, Curator:

https://pharmaceuticalintelligence.com/2014/08/19/the-multi-step-transfer-of-phosphate-bond-and-hydrogen-                          exchange-energy/

12. Studies of Respiration Lead to Acetyl CoA

https://pharmaceuticalintelligence.com/2014/08/18/studies-of-respiration-lead-to-acetyl-coa/

13. Lipid Metabolism

Author and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/08/15/lipid-metabolism/

14. Carbohydrate Metabolism

Author and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/08/13/carbohydrate-metabolism/

15. Update on mitochondrial function, respiration, and associated disorders

Larry H. Bernstein, MD, FCAP, Author and Curator

https://pharmaceuticalintelligence.com/2014/07/08/update-on-mitochondrial-function-respiration-and-associated-                   disorders/

16. Prologue to Cancer – e-book Volume One – Where are we in this journey?

Author and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/04/13/prologue-to-cancer-ebook-4-where-are-we-in-this-journey/

17. Introduction – The Evolution of Cancer Therapy and Cancer Research: How We Got Here?

Author and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/04/04/introduction-the-evolution-of-cancer-therapy-and-cancer-research-          how-we-got-here/

18. Inhibition of the Cardiomyocyte-Specific Kinase TNNI3K

Author and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/11/01/inhibition-of-the-cardiomyocyte-specific-kinase-tnni3k/

19. The Binding of Oligonucleotides in DNA and 3-D Lattice Structures

Author and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/05/15/the-binding-of-oligonucleotides-in-dna-and-3-d-lattice-structures/

20. Mitochondrial Metabolism and Cardiac Function

Author and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-metabolism-and-cardiac-function/

21. How Methionine Imbalance with Sulfur-Insufficiency Leads to Hyperhomocysteinemia

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/04/04/sulfur-deficiency-leads_to_hyperhomocysteinemia/

22. AMPK Is a Negative Regulator of the Warburg Effect and Suppresses Tumor Growth In Vivo

Author and Curator: Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2013/03/12/ampk-is-a-negative-regulator-of-the-warburg-effect-and-suppresses-         tumor-growth-in-vivo/

23. A Second Look at the Transthyretin Nutrition Inflammatory Conundrum

Author and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/12/03/a-second-look-at-the-transthyretin-nutrition-inflammatory-                         conundrum/

24. Mitochondrial Damage and Repair under Oxidative Stress

Author and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/10/28/mitochondrial-damage-and-repair-under-oxidative-stress/

25. Nitric Oxide and Immune Responses: Part 2

Author and Curator: Aviral Vatsa, PhD, MBBS

https://pharmaceuticalintelligence.com/2012/10/28/nitric-oxide-and-immune-responses-part-2/

26. Overview of Posttranslational Modification (PTM)

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/07/29/overview-of-posttranslational-modification-ptm/

27. Malnutrition in India, high newborn death rate and stunting of children age under five years

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/07/15/malnutrition-in-india-high-newborn-death-rate-and-stunting-of-                   children-age-under-five-years/

28. Update on mitochondrial function, respiration, and associated disorders

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/07/08/update-on-mitochondrial-function-respiration-and-associated-                  disorders/

29. Omega-3 fatty acids, depleting the source, and protein insufficiency in renal disease

Larry H. Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2014/07/06/omega-3-fatty-acids-depleting-the-source-and-protein-insufficiency-         in-renal-disease/

30. Introduction to e-Series A: Cardiovascular Diseases, Volume Four Part 2: Regenerative Medicine

Larry H. Bernstein, MD, FCAP, writer, and Aviva Lev- Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/04/27/larryhbernintroduction_to_cardiovascular_diseases-                                  translational_medicine-part_2/

31. Epilogue: Envisioning New Insights in Cancer Translational Biology
Series C: e-Books on Cancer & Oncology

Author & Curator: Larry H. Bernstein, MD, FCAP, Series C Content Consultant

https://pharmaceuticalintelligence.com/2014/03/29/epilogue-envisioning-new-insights/

32. Ca2+-Stimulated Exocytosis:  The Role of Calmodulin and Protein Kinase C in Ca2+ Regulation of Hormone                         and Neurotransmitter

Writer and Curator: Larry H Bernstein, MD, FCAP and
Curator and Content Editor: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/23/calmodulin-and-protein-kinase-c-drive-the-ca2-regulation-of-                    hormone-and-neurotransmitter-release-that-triggers-ca2-stimulated-exocy

33. Cardiac Contractility & Myocardial Performance: Therapeutic Implications of Ryanopathy (Calcium Release-                           related Contractile Dysfunction) and Catecholamine Responses

Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC
Author and Curator: Larry H Bernstein, MD, FCAP
and Article Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/08/28/cardiac-contractility-myocardium-performance-ventricular-arrhythmias-      and-non-ischemic-heart-failure-therapeutic-implications-for-cardiomyocyte-ryanopathy-calcium-release-related-                    contractile/

34. Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

Author and Curator: Larry H Bernstein, MD, FCAP Author: Stephen Williams, PhD, and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/08/26/role-of-calcium-the-actin-skeleton-and-lipid-structures-in-signaling-and-cell-motility/

35. Identification of Biomarkers that are Related to the Actin Cytoskeleton

Larry H Bernstein, MD, FCAP, Author and Curator

https://pharmaceuticalintelligence.com/2012/12/10/identification-of-biomarkers-that-are-related-to-the-actin-                           cytoskeleton/

36. Advanced Topics in Sepsis and the Cardiovascular System at its End Stage

Author: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/08/18/advanced-topics-in-Sepsis-and-the-Cardiovascular-System-at-its-              End-Stage/

37. The Delicate Connection: IDO (Indolamine 2, 3 dehydrogenase) and Cancer Immunology

Demet Sag, PhD, Author and Curator

https://pharmaceuticalintelligence.com/2013/08/04/the-delicate-connection-ido-indolamine-2-3-dehydrogenase-and-               immunology/

38. IDO for Commitment of a Life Time: The Origins and Mechanisms of IDO, indolamine 2, 3-dioxygenase

Demet Sag, PhD, Author and Curator

https://pharmaceuticalintelligence.com/2013/08/04/ido-for-commitment-of-a-life-time-the-origins-and-mechanisms-of-             ido-indolamine-2-3-dioxygenase/

39. Confined Indolamine 2, 3 dioxygenase (IDO) Controls the Homeostasis of Immune Responses for Good and Bad

Curator: Demet Sag, PhD, CRA, GCP

https://pharmaceuticalintelligence.com/2013/07/31/confined-indolamine-2-3-dehydrogenase-controls-the-hemostasis-           of-immune-responses-for-good-and-bad/

40. Signaling Pathway that Makes Young Neurons Connect was discovered @ Scripps Research Institute

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/26/signaling-pathway-that-makes-young-neurons-connect-was-                     discovered-scripps-research-institute/

41. Naked Mole Rats Cancer-Free

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/06/20/naked-mole-rats-cancer-free/

42. Late Onset of Alzheimer’s Disease and One-carbon Metabolism

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

https://pharmaceuticalintelligence.com/2013/05/06/alzheimers-disease-and-one-carbon-metabolism/

43. Problems of vegetarianism

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

https://pharmaceuticalintelligence.com/2013/04/22/problems-of-vegetarianism/

44.  Amyloidosis with Cardiomyopathy

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/03/31/amyloidosis-with-cardiomyopathy/

45. Liver endoplasmic reticulum stress and hepatosteatosis

Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2013/03/10/liver-endoplasmic-reticulum-stress-and-hepatosteatosis/

46. The Molecular Biology of Renal Disorders: Nitric Oxide – Part III

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/11/26/the-molecular-biology-of-renal-disorders/

47. Nitric Oxide Function in Coagulation – Part II

Curator and Author: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/11/26/nitric-oxide-function-in-coagulation/

48. Nitric Oxide, Platelets, Endothelium and Hemostasis

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/11/08/nitric-oxide-platelets-endothelium-and-hemostasis/

49. Interaction of Nitric Oxide and Prostacyclin in Vascular Endothelium

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/09/14/interaction-of-nitric-oxide-and-prostacyclin-in-vascular-endothelium/

50. Nitric Oxide and Immune Responses: Part 1

Curator and Author:  Aviral Vatsa PhD, MBBS

https://pharmaceuticalintelligence.com/2012/10/18/nitric-oxide-and-immune-responses-part-1/

51. Nitric Oxide and Immune Responses: Part 2

Curator and Author:  Aviral Vatsa PhD, MBBS

https://pharmaceuticalintelligence.com/2012/10/28/nitric-oxide-and-immune-responses-part-2/

52. Mitochondrial Damage and Repair under Oxidative Stress

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/10/28/mitochondrial-damage-and-repair-under-oxidative-stress/

53. Is the Warburg Effect the cause or the effect of cancer: A 21st Century View?

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/10/17/is-the-warburg-effect-the-cause-or-the-effect-of-cancer-a-21st-                 century-view/

54. Ubiquinin-Proteosome pathway, autophagy, the mitochondrion, proteolysis and cell apoptosis

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/10/30/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-                  proteolysis-and-cell-apoptosis/

55. Ubiquitin-Proteosome pathway, Autophagy, the Mitochondrion, Proteolysis and Cell Apoptosis: Part III

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2013/02/14/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-                   proteolysis-and-cell-apoptosis-reconsidered/

56. Nitric Oxide and iNOS have Key Roles in Kidney Diseases – Part II

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/11/26/nitric-oxide-and-inos-have-key-roles-in-kidney-diseases/

57. New Insights on Nitric Oxide donors – Part IV

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/11/26/new-insights-on-no-donors/

58. Crucial role of Nitric Oxide in Cancer

Curator and Author: Ritu Saxena, Ph.D.

https://pharmaceuticalintelligence.com/2012/10/16/crucial-role-of-nitric-oxide-in-cancer/

59. Nitric Oxide has a ubiquitous role in the regulation of glycolysis -with a concomitant influence on mitochondrial function

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/09/16/nitric-oxide-has-a-ubiquitous-role-in-the-regulation-of-glycolysis-with-         a-concomitant-influence-on-mitochondrial-function/

60. Targeting Mitochondrial-bound Hexokinase for Cancer Therapy

Curator and Author: Ziv Raviv, PhD, RN 04/06/2013

https://pharmaceuticalintelligence.com/2013/04/06/targeting-mitochondrial-bound-hexokinase-for-cancer-therapy/

61. Biochemistry of the Coagulation Cascade and Platelet Aggregation – Part I

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/11/26/biochemistry-of-the-coagulation-cascade-and-platelet-aggregation/

Genomics, Transcriptomics, and Epigenetics

  1. What is the meaning of so many RNAs?

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/08/06/what-is-the-meaning-of-so-many-rnas/

  1. RNA and the transcription the genetic code

Larry H. Bernstein, MD, FCAP, Writer and Curator

https://pharmaceuticalintelligence.com/2014/08/02/rna-and-the-transcription-of-the-genetic-code/

  1. A Primer on DNA and DNA Replication

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/07/29/a_primer_on_dna_and_dna_replication/

4. Synthesizing Synthetic Biology: PLOS Collections

Reporter: Aviva Lev-Ari

https://pharmaceuticalintelligence.com/2012/08/17/synthesizing-synthetic-biology-plos-collections/

5. Pathology Emergence in the 21st Century

Author and Curator: Larry Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/08/03/pathology-emergence-in-the-21st-century/

6. RNA and the transcription the genetic code

Writer and Curator, Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/08/02/rna-and-the-transcription-of-the-genetic-code/

7. A Great University engaged in Drug Discovery: University of Pittsburgh

Larry H. Bernstein, MD, FCAP, Reporter and Curator

https://pharmaceuticalintelligence.com/2014/07/15/a-great-university-engaged-in-drug-discovery/

8. microRNA called miRNA-142 involved in the process by which the immature cells in the bone  marrow give                              rise to all the types of blood cells, including immune cells and the oxygen-bearing red blood cells

Aviva Lev-Ari, PhD, RN, Author and Curator

https://pharmaceuticalintelligence.com/2014/07/24/microrna-called-mir-142-involved-in-the-process-by-which-the-                   immature-cells-in-the-bone-marrow-give-rise-to-all-the-types-of-blood-cells-including-immune-cells-and-the-oxygen-             bearing-red-blood-cells/

9. Genes, proteomes, and their interaction

Larry H. Bernstein, MD, FCAP, Writer and Curator

https://pharmaceuticalintelligence.com/2014/07/28/genes-proteomes-and-their-interaction/

10. Regulation of somatic stem cell Function

Larry H. Bernstein, MD, FCAP, Writer and Curator    Aviva Lev-Ari, PhD, RN, Curator

https://pharmaceuticalintelligence.com/2014/07/29/regulation-of-somatic-stem-cell-function/

11. Scientists discover that pluripotency factor NANOG is also active in adult organisms

Larry H. Bernstein, MD, FCAP, Reporter

https://pharmaceuticalintelligence.com/2014/07/10/scientists-discover-that-pluripotency-factor-nanog-is-also-active-in-           adult-organisms/

12. Bzzz! Are fruitflies like us?

Larry H Bernstein, MD, FCAP, Author and Curator

https://pharmaceuticalintelligence.com/2014/07/07/bzzz-are-fruitflies-like-us/

13. Long Non-coding RNAs Can Encode Proteins After All

Larry H Bernstein, MD, FCAP, Reporter

https://pharmaceuticalintelligence.com/2014/06/29/long-non-coding-rnas-can-encode-proteins-after-all/

14. Michael Snyder @Stanford University sequenced the lymphoblastoid transcriptomes and developed an
allele-specific full-length transcriptome

Aviva Lev-Ari, PhD, RN, Author and Curator

https://pharmaceuticalintelligence.com/014/06/23/michael-snyder-stanford-university-sequenced-the-lymphoblastoid-            transcriptomes-and-developed-an-allele-specific-full-length-transcriptome/

15. Commentary on Biomarkers for Genetics and Genomics of Cardiovascular Disease: Views by Larry H                                     Bernstein, MD, FCAP

Author: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/07/16/commentary-on-biomarkers-for-genetics-and-genomics-of-                        cardiovascular-disease-views-by-larry-h-bernstein-md-fcap/

16. Observations on Finding the Genetic Links in Common Disease: Whole Genomic Sequencing Studies

Author an curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/05/18/observations-on-finding-the-genetic-links/

17. Silencing Cancers with Synthetic siRNAs

Larry H. Bernstein, MD, FCAP, Reviewer and Curator

https://pharmaceuticalintelligence.com/2013/12/09/silencing-cancers-with-synthetic-sirnas/

18. Cardiometabolic Syndrome and the Genetics of Hypertension: The Neuroendocrine Transcriptome Control Points

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/12/cardiometabolic-syndrome-and-the-genetics-of-hypertension-the-neuroendocrine-transcriptome-control-points/

19. Developments in the Genomics and Proteomics of Type 2 Diabetes Mellitus and Treatment Targets

Larry H. Bernstein, MD, FCAP, Reviewer and Curator

https://pharmaceuticalintelligence.com/2013/12/08/developments-in-the-genomics-and-proteomics-of-type-2-diabetes-           mellitus-and-treatment-targets/

20. Loss of normal growth regulation

Larry H Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2014/07/06/loss-of-normal-growth-regulation/

21. CT Angiography & TrueVision™ Metabolomics (Genomic Phenotyping) for new Therapeutic Targets to Atherosclerosis

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/11/15/ct-angiography-truevision-metabolomics-genomic-phenotyping-for-           new-therapeutic-targets-to-atherosclerosis/

22.  CRACKING THE CODE OF HUMAN LIFE: The Birth of BioInformatics & Computational Genomics

Genomics Curator, Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/08/30/cracking-the-code-of-human-life-the-birth-of-bioinformatics-                      computational-genomics/

23. Big Data in Genomic Medicine

Author and Curator, Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/12/17/big-data-in-genomic-medicine/

24. From Genomics of Microorganisms to Translational Medicine

Author and Curator: Demet Sag, PhD

https://pharmaceuticalintelligence.com/2014/03/20/without-the-past-no-future-but-learn-and-move-genomics-of-                      microorganisms-to-translational-medicine/

25. Summary of Genomics and Medicine: Role in Cardiovascular Diseases

Author and Curator, Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/01/06/summary-of-genomics-and-medicine-role-in-cardiovascular-diseases/

 26. Genomic Promise for Neurodegenerative Diseases, Dementias, Autism Spectrum, Schizophrenia, and Serious                      Depression

Author and Curator, Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/02/19/genomic-promise-for-neurodegenerative-diseases-dementias-autism-        spectrum-schizophrenia-and-serious-depression/

 27.  BRCA1 a tumour suppressor in breast and ovarian cancer – functions in transcription, ubiquitination and DNA repair

Sudipta Saha, PhD

https://pharmaceuticalintelligence.com/2012/12/04/brca1-a-tumour-suppressor-in-breast-and-ovarian-cancer-functions-         in-transcription-ubiquitination-and-dna-repair/

28. Personalized medicine gearing up to tackle cancer

Ritu Saxena, PhD

https://pharmaceuticalintelligence.com/2013/01/07/personalized-medicine-gearing-up-to-tackle-cancer/

29. Differentiation Therapy – Epigenetics Tackles Solid Tumors

Stephen J Williams, PhD

      https://pharmaceuticalintelligence.com/2013/01/03/differentiation-therapy-epigenetics-tackles-solid-tumors/

30. Mechanism involved in Breast Cancer Cell Growth: Function in Early Detection & Treatment

     Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/17/mechanism-involved-in-breast-cancer-cell-growth-function-in-early-          detection-treatment/

31. The Molecular pathology of Breast Cancer Progression

Tilde Barliya, PhD

https://pharmaceuticalintelligence.com/2013/01/10/the-molecular-pathology-of-breast-cancer-progression

32. Gastric Cancer: Whole-genome reconstruction and mutational signatures

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/12/24/gastric-cancer-whole-genome-reconstruction-and-mutational-                   signatures-2/

33. Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine –                                                       Part 1 (pharmaceuticalintelligence.com)

Aviva  Lev-Ari, PhD, RN

http://pharmaceuticalntelligence.com/2013/01/13/paradigm-shift-in-human-genomics-predictive-biomarkers-and-personalized-medicine-part-1/

34. LEADERS in Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer                                         Personalized Treatment: Part 2

A Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/13/leaders-in-genome-sequencing-of-genetic-mutations-for-therapeutic-       drug-selection-in-cancer-personalized-treatment-part-2/

35. Personalized Medicine: An Institute Profile – Coriell Institute for Medical Research: Part 3

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/13/personalized-medicine-an-institute-profile-coriell-institute-for-medical-        research-part-3/

36. Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of                           Cancer Scientific Leaders @http://pharmaceuticalintelligence.com

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/13/7000/Harnessing_Personalized_Medicine_for_ Cancer_Management-      Prospects_of_Prevention_and_Cure/

37.  GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico
effect of the inhibitor in its “virtual clinical trial”

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/11/14/gsk-for-personalized-medicine-using-cancer-drugs-needs-alacris-             systems-biology-model-to-determine-the-in-silico-effect-of-the-inhibitor-in-its-virtual-clinical-trial/

38. Personalized medicine-based cure for cancer might not be far away

Ritu Saxena, PhD

  https://pharmaceuticalintelligence.com/2012/11/20/personalized-medicine-based-cure-for-cancer-might-not-be-far-away/

39. Human Variome Project: encyclopedic catalog of sequence variants indexed to the human genome sequence

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/11/24/human-variome-project-encyclopedic-catalog-of-sequence-variants-         indexed-to-the-human-genome-sequence/

40. Inspiration From Dr. Maureen Cronin’s Achievements in Applying Genomic Sequencing to Cancer Diagnostics

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/10/inspiration-from-dr-maureen-cronins-achievements-in-applying-                genomic-sequencing-to-cancer-diagnostics/

41. The “Cancer establishments” examined by James Watson, co-discoverer of DNA w/Crick, 4/1953

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/09/the-cancer-establishments-examined-by-james-watson-co-discover-         of-dna-wcrick-41953/

42. What can we expect of tumor therapeutic response?

Author and curator: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/12/05/what-can-we-expect-of-tumor-therapeutic-response/

43. Directions for genomics in personalized medicine

Author and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/01/27/directions-for-genomics-in-personalized-medicine/

44. How mobile elements in “Junk” DNA promote cancer. Part 1: Transposon-mediated tumorigenesis.

Stephen J Williams, PhD

https://pharmaceuticalintelligence.com/2012/10/31/how-mobile-elements-in-junk-dna-prote-cancer-part1-transposon-            mediated-tumorigenesis/

45. mRNA interference with cancer expression

Author and Curator, Larry H. Bernstein, MD, FCAP

 https://pharmaceuticalintelligence.com/2012/10/26/mrna-interference-with-cancer-expression/

46. Expanding the Genetic Alphabet and linking the genome to the metabolome

Aviva Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/2012/09/24/expanding-the-genetic-alphabet-and-linking-the-genome-to-the-               metabolome/

47. Breast Cancer, drug resistance, and biopharmaceutical targets

Author and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/09/18/breast-cancer-drug-resistance-and-biopharmaceutical-targets/

48.  Breast Cancer: Genomic profiling to predict Survival: Combination of Histopathology and Gene Expression                            Analysis

Aviva Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/2012/12/24/breast-cancer-genomic-profiling-to-predict-survival-combination-of-           histopathology-and-gene-expression-analysis

49. Gastric Cancer: Whole-genome reconstruction and mutational signatures

Aviva  Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/2012/12/24/gastric-cancer-whole-genome-reconstruction-and-mutational-                   signatures-2/

50. Genomic Analysis: FLUIDIGM Technology in the Life Science and Agricultural Biotechnology

Aviva Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/2012/08/22/genomic-analysis-fluidigm-technology-in-the-life-science-and-                   agricultural-biotechnology/

51. 2013 Genomics: The Era Beyond the Sequencing Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.

Aviva Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/2013_Genomics

52. Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1

Aviva Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/Paradigm Shift in Human Genomics_/

Signaling Pathways

  1. Proteins and cellular adaptation to stress

Larry H Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2014/07/08/proteins-and-cellular-adaptation-to-stress/

  1. A Synthesis of the Beauty and Complexity of How We View Cancer:
    Cancer Volume One – Summary

Author and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/03/26/a-synthesis-of-the-beauty-and-complexity-of-how-we-view-cancer/

  1. Recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes in
    serous endometrial tumors

Sudipta Saha, PhD

https://pharmaceuticalintelligence.com/2012/11/19/recurrent-somatic-mutations-in-chromatin-remodeling-ad-ubiquitin-           ligase-complex-genes-in-serous-endometrial-tumors/

4.  Prostate Cancer Cells: Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition

Stephen J Williams, PhD

https://pharmaceuticalintelligence.com/2012/11/30/histone-deacetylase-inhibitors-induce-epithelial-to-mesenchymal-              transition-in-prostate-cancer-cells/

5. Ubiquinin-Proteosome pathway, autophagy, the mitochondrion, proteolysis and cell apoptosis

Author and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/10/30/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-                   proteolysis-and-cell-apoptosis/

6. Signaling and Signaling Pathways

Larry H. Bernstein, MD, FCAP, Reporter and Curator

https://pharmaceuticalintelligence.com/2014/08/12/signaling-and-signaling-pathways/

7.  Leptin signaling in mediating the cardiac hypertrophy associated with obesity

Larry H. Bernstein, MD, FCAP, Reporter and Curator

https://pharmaceuticalintelligence.com/2013/11/03/leptin-signaling-in-mediating-the-cardiac-hypertrophy-associated-            with-obesity/

  1. Sensors and Signaling in Oxidative Stress

Larry H. Bernstein, MD, FCAP, Reporter and Curator

https://pharmaceuticalintelligence.com/2013/11/01/sensors-and-signaling-in-oxidative-stress/

  1. The Final Considerations of the Role of Platelets and Platelet Endothelial Reactions in Atherosclerosis and Novel
    Treatments

Larry H. Bernstein, MD, FCAP, Reporter and Curator

https://pharmaceuticalintelligence.com/2013/10/15/the-final-considerations-of-the-role-of-platelets-and-platelet-                      endothelial-reactions-in-atherosclerosis-and-novel-treatments

10.   Platelets in Translational Research – Part 1

Larry H. Bernstein, MD, FCAP, Reporter and Curator

https://pharmaceuticalintelligence.com/2013/10/07/platelets-in-translational-research-1/

11.  Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and
Cardiovascular Calcium Signaling Mechanism

Author and Curator: Larry H Bernstein, MD, FCAP, Author, and Content Consultant to e-SERIES A:
Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/12/disruption-of-calcium-homeostasis-cardiomyocytes-and-vascular-             smooth-muscle-cells-the-cardiac-and-cardiovascular-calcium-signaling-mechanism/

12. The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and
Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia,
Similarities and Differences, and Pharmaceutical Targets

     Author and Curator: Larry H Bernstein, MD, FCAP, Author, and Content Consultant to
e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC and
Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/08/the-centrality-of-ca2-signaling-and-cytoskeleton-involving-calmodulin-       kinases-and-ryanodine-receptors-in-cardiac-failure-arterial-smooth-muscle-post-ischemic-arrhythmia-similarities-and-           differen/

13.  Nitric Oxide Signalling Pathways

Aviral Vatsa, PhD, MBBS

https://pharmaceuticalintelligence.com/2012/08/22/nitric-oxide-signalling-pathways/

14. Immune activation, immunity, antibacterial activity

Larry H. Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2014/07/06/immune-activation-immunity-antibacterial-activity/

15.  Regulation of somatic stem cell Function

Larry H. Bernstein, MD, FCAP, Writer and Curator    Aviva Lev-Ari, PhD, RN, Curator

https://pharmaceuticalintelligence.com/2014/07/29/regulation-of-somatic-stem-cell-function/

16. Scientists discover that pluripotency factor NANOG is also active in adult organisms

Larry H. Bernstein, MD, FCAP, Reporter

https://pharmaceuticalintelligence.com/2014/07/10/scientists-discover-that-pluripotency-factor-nanog-is-also-active-in-adult-organisms/

Read Full Post »

Summary of Translational Medicine – e-Series A: Cardiovascular Diseases, Volume Four – Part 1


Summary of Translational Medicine – e-Series A: Cardiovascular Diseases, Volume Four – Part 1

Author and Curator: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

 

Part 1 of Volume 4 in the e-series A: Cardiovascular Diseases and Translational Medicine, provides a foundation for grasping a rapidly developing surging scientific endeavor that is transcending laboratory hypothesis testing and providing guidelines to:

  • Target genomes and multiple nucleotide sequences involved in either coding or in regulation that might have an impact on complex diseases, not necessarily genetic in nature.
  • Target signaling pathways that are demonstrably maladjusted, activated or suppressed in many common and complex diseases, or in their progression.
  • Enable a reduction in failure due to toxicities in the later stages of clinical drug trials as a result of this science-based understanding.
  • Enable a reduction in complications from the improvement of machanical devices that have already had an impact on the practice of interventional procedures in cardiology, cardiac surgery, and radiological imaging, as well as improving laboratory diagnostics at the molecular level.
  • Enable the discovery of new drugs in the continuing emergence of drug resistance.
  • Enable the construction of critical pathways and better guidelines for patient management based on population outcomes data, that will be critically dependent on computational methods and large data-bases.

What has been presented can be essentially viewed in the following Table:

 

Summary Table for TM - Part 1

Summary Table for TM – Part 1

 

 

 

There are some developments that deserve additional development:

1. The importance of mitochondrial function in the activity state of the mitochondria in cellular work (combustion) is understood, and impairments of function are identified in diseases of muscle, cardiac contraction, nerve conduction, ion transport, water balance, and the cytoskeleton – beyond the disordered metabolism in cancer.  A more detailed explanation of the energetics that was elucidated based on the electron transport chain might also be in order.

2. The processes that are enabling a more full application of technology to a host of problems in the environment we live in and in disease modification is growing rapidly, and will change the face of medicine and its allied health sciences.

 

Electron Transport and Bioenergetics

Deferred for metabolomics topic

Synthetic Biology

Introduction to Synthetic Biology and Metabolic Engineering

Kristala L. J. Prather: Part-1    <iBiology > iBioSeminars > Biophysics & Chemical Biology >

http://www.ibiology.org Lecturers generously donate their time to prepare these lectures. The project is funded by NSF and NIGMS, and is supported by the ASCB and HHMI.
Dr. Prather explains that synthetic biology involves applying engineering principles to biological systems to build “biological machines”.

Dr. Prather has received numerous awards both for her innovative research and for excellence in teaching.  Learn more about how Kris became a scientist at
Prather 1: Synthetic Biology and Metabolic Engineering  2/6/14IntroductionLecture Overview In the first part of her lecture, Dr. Prather explains that synthetic biology involves applying engineering principles to biological systems to build “biological machines”. The key material in building these machines is synthetic DNA. Synthetic DNA can be added in different combinations to biological hosts, such as bacteria, turning them into chemical factories that can produce small molecules of choice. In Part 2, Prather describes how her lab used design principles to engineer E. coli that produce glucaric acid from glucose. Glucaric acid is not naturally produced in bacteria, so Prather and her colleagues “bioprospected” enzymes from other organisms and expressed them in E. coli to build the needed enzymatic pathway. Prather walks us through the many steps of optimizing the timing, localization and levels of enzyme expression to produce the greatest yield. Speaker Bio: Kristala Jones Prather received her S.B. degree from the Massachusetts Institute of Technology and her PhD at the University of California, Berkeley both in chemical engineering. Upon graduation, Prather joined the Merck Research Labs for 4 years before returning to academia. Prather is now an Associate Professor of Chemical Engineering at MIT and an investigator with the multi-university Synthetic Biology Engineering Reseach Center (SynBERC). Her lab designs and constructs novel synthetic pathways in microorganisms converting them into tiny factories for the production of small molecules. Dr. Prather has received numerous awards both for her innovative research and for excellence in teaching.

VIEW VIDEOS

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=0

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=12

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=74

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=129

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=168

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk

 

II. Regulatory Effects of Mammalian microRNAs

Calcium Cycling in Synthetic and Contractile Phasic or Tonic Vascular Smooth Muscle Cells

in INTECH
Current Basic and Pathological Approaches to
the Function of Muscle Cells and Tissues – From Molecules to HumansLarissa Lipskaia, Isabelle Limon, Regis Bobe and Roger Hajjar
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/48240
1. Introduction
Calcium ions (Ca ) are present in low concentrations in the cytosol (~100 nM) and in high concentrations (in mM range) in both the extracellular medium and intracellular stores (mainly sarco/endo/plasmic reticulum, SR). This differential allows the calcium ion messenger that carries information
as diverse as contraction, metabolism, apoptosis, proliferation and/or hypertrophic growth. The mechanisms responsible for generating a Ca signal greatly differ from one cell type to another.
In the different types of vascular smooth muscle cells (VSMC), enormous variations do exist with regard to the mechanisms responsible for generating Ca signal. In each VSMC phenotype (synthetic/proliferating and contractile [1], tonic or phasic), the Ca signaling system is adapted to its particular function and is due to the specific patterns of expression and regulation of Ca.
For instance, in contractile VSMCs, the initiation of contractile events is driven by mem- brane depolarization; and the principal entry-point for extracellular Ca is the voltage-operated L-type calcium channel (LTCC). In contrast, in synthetic/proliferating VSMCs, the principal way-in for extracellular Ca is the store-operated calcium (SOC) channel.
Whatever the cell type, the calcium signal consists of  limited elevations of cytosolic free calcium ions in time and space. The calcium pump, sarco/endoplasmic reticulum Ca ATPase (SERCA), has a critical role in determining the frequency of SR Ca release by upload into the sarcoplasmic
sensitivity of  SR calcium channels, Ryanodin Receptor, RyR and Inositol tri-Phosphate Receptor, IP3R.
Synthetic VSMCs have a fibroblast appearance, proliferate readily, and synthesize increased levels of various extracellular matrix components, particularly fibronectin, collagen types I and III, and tropoelastin [1].
Contractile VSMCs have a muscle-like or spindle-shaped appearance and well-developed contractile apparatus resulting from the expression and intracellular accumulation of thick and thin muscle filaments [1].
Schematic representation of Calcium Cycling in Contractile and Proliferating VSMCs

Schematic representation of Calcium Cycling in Contractile and Proliferating VSMCs

 

Figure 1. Schematic representation of Calcium Cycling in Contractile and Proliferating VSMCs.

Left panel: schematic representation of calcium cycling in quiescent /contractile VSMCs. Contractile re-sponse is initiated by extracellular Ca influx due to activation of Receptor Operated Ca (through phosphoinositol-coupled receptor) or to activation of L-Type Calcium channels (through an increase in luminal pressure). Small increase of cytosolic due IP3 binding to IP3R (puff) or RyR activation by LTCC or ROC-dependent Ca influx leads to large SR Ca IP3R or RyR clusters (“Ca -induced Ca SR calcium pumps (both SERCA2a and SERCA2b are expressed in quiescent VSMCs), maintaining high concentration of cytosolic Ca and setting the sensitivity of RyR or IP3R for the next spike.
Contraction of VSMCs occurs during oscillatory Ca transient.
Middle panel: schematic representa tion of atherosclerotic vessel wall. Contractile VSMC are located in the media layer, synthetic VSMC are located in sub-endothelial intima.
Right panel: schematic representation of calcium cycling in quiescent /contractile VSMCs. Agonist binding to phosphoinositol-coupled receptor leads to the activation of IP3R resulting in large increase in cytosolic Ca calcium pumps (only SERCA2b, having low turnover and low affinity to Ca depletion leads to translocation of SR Ca sensor STIM1 towards PM, resulting in extracellular Ca influx though opening of Store Operated Channel (CRAC). Resulted steady state Ca transient is critical for activation of proliferation-related transcription factors ‘NFAT).
Abbreviations: PLC – phospholipase C; PM – plasma membrane; PP2B – Ca /calmodulin-activated protein phosphatase 2B (calcineurin); ROC- receptor activated channel; IP3 – inositol-1,4,5-trisphosphate, IP3R – inositol-1,4,5- trisphosphate receptor; RyR – ryanodine receptor; NFAT – nuclear factor of activated T-lymphocytes; VSMC – vascular smooth muscle cells; SERCA – sarco(endo)plasmic reticulum Ca sarcoplasmic reticulum.

 

Time for New DNA Synthesis and Sequencing Cost Curves

By Rob Carlson

I’ll start with the productivity plot, as this one isn’t new. For a discussion of the substantial performance increase in sequencing compared to Moore’s Law, as well as the difficulty of finding this data, please see this post. If nothing else, keep two features of the plot in mind: 1) the consistency of the pace of Moore’s Law and 2) the inconsistency and pace of sequencing productivity. Illumina appears to be the primary driver, and beneficiary, of improvements in productivity at the moment, especially if you are looking at share prices. It looks like the recently announced NextSeq and Hiseq instruments will provide substantially higher productivities (hand waving, I would say the next datum will come in another order of magnitude higher), but I think I need a bit more data before officially putting another point on the plot.

 

cost-of-oligo-and-gene-synthesis

cost-of-oligo-and-gene-synthesis

Illumina’s instruments are now responsible for such a high percentage of sequencing output that the company is effectively setting prices for the entire industry. Illumina is being pushed by competition to increase performance, but this does not necessarily translate into lower prices. It doesn’t behoove Illumina to drop prices at this point, and we won’t see any substantial decrease until a serious competitor shows up and starts threatening Illumina’s market share. The absence of real competition is the primary reason sequencing prices have flattened out over the last couple of data points.

Note that the oligo prices above are for column-based synthesis, and that oligos synthesized on arrays are much less expensive. However, array synthesis comes with the usual caveat that the quality is generally lower, unless you are getting your DNA from Agilent, which probably means you are getting your dsDNA from Gen9.

Note also that the distinction between the price of oligos and the price of double-stranded sDNA is becoming less useful. Whether you are ordering from Life/Thermo or from your local academic facility, the cost of producing oligos is now, in most cases, independent of their length. That’s because the cost of capital (including rent, insurance, labor, etc) is now more significant than the cost of goods. Consequently, the price reflects the cost of capital rather than the cost of goods. Moreover, the cost of the columns, reagents, and shipping tubes is certainly more than the cost of the atoms in the sDNA you are ostensibly paying for. Once you get into longer oligos (substantially larger than 50-mers) this relationship breaks down and the sDNA is more expensive. But, at this point in time, most people aren’t going to use longer oligos to assemble genes unless they have a tricky job that doesn’t work using short oligos.

Looking forward, I suspect oligos aren’t going to get much cheaper unless someone sorts out how to either 1) replace the requisite human labor and thereby reduce the cost of capital, or 2) finally replace the phosphoramidite chemistry that the industry relies upon.

IDT’s gBlocks come at prices that are constant across quite substantial ranges in length. Moreover, part of the decrease in price for these products is embedded in the fact that you are buying smaller chunks of DNA that you then must assemble and integrate into your organism of choice.

Someone who has purchased and assembled an absolutely enormous amount of sDNA over the last decade, suggested that if prices fell by another order of magnitude, he could switch completely to outsourced assembly. This is a potentially interesting “tipping point”. However, what this person really needs is sDNA integrated in a particular way into a particular genome operating in a particular host. The integration and testing of the new genome in the host organism is where most of the cost is. Given the wide variety of emerging applications, and the growing array of hosts/chassis, it isn’t clear that any given technology or firm will be able to provide arbitrary synthetic sequences incorporated into arbitrary hosts.

 TrackBack URL: http://www.synthesis.cc/cgi-bin/mt/mt-t.cgi/397

 

Startup to Strengthen Synthetic Biology and Regenerative Medicine Industries with Cutting Edge Cell Products

28 Nov 2013 | PR Web

Dr. Jon Rowley and Dr. Uplaksh Kumar, Co-Founders of RoosterBio, Inc., a newly formed biotech startup located in Frederick, are paving the way for even more innovation in the rapidly growing fields of Synthetic Biology and Regenerative Medicine. Synthetic Biology combines engineering principles with basic science to build biological products, including regenerative medicines and cellular therapies. Regenerative medicine is a broad definition for innovative medical therapies that will enable the body to repair, replace, restore and regenerate damaged or diseased cells, tissues and organs. Regenerative therapies that are in clinical trials today may enable repair of damaged heart muscle following heart attack, replacement of skin for burn victims, restoration of movement after spinal cord injury, regeneration of pancreatic tissue for insulin production in diabetics and provide new treatments for Parkinson’s and Alzheimer’s diseases, to name just a few applications.

While the potential of the field is promising, the pace of development has been slow. One main reason for this is that the living cells required for these therapies are cost-prohibitive and not supplied at volumes that support many research and product development efforts. RoosterBio will manufacture large quantities of standardized primary cells at high quality and low cost, which will quicken the pace of scientific discovery and translation to the clinic. “Our goal is to accelerate the development of products that incorporate living cells by providing abundant, affordable and high quality materials to researchers that are developing and commercializing these regenerative technologies” says Dr. Rowley

 

Life at the Speed of Light

http://kcpw.org/?powerpress_pinw=92027-podcast

NHMU Lecture featuring – J. Craig Venter, Ph.D.
Founder, Chairman, and CEO – J. Craig Venter Institute; Co-Founder and CEO, Synthetic Genomics Inc.

J. Craig Venter, Ph.D., is Founder, Chairman, and CEO of the J. Craig Venter Institute (JVCI), a not-for-profit, research organization dedicated to human, microbial, plant, synthetic and environmental research. He is also Co-Founder and CEO of Synthetic Genomics Inc. (SGI), a privately-held company dedicated to commercializing genomic-driven solutions to address global needs.

In 1998, Dr. Venter founded Celera Genomics to sequence the human genome using new tools and techniques he and his team developed.  This research culminated with the February 2001 publication of the human genome in the journal, Science. Dr. Venter and his team at JVCI continue to blaze new trails in genomics.  They have sequenced and a created a bacterial cell constructed with synthetic DNA,  putting humankind at the threshold of a new phase of biological research.  Whereas, we could  previously read the genetic code (sequencing genomes), we can now write the genetic code for designing new species.

The science of synthetic genomics will have a profound impact on society, including new methods for chemical and energy production, human health and medical advances, clean water, and new food and nutritional products. One of the most prolific scientists of the 21st century for his numerous pioneering advances in genomics,  he  guides us through this emerging field, detailing its origins, current challenges, and the potential positive advances.

His work on synthetic biology truly embodies the theme of “pushing the boundaries of life.”  Essentially, Venter is seeking to “write the software of life” to create microbes designed by humans rather than only through evolution. The potential benefits and risks of this new technology are enormous. It also requires us to examine, both scientifically and philosophically, the question of “What is life?”

J Craig Venter wants to digitize DNA and transmit the signal to teleport organisms

https://pharmaceuticalintelligence.com/2013/11/01/j-craig-venter-wants-to-digitize-dna-and-transmit-the-signal-to-teleport-organisms/

2013 Genomics: The Era Beyond the Sequencing of the Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.

https://pharmaceuticalintelligence.com/2013/02/11/2013-genomics-the-era-beyond-the-sequencing-human-genome-francis-collins-craig-venter-eric-lander-et-al/

Human Longevity Inc (HLI) – $70M in Financing of Venter’s New Integrative Omics and Clinical Bioinformatics

https://pharmaceuticalintelligence.com/2014/03/05/human-longevity-inc-hli-70m-in-financing-of-venters-new-integrative-omics-and-clinical-bioinformatics/

 

 

Where Will the Century of Biology Lead Us?

By Randall Mayes

A technology trend analyst offers an overview of synthetic biology, its potential applications, obstacles to its development, and prospects for public approval.

  • In addition to boosting the economy, synthetic biology projects currently in development could have profound implications for the future of manufacturing, sustainability, and medicine.
  • Before society can fully reap the benefits of synthetic biology, however, the field requires development and faces a series of hurdles in the process. Do researchers have the scientific know-how and technical capabilities to develop the field?

Biology + Engineering = Synthetic Biology

Bioengineers aim to build synthetic biological systems using compatible standardized parts that behave predictably. Bioengineers synthesize DNA parts—oligonucleotides composed of 50–100 base pairs—which make specialized components that ultimately make a biological system. As biology becomes a true engineering discipline, bioengineers will create genomes using mass-produced modular units similar to the microelectronics and computer industries.

Currently, bioengineering projects cost millions of dollars and take years to develop products. For synthetic biology to become a Schumpeterian revolution, smaller companies will need to be able to afford to use bioengineering concepts for industrial applications. This will require standardized and automated processes.

A major challenge to developing synthetic biology is the complexity of biological systems. When bioengineers assemble synthetic parts, they must prevent cross talk between signals in other biological pathways. Until researchers better understand these undesired interactions that nature has already worked out, applications such as gene therapy will have unwanted side effects. Scientists do not fully understand the effects of environmental and developmental interaction on gene expression. Currently, bioengineers must repeatedly use trial and error to create predictable systems.

Similar to physics, synthetic biology requires the ability to model systems and quantify relationships between variables in biological systems at the molecular level.

The second major challenge to ensuring the success of synthetic biology is the development of enabling technologies. With genomes having billions of nucleotides, this requires fast, powerful, and cost-efficient computers. Moore’s law, named for Intel co-founder Gordon Moore, posits that computing power progresses at a predictable rate and that the number of components in integrated circuits doubles each year until its limits are reached. Since Moore’s prediction, computer power has increased at an exponential rate while pricing has declined.

DNA sequencers and synthesizers are necessary to identify genes and make synthetic DNA sequences. Bioengineer Robert Carlson calculated that the capabilities of DNA sequencers and synthesizers have followed a pattern similar to computing. This pattern, referred to as the Carlson Curve, projects that scientists are approaching the ability to sequence a human genome for $1,000, perhaps in 2020. Carlson calculated that the costs of reading and writing new genes and genomes are falling by a factor of two every 18–24 months. (see recent Carlson comment on requirement to read and write for a variety of limiting  conditions).

Startup to Strengthen Synthetic Biology and Regenerative Medicine Industries with Cutting Edge Cell Products

https://pharmaceuticalintelligence.com/2013/11/28/startup-to-strengthen-synthetic-biology-and-regenerative-medicine-industries-with-cutting-edge-cell-products/

Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

https://pharmaceuticalintelligence.com/2013/05/17/synthetic-biology-on-advanced-genome-interpretation-for-gene-variants-and-pathways-what-is-the-genetic-base-of-atherosclerosis-and-loss-of-arterial-elasticity-with-aging/

Synthesizing Synthetic Biology: PLOS Collections

https://pharmaceuticalintelligence.com/2012/08/17/synthesizing-synthetic-biology-plos-collections/

Capturing ten-color ultrasharp images of synthetic DNA structures resembling numerals 0 to 9

https://pharmaceuticalintelligence.com/2014/02/05/capturing-ten-color-ultrasharp-images-of-synthetic-dna-structures-resembling-numerals-0-to-9/

Silencing Cancers with Synthetic siRNAs

https://pharmaceuticalintelligence.com/2013/12/09/silencing-cancers-with-synthetic-sirnas/

Genomics Now—and Beyond the Bubble

Futurists have touted the twenty-first century as the century of biology based primarily on the promise of genomics. Medical researchers aim to use variations within genes as biomarkers for diseases, personalized treatments, and drug responses. Currently, we are experiencing a genomics bubble, but with advances in understanding biological complexity and the development of enabling technologies, synthetic biology is reviving optimism in many fields, particularly medicine.

BY MICHAEL BROOKS    17 APR, 2014     http://www.newstatesman.com/

Michael Brooks holds a PhD in quantum physics. He writes a weekly science column for the New Statesman, and his most recent book is The Secret Anarchy of Science.

The basic idea is that we take an organism – a bacterium, say – and re-engineer its genome so that it does something different. You might, for instance, make it ingest carbon dioxide from the atmosphere, process it and excrete crude oil.

That project is still under construction, but others, such as using synthesised DNA for data storage, have already been achieved. As evolution has proved, DNA is an extraordinarily stable medium that can preserve information for millions of years. In 2012, the Harvard geneticist George Church proved its potential by taking a book he had written, encoding it in a synthesised strand of DNA, and then making DNA sequencing machines read it back to him.

When we first started achieving such things it was costly and time-consuming and demanded extraordinary resources, such as those available to the millionaire biologist Craig Venter. Venter’s team spent most of the past two decades and tens of millions of dollars creating the first artificial organism, nicknamed “Synthia”. Using computer programs and robots that process the necessary chemicals, the team rebuilt the genome of the bacterium Mycoplasma mycoides from scratch. They also inserted a few watermarks and puzzles into the DNA sequence, partly as an identifying measure for safety’s sake, but mostly as a publicity stunt.

What they didn’t do was redesign the genome to do anything interesting. When the synthetic genome was inserted into an eviscerated bacterial cell, the new organism behaved exactly the same as its natural counterpart. Nevertheless, that Synthia, as Venter put it at the press conference to announce the research in 2010, was “the first self-replicating species we’ve had on the planet whose parent is a computer” made it a standout achievement.

Today, however, we have entered another era in synthetic biology and Venter faces stiff competition. The Steve Jobs to Venter’s Bill Gates is Jef Boeke, who researches yeast genetics at New York University.

Boeke wanted to redesign the yeast genome so that he could strip out various parts to see what they did. Because it took a private company a year to complete just a small part of the task, at a cost of $50,000, he realised he should go open-source. By teaching an undergraduate course on how to build a genome and teaming up with institutions all over the world, he has assembled a skilled workforce that, tinkering together, has made a synthetic chromosome for baker’s yeast.

 

Stepping into DIYbio and Synthetic Biology at ScienceHack

Posted April 22, 2014 by Heather McGaw and Kyrie Vala-Webb

We got a crash course on genetics and protein pathways, and then set out to design and build our own pathways using both the “Genomikon: Violacein Factory” kit and Synbiota platform. With Synbiota’s software, we dragged and dropped the enzymes to create the sequence that we were then going to build out. After a process of sketching ideas, mocking up pathways, and writing hypotheses, we were ready to start building!

The night stretched long, and at midnight we were forced to vacate the school. Not quite finished, we loaded our delicate bacteria, incubator, and boxes of gloves onto the bus and headed back to complete our bacterial transformation in one of our hotel rooms. Jammed in between the beds and the mini-fridge, we heat-shocked our bacteria in the hotel ice bucket. It was a surreal moment.

While waiting for our bacteria, we held an “unconference” where we explored bioethics, security and risk related to synthetic biology, 3D printing on Mars, patterns in juggling (with live demonstration!), and even did a Google Hangout with Rob Carlson. Every few hours, we would excitedly check in on our bacteria, looking for bacterial colonies and the purple hue characteristic of violacein.

Most impressive was the wildly successful and seamless integration of a diverse set of people: in a matter of hours, we were transformed from individual experts and practitioners in assorted fields into cohesive and passionate teams of DIY biologists and science hackers. The ability of everyone to connect and learn was a powerful experience, and over the course of just one weekend we were able to challenge each other and grow.

Returning to work on Monday, we were hungry for more. We wanted to find a way to bring the excitement and energy from the weekend into the studio and into the projects we’re working on. It struck us that there are strong parallels between design and DIYbio, and we knew there was an opportunity to bring some of the scientific approaches and curiosity into our studio.

 

 

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What comes after finishing the Euchromatic Sequence of the Human Genome?

Author and Curator: Larry H Bernstein, MD, FCAP 

 

 

  1. Finishing the euchromatic sequence of the human genome.

    Oct 21 2004 ; 431(7011): 931-45.   http://dx.doi.org/10.1038/nature03001
    International Human Genome Sequencing Consortium.

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. They then worked to complete a genome sequence with high accuracy and completeness. The result of this is reported in Nature (2004), here cited. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers approximately 99% of the euchromatic genome and is accurate to an error rate of approximately 1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human genome seems to encode only 20,000-25,000 protein-coding genes
PMID: 15496913 [PubMed – indexed for MEDLINE]

Comment in Human genome: end of the beginning. [Nature. 2004]

 

  1. Human genome:  End of the beginning

Lincoln D. Stein
Nature 21 Oct 2004; 431, 915-916 |   http://dx.doi.org/10.1038/431915a

Just over three years ago, a first draft of the human genome sequence had been completed. Gaps and errors remained, but the job of fixing those problems is now largely done.

The featured article in this issue of Nature, entitled “Finishing the euchromatic sequence of the human genome”, has been authored by members of the International Human Genome Sequencing Consortium (IHGSC).  It is the latest, but by no means the last, milestone in this historic project.

Early in 2001, the duelling IHGSC (public) and Celera Corporation (private) groups published papers in Nature2 and Science3describing the completion of so-called ‘draft’ sequences. These sequences have revolutionized molecular biology by largely eliminating the need to clone and sequence genes involved in human health and disease.

But the draft sequences were far from perfect. Some 10% of the so-called ‘euchromatin’ — the gene-rich portion of the genome — and some 30% of the genome as a whole (which includes the gene-poor regions of ‘heterochromatin’), were not disclosed. There were hundreds of thousands of gaps, and there were misassembled regions where portions of the genome were flipped or misplaced. As a result, large-scale analyses of the genome, had to contend with numerous uncertainties and artefacts. For example, studies of the dying remnants of genes that have accumulated mutations that render them non-functional, left the possibility that such a ‘pseudogene’ was a sequencing error.

Since the publication of the drafts, the IHGSC sequencing centers have quietly undertaken a laborious ‘finishing’ process, in which each gap in the draft was individually examined and subjected to a battery of steps involving cloning and resequencing stretches of DNA. The sequence announced today has just 341 gaps remaining, and consists of contiguous runs of sequence averaging 38 million base pairs. The authors estimate that the finished sequence covers 99% of the euchromatic portion of the genome and that the overall error rate is less than 1 error per 100,000 base pairs. This substantially exceeds the original goals for the project.

The finishing procedure roughly doubled the total time and cost of the project. Does it contribute anything new to our understanding of the genome? It does indeed, and to prove the point the authors of the current paper1 describe several large-scale analyses of the genome that would have been difficult to perform on the draft sequence. One analysis studied the processes of gene birth and death. The authors find 1,183 human genes that show evidence of having been recently ‘born’ by a process of gene duplication and divergence. They also find 37 genes that seem to have recently ‘died’ by acquiring a mutation that rendered the gene non-functional. The resulting pseudogene then slowly degrades and disappears.

The authors then use the finished sequence to map out segmental duplications — large regions of the genome that have duplicated. They find 5% of the genome involved in segmental duplications, and the duplications are distributed widely across the chromosomes. The nature and extent of such duplications sheds light on the evolution of the human genome, and is needed for studying the many medically relevant disorders that are involved in segmental duplications.

Another paper in this issue, by She et al.4 (page 927), directly compares the outcomes of this second analysis with results obtained on an unfinished version of the human genome (an improved version of the Celera draft). She et al. find that the draft version artefactually ‘simplifies’ the genome by eliminating many duplicated regions. Their results bear on one of the highly publicized differences between the public and private genome projects. The public project used an older strategy in which the genome was first cloned into bacterial artificial chromosomes (BACs); the clones were then mapped, and each clone was sequenced and their sequences assembled individually. Celera championed an untested technique, ‘whole-genome shotgun’ (WGS), in which the entire genome was shattered into bite-size pieces, sequenced, and then assembled by software in one conceptually simple step.

Celera proved that the WGS technique is both technically feasible and provides a dramatic cost-saving over the clone-by-clone approach. The Celera draft has had a significant impact on the public project. Almost all genome-sequencing projects since then have used some form of WGS. The cautionary results contained in the new papers from the IHGSC1 and She et al.4argue for a hybrid strategy in which WGS is supplemented by a modest amount of BAC cloning and mapping. This would protect draft WGS sequences from some of the ‘simplification’ reported by She et al. and provide the clones needed for finishing selected regions of special interest.

What is next for the human genome project?

1)       Develop the definitive catalogue of protein-coding genes – estimated to be between 20,000 and 25,000.

a)       Natural selection ensures that functional regions are more highly conserved than non-functional ones, so a comparative approach highlights candidate protein-coding regions.

b)       The same approach shows promise for finding other functional elements such as gene promoters, which control the timing and level of expression of genes, and micro-RNAs, which have been implicated as regulatory agents of many developmental processes.

2)       Sequencing the remaining 20% of the genome that lies within heterochromatin, the gene-poor, highly   repetitive sequence that is implicated in the processes of chromosome replication and maintenance.

a)       The repetitiveness ofheterochromatin means that it cannot be tackled using current sequencing methods, and new technologies will have to be developed to attack it.

We are only at the end of the beginning: ahead lies another mountain range that we will need to map out and explore as we seek to understand how all the parts revealed by the genome sequence work together to make life.

References

  1. International Human Genome Sequencing Consortium Nature 431, 931−945 (2004). | Article |
  2. International Human Genome Sequencing Consortium Nature 409, 860−921 (2001). | Article | PubMed | ISI | ChemPort |
  3. Venter, J. C. et alScience 291, 1304−1351 (2001). | Article | PubMed | ISI | ChemPort |
  4. She, X. et alNature 431, 927−930 (2004). | Article |

 

  1. Shotgun sequence assembly and recent segmental duplications within the human genome

Xinwei She1, Zhaoshi Jiang1, Royden A. Clark2, Ge Liu2, Ze Cheng1, et al.
Nature 431, 927-930 (21 Oct 2004) |    http://dx.doi.org/10.1038/nature03062;

Complex eukaryotic genomes are now being sequenced at an accelerated pace primarily using whole-genome shotgun (WGS) sequence assembly approaches. WGS assembly was initially criticized because of its perceived inability to resolve repeat structures within genomes. Here, we quantify the effect of WGS sequence assembly on large, highly similar repeats by comparison of the segmental duplication content of two different human genome assemblies. Our analysis shows that large (> 15 kilobases) and highly identical (> 97%) duplications are not adequately resolved by WGS assembly. This leads to significant reduction in genome length and the loss of genes embedded within duplications. Comparable analyses of mouse genome assemblies confirm that strict WGS sequence assembly will oversimplify our understanding of mammalian genome structure and evolution; a hybrid strategy using a targeted clone-by-clone approach to resolve duplications is proposed.

Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington
Department of Genetics, Case Western Reserve University, Cleveland, Ohio
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland
Applied Biosystems,  and
The Center for the Advancement of Genomics, Rockville, Maryland

 

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