2013 Genomics: The Era Beyond the Sequencing of the Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.
Curator: Aviva Lev-Ari, PhD, RN
One decade following the completion of the Sequencing of the Human Genome — the field of Genomics, the discipline that has emerged as a result of project completion has FOUR concentrations:
GENOME SEQUENCING AND ANNOTATION
Before the middle of the twentieth century, the gene was an abstract concept thought to physically resemble a “bead on a string,” and within the scientific community, it was accepted that each gene was associated with a single protein, enzyme, or metabolic disorder. However, this began to change during the 1950s with the birth of modern molecular genetics. In 1952, Alfred Hershey and Martha Chase proved that DNA was themolecule of heredity, and shortly thereafter, Watson, Crick, Franklin, and Wilkins solved the three-dimensional structure ofDNA. By 1959, Jerome Lejeune had demonstrated that Down syndrome was linked to chromosomal abnormalities (Lejeune et al., 1959). Next, the 1961 discovery of mRNA (Jacob & Monod, 1964) and the 1966 cracking of the genetic code (Figure 1; Nirenberg et al., 1966) made it possible to predict proteinsequences based on DNA sequence alone. Nonetheless, although it was well established by this time that DNA was the heredity material and that each nucleus must contain the complete DNA required to instruct the chemical processes of anorganism, the details of reading individual gene sequences, let alone whole genomes, were out of the technical grasp of scientists.
A large part of the reason for this inability to read genesequences was the fact that there were simply very few sequences available to read; furthermore, the tools required to identify, isolate, and manipulate desired stretches of DNA were just evolving. Then, during the late 1960s and early 1970s, the combined work of several groups of researchers culminated in the isolation of proteins from prokaryotes using DNA cut at specific sites and spliced with DNA from other species(Meselson & Yuan, 1968; Jackson et al., 1972; Cohen et al., 1973). With these tools in place, the recombinant DNA age was about to allow scientists to start cloning genes en masse for the first time. Indeed, with the advent of Maxam-Gilbert DNAsequencing in the mid-1970s (Maxam & Gilbert, 1977), it actually became possible to read the entire sequence of a clonedgene, perhaps 1,000 to 30,000 base pairs long, with relative ease.
Collins and Other Researchers Master Gene Mapping
Thanks to these advances, mapping of important disease genes was all the rage by the 1980s, and Francis Collins was one of the masters of this process. Collins made a name for himself by discovering the location of three important disease genes—those responsible for cystic fibrosis, Duchenne muscular dystrophy, and Huntington’s disease. The accomplishments were a result of both cutting-edge cloning techniques like chromosome jumping (Collins et al., 1987; Richards et al., 1988) and plain perseverance. Collins wasn’t the only researcher actively “gene hunting” at this time, however; hundreds of other investigators were also racing to publish detailed descriptions of every new disease gene found.
During the 1980s, the importance of genes was obvious, but determining their location on chromosomes or their sequence of DNA nucleotides was laborious. Early studies of the genome were technically challenging and slow. Reagents were expensive, and the conditions for performing many reactions were temperamental. It therefore took several years to sequence single genes, and most genes were only partially cloned and described. Scientists had already reached the milestone of fully sequencing their first genome—that of the FX174 bacteriophage, whose 5,375 nucleotides had been determined in 1977 (Sanger et al., 1977b)—but this endeavor proved much easier than sequencing the genomes of more complex life forms. Indeed, the prospect of sequencing the 1 million base pairs of the E. coli genome or the 3 billion nucleotides of the humangenome seemed close to impossible. For example, an article published in the New York Times in 1987 noted that only 500 human genes had been sequenced (Kanigel, 1987). At the time, that was thought to be about 1% of the total, and given the pace of discovery, it was believed that complete sequencing of the human genome would take at least 100 years.
In addition to questions about the technical challenges and costs associated with sequencing large genomes, a number of concerns about the scientific basis of these endeavors were also raised. Why spend the time, money, and resources to sequence the whole genome when only a small percentage of it was actually genes? With the huge scale of these projects, there was a logic to prioritizing certain tasks over others—specifically, the target sequencing of coding sequences (genes). Thus, instead of sequencing the raw genome, many researchers sought to study cDNA collections; these are DNA strands that are generated by collecting mRNA from a tissue, then converting it back to complementary DNA. Because cDNA starts as a message in a cell, it represents an actively expressed gene. Moreover, because cells behave differently in different tissues and at different developmental stages, specialized cDNA libraries are valuable tools for assessing what specific genes are at work in a cell at any given time. Scientists could therefore use these libraries to prioritize their sequencing in order to focus on coding sequences first.
At the same time, researchers were also working to identify many more polymorphic genetic markers to use as tools in genemapping. Polymorphisms are the individual DNA base changes that make each of us unique at the level of DNA. The number of known human polymorphisms and microsatellite repeats increased to more than 2,000 by 1992—or 1 per every 2.5 million bases or so (Weissenbach et al., 1992). As researchers characterized more and more polymorphic markers, their chances ofmapping a gene of interest to its chromosomal location increased dramatically.
Venter Combines Approaches to Make Sequencing Faster and Less Expensive
Thus, by the late 1980s, multiple approaches for sequencingDNA were in use, but costs and time constraints were still a limiting factor to research. However, this all began to change with the work of National Institutes of Health (NIH) scientist J. Craig Venter. For several years, Venter had been using automated DNA sequencers to sequence portions of chromosomes associated with Huntington’s disease and myotonic dystrophy (Adams et al., 1991, 1992). Next, Venter tapped collections of cDNA molecules made from brain tissues. Then, in a 1991 paper, he described how he harnessed the power of his high-tech equipment to sequence more than 600 expressed sequence tags (ESTs) from a brain cDNA collection, identifying about half of them as genes, far more than anyone else had ever reported in a single paper to date. Not only did Venter’s paper make an impact, but so did his claims that in his laboratory alone, he could sequence as many as 10,000 ESTs a year at the low cost of $0.12/base. The next year, in a second paper, Venter published the sequences of more than 2,000 genes, although some were incomplete. This brought the total to 2,500 genes sequenced in one laboratory, which was as many as had been sequenced in the entire world to that point (Figure 2).
Many scientists spoke out in criticism of Venter’s brash approach. They noted that by sequencing ESTs, Venter was missing promoter sequences and other sites on DNA that were important for the regulation of gene expression. Furthermore, many critics argued that a focus on cheap volume was no substitute for careful, painstaking science. However, Venter’s speed also spurred other groups—namely, the NIH effort led by James Watson—to step up their efforts to finish the Human Genome Project sooner.
In 1992, Venter left the NIH and, with the help of a venture capitalist, started a nonprofit research institute at which he quickly set up 30 automated sequencers. Venter’s aim in doing so was to complete the sequencing of the human genomefaster than the government-backed (“public”) effort. This competition would later culminate in the simultaneous publication of the draft human genome sequence by both public and private efforts, ahead of schedule and below budget.
The events that occurred from the discovery of DNA’s structure and role as a heredity molecule up through Venter’s high-throughput EST experiments roughly delimit what is now known as the pregenomic era of molecular biology. The molecular tools and methods developed during this era were essential to reaching the milestone of sequencing the entire humangenome.
References and Recommended Reading
Adams, M. D., et al. Complementary DNA sequencing: “Expressed sequence tags” and the Human Genome Project. Science252, 1651–1656 (1991)
———. Sequence identification of 2,375 human brain genes. Nature 355, 632–634 (1992) doi:10.1038/355632a0 (link to article)
Cohen, S. N., et al. Construction of biologically functional bacterial plasmids in vitro. Proceedings of the National Academy of Sciences 70, 3240–3244 (1973)
Collins, F. S., et al. Construction of a general human chromosome jumping library, with application to cystic fibrosis. Science235, 1046–1049 (1987)
Dulbecco, R. A turning point in cancer research: Sequencing the human genome. Science 231, 1055–1056 (1986) doi:10.1126/science.3945817
Jackson, D. A., et al. Biochemical method for inserting new genetic information into DNA of simian virus 40: Circular SV40 DNA molecules containing lambda phage genes and the galactose operon of Escherichia coli. Proceedings of the National Academy of Sciences 69, 2904–2909 (1972)
Jacob, F., & Monod, J. Biochemical and genetic mechanisms of regulation in the bacterial cell. Bulletin de Societe Chimique de France 46, 1499–1532 (1964)
Kanigel, R. The genome project. New York Times, 13 December (1987)
Lejeune, J., et al. Mongolism: A chromosomal disease (trisomy). Bulletin de l’Academie Nationale de Medecine 143, 256–265 (1959)
Maxam, A., & Gilbert, W. A new method of sequencing DNA. Proceedings of the National Academy of Sciences 74, 560–564 (1977)
Meselson, M., & Yuan, R. DNA restriction enzyme from E. coli. Nature 217, 1110–1114 (1968)
Nirenberg, M. W., et al. The RNA code and protein synthesis. Cold Spring Harbor Symposia on Quantitative Biology 31, 11–24 (1966)
Richards, J. E., et al. Chromosome jumping from D4S10 (G8) toward the Huntington disease gene. Proceedings of the National Academy of Sciences 5, 6437–6441 (1988)
Sanger, F., et al. Nucleotide sequence of bacteriophage phi X174 DNA. Nature 265, 687–695 (1977a) (link to article)
Sanger, F., et al. DNA sequencing with chain-terminating inhibitors. Proceedings of the National Academy of Sciences 74, 5463–5467 (1977b)
Weissenbach, J., et al. A second-generation linkage map of the human genome. Nature 359, 794–801 (1992) doi:10.1038/359794a0 (link to article)
Davies, K. Cracking the Genome: Inside the Race to Unlock Human DNA (New York, Free Press, 2001)
Contributors to Genomics recognized by Dan David Prize Awards
Laureates 2012 – 2012 Future – Genome Research
Founding Director, Broad Institute Harvard and MIT and director of its Genome Biology Program, Cambridge, MA, USA
Prof. Eric Lander has been a major intellectual force in genomics research. Building on his background in mathematics, he placed genomics on a firm quantitative foundation.
With David Botstein and Phil Green he developed algorithms to allow effective use of polymorphism data for genetic mapping and published the first genetic linkage map of the human genome. As the human genome project got underway, he demonstrated an unusual ability to innovate in the organization of high-throughput methods first in creating genetic maps of the mouse and rat genomes and later as a major contributor to the Human Genome Project.
Lander was a powerful and respected voice in the planning and execution of the genome project. The Center he led contributed much of the data, he pioneered many of the analyses of genome sequence data, and he led in the writing of the landmark publication describing the Human Genome Project first as a draft sequence in Nature, 2001 and later as a full sequence in Nature, 2004. This has become the standard human reference sequence.
Lander has also been at the forefront of applying the genome sequence to the study of human disease, generating the first deep SNP catalogs, applying them to understand the haploid structure of the genome and more recently, championing the use of common variation to the study of complex traits. He has led efforts to understand the functional elements of the human genome, generating genome sequence from multiple other mammals to delineate the conserved elements and to define noncoding RNAs and characterize chromatin states.
Among Prof. Lander’s awards are: Honorary Degree, Columbia University; Honorary Doctorate, Lund University, Sweden; Honorary Doctorate, University of Massachusetts at Lowell; Gairdner Foundation International Award, Canada; Max Delbruck Medal, Berlin; Honorary Doctorate, Mount Sinai School of Medicine, New York; Honorary Doctorate, Tel Aviv Universtiy; Millennium Lecturer, The White House; Member of the American Academy of Arts and Sciences; Member of the American Academy of Achievement; and Member of the U.S. National Academy of Sciences.
Beyond his immediate scientific contributions, Eric Lander has attracted talented investigators to the field and fostered their careers. He has also served the community, most recently as co-Chair of the President’s Council of Advisors on Science and Technology.
Eric S. Lander, Ph.D.
By Karen Hopkin
In many ways, Eric Lander’s career has taken as many twists and turns as there are in the helical strands of DNA that he now spends his time trying to decode. Before turning his attention to the human genome, Lander worked as a mathematician, an economist, and even a newspaper reporter, amassing an impressive array of awards and achievements along the way. If the equation that describes Lander’s life story has a common denominator, it would have to be his pursuit of intellectual challenge.
It all began with math. From the start, he was captivated by the power and beauty of numbers. “Math is so elegant. Ideas dovetail perfectly with other ideas to form beautiful intellectual edifices,” he says. What’s more, these mathematical constructions can be used to describe and understand the world around us—making mathematics, to Lander’s mind, the purest product of human thought and “the highest form of crystallized abstraction.”
Lander was a master of mathematics. He placed second in a national math test and h ad the highest grades in his class at Stuyvesant High, one of New York City’s top schools for students who show a talent in math or science. His paper on quasi-perfect numbers—which the 17-year-old Lander proved exist only in theory—won him the Westinghouse Prize. His work at Princeton, where he received his undergraduate degree in mathematics, earned him a Rhodes scholarship at Oxford University. There, Lander completed his graduate degree in pure mathematics. He was well on his way to living his life as a chalk-stained mathematician, but he realized something was missing. “I loved pure mathematics,” says Lander. “But I didn’t want to make it a life.”
“Mathematics is kind of monastic,” he notes. “It’s a very lonely and individual pursuit. And I’m not a very good monk. I like doing things with people.”
This connection with people set into motion the series of happy accidents that would eventually draw Lander into a biology lab. When Lander returned from Oxford, a Princeton professor sent Lander’s résumé to a statistician at Harvard’s School of Public Health, who passed it along to someone at the Business School. Lander was offered a job at Harvard—teaching economics. “I knew no economics whatsoever,” he admits. “But I figured you can learn that stuff.”
Lander was a quick study and a decent teacher, but economics did not provide him with the intellectual stimulation he needed. Fortunately, his little brother did. Arthur Lander, a neuroscientist by training, sent his sibling some papers about mathematical neurobiology. Lander realized that he couldn’t fully understand the research until he learned a bit more about neurobiology. And he couldn’t handle the neurobiology without studying some cell biology, which he couldn’t grasp until he tackled molecular biology. So Lander opted to audit a biology course at Harvard and spent his evenings cloning fruit fly genes in the lab. “I essentially picked up biology on the street corner,” he says with a smile. Of course, in Cambridge—home of Harvard and the Massachusetts Institute of Technology—people who hang out on street corners are just as likely to be discussing biology as anything else.
After a lecture one night, Lander ran into David Botstein, a geneticist at MIT who had developed methods for scanning the genome to find an individual gene that may play a role in disease. He was hoping next to develop a means to untangle the genetics behind more complex human disorders that are thought to arise from subtle disturbances in dozens or hundreds of genes—cancer, diabetes, schizophrenia, even obesity.
The two got to arguing (as good New Yorkers will) about how statistics could be used to search for the genes involved in complex human diseases. Soon, they had the outline of a solution. Lander secured a position as a fellow at the Whitehead Institute for Biomedical Research, where he set to work on the problem. The appointment was a bit unusual—Lander was still a professor at the Harvard Business School—but he made enough progress to receive a MacArthur fellowship for his efforts.
Now a geneticist, Lander joined MIT as a tenured faculty member and a year later he launched the Whitehead Institute/MIT Center for Genome Research, becoming director of one of the first genome sequencing centers in the world. “It was a chaotic career path,” notes Lander. “But everything worked out okay.”
As head of the center, Lander helped build a series of maps that show the basic layout of the human and mouse genomes. In addition to providing the scaffolding needed to assemble the full human genome sequence, completed last year, these maps have proved useful for pinpointing the location of genes involved in disease. For Lander, that’s what his efforts are all about. “Disease is my motivation,” he says. “All the information about one’s risk for disease is hiding in the genome. The goal is to tease out that information.
“A cell already knows what it will be, what it will do,” he adds. “So it’s just a matter of persuading the cell to tell us what it knows.” Lander knows how to be persuasive. Already he and his colleagues at the Whitehead Institute have teased out genes involved in diabetes and gained knowledge that will help scientists diagnose and treat cancers. Whitehead researchers have produced approximately one-third of the human genome sequence. But prying the secrets from the human genome is work that is really just beginning.
The first problem: The human genome is big. Imagine someone dumping 1,000 volumes of the Encyclopaedia Britannica in your living room, says Lander. “How would you tackle all that information? Would you read all the spines first? Or would you start at ‘aardvark’ and go from there?”
But size isn’t the only obstacle. The human genome is also written in code. Scientists are still learning how to decipher the information encrypted in the 3 billion letters that provide the instructions for assembling and operating a human being. The human genome may represent a “book of life,” but it is not yet an open book.
“Looking at the genome is not like looking down at Earth from space and seeing all the clouds and oceans,” says Lander. “You have to think of the questions you want to ask. And then you have to figure out how to ask them.
“That’s my main job,” says Lander. “Thinking about the questions.”
Asking these questions often requires new techniques. And for someone who loves data, who wants answers, the waiting can be the hardest part. “Most days are spent just getting things ready,” says Lander. “So you have to be reasonably good at delayed gratification.” For example, before Lander and his team could build a map of the human genome, they spent months developing new biochemical procedures, new robotics, and new analytical software. “Once everything was in place, making the map was fun.”
Biology may involve a lot of grunt work—certainly more than mathematics does—but Lander doesn’t seem to mind. “The highs, when they come, are better than anything you could imagine.
“Getting to pursue new ideas and new directions, always thinking about new things—it’s intoxicating, it’s addicting,” he says. “I could never give it up.”
J. CRAIG VENTER
Laureates 2012 – 2012 Future – Genome Research
Founder, Chairman, and President of the J. Craig Venter Institute, Rockville, MD and La Jolla, CA, USA and CEO of Synthetic Genomics Inc., La Jolla, CA, USA.
Dr. J. Craig Venter has made numerous contributions to genomics—from ESTs and the first genome of a living species, to the human genome and environmental genomics, to the most recent accomplishments of constructing the first synthetic bacterial cell.
Venter’s initial efforts focused on identifying human genes through random cDNA sequencing (through the use of expressed sequence tags or ESTs) which identified fragments of about half the human genes in his 1995 publication.
Venter led the group that produced the first full sequence of a bacterium, H. influenza, using their whole genome shotgun approach. Five years later, Venter co-founded a company, Celera Genomics, to extend the whole genome shotgun method with newly developed algorithms and instrumentation to sequence the drosophila, human, mouse, rat and mosquito genomes. His group published a draft human sequence simultaneously with the publicly-funded Human Genome Project in 2001.
Venter went on to apply high-throughput sequencing to ocean microbial populations and the human gut, contributing greatly to the rapidly expanding field of metagenomics. More recently, Venter has focused much of his group’s efforts on synthetic genomics, first synthesizing the phix-174 viral genome and transplanting the genome of M. mycoides into a cell of a related species. In 2010 he and the team combined those two technologies, using synthetic oligo-nucleotides to recreate a 1.1 million base pair bacterial genome, and placed it in a new host, thereby constructing the largest synthetically made genome and the first synthetic bacterial cell.
Dr. Venter has received numerous awards and honors including: The 2008 National Medal of Science; Washington, DC, Member, National Academy of Sciences, Washington, DC; Member of the American Society of Microbiology; Honorary Doctor of Science – Syracuse University; the Benjamin Rush Medal – College of William and Mary, VA; Honorary Doctor of Science – Mount Sinai School of Medicine, New York; Scientist of the Year – ARCS Foundation, San Diego; Doctor of Science Honoris Causa – University of Melbourne; Doctorat Honoris Causa – University of Montreal; Doctor of Science Honoris Causa – Imperial College, London; Scripps Institute of Oceanography Nierenberg Prize, La Jolla, CA; Honorary Doctor of Science, Chung Yuan University, Taipei; Presidential Distinguished Scientific Award; World Health Award, Presented by Mikhail Gorbachev, World Awards, Vienna, Austria; University College London Prize in Clinical Science – London, England; Honorary Doctor of Technology, Royal Institute of Technology, Stockholm, Sweden; Medal of the Presidency, Italian Republic, Rimini, Italy; Prince of Asturias Award for Technical and Scientific Research; Fellow, American Academy of Arts and Sciences, Washington, DC; and the Exceptional Service Award for Exploring Genomes.
Laureates 2012 – 2012 Future – Genome Research
Anthony B. Evnin Professor of Genomics; Director, Lewis-Sigler Institute for Integrative Genomics; Director, Certificate Program in Quantitative and Computational Biology, Princeton University, Princeton, NJ, USA
Prof. David Botstein has been the intellectual leader of genomics since its inception. He created modern human genetics, championed the Human Genome Project, devised microarrays to exploit genome information for the global assessment of gene expression and has fostered systems biology. He has mentored numerous young scientists in the field, first at MIT, later at Stanford and most recently at Princeton.
Botstein’s 1980 paper “Construction of a Genetic Linkage Map in Man Using Restriction Fragment Length Polymorphisms” was the first to explicitly argue that it would be possible to build a sufficiently dense map of markers through the human genome to permit the mapping of disease genes in families by monitoring the transmission of those markers and disease status through the families. The vision outlined in this paper provided not only the clearest early motivation for the initiation of the human genome project, but its clarity and beauty drew many scientists into the field of genomics.
Following these seminal contributions he has been an intellectual participant in many of the most important key developments in genomics, the most prominent examples of which are: a) the development along with Pat Brown of methods to measure and statistically analyze gene expression profiles and apply these methods to the identification of subtypes of cancer. It would be impossible to overstate the impact of this work both in terms of basic biological research and the direction of thinking about molecular taxonomies of disease; b) articulation of the need to organize genes into biological groupings to permit systematic pathway analyses, and the initiation of generic systems to do so. Interestingly, these last areas are clear antecedents of what is now coming to be known as systems biology and which David Botstein is again one of the key intellectual figures.
Among Prof. Botstein’s awards and honors are: Member of the US National Academy of Sciences, the Eli Lilly and Company Award in Microbiology, the Genetics Society of America Medal, the Allen Award of the American Society of Human Genetics, and the Gruber Prize in Genetics.
MARCUS FELDMAN -
Laureates 2011 – 2011 Past – Evolution
Professor, Department of Biology, Stanford University, Stanford, CA, USA
Prof. Feldman has produced conceptual results of broad interest in the domain of animal and plant evolution. His work has led to highly focused insights of cultural significance such as the out-of-Africa model of human evolution, as well as cultural preferences in different civilizations. His work not only explores basic scientific topics, but investigates the societal consequences of the conclusions he draws in terms of models of evolution.
Prof. Feldman originated the quantitative theory of genetic modifiers of recombination, mutation, and dispersal. His work was the first to show that the pattern of interactions among genes determined whether sex would evolve.
With Cavalli-Sforza, he originated the quantitative theory of cultural evolution. The application of this theory to the culture of son preference in China, and his work on the significance of male/female birth ratio in that country, seems likely to have very important social management consequences, leading to attempts by the Chinese authorities to reduce this preference.
Prof. Feldman demonstrated that today’s world wide pattern of genomic variation is largely due to the sequence of human migrations over the 60,000 years since modern humans left Africa. His finding that about 10 percent of genomic variation is between continents has inspired much of the subsequent discussion on the meaning of race.
Prof. Feldman and collaborators originated “niche construction,” a generalization of evolutionary theory that stresses the feedbacks between organismic evolution and environmental dynamics, demonstrating via his model that phenotypes have a much more active role in evolution than previously thought. This has profoundly influenced subsequent work in evolutionary ecology.
Feldman’s findings have triggered the development of new scientific fields in both the humanities and life sciences. He sheds light on many key issues of evolution, including hominid evolution and the evolution of culture. Feldman has done much demographic work on trends important to humanity’s future.
Among Marcus Feldman’s honors are Elected Fellow, American Association for the Advancement of Science; Elected Member, American Academy of Arts and Sciences; Doctor Pholosophiae Honoris Causa, Hebrew University Jerusalem; Doctor Philosophiae Honoris Causa, Tel Aviv University; member of the editorial boards of various scientific journals; and a member of various international committees and foundations.
Laureates 2011 – 2011 Future – Ageing-Facing the Challenge
Professor of Genetics, Department of Molecular Biology, Massachusetts General Hospital, Harvard University
Gary Ruvkun has made a major contribution to the future of human health with the discovery of conserved hormonal signaling pathways with universal influence on animal aging. He is a key figure in defining the genetic basis for human health during aging with his discovery of a core set of hormonal signals and signaling pathways that regulate aging and lifespan in animal models, that are likely to act in humans as well.
In a series of reports starting in the early 1990s Ruvkun defined an insulin signaling pathway that regulates aging in the C. elegans worm and showed that the essential elements of this pathway are conserved in mice and humans. He discovered that like mammals, C. elegans uses an insulin-like signaling pathway to control its metabolism and longevity, suggesting that insulin-like regulation of longevity and metabolism is ancient and universal.
The Ruvkun lab discovered the molecular identity of the many genes in the pathway, including the daf-2insulin receptor, the many insulins that act upstream of the daf-2 receptor, the signal transduction components downstream of the insulin receptor such as age-1, daf-18, pdk-1, akt-1, and akt-2, and the downstream transcription factors daf-16 and daf-3, to reveal the signaling pathway from hormone to membrane receptor to the gene expression changes in the nucleus that regulate metabolism and longevity. Their finding by that the DAF-16/FoxO transcription factor is coupled to insulin signaling via conserved interactions with the kinases AKT and PDK also points to these transcriptional cascades as key in metabolic responses to insulin. This finding has been important for understanding the defects in diabetes as well as for aging research, since the mammalian orthologs of daf-16, the FoxO transcription factors, are regulated by insulin and are emerging now as key outputs of insulin signaling.
Recent insulin signaling mutant analyses in mouse and humans have validated the generality of these discoveries to other animals. Not surprisingly, an insulin-like pathway is now a major theme in animal aging regulation, with many reports of insulin-like regulation of lifespan in Drosophila, mouse, and even human beginning to emerge.
This work had an enormous impact on aging research relevant to longevity and later-life health. These findings catalyzed developments across biogerontology by defining hormone interventions with direct relevance to clinical practice and drug development.
Ruvkun is now using RNAi screens and comparative genomics to reveal the downstream genes regulated by insulin signaling. He discovered a connection between longevity and small RNA pathways, with the production of specific small RNA factors induced in long lived mutant animals.
Among Gary Ruvkun’s awards are: Benjamin Franklin Medal, Franklin Institute; Albert Lasker Award for Basic Medical Research; member of the American Academy of Arts and Sciences; and member of the National Academy of Sciences.
Laureates 2005 – 2005 Future – Materials Science – Tissue Engineering
Robert Langer is the Kenneth L. Germeshausen Professor of Chemical and Biomedical Engineering at the Massachusetts Institute of Technology, USA.
Prof. Langer has pioneered the field of biomaterials and tissue engineering. He has contributed to the development of biocompatible polymers for drug delivery and synthetic polymers to form specific tissue structures creating the field of tissue engineering. His work has allowed the controlled release of macromolecules using biocompatible polymers.
Prof. Langer is also responsible for the creation of numerous novel biomaterials, such as shape memory polymers and materials with switchable surfaces, aerosols and microchips. His work has led to the development of synthetic polymers to deliver cells to form specific tissue structures.
He has been a prolific contributor to this new field of materials science. He has mentored numerous students and post docs who have themselves become leaders in the field.
In 2002 he was awarded the Charles Stark Draper Prize of the NAE. He has won numerous other awards and is one of the few people who have been elected to all three US National Academies (Science, Engineering and Medicine).
ROBERT H. WATERSTON
Laureates 2002 – 2002 Future – Life Sciences
Prof. Robert H. Waterston (born 1943 in Michigan, USA) obtained a bachelor’s degree in engineering from Princeton University in 1965 and received both a medical degree and a doctorate in pathology from the University of Chicago in 1972. After a postdoctoral fellowship at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England, Prof. Waterston joined the Washington University faculty in 1976. He is James S. McDonnel Professor of Genetics, head of the Department of Genetics, and director of the School of Medicine’s Genome Sequencing Center, which he founded in 1993. The center was a principal member of the International Human Genome Sequencing Consortium, the public effort to complete the working draft.
He was a recipient of an American Heart Association Established Investigator Award from 1980 to 1985, and held a John Simon Guggenheim Fellowship from 1985 to 1986. He has served as a member of several NIH study sections and as chairman of the NIH’s Molecular Cytology Study Section. He currently serves on the NIH Advisory Council.
Prof. Waterston is a member of Sigma Xi, Alpha Omega Alpha, the Genetics Society and the American Society of Cell Biology. He has published more than 70 peer-reviewed scientific articles.
“It’s powerful information, and the potential benefits are enormous,” Prof. Waterston says. “We all have a responsibility to educate ourselves about the issues. To realize its great promise, scientific information of this sort must be available in an unrestricted form to citizens and scientists everywhere.”
“For the next hundred years, scientists will use these foundations to make increasingly detailed discoveries about how human beings and other organisms work,” says geneticist Robert H. Waterston of the advances in genetics research. “As a result, more and more will be understood about all aspects of human health, behavior, and disease – and ultimately about therapy and prevention.”
Laureates 2002 – 2002 Future – Life Sciences
subsequently received the Nobel Prize for Medicine in 2002.
Sir John Sulston graduated from Cambridge University in 1963. After completing his Ph.D. on the chemical synthesis of DNA, he moved to the USA to study prebiotic chemistry (the origins of life on Earth). In 1969, Sir John joined Sydney Brenner’s group at the Medical Research Council Laboratory of Molecular Biology in Cambridge where he studied the biology and genetics of the nematode worm, Caenorhabditis elegans. He and his team collaborated with Bob Waterston at Washington University in the USA to sequence the genome of this model organism. In 1992, Sir Sulston was appointed the first Director of the Sanger Centre in Cambridgeshire, which is behind the UK’s contribution to the international Human Genome Project. He stepped down as Director in September 2000.
Sir John Sulston is co-author with Georgina Ferry of The Common Thread: A Story of Science, Politics, Ethics and the Human Genome, to be published by Bantam Press in February 2002. The book tells the story of the sequencing of the human genome from the point of view of one of its leading figures, and discusses what the achievement means for future medical treatments and our understanding of ourselves. In light of the recent ‘gene rush’ by companies to stake claims to parts of the genome, the authors argue that the information it contains should be freely available for the benefit of all, and not carved up for private profit. “The human genome will be the foundation of biology for decades, centuries or millennia to come”.
Laureates 2002 – 2002 Future – Life Sciences
subsequently received the Nobel Prize for Medicine in 2002.
Prof. Sydney Brenner’s sustained contributions during the course of a scientific career spanning 40 years are exceptional both in their novelty and in their impact on biology.
During 1957 – 1973, he provided fundamental insights into the genetic code. In 1957, he produced a theoretical paper that presented a formal demonstration of the impossibility of all overlapping codes, insisting that further efforts in deciphering the genetic code be restricted to non-overlapping codes. In 1961 he, together with Francis Crick and others, published evidence for the triphet nature of the genetic code deduced from the frame-shift mutagenesis experiments, which remain a tour de force. He published, together with Fran?ois Jacob and Matthew Meselson, their discovery of messenger RNA, a finding that provided fundamental insights into translation of the genetic code. In 1964 and succeeding years, Prof. Brenner and others published a demonstration of the colinearity of a gene and deciphered nonsense codons by genetics. During the mid-1960s Prof. Brenner, together with Fran?ois Jacob and Fran?ois Cuzin, established the fundamental principles underlying the regulation of DNA replication in E coli. From 1974 to 1990, Prof. Brenner and his colleagues introduced the eukaryotic model C. elegans and demonstrated its utility for studying development. He developed the genetic methodology for dissecting the organism’s developmental program, especially of the nervous system. His students have proved the wisdom of his choice by extending the model to aging and apoptosis. Now that the genome sequence of C. elegans is complete, the usefulness of this system is greatly enhanced. During the 1980s and 1990s, Prof. Brenner made great political and scientific contributions to the establishment of recombinant NDA technology in general and to the human genome project in particular. Among other things, he introduced the study of the putter fish, one of the very few vertebrate organisms to have very little “junk” DNA.
Prof. Sydney Brenner was born in South Africa on 13 January 1927 and studied medicine and science at the University of Witwatersrand, Johannesburg . He went on to Oxford, working in the Physical Chemistry Laboratory, and and receiveed a degree of D.Phil. in 1952. After a brief return to South Africa, he joined the MRC Unit in the Cavendish Laboratory at Cambridge in 1956. He worked here and in its successor, the MRC Laboratory of Molecular Biology at Cambridge, where he was Director from 1979 to 1987. In 1987 he became Director of the MRC Unit of Molecular Genetics, retiring in 1992 from the MRC. He is now Director of the Molecular Sciences Institute, a private research institute in Berkeley, California.
Last year, aged 74, Prof. Brenner accepted an offer to become a research professor at the Salk Institute for Biological Studies. He said: “I don’t want to retire to play golf. Science is one’s hobby and one’s work and one’s pleasure.”