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HeLa DNA: Lacks family and the N.I.H. settled on an agreement: the data from both studies should be stored in the institutes’ database of Genotypes and Phenotypes

Reporter: Aviva Lev-Ari, PhD, RN

 

A Family Consents to a Medical Gift, 62 Years Later

Henrietta Lacks was only 31 when she died of cervical cancer in 1951 in a Baltimore hospital. Not long before her death, doctors removed some of her tumor cells. They later discovered that the cells could thrive in a lab, a feat no human cells had achieved before.

Lacks Family, via The Henrietta Lacks Foundation — Henrietta Lacks in the 1940s.

Soon the cells, called HeLa cells, were being shipped from Baltimore around the world. In the 62 years since — twice as long as Ms. Lacks’s own life — her cells have been the subject of more than 74,000 studies, many of which have yielded profound insights into cell biology, vaccines, in vitro fertilization and cancer.

But Henrietta Lacks, who was poor, black and uneducated, never consented to her cells’ being studied. For 62 years, her family has been left out of the decision-making about that research. Now, over the past four months, the National Institutes of Health has come to an agreement with the Lacks family to grant them some control over how Henrietta Lacks’s genome is used.

“In 20 years at N.I.H., I can’t remember something like this,” Dr. Francis S. Collins, the institute’s director, said in an interview.

The agreement, which does not provide the family with the right to potential earnings from future research on Ms. Lacks’s genome, was prompted by two projects to sequence the genome of HeLa cells, the second of which was published Wednesday in the journal Nature.

Though the agreement, which was announced Wednesday, is a milestone in the saga of Ms. Lacks, it also draws attention to a lack of policies to balance the benefits of studying genomes with the risks to the privacy of people whose genomes are studied — as well as their relatives.

As the journalist Rebecca Skloot recounted in her 2010 best-seller, “The Immortal Life of Henrietta Lacks,” it was not until 1973, when a scientist called to ask for blood samples to study the genes her children had inherited from her, that Ms. Lacks’s family learned that their mother’s cells were, in effect, scattered across the planet.

Some members of the family tried to find more information. Some wanted a portion of the profits that companies were earning from research on HeLa cells. They were largely ignored for years.

Ms. Lacks is survived by children, grandchildren and great-grandchildren, many still living in or around Baltimore.

And this March they experienced an intense feeling of déjà vu.

Scientists at the European Molecular Biology Laboratory published the genome of a line of HeLa cells, making it publicly available for downloading. Another study, sponsored by the National Institutes of Health at the University of Washington, was about to be published in Nature. The Lacks family was made aware of neither project.

“I said, ‘No, this is not right,’ ” Jeri Lacks Whye, one of Henrietta Lacks’s grandchildren, said in an interview. “They should not have this up unless they have consent from the family.”

Officials at the National Institutes of Health now acknowledge that they should have contacted the Lacks family when researchers first applied for a grant to sequence the HeLa genome. They belatedly addressed the problem after the family raised its objections.

The European researchers took down their public data, and the publication of the University of Washington paper was stopped. Dr. Collins and Kathy L. Hudson, the National Institutes of Health deputy director for science, outreach and policy, made three trips to Baltimore to meet with the Lacks family to discuss the research and what to do about it.

“The biggest concern was privacy — what information was actually going to be out there about our grandmother, and what information they can obtain from her sequencing that will tell them about her children and grandchildren and going down the line,” Ms. Lacks Whye said.

The Lacks family and the N.I.H. settled on an agreement: the data from both studies should be stored in the institutes’ database of genotypes and phenotypes. Researchers who want to use the data can apply for access and will have to submit annual reports about their research. A so-called HeLa Genome Data Access working group at the N.I.H. will review the applications. Two members of the Lacks family will be members. The agreement does not provide the Lacks family with proceeds from any commercial products that may be developed from research on the HeLa genome.

With this agreement in place, the University of Washington researchers were then able to publish their results. Their analysis goes beyond the European study in several ways. Most important, they show precisely where each gene is situated in HeLa DNA.

A human genome is actually two genomes, each passed down from a parent. The two versions of a gene may be identical, or they may carry genetic variations setting them apart.

“If you think of the variations as beads on a string, you really have two strings,” said Dr. Jay Shendure, who led the Washington genome study. “The way we sequence genomes today, for the most part we just get a list of where the genes are located, but no information about which ones are on which string.”

Dr. Shendure and his colleagues have developed new methods that allow them to gather that information. By reconstructing both strings of the HeLa genome, they could better understand how Ms. Lacks’s healthy cells had been transformed over the past 60 years.

For example, they could see how Ms. Lacks got cancer. Cervical cancer is caused by human papillomavirus infections. The virus accelerates the growth of infected cells, which may go on to become tumors.

Dr. Shendure and his colleagues discovered the DNA of a human papillomavirus embedded in Ms. Lacks’s genome. By landing at a particular spot, Ms. Lacks’s virus may have given her cancer cells their remarkable endurance.

“That’s one of the frequent questions that I and the Lacks family get whenever we talk about this stuff,” Ms. Skloot said. “The answer was always, ‘We don’t know.’ Now, there’s at least somewhat of an answer: because it happened to land right there.”

Richard Sharp, the director of biomedical ethics at the Mayo Clinic, said he thought the agreement “was pretty well handled.” But he warned that it was only a “one-off solution,” rather than a broad policy to address the tension between genome research and the privacy of relatives, now that recent research has demonstrated that it is possible to reveal a person’s identity through sequencing.

Dr. Sharp considered it impractical to set up a working group of scientists and relatives for every genome with these issues. “There’s absolutely a need for a new policy,” he said.

Eric S. Lander, the founding director of the Broad Institute, a science research center at Harvard and M.I.T., said resolving these issues was crucial to taking advantage of the knowledge hidden in our genomes.

“If we are going to solve cancer, it’s going to take a movement of tens of thousands, or hundreds of thousands, of patients willing to contribute information from their cancer genomes towards a common good,” Dr. Lander said. “We are going to need to have ways to have patients feel comfortable doing that. We can’t do it without a foundation of respect and trust.”

SOURCE

 

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Discovery of Causal gene mutation responsible for two dissimilar neurological diseasesAmyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD)

 

Reporter: Aviva Lev-Ari, PhD, RN

Expanding the Genetics of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD)

Ground-breaking study, identifying a causal gene mutation for two dissimilar neurological diseases.

 

TALK Date:

Wednesday, August 7

Time:

10:00 am PT / 1:00 pm ET

Speakers:

Bryan Traynor, MD, Ph.D.

Investigator Head, Neuromuscular Diseases Research Unit 

Laboratory of Neurogenetics National Institute of Aging, National Institutes of Health 

Abstract

Dr. Bryan Traynor and his team participated in a ground-breaking international study, identifying a causal gene mutation responsible for two dissimilar neurological diseases, ALS and FTD. As members of a worldwide consortium, his research team used next-generation sequencing to identify a large hexanucleotide repeat that disrupts the C9ORF72 gene located on chromosome 9. The mutation accounts for approximately 40% of all familial cases of ALS and FTD in European and North American populations, and also ~1% of Alzheimer’s disease cases. ALS, also known as Lou Gehrig’s disease, is a fatal neurodegenerative disorder that leads to rapidly progressive paralysis and respiratory failure. Frontotemporal dementia (FTD) is the most common form of dementia in the population under the age of 65. 

This landmark discovery has impacted how these neurological disorders are diagnosed, investigated and perceived. It also provides a distinct therapeutic target for gene therapy efforts aimed at ameliorating these diseases. 

SOURCE

Illumina

illumina@admail.directeffectmedia.com

 

 

 

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ASHG to Maintain Information of to shut down National Genetics Coalition

Reporter: Aviva Lev-Ari, PhD, RN

 

National Genetics Coalition to Shut Down,

July 30, 2013

NEW YORK (GenomeWeb News) – The National Coalition for Health Professional Education in Genetics (NCHPEG), an interdisciplinary group of leaders from a range of public and private organizations funded by the National Institutes of Health, will shut down next month due to funding constraints, according to the National Human Genome Research Institute.

The genetics and genomics education information that NCHPEG has compileds and made available via its website will be maintained by the American Society of Human Genetics, ASHG executive VP and former NCHPEG executive director Joseph McInerney said.

NCHPEG launched in 1996 after current NIH Director Francis Collins and Kathy Hudson, current NIH director for science, outreach, and policy, began talking with the American Medical Association and the American Nurses Association about the need for educating healthcare providers about genetics and genomics. Those discussions led to the creation of the group, which has been funded by NHGRI, the National Center for Advancing Translational Sciences, the NIH Office of Rare Diseases, and several other government agencies and non-profit foundations.

NCHPEG is slated to close down on Aug. 31. When the coalition began, there were few applications for genomics-related applications in healthcare that doctors encountered.

“A lot has changed since then,” NCHPEG Executive Director Joan Scott said in a statement. “There are many more clinical applications of genomics available and a growing awareness within the healthcare provider community that they need to be thinking about incorporating them into practice. We see more institutions and organizations developing initiatives to bring genomics into the clinic.”

The coalition’s core aim has been to provide genetics and genomics professional education tools through partnerships with specific communities and collaborations.

To that end, it has developed a number of documents, products, and programs to provide core competencies and educational programs in genetics, genomics, and family history for healthcare professionals.

The group has developed special programs aimed at helping physicians recognize increased genetic risk for cancer, and helping nutritionists, physician’s assistants, dentists, nurses, and others understand genetics and genomics.

McInerney said that ASHG will work over the next six months to determine whether the society wants to become more deeply involved in offering educational programs to healthcare providers.

“But we have to be thoughtful. NCHPEG is closing as a direct result of the current funding climate. We have to determine where our funding for education programs would come from if our board decides to take this on,” he explained.

McInerney said that during his time at NCHPEG, the group distributed thousands of publications on genomics education.

“Our premise was that healthcare professionals want to be up-to-date on all areas of medicine. Many of them already felt like the field of genetics and genomics was snowballing and they wanted to be ready,” he said.

SOURCE

http://www.genomeweb.com//node/1259986?utm_source=SilverpopMailing&utm_medium=email&utm_campaign=Health%20Genetics%20Program%20to%20Shutter;%20Foundation%20Medicine%20Files%20for%20IPO;%20Intrexon%20Prices%20IPO;%20More%20-%2007/30/2013%2004:05:00%20PM

 

 

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Reporter: Aviva Lev-Ari, PhD,RN

 

Functional Genomics Screening Strategies: Part One

Utilizing RNA Interference (RNAi) Screens

to Explore Drug Targets and Cellular Pathways

Boston, MA | September 24-25, 2013

Dr. Scott Martin, Team Leader for RNAi Screening at NIH’s Chemical Genomics Center, to Present “Swimming in the Deep End – Sources Leading to a False Sense of Security in RNAi Screen Data” at Functional Genomics Screening Strategies Conference

There has been a growing skepticism surrounding RNAi data and the validity of hits arising from largescale RNAi screens. Much of this comes from a lack of agreement between screens conducted in similar biological systems and difficulty in validating published screen hits. In light of these realities, we must rethink some widely held beliefs about screening and validation strategies. These issues and relevant data will be discussed.

 

Functional Genomics Screening Strategies: Part Two

Exploring Novel Screening Platforms and Cellular

Models for Next-Generation Screens

Boston, MA | September 25-26, 2013

The second half of Functional Genomics Screening Strategies will explore the use of chemical genomics screens, microRNA (miRNA) and long non-coding RNA (lncRNA) screens and the transition into advanced cellular models such as, 3D cell cultures, co-cultures and stem cells that will launch the next generation of functional screens. Screening experts from pharma/biotech as well as from academic and government labs will share their experiences leveraging the utility of such diverse screening platforms and models for a wide range of applications.

 SOURCE

 

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Impact of Sequestration on the National Institutes of Health

Reporter: Aviva Lev-Ari, PhD, RN

Article ID #59: Impact of Sequestration on the National Institutes of Health. Published on 6/4/2013

WordCloud Image Produced by Adam Tubman

UPDATED 6/5/2013

GenomeWeb Feature: Researchers Weigh in on Grants in the Time of Sequester

June 05, 2013

NEW YORK (GenomeWeb News) – When Nicholas Navin’s R01 grant to use single-cell sequencing to study tumor evolution in breast cancer was first funded in 2012, it was funded at 83 percent of the requested budget.

Because of the sequester, Navin’s grant now will be cut a further 6 percent. In addition, he has only been given funding for the next three months.

“After those three months, I assume that it will continue to be funded for the rest of the year,” said Navin, an assistant professor at the University of Texas MD Anderson Cancer Center, “but they only give you enough funding to support you for three months.”

The sequester — the across-the-board cuts to the US budget that were implemented at the beginning of March — has led to budget decreases across the federal government, including at research funding agencies like the National Institutes of Health and the National Science Foundation. The cuts exacerbated what was seen by many as an already tight funding situation that was not keeping pace with inflation, making it increasingly difficult for researchers to fund their work.

Steven Salzberg, a professor at Johns Hopkins University School of Medicine, recently had a grant rejected that was ranked in the top 11th percent of applications. In the past, he’s had grants funded that were in the 16th percentile or 17th percentile.

“They are funding, one would hope, grants at the 11th percentile, but not this particular one,” he said. “So you have to resubmit it or you can give up. Those are your two choices.”

As budgets decline and competition for grants increase, researchers are submitting more proposals and are beginning to look elsewhere for funding. At the same time, they are wondering what the effect of sequestration will be on science and scientists, particularly early career investigators. Still, there are steps investigators can take to try to get their proposal to stand out.

Cuts and effect

Because of the sequester, both NIH and NSF have seen their budgets fall about 5 percent. For this fiscal year, NIH’s budget is about $29.15 billion, as compared to $30.86 billion for fiscal year 2012. At the same time, NSF has about $6.9 billion for 2013, compared to last year’s $7.0 billion.

To cope with these decreases, NIH has cut all noncompeting renewals by 4.5 percent, but other changes were mostly left up to the various institutes that comprise NIH. For example, NHGRI, like other parts of NIH, is cutting noncompeting renewals, but it is not touching small grants, which it defines as ones with commitments of $250,000 or less and that typically are funded through R03 or R21 mechanisms. In addition, NHGRI won’t be giving future inflationary increases to competing applications.

“NHGRI deals with such a relatively small number of grants that we can look at each one individually and make decisions on the basis of how that particular application addresses institute aims and what the application needs in order to be successful,” Mark Guyer, the deputy director of NHGRI, told GenomeWeb Daily News. “Almost everything we do is really on a case-by-case basis beyond the across-the-board cuts to non-competing.”

The sequester, though, comes on the heels of years of small increases to funding agencies’ budgets. While the NIH budget went through an unprecedented doubling between about 1998 and 2003, it has since languished, with increases that typically did not keep pace with inflation.

“The field generally was in dire straits [heading into the sequester], given the very low payline by NIH, for example, and even NSF,” said Sarah Tishkoff, a professor at the University of Pennsylvania.

Salzberg noted that the two NIH R01 grants that he already has — awarded prior to the sequester — were cut about 15 percent to 20 percent. This, he added, was done “administratively because of budget reasons, not because of the peer review.”

“Now [the sequester] comes along and makes it even worse,” Tishkoff added.

Overall, NIH has estimated that it will fund nearly 8,300 competing research grants for FY2013, a decrease of about 700 from last year.

NHGRI also said that, in the face of the sequester, it is aiming to keep the average size of the awards it makes for FY2013 similar to the sizes of those it gave out in FY2012 — meaning that it will be giving out fewer total awards. Competition for grants, then, will become increasingly competitive.

“The [scientific] opportunities over the last decade at least and certainly into the foreseeable future are increasing hand over fist … and available funding is not keeping up with that,” Guyer said. “So necessarily things have gotten more competitive, and the sequester approach to managing the federal budget has only exacerbated the competitive aspects of things.”

As fewer proposals get funded and there’s less money to go around, many investigators may find themselves submitting more proposals to a number of funders.

“I am looking at submitting [more] proposals because it looks like funding is tight, and it is going to remain tight,” Salzberg told GWDN. “Unfortunately this produces a vicious cycle where many of us feel like our chances of getting funded are lower, therefore we should submit more proposals, but that then in return reduces the percentage that gets funded.”

It also increases the amount of time researchers spend reviewing proposals.

Others are looking to supplement their funds by turning to alternative funding sources. Navin, for example, is looking at private foundations and other organizations that fund cancer research, such as the Susan G. Komen Foundation or the Damon Runyon Cancer Research Foundation.

There, he said, he may have a few options given that he studies breast cancer. Other researchers, he noted, may not have such options. “I know some of my colleagues that work on colon cancer or some of the more rare cancers like testicular cancer or bladder cancer, they really have a hard time finding funding now,” he said.

In addition, cuts and uncertainty about future reductions in funding could make a lab a precarious place. After such budget cuts or in anticipation of cuts, some labs have slowed down their growth or have even begun to let people go.

Salzberg said that, as a computational biologist, his main expenses are the salaries of the students, postdocs, and staff who power his lab.

“[The funding situation] also makes me much more reluctant to hire postdocs or any new staff because I don’t have any more money coming in. You need more money to hire new people,” he said. He added that he still gets a number of requests from people looking for positions, but “I don’t have the funding for a new postdoc. Until I get some new funding that’s what I’ll keep saying.”

“I’ve seen [colleagues’] grants just get slashed by huge amounts,” Tishkoff added, noting that she’s seen technicians beginning to lose their jobs.”[Investigators] either have to cut some of the staff or they have to cut one of the aims.”

And as grant budgets are cut, researchers have to accomplish their research aims with less, and this often means cutting back on some of the science they would like to have done.

“Because they cut the budget, you have to cut the scope,” Salzberg said. “You still do the work, but you don’t do all the things that you want to do.”

Navin, for example, is looking to use a smaller study size, even though that’ll affect the statistical power of his work.

And that’s for the grants that get funded.

“Some projects just aren’t getting done,” Salzberg added. “[My grant] that wasn’t funded was a different project and we’re not going to do it.”

This, he said, may lead to delays in improvements to healthcare. New treatments and drugs will come, he said, but it may be in 20 years rather than in 10 years or 15 years.

Concern for new investigators

One common fear is that the sequester will disproportionately affect new investigators as they try to start labs and fund them or even dissuade them from pursuing a career in academia.

“It looks like it is disturbing a lot of young people and influencing the way that they are thinking about a potential career,” Guyer said.

Tishkoff added that she is worried that junior scientists will see how the more senior people are struggling to find funding, and opt out. “[New investigators] have to get grants if they want to get tenure. They have to get grants to be successful and to continue to be a scientist in the future,” she said.

“That’s the question that I get over and over again” from students and postdocs, Navin added. “What’s it going to be like in … five to 10 years?”

“I try to stay optimistic and tell them that there will be funding, but it is hard to predict the future,” he said.

Still, junior scientists may look for careers in industry or outside of the research realm.

“I think that when they hear all of this gloom and doom talk going on, it is really discouraging them. And that makes me really worried that we are losing talented scientists,” Tishkoff said. She added that she’s noticed that people with computational biology or bioinformatic backgrounds seem to be heading to industry.

Salzberg added that the field may never even know what it is losing. “People will leave the field — they won’t announce it — they just go get a job doing something else,” he said. “Generally, you lose that [talent] forever because that person doesn’t come back.”

Funding agencies like NIH do have mechanisms in place to try to help new investigators get grants. For example, proposals from new investigators are reviewed separately from ones submitted by established PIs. That way, early-career researchers compete against each other, rather than against those with more experience.

Further, in its policy statement for this fiscal year, NIH said that it would continue to support new investigators applying for R01 grants with success rates similar to those of established PIs.

“I really think they are doing as much as they can, but there is a bottom line,” Tishkoff noted. “If you do not have the money to give out, then it is going to be more and more and more competitive. That’s just how it is.”

NHGRI, in its own policy statement, said that it is “very flexible” in supporting early-stage investigators by not reducing recommended budgets if possible, by giving special consideration when applying for renewals to avoid gaps in funding, and by its Pathway to Independence Awards, which are targeted to postdocs who are moving toward running their own lab.

Outside of federal support, there are also a number of grants that specifically fund new investigators, such as the David and Lucile Packard Foundation Fellowships for Science and Engineering, Burroughs Wellcome Fund Career Awards, or the Sloan Research Fellowship, among others.

Tips for getting a grant

With increased competition for a smaller pot of money, submitting a well-crafted grant proposal might help it stick out from the rest in the pile. While some researchers may be quickly churning out as many proposals as they can, Tishkoff said that approach may not be the best one.

“The fact is it’s now even more competitive, it is even more important that people are taking time to really work on the grants carefully and not try to rush through them,” she told GWDN.

Still, submit a proposal quickly. “Don’t wait to apply for your first grant,” Salzberg said. “Very few people get funded on their first time around. You learn a lot from the reviews you get back.”

For his first grant, Salzberg partnered with a senior colleague to be a co-PI on the grant. “You can learn a lot about grantsmanship that way,” he said. “And then if the senior colleague gets funded, then you get some money out of that.” In addition, “you also learn some of the administrative hoops.”

Once on a grant, investigators begin to be invited to review panels that evaluate such grant proposals. “That’s a very valuable experience,” Salzberg said. “The first couple of times you are on a review panel, you learn a tremendous amount because you see a lot of other people’s grant applications and you see what the reviewers are saying about them.”

Tishkoff said one common problem she’s seen, particularly among new investigators, is that the proposals can feel hurried and too full of jargon. “You’ve got to take your time, write clearly in a manner that a general scientist can understand,” she said, adding that investigators have to sell their idea to a “broad scientific audience [and] make the point of why it is cutting edge and important and advances the field.”

Having other, more senior people look over a proposal is often a key step, she added, saying that she’s seen applications in which there were simple errors like numbers not adding up that could have easily been avoided by having someone else take a look at it.

An oft-overlooked step, by new and established PIs alike, is getting in touch with their program officers. “Start out talking to NIH program people as soon as possible,” Guyer said.

Program officers can provide information on funding mechanisms, initiatives, and budgets, and offer feedback on how project ideas fit within institutes’ priorities. “And we think, at least we tell ourselves, that it can help save people a lot of wasted time,” he added.

Tishkoff said that she typically calls up her program officer when she’s thinking about and applying for a grant to see how her idea fits with what the institute is interested in funding and to discuss a potentially reasonable budget.

“You could say, ‘I am thinking about applying for this, this, and this. Is that something that you or this institute would be interested in funding?'” she said. “And so you can try to aim to make your proposal fit with what their goals are at the moment.”

“Secondly, I always tell them, ‘OK, here’s the budget I have in mind. Is that going to be realistic or not?'” she added.

And once, she said, she was told her budget for what she called an “all-in-one, big giant grant” was too high to be funded. Instead, Tishkoff broke that large, all-inclusive grant into smaller, more focused projects, and she stripped the budgets to the bare bones.

However, not all proposals will be funded, even well-written ones. “There’s no magic bullet here, though, it’s just times are tough,” Salzberg added. “If they are only funding 10 percent of proposals, then whatever happens, 90 percent of them are going to be rejected, so try to be in the top 10 percent, but we can’t all be in the top 10 percent all the time.”

Navin added that those who get rejected should not give up and should keep submitting. “I just think you have to be very optimistic, be an eternal optimist and just keep submitting your grants to as many different funding agencies as possible,” he said. “And eventually, if it is a good idea, it’ll get funded.”

The next fiscal cycle

While fiscal year 2013 is more than half over, the US federal budget for fiscal year 2014 isn’t yet set, so what is in store for research funding — and whether the sequester will continue —isn’t clear.

The Obama administration released its budget proposal for FY 2014 in April, which would replace the sequester. It called for $31.3 billion for the National Institutes of Health — an increase of 1.5 percent over the FY 2012 budget — and $7.6 billion for the National Science Foundation — an 8.4 percent increase over its FY 2012 appropriation.

The budget, though, needs to pass Congress.

“We’re making plans for FY ’14 on the basis of what the administration presented as a budget,” Guyer said. “We’re hoping the Congress can do better than that. On the other hand, we are realistic.”

Ciara Curtin is GenomeWeb’s science features editor as well as the editor of the Daily Scan and Careers blogs. E-mail Ciara Curtinand follow @DailyScan, and @CareersGW on Twitter.

Fact sheet: Impact of Sequestration on the National Institutes of Health

The National Institutes of Health is the nation’s medical research agency and the leading supporter of biomedical research in the world. NIH’smission is to seek fundamental knowledge about the nature and behavior of living systems and apply that knowledge to enhance health, lengthen life, and reduce the burdens of illness and disability. Due in large measure to NIH research, a person born in the United States today can expect to live nearly 30 years longer than someone born in 1900.

More than 80 percent of the NIH’s budget goes to over 300,000 research personnel at more than 2,500 universities and research institutions throughout the United States. In addition, about 6,000 scientists work in NIH’s own Intramural Research laboratories, most of which are on the NIH main campus in Bethesda, Md. The main campus is also home to theNIH Clinical Center, the largest hospital in the world totally dedicated to clinical research.

Sequestration:

On March 1, 2013, as required by statute, President Obama signed an order initiating sequestration. The sequestration requires NIH to cut 5 percent or $1.55 billion of its fiscal year (FY) 2013 budget. NIH must apply the cut evenly across all programs, projects, and activities (PPAs), which are primarily NIH institutes and centers. This means every area of medical research will be affected.

NIH FY2013 operating plans:

NIH FY2013 Operating Plan

NIH FY2013 Operating Plan Mechanism Table

NIH Guide Notice: Fiscal Policy for Grant Awards FY2013

NIH Institutes and Centers FY2013 Funding Strategies

The estimated numbers:

(FY 2013 figures compared to FY 2012)

While much of these decreases are due to sequester, NIH funding is always a dynamic situation with multiple drivers:

  • Approximately 700 fewer competitive research project grants issued
  • Approximately 750 fewer new patients admitted to the NIH Clinical Center
  • No increase in stipends for National Research Service Award recipients in FY2013

The impact:

  • Delay in medical progress:
    • Medical breakthroughs do not happen overnight. In almost all instances, breakthrough discoveries result from years of incremental research to understand how disease starts and progresses.
    • Even after the cause and potential drug target of a disease is discovered, it takes on average 13 years and $1 billion to develop a treatment for that target.
    • Therefore, cuts to research are delaying progress in medical breakthroughs, including:
      • development of better cancer drugs that zero in on a tumor with fewer side effects
      • research on a universal flu vaccine that could fight every strain of influenza without needing a yearly shot.
      • prevention of debilitating chronic conditions that are costly to society and delay development of more effective treatments for common and rare diseases affecting millions of Americans.
  • Risk to scientific workforce:
    • NIH drives job creation and economic growth. NIH research funding directly supports hundreds of thousands of American jobs and serves as a foundation for the medical innovation sector, which employs 1 million U.S. citizens. Cuts to NIH funding will have an economic impact in communities throughout the U.S. For every six applications submitted to the NIH, only one will be funded. Sequestration is reducing the overall funding available for grants. See the history of NIH funding success rates.

Frequently asked questions:

How many fewer grants will be awarded?
Approximately 700 fewer research project grants compared to FY 2012.

Have the institutes and centers announced their adjusted paylines based on these cuts?
The adjusted NIH Institute and Center (IC) paylines and funding strategies can be found here:http://grants.nih.gov/grants/financial/index.htm#strategies

What percent cut will be made to existing grants?
Reductions to noncompeting research project grants (RPG) vary depending on the circumstances of the particular IC. The NIH-wide average is -4.7 percent.

Will the duration of existing grants be shortened to accommodate the cuts?
In general, no.

Will all grants receive the same percentage cut or will some grants be cut more than others?
Institutes and centers have flexibility to accommodate the new budget level in a fashion that allows them to meet their scientific and strategic goals. As noted above, there are different percentages for different ICs, and in some cases for different mechanisms within an IC (RPGs, Centers, etc.). In addition, there may be reductions to grants for reasons other than sequestration, as is the case every year.

Will certain areas of science that are at a critical juncture be affected by these cuts? 
All areas of science are expected to be affected.

Will some areas of science be affected more than others?
The sequester does not stipulate the precise reduction to each scientific area. However, it is likely that most scientific areas will be reduced by about 5 percent because the sequester is being applied broadly at the NIH institute and center level.

What will be the impact of these cuts to NIH’s intramural research at its Bethesda campus and off-campus facilities?
The impact on NIH’s intramural research is substantial, especially because it applies retroactively to spending since Oct. 1, 2012. That can double the effect — a full year’s cut has to be absorbed in less than half a year.

Will NIH be furloughing or cutting employees at its NIH campus and off-campus facilities?
There are no current plans to do so. At present, HHS is pursuing non-furlough administrative cost savings such as delayed/forgone hiring and reducing administrative services contracts so that furloughs and layoffs can be avoided. Additionally, employee salaries at NIH make up a very small percentage (only 7 percent) of the NIH budget.

How will current patients at the NIH Clinical Center be affected?
Services to patients will not be reduced.

Will the NIH Clinical Center see fewer patients because of the cuts?
Approximately 750 fewer new patients will be admitted to the NIH Clinical Center hospital in 2013 or a decrease from 10,695 new patients in 2012 to approximately 9,945 new patients in 2013. While much of this decrease is due to funding, clinical activity is always a dynamic situation with multiple drivers.

Will the sequester cut need to be applied to the FY 2014 budget?
The President’s FY 2014 Budget would replace sequestration and reduce the deficit in a balanced way. The President is ready to work with Congress to further reduce deficits while continuing to make critical investments.

About the National Institutes of Health (NIH): NIH, the nation’s 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. For more information about NIH and its programs, visit www.nih.gov.

NIH…Turning Discovery Into Health®

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Discovery on Target: Industry’s Preeminent Event on Novel Drug Targets 

Reporter: Aviva Lev-Ari, PhD, RN

 

ABOUT THIS CONFERENCE

Cambridge Healthtech Institute’s tenth annual conference on Functional Genomics Screening Strategies will cover the latest in the use of RNA interference (RNAi) screens, combination (RNAi and small molecule) screens, chemical genomics and phenotypic screens, for identifying and validating new drug targets and exploring unknown cellular pathways. The first half of the conference will focus on the design and use of RNAi screens, while the second half will explore the use of chemical genomics screens, microRNA (miRNA) and long non-coding RNA (LncRNA) screens and the transition into advanced cellular models such as, 3D cell cultures, co-cultures and stem cells that will launch the next-generation of functional screens. Screening experts from pharma/biotech as well as from academic and government labs will share their experiences leveraging the utility of such diverse screening platforms and models for a wide range of applications.

SUGGESTED EVENT PACKAGE:

September 23: Setting Up Effective RNAi Screens: Getting From Design to Data Short Course
September 24 – 25: Functional Genomic Screening Strategies Conference Part One
September 25: Setting Up Effective Functional Screens Using 3D Cell Cultures Dinner Short Course
September 25 – 26: Functional Genomic Screening Strategies Conference Part Two

 

WHERE AND HOW TO APPLY SIRNA AND SHRNA SCREENS

Comparative Analysis of Arrayed RNAi Screening Performance of siRNA versus shRNA at Genome-Scale

Hakim Djaballah, Ph.D., Director, HTS Core Facility, Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center

 

RNAi Screening: Strategies, Examples and Outcomes

David Root, Ph.D., Director, RNAi Platform and Project Leader, The RNAi Consortium, The Broad Institute of MIT and Harvard

 

Swimming in the Deep End – Sources Leading to a False Sense of Security in RNAi Screen Data

Scott Martin, Ph.D., Team Leader, RNAi Screening, NIH Chemical Genomics Center, NIH Center for Translational Therapeutics, National Institutes for Health

 

Rebuilding the RNAi Screen

Eugen Buehler, Ph.D., Group Leader, Informatics, National Center for Advancing Translational Sciences, National Institutes of Health

 

Genetic Strategies for Investigating Host-Virus Interactions

Abraham Brass, M.D., Ph.D., Assistant Professor, Department of Microbiology and Physiology Systems, University of Massachusetts Medical School

 

PANEL DISCUSSION: Advanced RNAi Screening: Strengths, Caveats and Pitfalls at Reaching the 14-Year Milestone

Moderator: Christophe Echeverri, Ph.D., CEO & CSO, Cenix BioScience USA, Inc.

Panelists:

Caroline Shamu, Ph.D., Director, ICCB-Longwood Screening Facility, Harvard Medical School

David Root, Ph.D., Director, RNAi Platform and Project Leader, The Broad Institute

Hakim Djaballah, Ph.D., Director, HTS Core Facility, Memorial Sloan Kettering Cancer Center

Scott Martin, Ph.D., Team Leader, RNAi Screening, NIH Chemical Genomics Center

 

 

EXPLORING DIVERSE APPLICATIONS

RNAi Screening to Enable Translational R&D For Oncology and Immuno-Oncology Target Discovery

Namjin Chung, Ph.D., Senior Research Investigator, Applied Genomics, Bristol-Myers Squibb Co.

 

Target Identification and Validation of Novel Ion Channels in Cancer

Alex Gaither, Ph.D., Research Investigator II, Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research

 

Cell-Based Functional Profiling of Lipid-Traits and Cardiovascular Disease

Heiko Runz, M.D., Group Leader, Molecular Metabolic Disease Unit, Institute of Human Genetics; Group Leader, University of Heidelberg

 

Use of Functional Genomics to Identify Patients at High Risk for Recurrence of Hepatitis C Following Liver Transplantation

Robert Carithers, M.D., Professor of Medicine, Director, Liver Care Line; Medical Director, Liver Transplant Program, University of Washington Medical Center

CellectaPooled RNAi Genetic Screening to Identify Functional Genes and Novel Drug Targets

Paul Diehl, Director, Business Development, Cellecta, Inc.

 

TECHNOLOGY PANEL: Tools for Next-Generation Functional Genomics Screens

Moderator: Christophe Echeverri, Ph.D., CEO & CSO, Cenix BioScience USA, Inc.

This panel will bring together 4-5 technical experts from leading technology and service companies to discuss screening trends and improvements in assay platforms and reagents that users can expect to see in the near future.

(Opportunities Available for Sponsoring Panelists)

 

 

COMBINING USE OF RNAI AND OTHER TECHNOLOGIES

siRNA Screening and RNA-seq for Identification of Targets for the Treatment of Alzheimer’s Disease

Paul Kassner, Ph.D., Director, Research, Amgen, Inc.

 

Fusing RNAi Screening and Gene Expression Analyses to Reveal Pathway Responses

Alexander Bishop, Ph.D., Assistant Professor, Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio

http://www.discoveryontarget.com/RNAi-Screens-Functional-Genomics/ 

 

 

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CT Angiography (CCTA) Reduced Medical Resource Utilization compared to Standard Care reported in JACC

Reporter: Aviva Lev-Ari, PhD, RN

Updated on 10/24/2022

CCTA Effective in Pre-procedural Planning of Myocardial Revascularization Interventions

Image showing a co-registration of invasive coronary angiography (A), coronary CTA and straight MPR (panel B and C) with CTA cross sections (panel D), corresponding OCT cross sections and longitudinal OCT view (E).

September 13, 2022 — The latest expert consensus document from the Society of Cardiovascular Computed Tomography (SCCT), co-published with EuroIntervention, describes Coronary CT Angiography (CCTA) as an effective tool for interventional cardiologists to prepare and optimize the coronary procedure.

Pre-procedural Planning of Coronary Revascularization by Cardiac Computed Tomography,” published in Journal of Cardiovascular Computed Tomography (JCCT), states that CCTA combined with fractional flow reserve (CT-FFR) or stress CT myocardial perfusion imaging (CT-MPI) can provide a comprehensive anatomical and physiological roadmap for coronary revascularization.

The expert consensus document explains that CCT may emerge in the field of interventional cardiology as no longer “a mere diagnostic tool,” as it was when first introduced into clinical practice more than 15 years ago.

According to the writing group, led by Daniele Andreini, MD, PhD, FSCCT of Centro Cardiologico Monzino in Milan, Italy, the potential value of CCTA to plan and guide interventional procedures lies in the wide information it can provide, including its accuracy for plaque and calcium characterization.

Andreini and his co-authors explain that, with its 3-dimensional nature and physiological assessment, CCTA is the only non-invasive imaging modality to assess Syntax Score and Syntax Score II, which enable the Heart Team to select the mode of revascularization (PCI or CABG) for patients with complex disease based on long-term mortality.

Additionally, CCTA may help in identifying anatomical characteristics of chronic total occlusions (CTO) that are associated with increased complexity of CTO percutaneous coronary intervention (PCI).

Before PCI, CCTA has the potential to be used to overcome some limitations of conventional invasive coronary angiography (ICA), including vessel foreshortening and difficulties in selecting optimal projections, with particular importance in bifurcation and ostial lesions.

For more information: www.scct.org

CT Scanner Delivers Less Radiation

Faster, more sensitive scans and better image processing may reduce the risk of x-ray-related cancers.

 WHY IT MATTERS

A new CT scanner exposes patients to less radiation while providing doctors with clearer images to help with diagnoses, according to researchers at the National Institutes of Health.

“CT” stands for Computerized Tomography, which involves combining lots of x-ray images taken from different angles into a three-dimensional view of what’s inside the body. The technology can be especially useful for diagnoses in emergency situations, and the number of CT scans in recent years has increased dramatically, says Marcus Chen, a cardiovascular imager at the National Heart, Lung and Blood Institute, in Bethesda, Maryland.  But the increase in the use of CT scans raises concerns about the amount of radiation to which patients are exposed, says Chen.

The risk of developing cancer from the radiation delivered by one CT scan is low, but the large number of scans performed each year—more than 70 million—translates to a significant risk. Researchers at the National Cancer Institute estimated that the 72 million CT scans performed in the U.S. in 2007 could lead to 29,000 new cancers. On average, the organ studied in a CT scan of an adult receives around 15 millisieverts of radiation, compared with roughly 3.1 millisieverts of radiation exposurefrom natural sources each year.

This concern has led researchers to seek ways to reduce the amount of radiation exposure a patient receives in a scan. They are working to improve both hardware, to make the scans go faster and need less repetition, and software, to process the x-ray data better (see “Clear CT Scans with Less Radiation”).

The new CT scanning system, from Toshiba Medical, combines several improvements to reduce radiation exposure. The overall body of a CT scanner is shaped like a large ring. An x-ray tube and a detector spin separately in the ring, opposite one another, and a patient lies in the center.  X-rays travel through the patient as they are delivered by the tube and captured by the detectors. The new Toshiba machine has five times as many detectors as most machines, which means that more of an organ can be captured at a time, decreasing the number of passes of the scanner required.

The x-ray components in the new system also spin faster—it takes only 275 milliseconds for them to complete a rotation, instead of 350 millisesconds—which means a patient gets irradiated for less time. In cases where doctors are looking at a moving organ such as the heart, the faster spinning also reduces the number of times a doctor may need to try to get a good image. “It’s like having faster film in your camera,” says Chen.  Changes to the way the system generates x-rays and computes the images also mean patients spend less time getting hit with radiation.

Chen and colleagues at the National Heart Lung and Blood Institute used the Toshiba system to examine 107 adult patients of different ages and sizes for plaque buildup and cardiovascular problems. Patient size matters because more x-rays are required to image a larger person. “A lot of imaging centers will use one setting for all patients,” says Chen. “You get beautiful image quality on everybody, but the downside is that some patients get more radiation than they probably should.” In his study, the system takes a quick preliminary scan that uses low-dose x-rays to figure out how big a patient is and how much radiation will be needed for the diagnostic image.

Most patients who got a scan in the new Toshiba machine received 0.93 millisieverts of radiation, and almost every patient received less than 4 millisieverts. Radiation exposure was decreased by as much as 95 percent relative to other CT scanners currently in use.

http://www.linkedin.com/profile/view?id=87597&trk=tab_pro

The reader is advised to review Alternative #3 in the following article, published on 3/10/2013, including the Editorial in NEJM by Dr. Redberg, UCSF, included in the article, prior to reading the content, below — as background on this important topic having the potential to change best practice and standard of care in the ER/ED.

Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI – Corus CAD, hs cTn, CCTA

CCTA for Chest Pain Cuts Costs, Admissions

By Eric Barnes, AuntMinnie.com staff writer

May 14, 2013 — One of the largest studies yet comparing medical resource use and outcomes among chest pain patients found that coronary CT angiography (CCTA) reduced medical resource utilization compared to standard care, generating fewer hospital admissions and shorter emergency room stays, researchers reported in the Journal of the American College of Cardiology.

The retrospective study compared matched cohorts of nearly 1,000 patients presenting with chest pain before and after implementation of routine CCTA evaluation. The study team from Stony Brook, NY, and two other institutions found that patients receiving the standard workup for chest pain — which is to say, mostly observation — were admitted to the hospital almost five times as frequently as patients receiving CT. The standard workup patients also had significantly longer stays when admitted.

The rates of invasive angiography without revascularization and recidivism were also much higher for patients receiving standard care (JACC, May 14, 2013).

“I think the take-home message is that CT done correctly by experts with the resources to do it correctly on a routine basis is not only safe and feasible, but reduces healthcare resource utilization,” said lead author Dr. Michael Poon, from Stony Brook Medical Center, in an interview with AuntMinnie.com.

More than $10 billion in costs

Caring for chest pain is an expensive proposition in the U.S., costing upward of $10 billion a year for some 6 million emergency department (ED) visits. To reduce the problem of overcrowded emergency rooms, some hospitals have implemented chest pain evaluation units, but the care isn’t comprehensive or necessarily all that helpful, Poon said.

“It has been a problem and a major dilemma for emergency rooms because for most patients, it’s a false alarm,” he said. “I would say nine out of 10 are false alarms, but how to pick out that one is very tricky and costly. So what most hospitals tend to do is a one-size-fits-all policy where everybody gets blood tests and an electrocardiogram, and they keep patients in the ED for an extended period of time. So if you come in Friday, you may stay until Monday.”

Coronary CTA has been shown to be safe and cost-effective for acute chest pain evaluation in several smaller studies and in three smaller multicenter trials, but those studies have been limited by a lack of CT availability outside of weekdays and office hours, while EDs must operate 24/7, Poon said.

“All of those studies were done in a randomized, controlled fashion and in an artificial environment,” where each patient was randomized to either a stress test or CT during weekday office hours, Poon said. “But in real life, there is no such thing; it cannot be done.”

More often, chest pain patients get a couple of tests and several hours of observation before they are sent home.

Poon and colleagues from Stony Brook, William Beaumont Hospital, and the University of Toronto wanted to do a “real-world” observational study to show that CT remained cost-effective and efficient for triaging chest pain patients.

The study sought to compare the overall impact of CT on clinical outcomes and efficacy, when comparing CCTA and the hospital’s standard evaluation for the triage of chest pain patients, with CCTA available 12 hours a day, seven days a week.

From a total of 9,308 patients with a chest pain diagnosis upon admission, the study used a matched sample of 894 patients without a history of coronary artery disease and without positive troponin or ischemic changes on an electrocardiogram.

Patients undergoing CT were scanned on a 64-detector-row scanner (LightSpeed VCT, GE Healthcare) following administration of iodinated contrast and metoprolol as a beta-blocker for those with heart rates faster than 65 beats per minute (bpm).

Those with a body mass index (BMI) less than 30 were scanned at 100 kV, while those with a BMI between 30 and 50 were scanned at 120 kV. Retrospective gating was reserved for patients whose heart rates remained above 65 bpm. Obstructive stenosis was defined as 50% or greater lumen narrowing.

CT choice faster, more efficient

The results showed a lower overall admission rate of 14% for CCTA, compared with 40% for the standard of care (p < 0.001). In fact, patients undergoing standard evaluation were 5.5 times more likely to be admitted (p < 0.001) than CCTA patients.

The length of stay in the ED was 1.6 times longer for standard care (p < 0.001) than for CCTA. For patients undergoing CCTA, the median radiation dose was 5.88 mSv.

“We also showed that the recidivism rate is higher for standard of care, meaning that they come back within one month with recurrent chest pain,” Poon said. The odds of returning to the ED within 30 days were five times greater for patients in the standard evaluation group (odds ratio, 5.06; p = 0.022).

“In the era of Obamacare, this is a penalty to the hospital; you don’t want the patient returning within one month with the same diagnosis,” he said. When that happens, “you’re not only not getting paid, you have to pay a penalty. It’s a double whammy. We also show that downstream invasive coronary angiography is significantly less in the CCTA arm.”

More invasive angiography

Patients receiving standard care were seven times more likely to undergo invasive coronary angiography without revascularization (odds ratio, 7.17; p ≤ 0.001), while neither patient group was significantly more likely to undergo revascularization.

“Many physicians use [catheterization] as a way of getting patients in and out of the hospital,” Poon said. However, the cost is more than $10,000 per procedure.

The high rate of angiography without revascularization in the standard care group was not seen in the Rule Out Myocardial Infarction/Ischemia Using Computer Assisted Tomography (ROMICAT) I and II trials, where all patients in the standard care group underwent stress testing before angiography was considered, he said.

Poon credited the ROMICAT trials’ routine use of stress tests with diminishing CT’s relative advantage in resource use. “In the real world, that is not available,” he said. The present study, in which only about 20% of the standard care patients underwent stress tests, is more realistic.

Finally, Poon and colleagues showed no difference in rates of myocardial infarction between CT and the standard of care within the first 30 days of follow up. However, that is changing as patients are followed for longer time periods, he noted.

“We see a trend starting to diverge in our next report, which follows [patients] for six months,” he said. “You see a lot more acute myocardial infarction in the standard care arm, and we’re going to extend it for a year.”

The authors concluded that using CCTA to rule out acute coronary syndromes in low-risk chest pain patients is likely to improve doctors’ ability to triage patients with the common presentation of chest pain. The result of this approach appears to be fewer hospital admissions, shorter stays, less recidivism, less invasive angiography, and better patient outcomes.

In any case, Poon said, the study method is permanent at Stony Brook University, where the standard of care now incorporates CCTA.

“We didn’t stop doing it after the study,” he said. “If you look at some of the randomized, controlled studies, they actually went back to the standard of care.” They had to because those kinds of protocols are only practical with a grant.

Related Reading

CORE 320 study evaluates CCTA and SPECT for CAD diagnosis, March 25, 2013

Study affirms CCTA’s value to rule out myocardial infarction, March 19, 2013

CCTA predicts heart attack in people without risk factors, February 19, 2013

Study: Use CCTA 1st for lower-risk chest pain patients, February 4, 2013

2010 CCTA appropriateness criteria yield mixed results, January 31, 2013
Copyright © 2013 AuntMinnie.com

http://www.auntminnie.com/index.aspx?sec=sup&sub=cto&pag=dis&ItemID=103419&wf=5447

Other related articles on this Open Access Online Scientific Journal include the following:

Economic Toll of Heart Failure in the US: Forecasting the Impact of Heart Failure in the United States – A Policy Statement From the American Heart Association

Aviva Lev-Ari, PhD, RN, 4/25/2013

http://pharmaceuticalintelligence.com/2013/04/25/economic-toll-of-heart-failure-in-the-us-forecasting-the-impact-of-heart-failure-in-the-united-states-a-policy-statement-from-the-american-heart-association/

Diagnosis of Cardiovascular Disease, Treatment and Prevention: Current & Predicted Cost of Care and the Promise of Individualized Medicine Using Clinical Decision Support Systems

Larry H Bernstein, MD, FACP and Aviva Lev-Ari, PhD, RN, Curator, 5/15/2013

http://pharmaceuticalintelligence.com/2013/05/15/diagnosis-of-cardiovascular-disease-treatment-and-prevention-current-predicted-cost-of-care-and-the-promise-of-individualized-medicine-using-clinical-decision-support-systems-2/

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Reporter: Aviva Lev-Ari, PhD, RN

Cause for Increased Cardiovascular Risk: proatherosclerotic metabolite, trimethylamine-N-oxide (TMAO).

Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk

W.H. Wilson Tang, M.D., Zeneng Wang, Ph.D., Bruce S. Levison, Ph.D., Robert A. Koeth, B.S., Earl B. Britt, M.D., Xiaoming Fu, M.S., Yuping Wu, Ph.D., and Stanley L. Hazen, M.D., Ph.D.

N Engl J Med 2013; 368:1575-1584April 25, 2013DOI: 10.1056/NEJMoa1109400

BACKGROUND

Recent studies in animals have shown a mechanistic link between intestinal microbial metabolism of the choline moiety in dietary phosphatidylcholine (lecithin) and coronary artery disease through the production of a proatherosclerotic metabolite, trimethylamine-N-oxide (TMAO). We investigated the relationship among intestinal microbiota-dependent metabolism of dietary phosphatidylcholine, TMAO levels, and adverse cardiovascular events in humans.

METHODS

We quantified plasma and urinary levels of TMAO and plasma choline and betaine levels by means of liquid chromatography and online tandem mass spectrometry after a phosphatidylcholine challenge (ingestion of two hard-boiled eggs and deuterium [d9]-labeled phosphatidylcholine) in healthy participants before and after the suppression of intestinal microbiota with oral broad-spectrum antibiotics. We further examined the relationship between fasting plasma levels of TMAO and incident major adverse cardiovascular events (death, myocardial infarction, or stroke) during 3 years of follow-up in 4007 patients undergoing elective coronary angiography.

RESULTS

Time-dependent increases in levels of both TMAO and its d9 isotopologue, as well as other choline metabolites, were detected after the phosphatidylcholine challenge. Plasma levels of TMAO were markedly suppressed after the administration of antibiotics and then reappeared after withdrawal of antibiotics. Increased plasma levels of TMAO were associated with an increased risk of a major adverse cardiovascular event (hazard ratio for highest vs. lowest TMAO quartile, 2.54; 95% confidence interval, 1.96 to 3.28; P<0.001). An elevated TMAO level predicted an increased risk of major adverse cardiovascular events after adjustment for traditional risk factors (P<0.001), as well as in lower-risk subgroups.

CONCLUSIONS

The production of TMAO from dietary phosphatidylcholine is dependent on metabolism by the intestinal microbiota. Increased TMAO levels are associated with an increased risk of incident major adverse cardiovascular events. (Funded by the National Institutes of Health and others.)

Supported by grants from the National Institutes of Health and its Office of Dietary Supplements (R01HL103866 and 1P20HL113452). The clinical study GeneBank was supported by grants from the National Institutes of Health (P01HL098055, P01HL076491, R01HL103931, and R01DK080732) and a Cleveland Clinic/Case Western Reserve University Clinical and Translational Science Award (UL1TR000439). Dr. Hazen was supported by a gift from the Leonard Krieger Fund. Mass spectrometry instrumentation used was housed within the Cleveland Clinic Mass Spectrometry Facility with partial support through a Center of Innovation by AB SCIEX.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank Linda Kerchenski and Cindy Stevenson for their assistance in recruitment of study participants and Amber Gist and Naomi Bongorno for their assistance in the preparation of earlier versions of the figures and the manuscript.

SOURCE INFORMATION

From the Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland.

Address reprint requests to Dr. Hazen at the Cleveland Clinic, 9500 Euclid Ave. NC-10, Cleveland, OH 44195, or at hazens@ccf.org.

http://www.nejm.org/doi/full/10.1056/NEJMoa1109400?query=genetics

EDITORIAL

Gut Microbiota, the Genome, and Diet in Atherogenesis

Joseph Loscalzo, M.D., Ph.D.

N Engl J Med 2013; 368:1647-1649April 25, 2013DOI: 10.1056/NEJMe1302154

This article has no abstract; the first 100 words appear below.

The Galtonian distinction between the influence of genetics and environment on phenotype is now widely recognized as an overly simplistic dichotomy. Genes and environmental factors interact in myriad ways to modulate and modify the biology of all living organisms, challenging the notion that these two principal determinants of phenotype can ever truly act independently of each other. Environmental exposures and experiences can have a direct influence on the expression of genes through epigenetic processes or on the function of gene products through post-translational modification. Likewise, genetic factors influence the consequences of environmental exposures or stresses on the organism.

 

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Reporter: Aviva Lev-Ari, PhD, RN

Gene found that regenerates heart tissue

DALLAS – April 17, 2013 – Researchers at UT Southwestern Medical Center have identified a specific gene that regulates the heart’s ability to regenerate after injuries.

Scientists led by Dr. Hesham Sadek have demonstrated that the gene Meis1 regulates the regenerative capability of newborn hearts.

Scientists led by Dr. Hesham Sadek have demonstrated that the gene Meis1 regulates the regenerative capability of newborn hearts.

The function of the gene, called Meis1, in the heart was not known previously. The findings of the UTSW investigation are available online in Nature.

“We found that the activity of the Meis1 gene increases significantly in heart cells soon after birth, right around the time heart muscle cells stop dividing. Based on this observation we asked a simple question: If the Meis1 gene is deleted from the heart, will heart cells continue to divide through adulthood? The answer is ‘yes’,” said Dr. Hesham Sadek, assistant professor of internal medicine in the division of cardiology, and senior author of the study.

In 2011, Dr. Sadek’s laboratory showed that the newborn mammalian heart is capable of a vigorous, regenerative response to injury through division of its own cells. As the newborn develops, the heart rapidly loses the ability to regenerate and to repair injuries such as heart attacks.

The research team demonstrated that deletion of Meis1 extended the proliferation period in the hearts of newborn mice, and also re-activated the regenerative process in the adult mouse heart without harmful effect on cardiac functions. This new finding demonstrates that Meis1 is a key factor in the regeneration process, and the understanding of the gene’s function may lead to new therapeutic options for adult heart regeneration. The findings also provide a possible alternative to current adult heart regeneration research, which focuses on the use of stem cells to replace damaged heart cells.

Meis1 is a transcription factor, which acts like a software program that has the ability to control the function of other genes. In this case, we found that Meis1 controls several genes that normally act as brakes on cell division,” Dr. Sadek said. “As such, Meis1 could possibly be used as an on/off switch for making adult heart cells divide. If done successfully, this ability could introduce a new era in treatment for heart failure.”

According to the American Heart Association, almost 6 million people in the U.S. have heart failure, which occurs when the heart cannot pump enough blood and oxygen to support other organs. Heart disease is the leading cause of death for both men and women in the country, according to the Centers for Disease Control and Prevention.

The study received support from the American Heart Association, the Gilead Research Scholars Program in Cardiovascular Disease, the Foundation for Heart Failure Research, and the National Institutes of Health.

The co-first authors of the study are Dr. Ahmed I. Mahmoud, who is now a postdoctoral fellow at Harvard University; Dr. Fatih Kocabas, who is now a postdoctoral fellow at North American College; and Dr. Shalini A. Muralidhar, a postdoctoral research fellow II of internal medicine. Other researchers at UT Southwestern involved in the study are Wataru Kimura, a visiting senior researcher of internal medicine; Ahmed Koura, now a medical student at Ain Shams University in Egypt; Dr. Enzo Porrello, research fellow and faculty member at the University of Queensland in Australia; and Suwannee Thet, a research associate of internal medicine.

About UT Southwestern Medical Center
UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty includes many distinguished members, including five who have been awarded Nobel Prizes since 1985. Numbering more than 2,700, the faculty is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in 40 specialties to nearly 100,000 hospitalized patients and oversee more than 2.1 million outpatient visits a year.

Media Contact: Remekca Owens
214-648-9344
remekca.owens@utsouthwestern.edu

 http://www.utsouthwestern.edu/newsroom/news-releases/year-2013/april/heart-sadek.html?goback=.gde_4842427_member_233989854

Genetics: A gene of rare effect

A mutation that gives people rock-bottom cholesterol levels has led geneticists to what could be the next blockbuster heart drug.

09 April 2013
ADAPTED FROM: PETER DAZELEY/GETTY

When Sharlayne Tracy showed up at the clinical suite in the University of Texas (UT) Southwestern Medical Center in Dallas last January, the bandage wrapped around her left wrist was the only sign of anything medically amiss. The bandage covered a minor injury from a cheerleading practice led by Tracy, a 40-year-old African American who is an aerobics instructor, a mother of two and a college student pursuing a degree in business. “I feel like I’m healthy as a horse,” she said.

Indeed, Tracy’s well-being has been inspiring to doctors, geneticists and now pharmaceutical companies precisely because she is so normal. Using every tool in the modern diagnostic arsenal — from brain scans and kidney sonograms to 24-hour blood-pressure monitors and cognitive tests — researchers at the Texas medical centre have diagnostically sliced and diced Tracy to make sure that the two highly unusual genetic mutations she has carried for her entire life have produced nothing more startling than an incredibly low level of cholesterol in her blood. At a time when the target for low-density lipoprotein (LDL) cholesterol, more commonly called ‘bad cholesterol’, in Americans’ blood is less than 100 milligrams per decilitre (a level many people fail to achieve), Tracy’s level is just 14.

A compact woman with wide-eyed energy, Tracy (not her real name) is one of a handful of African Americans whose genetics have enabled scientists to uncover one of the most promising compounds for controlling cholesterol since the first statin drug was approved by the US Food and Drug Administration in 1987. Seven years ago, researchers Helen Hobbs and Jonathan Cohen at UT-Southwestern reported1 that Tracy had inherited two mutations, one from her father and the other from her mother, in a gene called PCSK9, effectively eliminating a protein in the blood that has a fundamental role in controlling the levels of LDL cholesterol. African Americans with similar mutations have a nearly 90% reduced risk of heart disease. “She’s our girl, our main girl,” says Barbara Gilbert, a nurse who has drawn some 8,000 blood samples as part of Cohen and Hobbs’ project to find genes important to cholesterol metabolism.

Of all the intriguing DNA sequences spat out by the Human Genome Project and its ancillary studies, perhaps none is a more promising candidate to have a rapid, large-scale impact on human health than PCSK9. Elias Zerhouni, former director of the US National Institutes of Health (NIH) in Bethesda, Maryland, calls PCSK9 an “iconic example” of translational medicine in the genomics era. Preliminary clinical trials have already shown that drugs that inhibit the PCSK9 protein — used with or without statins — produce dramatic reductions in LDL cholesterol (more than 70% in some patients). Half-a-dozen pharmaceutical companies — all aiming for a share of the global market for cholesterol-reducing drugs that could reach US$25 billion in the next five years according to some estimates — are racing to the market with drugs that mimic the effect of Tracy’s paired mutations.

Free interview

Stephen Hall talks about Sharlayne’s unusual condition and whether similar cases might lead to a new line of drugs.

Zerhouni, now an in-house champion of this class of drug as an executive at drug firm Sanofi, headquartered in Paris, calls the discovery and development of PCSK9 a “beautiful story” in which researchers combined detailed physical information about patients with shrewd genetics to identify a medically important gene that has made “super-fast” progress to the clinic. “Once you have it, boy, everything just lines up,” he says. And although the end of the PCSK9 story has yet to be written — the advanced clinical trials now under way could still be derailed by unexpected side effects — it holds a valuable lesson for genomic research. The key discovery about PCSK9‘s medical potential was made by researchers working not only apart from the prevailing scientific strategy of genome research over the past decade, but with an almost entirely different approach.

As for Tracy, who lives in the southern part of Dallas County, the implications of her special genetic status have become clear. “I really didn’t understand at first,” she admits. “But now I’m watching ads on TV [for cholesterol-lowering drugs], and it’s like, ‘Wow, I don’t have that problem’.”

A heart problem

Cardiovascular disease is — and will be for the foreseeable future, according to the World Health Organization — the leading cause of death in the world, and its development is intimately linked to elevated levels of cholesterol in the blood. Since their introduction, statin drugs have been widely used to lower cholesterol levels. But Jan Breslow, a physician and geneticist at Rockefeller University in New York, points out that up to 20% of patients cannot tolerate statins’ side effects, which include muscle pain and even forgetfulness. And in many others, the drugs simply don’t control cholesterol levels well enough.

The search for better treatments for heart disease gained fresh impetus after scientists published the draft sequence of the human genome in 2001. In an effort to identify the genetic basis of common ailments such as heart disease and diabetes, geneticists settled on a strategy based on the ‘common variant hypothesis’. The idea was that a handful of disease-related versions (or variants) of genes for each disease would be common enough — at a frequency of roughly 5% or so — to be detected by powerful analyses of the whole genome. Massive surveys known as genome-wide association studies compared the genomes of thousands of people with heart disease, for example, with those of healthy controls. By 2009, however, many scientists were lamenting the fact that although the strategy had identified many common variants, each made only a small contribution to the disease. The results for cardiovascular disease have been “pretty disappointing”, says Daniel Steinberg, a lipoprotein expert at the University of California, San Diego.

Single-minded: Helen Hobbs and Jonathan Cohen’s approach to heart-disease genetics yielded a target for drugs that could compete with statins.MISTY KEASLER/REDUX/EYEVINE

More than a decade earlier, in Texas, Hobbs and Cohen had taken the opposite tack. They had backgrounds in Mendelian, or single-gene, disorders, in which an extremely rare variant can have a big — often fatal — effect. They also knew that people with a particular Mendelian disorder didn’t share a single common mutation in the affected gene, but rather had a lot of different, rare mutations. They hypothesized that in complex disorders, many different rare variants were also likely to have a big effect, whereas common variants would have relatively minor effects (otherwise natural selection would have weeded them out). “Jonathan and I did not see any reason why it couldn’t be that rare variants cumulatively contribute to disease,” Hobbs says. To find these rare variants, the pair needed to compile detailed physiological profiles, or phenotypes, of a large general population. Cohen spoke of the need to “Mendelize” people — to compartmentalize them by physiological traits, such as extremely high or low cholesterol levels, and then look in the extreme groups for variations in candidate genes known to be related to the trait.

The pair make a scientific odd couple. Hobbs, who trained as an MD, is gregarious, voluble and driven. Cohen, a soft-spoken geneticist from South Africa, has a laid-back, droll manner and a knack for quantitative thinking. In 1999, they set out to design a population-based study that focused on physical measurements related to heart disease. Organized with Ronald Victor, an expert on high blood pressure also at UT Southwestern, and funded by the Donald W. Reynolds Foundation in Las Vegas, Nevada, the Dallas Heart Study assembled exquisitely detailed physiological profiles on a population of roughly 3,500 Dallas residents2. Crucially, around half of the participants in the study were African Americans, because the researchers wanted to probe racial differences in heart disease and high blood pressure. The team measured blood pressure, body mass index, heart physiology and body-fat distribution, along with a battery of blood factors related to cholesterol metabolism — triglycerides, high-density lipoprotein (HDL) cholesterol and LDL cholesterol. In the samples of blood, of course, they also had DNA from each and every participant.

As soon as the database was completed in 2002, Hobbs and Cohen tested their rare-variant theory by looking at levels of HDL cholesterol. They identified the people with the highest (95th percentile) and lowest (5th percentile) levels, and then sequenced the DNA of three genes known to be key to metabolism of HDL cholesterol. What they found, both in Dallas and in an independent population of Canadians, was that the number of mutations was five times higher in the low HDL group than in the high group3. This made sense, Cohen says, because most human mutations interfere with the function of genes, which would lead to the low HDL numbers. Published in 2004, the results confirmed that rare, medically important mutations could be found in a population subdivided into extreme phenotypes.

Armed with their extensive database of cardiovascular traits, Hobbs and Cohen could now dive back into the Dallas Heart Study whenever they had a new hypothesis about heart disease and, as Cohen put it, “interrogate the DNA”. It wasn’t long before they had an especially intriguing piece of DNA at which to look.

The missing link

In February 2003, Nabil Seidah, a biochemist at the Clinical Research Institute of Montreal in Canada, and his colleagues reported the discovery of an enigmatic protein4. Seidah had been working on a class of enzymes known collectively as proprotein convertases, and the researchers had identified what looked like a new member of the family, called NARC-1: neural apoptosis-regulated convertase 1.

“We didn’t know what it was doing, of course,” Seidah says. But the group established that the gene coding the enzyme showed activity in the liver, kidney and intestines as well as in the developing brain. The team also knew that in humans the gene mapped to a precise genetic neighbourhood on the short arm of chromosome 1.

That last bit of geographical information pointed Seidah to a group led by Catherine Boileau at the Necker Hospital in Paris. Her team had been following families with a genetic form of extremely high levels of LDL cholesterol known as familial hypercholesterolaemia, which leads to severe coronary artery disease and, often, premature death. Group member Marianne Abifadel had spent five fruitless years searching a region on the short arm of chromosome 1 for a gene linked to the condition. When Seidah contacted Boileau and told her that he thought NARC-1 might be the gene she was looking for, she told him, “You’re crazy”, Seidah recalls. Seidah bet her a bottle of champagne that he was correct; within two weeks, Boileau called back, saying: “I owe you three bottles.”

“The PCSK9 story is a terrific example of an up-and-coming pattern of translational research.”

In 2003, the Paris and Montreal groups reported that the French families with hypercholesterolaemia had one of two mutations in this newly discovered gene, and speculated that this might cause increased production of the enzyme5. Despite Seidah’s protests, the journal editors gave both the gene and its protein product a new name that fit with standard nomenclature: proprotein convertase subtilisin/kexin type 9, or PCSK9. At around the same time, Kara Maxwell in Breslow’s group at Rockefeller University6 and Jay Horton, a gastroenterologist at UT-Southwestern7 also independently identified the PCSK9 gene in mice and revealed its role in a previously unknown pathway regulating cholesterol8.

The dramatic phenotype of the French families told Hobbs that “this is an important gene”. She also realized that in genetics, mutations that knock out a function are much more common than ones that amplify function, as seemed to be the case with the French families. “So immediately I’m thinking, a loss-of-function mutation should manifest as a low LDL level,” she says. “Let’s go and see if that’s true.”

Going to extremes

Hobbs and Cohen had no further to look than in the extreme margins of people in the Dallas Heart Study. In quick order, they identified the highest and lowest LDL readings in four groups: black women, black men, white women and white men. They then resequenced the PCSK9 gene in the low-cholesterol groups, looking for mutations that changed the make-up of the protein.

They found seven African Americans with one of two distinct ‘nonsense’ mutations in PCSK9 — mutations that essentially aborted production of the protein. Then they went back and looked for the same mutations in the entire population. Just 2% of all black people in the Dallas study had either of the two PCSK9 mutations — and those mutations were each associated with a 40% reduction of LDL cholesterol in the blood9. (The team later detected a ‘missense mutation’ in 3% of white people, which impaired but did not entirely block production of the protein.) The frequency of the mutations was so low, Hobbs says, that they would never have shown up in a search for common variants.

When Hobbs and Cohen published their findings in 2005, they suggested that PCSK9 played a crucial part in regulating bad cholesterol, but said nothing about whether the mutations had any effect on heart disease. That evidence came later that year, when they teamed up with Eric Boerwinkle, a geneticist at the University of Texas Health Science Center in Houston, to look forPCSK9 mutations in the Atherosclerosis Risk in Communities (ARIC) study, a large prospective study of heart disease that had been running since 1987. To experts such as Steinberg, the results10 — published in early 2006 — were “mind-blowing”. African Americans in ARIC who had mutations in PCSK9 had 28% less LDL cholesterol and an 88% lower risk of developing heart disease than people without the mutations. White people with the less severe mutation in the gene had a 15% reduction in LDL and a 47% reduced risk of heart disease.

How did the gene exert such profound effects on LDL cholesterol levels? As researchers went on to determine11, the PCSK9 protein normally circulates in the bloodstream and binds to the LDL receptor, a protein on the surface of liver cells that captures LDL cholesterol and removes it from the blood. After binding with the receptor, PCSK9 escorts it into the interior of the cell, where it is eventually degraded. When there is a lot of PCSK9 (as in the French families), there are fewer LDL receptors remaining to trap and remove bad cholesterol from the blood. When there is little or no PCSK9 (as in the black people with mutations), there are more free LDL receptors, which in turn remove more LDL cholesterol.

“We didn’t understand why everybody wasn’t doing what we were doing.”

The UT-Southwestern group, meanwhile, went back into the community looking for family members who might carry additional PCSK9 mutations. In September 2004, Gilbert, the nurse known as ‘the cholesterol lady’ in south Dallas because of her frequent visits, knocked on the door of Sharlayne Tracy’s mother, an original member of the Dallas Heart Study. Gilbert tested Tracy, as well as her sister, brother and father. “They tested all of us, and I was the lowest,” Tracy says. Zahid Ahmad, a doctor working with Hobbs at UT-Southwestern, was one of the first to look at Tracy’s lab results. “Dr Zahid was in awe,” Tracy recalled. “He said, ‘You’re not supposed to be so healthy!’.”

It wasn’t just that her LDL cholesterol measured 14. As a person with two dysfunctional copies of the gene — including a new type of mutation — Tracy was effectively a human version of a knockout mouse. The gene had been functionally erased from her genome, and PCSK9 was undetectable in her blood without any obvious untoward effects. The genomics community might have been a little slow to understand the significance, Hobbs says, “but the pharmaceutical companies got it right away”.

The next statin?

This being biology, however, the road to the clinic was not completely smooth. The particular biology of PCSK9 has so far thwarted efforts to find a small molecule that would interrupt its interaction with the LDL receptor and that could be packaged in a pill. But the fact that the molecule operates outside cells means that it is vulnerable to attack by monoclonal antibodies — one of the most successful (albeit most expensive) forms of biological medicine.

The results of early clinical trials have caused a stir. Regeneron Pharmaceuticals of Tarrytown, New York, collaborating with Sanofi, published phase II clinical-trial results12 last October showing that patients with high LDL cholesterol levels who had injections every two weeks of an anti-PCSK9 monoclonal antibody paired with a high-dose statin saw their LDL cholesterol levels fall by 73%; by comparison, patients taking high-dose statins alone had a decrease of just 17%. Last November, Regeneron and Sanofi began to recruit 18,000 patients for phase III trials that will test the ability of their therapy to cut cardiovascular events, including heart attacks and stroke. Amgen of Thousand Oaks, California, has also launched several phase III trials of its own monoclonal antibody after it reported similarly promising results13. Among other companies working on PCSK9-based therapies are Pfizer headquartered in New York, Roche based in Basel, Switzerland, and Alnylam Pharmaceuticals of Cambridge, Massachusetts. (Hobbs previously consulted for Regeneron and Pfizer, and now sits on the corporate board of Pfizer.)

Not everyone is convinced that a huge market awaits this class of cholesterol-lowering drugs. Tony Butler, a financial analyst at Barclays Capital in New York, acknowledges the “beautiful biology” of the PCSK9 story, but wonders if the expense of monoclonal drugs — and a natural reluctance of both patients and doctors to use injectable medicines — will constrain potential sales. “I have no idea what the size of the market may be,” he says.

“Everything hinges on the phase III side effects,” says Steinberg. So far, the main side effects reported have been minor, such as reactions at the injection site, diarrhoea and headaches. But animal experiments have raised potential red flags: the Montreal lab reported in 2006 that knocking out the gene in zebrafish is lethal to embryos14. That is why the case of Tracy was “very, very helpful” to drug companies, says Hobbs. Although her twin mutations have essentially deprived her of PCSK9 throughout her life, doctors have found nothing abnormal about her.

That last point may revive a debate in the cardiology community: should drug therapy to lower cholesterol levels, including statins and the anti-PCSK9 medicines, if they pan out, be started much earlier in patients than their 40s or 50s? That was the message Steinberg took from the people withPCSK9 mutations in the ARIC study — once he got over his shock at the remarkable health effects. “My first reaction was, ‘This must be wrong. How could that be?’And then it hit me — these people had low LDL from the day they were born, and that makes all the difference.” Steinberg argues that cardiologists “should get off our bums” and reach a consensus about beginning people on cholesterol-lowering therapy in their early thirties. But Breslow, a former president of the American Heart Association, cautions against being too aggressive too soon. “Let’s start out with the high-risk individuals and see how they do,” he says.

Not long after Hobbs and Cohen published their paper in 2006, they began to get invited to give keynote talks at major cardiology meetings. Soon after, the genetics community began to acknowledge the strength of their approach. In autumn 2007, then-NIH director Zerhouni organized a discussion at the annual meeting of the institutes’ directors to raise the profile of the rare-variant approach and contrast it with genome-wide studies. “Obviously, the two approaches are opposed to each other, and the question was, what was the relative value of each?” says Zerhouni. “I thought the PCSK9 story was a terrific example of an up-and-coming pattern of translational research” — indeed, he adds, “a harbinger of things to come”.

Hobbs and Cohen might not have found their gene if they had not had a hunch about where to look, but improved sequencing technology and decreasing costs now allow genomicists to incorporate the rare variant approach and to mount large-scale sweeps in search of such variants. “Gene sequencing is getting cheap enough that if there’s another gene like PCSK9 out there, you could probably find it genome-wide,” says Jonathan Pritchard, a population biologist at the University of Chicago, Illinois.

“What was amazing to us,” says Hobbs, “was that the genome project was spending all this time, energy, effort sequencing people, and they weren’t phenotyped, so there was no potential for discovery. We didn’t understand, and couldn’t understand, why everybody wasn’t doing what we were doing. Particularly when we started making discoveries.”

Nature

 496,

152–155

(11 April 2013)

doi:10.1038/496152a

References

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  3. Cohen, J. C. et al. Science 305, 869–872 (2004).

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  4. Seidah, N. G. et al. Proc. Natl Acad. Sci. USA 100, 928–933 (2003).

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  5. Abifadel, M. et al. Nature Genet. 34, 154–156 (2003).

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  6. Maxwell, K. N., Soccio, R. E., Duncan, E. M., Sehayek, E. & Breslow, J. L. J. Lipid Res. 44,2109–2119 (2003).

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  7. Horton, J. D. et al. Proc. Natl Acad. Sci. USA 100, 12027–12032 (2003).

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  8. Maxwell, K. N. & Breslow, J. L. Proc. Natl Acad. Sci. USA 101, 7100–7105 (2004).

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  9. Cohen, J. et al. Nature Genet. 37, 161–165 (2005).

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  10. Cohen, J. C., Boerwinkle, E., Mosley, T. H. Jr & Hobbs, H. H. N. Engl. J. Med. 354, 1264–1272(2006).

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Reporter: Aviva Lev-Ari, PhD, RN

The reader is encourage to review the following ANALYSIS of this subject matter:

Genomics & Genetics of Cardiovascular DiseaseDiagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013

and

10 Years On, Still Much To Be Learned From Human Genome Map

Advances made in genetics of disease, but creating new drugs more complex than first thought

By Amanda Gardner
HealthDay Reporter

FRIDAY, April 12 (HealthDay News) — As scientists mark the 10th anniversary Sunday of the completion of the Human Genome Project, they will note how that watershed effort has led to the discovery of the genetic underpinnings of almost 5,000 diseases.

And it has made it possible to develop personalized treatments that have prolonged the lives of many.

But the scientists will also acknowledge that, while the project has unlocked many mysteries that once shrouded diseases, there’s still much to be learned before new drugs can be developed to target illness-causing mutations in human DNA.

“What we’ve learned over the past 10 years is that we’re still far from really understanding the complexity of the human genome,” said Eric Schadt, chairman of genetics and genomic sciences at Mount Sinai Icahn School of Medicine in New York City. “Human disease is way more complicated than the old view that single hits to single genes cause diseases.

“In most forms of diseases, it’s whole constellations of genes operating in networks,” Schadt explained. “That becomes a much harder problem. How do you target networks with a single drug?

“We keep learning how much we really don’t know and how much further we need to go,” he added. “That’s the big story.”

A decade ago, the Human Genome Project was hailed as a major milestone because researchers identified all of the nearly 25,000 genes in human DNA and sequenced the 3 billion chemical base pairs comprising that DNA.

The feat took 13 years and cost close to $3 billion, but the genetic information gleaned from the project gave scientists the tools needed to pinpoint how changes in specific genes could kick-start some diseases.

One of the most tangible benefits of the project has been the development of ever more sophisticated sequencing technology and a dramatic lowering of the cost of using that technology.

Today, the cost of sequencing one human genome is closer to $5,000 and can be done in a day or two, said Dr. Eric Green, director of the National Human Genome Research Institute in Bethesda, Md.

What that means is that the pace of research, and its attendant discoveries, has been accelerated.

When the project first began, scientists knew the genetic basis of about 53 diseases. Today, that number is close to 5,000, Green noted. That means doctors can now test patients to see if they carry gene mutations that raise their risk for certain diseases, and counsel them accordingly on ways they might prevent or delay illness. There are currently almost 2,000 genetic tests for specific diseases or conditions, according to the U.S. National Institutes of Health.

There have also been breakthroughs with some rare diseases.

In 2011, 6-year-old Nicholas Volker became the first child to be saved by the new technology. He had undergone a hundred surgeries, including the removal of his colon, as doctors tried to identify his mysterious bowel disease. Genomic sequencing uncovered a genetic mutation that could be treated with a bone marrow transplant consisting of cells from umbilical cord blood.

“Knowing more of the basic genetics that makes up an individual has allowed us to diagnose far more genetic diseases,” said Dr. Barbara Pober, a medical geneticist at the Frank H. Netter, M.D. School of Medicine at Quinnipiac University in North Haven, Conn.

Once a diagnosis has been made, doctors can now use gene sequencing to determine treatment for some diseases. For instance, breast cancer patients can be tested to see how they will respond to the drug Herceptin. HIV patients can be tested to determine their response to the drug abacavir. And those on the widely used blood thinner warfarin can be tested to determine the most effective dose, according to the NIH.

The field of pharmacogenetics, still in its infancy, enables doctors to use a patient’s genetic information to figure out which cancer drugs the patient will best respond to before treatment even starts.

The U.S. Food and Drug Administration now includes genetic information on labeling for more than 100 drugs, up from just four 10 years ago, Green said.

The goal of developing new drugs to target diseases with genetic roots, however, will take much longer to realize.

Although the NIH states that there are roughly 350 biotechnological products currently being tested in clinical trials, new drugs take a decade or more to develop. Not only that, the knowledge gained from the Human Genome Project has actually made the field of genetic medicine even more complex. Scientists are finding that many diseases are triggered by interaction involving multiple gene variants, making it difficult to design a treatment that targets all the culprits in a particular illness.

And the complexities don’t end there.

Not long ago, scientists discovered that so-called “junk” DNA, which makes up 98 percent of the genome, is not junk at all but serves critical regulatory functions.

What’s more, about 10 percent of the human genome still hasn’t been sequenced and can’t be sequenced by existing technology, Green added. “There are parts of the genome we didn’t know existed back when the genome was completed,” he said.

More information

For more on developments over the past 10 years, visit the Human Genome Projectwebsite.

SOURCES: Eric Green, M.D., Ph.D., director, National Human Genome Research Institute, Bethesda, Md.; Barbara Pober, M.D., professor, medical sciences, Frank H. Netter, M.D., School of Medicine, Quinnipiac University, North Haven, Conn.; Eric Schadt, Ph.D., professor and chairman, department of genetics and genomic sciences, Mount Sinai Icahn School of Medicine, New York City

Last Updated: April 12, 2013

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