T H E   N I H    C A T A L Y S T      M A R C H  –  A P R I L   2003


by Celia Hooper

Eric Green

Befitting its domain—one of the most dynamic and rapidly evolving fields of biomedical research—10-year-old NHGRI has been led by the youthful and energetic. Its second scientific director is no exception.

The new SD, Eric Green, was selected from the intramural program after a worldwide search and following the departure of Jeff Trent late last year. Green, 43, also continues to maintain his laboratory research program in the Genome Technology Branch and to serve as the director of the NIH Intramural Sequencing Center.

On the Move

Under Green’s leadership, the more-than-400-person, approximately $90-million intramural program is churning: New programs are sprouting, cores are evolving and teaming up with scientists in and out of the institute, and both intramural and extramural NHGRI constituencies are planning celebrations and zooming off with a new research roadmap, drawn up through a year-long exercise.

Green spoke to The NIH Catalyst in January and said he doesn’t think his youthfulness accounts for his success. But he says it also hasn’t hurt. "A decade ago, this institute was led by two people [Director Francis Collins and SD Trent] who were then roughly my age. I would argue it has done quite well."

The institute-wide planning process gave NHGRI a chance to study its progress and look ahead. The resulting new vision for genomics research will be a prominent feature of NHGRI’s joint celebration of the completion of the human genome sequence and the 50th anniversary of the discovery of the double-helical structure of DNA in April (see below).

"If I were to name one theme of the intramural program in the first decade," Green says, "it has been figuring out what are the best ways to use the fruits of the Human Genome Project [HGP] for doing research into human genetic diseases–medical genetics, cancer genetics, gene therapy, genetic medicine, . . . what’s the best way to do such research in this new exciting era?"

Adieu Dichotomy

By contrast, the extramural program was intensely focused on obtaining the sequence of the human genome. "So for a long time, there was this huge dichotomy: Extramural did the HGP; intramural did applications of genomics and genetics," Green says. But as the new vision emerges, he predicts, the extramural program "is going to start looking a lot more like what the intramural program has been building—with a major emphasis on applying genomics to research into health and disease."


In addition to its fee-for-service sequencing services, Eric Green’s "baby," as he calls the NIH Intramural Sequencing Center (NISC), has exciting new projects underway.

"The coolest thing we are doing now is a major effort on behalf of the Human Genome Project to investigate which additional animal species to sequence in the future," Green says.

In conjunction with Green’s laboratory in the Genome Technology Branch, NISC is doing some reconnaissance work—taking carefully selected regions of the genome and then sequencing them in about two dozen animal species. The resulting sequences are compared and contrasted to see what and how much is to be learned from each genome’s tale. "Did you learn a lot? Did you learn a little? Would it be worth getting the whole genome?" The main focus will be on vertebrates, Green says, because the ultimate goal is to get the most help in interpreting the human genome.

Sampling the same region from each genome, NISC has sequenced DNA from baboon, chimpanzee, macaque, lemur, gorilla, dog, cat, cow, pig, rabbit, opossum, platypus, chicken, zebrafish, and pufferfish, for starters. "It’s a real Noah’s ark project, with many more species to come," Green says—a perfect-sized project for NISC as a mid-sized sequencing center.

The reconnaissance will include a few more distantly related species, Green says, because "we actually don’t know the right points on the evolutionary tree to sample to maximally understand genome function and evolution."

Sampling small bits of sequence—maybe 1 percent of each animal’s genome—before committing to an entire genome will help assure that the most informative genomes get the full work-up, maximizing the benefit-cost ratio.

In addition to giving scientists "a sneak preview of the future," when as many as a dozen or more vertebrate genomes will have been sequenced, the reconnaissance project will also give computational biologists some datasets, "to allow them to start building tools to better compare and analyze genomes," Green says.


Green says the vanishing dichotomy reflects visionary planning by NHGRI’s leadership. "They were saying ‘this is where the puck is going to be in the future. . . . We’re going to start going there now’"—and that’s why, Green says, the intramural program is now ideally positioned and equipped.

"There will be fabulous new opportunities for interfacing genomics and genetics with clinical research," he says. "The most distinguishing feature of the intramural program at this campus . . . is the great infrastructure for doing clinical research. . . . Now let’s figure out how best to harness it for answering challenging questions in genetics and genomics."

The Luxury of Risk Taking

Green observes that "it’s not entirely clear which aspects of genetics, especially whe applied to clinical problems, are going to be best performed on a large scale vs. a smaller scale. I think that’s something we all have to learn and almost handle on a case-by-case basis," he says. But he expects NHGRI will be able to tackle any size project, large, small, and in-between.

Intramural research, he says, "will always take advantage of the luxury we have of secure funding and, coming with that, the opportunity to do higher-risk research." NHGRI’s intramural emphasis on technology development—for example, in the areas of genome mapping and functional genomics—has reflected this, he observes. "Part of the reason we were able to do that effectively, I believe, is because we could move quickly on something, even if it was risky."

One high-risk proposition would be tackling rare diseases–"beyond just knowing what the gene is, being able to develop therapies or at least explore therapeutic options." Green notes that rare diseases are a particular interest for his new clinical director, Bill Gahl.

Another high-risk research path still being pursued in NHGRI is clinical gene-therapy trials. The program’s basic research into vector biology and design could help advance the problem-plagued gene-therapy field and presage a new generation of clinical trials down the road, Green says.

Core Strengths

One cultural feature of NHGRI that has and will continue to serve the intramural program well is its penchant for interaction and its collegiality. Green notes that much of the work by NHGRI investigators in identifying disease genes was carried out in collaboration with intramural investigators in other institutes who were experts in the diseases or physiological system in which the genes play a role.

Green says these partnerships "led to some fabulous sets of experiments," and he cites as an example his own lab’s work with NIDCD in the identification and characterization of a gene responsible for a common form of inherited deafness. This sort of teamwork, he says, "leads to first-rate studies and first-rate publications."

NHGRI’s technical cores and centers provide other examples of fruitful collegiality. The Center for Inherited Disease Research on the Bayview campus in Baltimore does large-scale genotyping for intramural and extramural investigators. Green’s own NIH Intramural Sequencing Center (see "Bringing Up ‘Baby.’") was established by 14 cooperating institutes and has cranked out scores of large-scale sequencing projects for intramural investigators on a fee-for-service basis.


One organizational experiment underway at NHGRI is a perhaps trendy new category of scientific staff called "associate investigators."
NHGRI’s scientific director, Eric Green, says his institute launched the program about 18 months ago and now has 16 associate investigators. "This is very novel," he says. "Other institutes have been talking to me about this."

Neither a hiring mechanism nor an official government designation, the title instead describes a group of researchers who provide vital scientific leadership in the institute—people who must be at the table when it comes to faculty meetings or critical research planning but who are not investigators with their own independent research funding. The associate investigators are all assigned to particular branches within the institute. Their work is considered part of the total program of the branch during its quadrennial review.

Comparing associate investigators to research-track faculty at universities, Green says, "We regard them as faculty members, and we wanted to acknowledge their role as leaders within the institute." In terms of professional designation, most of the associate investigators are staff scientists, but not all. "And there are some staff scientists who are not associate investigators," Green adds.

Green says there also is a mixture of fields represented by associate investigators, including informatics staff, core directors, genetics counselors, a bioethicist, the associate clinical director, and key leaders in production genomics facilities. He’s happy with the institute’s current mix of senior investigators, investigators, and associate investigators.

In Green’s view, the concept of the associate investigator is very much in keeping with the need in the genome era for "more interdisciplinary, multidisciplinary, and larger consortium-like efforts." He says this has actually been a hallmark of the 10-year-old NHGRI since its inception, which included supportive cores specializing in particular technical areas.

"We’ve developed a culture of recognizing that to do contemporary genetics and genomics research, it’s not just about individual people working in individual labs doing individual projects," Green says. "The foundation of our institute was built to include . . . infrastructure that investigators could tap into." With technology evolving rapidly, high-level expertise is required. "If you want to have state-of-the-art sequencing, genotyping, microarrays, or computational biology, you have to have state-of-the-art good people who are running those facilities" and "deserve recognition as faculty."

The Associate Investigator Program "may be one of the reasons we have really good people at our institute," Green brags, "not just at the very top, but throughout our ranks."


Two keys to successful technical cores and centers, Green says, are ongoing evaluation of the size and need for the core, and being ready to discard the old in favor of better new approaches. "If you are going to develop cutting-edge techniques, you’ve got to be ready to retire old ones."

Intramural scientists in other institutes have also tapped into NHGRI’s expertise in microarray development and application under Trent’s leadership, and others have benefited from NHGRI’s developments in computational genomics—including new tools available on the web.

Still others have kept up with the fierce pace of genetics discovery through a lecture series called "Current Topics in Genome Analysis," which Green, along with Deputy SD Andy Baxevanis, has organized and run about every 18 months. "Close to 2,000 people have sat through those lectures," Green says. "Nobody asked us to do it—we just did it."

Looking ahead, Green is excited about a joint venture with NICHD to create "what’s going to be one of the largest zebrafish facilities in the world. It’s going to be built on this campus because we recognize that zebrafish, as a genetic model, is incredibly important"—or will be very soon, with the imminent completion of the sequencing of the zebrafish genome by the Sanger Institute in England.

In addition to providing state-of-the-art facilities for NHGRI’s three zebrafish investigators—and no doubt many collaborators—Green says NHGRI is also in early pilot stages of developing a resource, potentially for the world, of zebrafish mutants.

The Genome Culture–
And the Future of Genomics

"We have a culture in our institute—it’s the genome culture—that if you do good work and it’s good for you, that’s wonderful; if you do good work and it’s good for more than just your lab, it’s even better." This mindset, says Green, is heavily rewarded and highly regarded—and it’s been gratifying to him personally to see junior investigators embracing it as they rise through the ranks.

The institute also continues to build new schemes for creating an even more robust academic and intellectual environment, including its Associate Investigators Program (see "Fresh Fields" at right) and a Visiting Investigators Program; the latter brings to NHGRI roughly one scientist a year from outside NIH—typically on sabbatical—and pays partial salary and research support.

Green says the visitors often come to acquire expertise in genetics or genomics or to use the help of NHGRI’s technical cores to get over the next hurdle in a research project.

From new schemes to a culture of collegiality, NHGRI’s intramural program is beautifully suited for contemporary biomedical research, Green thinks. And it’s in a great position, he says, to find answers to the key questions of the newly entered genomic era: "How do you take a conventional laboratory, say a half-dozen or a dozen people, and grapple with massive datasets, even at a computational level? How do you study thousands of genes all at once using technologies like microarrays? How do you mine this information efficiently to find genes and show those that are implicated in human disease? How do you grapple with the complexities of diseases that have multiple genetic components?"

These questions—these "hard, hard problems"—are what the future is all about, Green says, and "they’re the ones that our program wants to tackle."


Carrying the NHGRI Torch: New SD Eric Green

NHGRI’s new scientific director isn’t exactly green, even if he is Eric Green. Six years of building the NIH Intramural Sequencing Center (NISC) from the ground up have given him experience and perspective in team-building, science management, and coping with the special challenges of getting science done in government labs.

The number-one lesson thus far, Green says, is that "you always benefit by doing things in a collegial way." This approach was a key to the success of NISC, a 35-person, state-of-the-art DNA sequencing facility that has defied expectations, almost from the outset.

"Nobody ever thought we could build a 35-person group–never thought we’d be able to hire that many people, acquire and spend that kind of money, get the equipment, get the space." In fact, Green says, he was a little surprised himself. "Nine and a half years ago, when I left Washington University [St. Louis, Mo.], I consciously thought I was making a decision never to do large-scale genomics again. I was leaving a large genome center and Francis [Collins] was recruiting me. I knew I was doing the right thing, but I thought I’d never be able to have a large genome group—greater than, say, 15 or 20 people. I shouldn’t have thought that."

The trait that built the lab and that he takes with him to his job as SD was boldness. "That’s another theme of our institute—be bold. Don’t say ‘it will never work in the government.’ We proved them wrong with NISC. . . . If you have a good idea, be bold about it."

Also important to Green was having creative ideas and being able to rely on the people around him as he juggled responsibilities. "When you tackle a pet project that involves this many people and a lot of money and a lot of space, you have to learn how to multitask" and surround yourself with "good people who can take charge and get things done." 

"What I think we’ve accomplished at NISC is getting good people and giving them a chance to run the place—that’s what we want to continue to do for the whole intramural program," Green says.




Variously regarded as the "cruelest month," the month of showers, and the bane of taxpayers, April in the year 2003 takes on new luster. It is during that month, says NHGRI director Francis Collins, that "we [will] declare the sequence of the human genome essentially finished, and we will also celebrate the 50th anniversary of the Watson and Crick publication [describing the structure of DNA] that appeared in Nature on April 25, 1953."

These two causes for celebration have inspired the federal government to proclaim April as "Human Genome Month" and April 25 as "DNA Day."

A series of commemorative events will take place in the Washington area April 13 through 16th, including:

A preview April 13 of a genomic exhibit, "Genome: How Life Works," at the Smithsonian Institution’s Arts and Industries Building. Produced by Clear Channel Communications with support from Pfizer, Inc., the full exhibit will open at the Smithsonian in June 2003.

A half-day scientific symposium, "Linking the Double Helix with Health: Genetics in Nursing," the afternoon of April 13, 2:00 p.m–6:30 p.m., at Georgetown University School of Nursing, St. Mary’s hall, sponsored in part by NINR.

A two-day scientific symposium, "From Double Helix to Human Sequence—and Beyond," April 14–15 at NIH’s Natcher Conference Center, which will be webcast within NIH and to institutions around the world. Participants—including James Watson and members of the International Human Genome Sequencing Consortium—will describe the science and history of the Human Genome Project. The symposium will explore the future of science and medicine made possible by breakthroughs in genomic science and will include the unveiling of NHGRI’s plan for the future of genomics and the institute. For more information about this event, contact Allison Peck at (301) 451-8323 or by e-mail.

A half-day public symposium, "Bringing the Genome to You," will be held the morning of April 15 at the Smithsonian’s National Museum of Natural History. The talks are designed to convey how genomics influences health and society. For more information, contact Mini Nair at (301) 402-0955 or by e-mail. If you are interested in receiving this videocast, please contact Maggie Bartlett at (301) 594-0632 or by e-mail.

A half-day scientific symposium, "Genetic and Gene-Environment Interaction in Human Health and Disease," April 16, 8:30 a.m.–12:30 p.m., at Masur Auditorium, Building 10, sponsored by NIEHS, in collaboration with NHGRI and NIAAA. For more info and to register, visit this site.

An all-day scientific symposium, "Genes, Brain, Behavior: Before and Beyond Genomics," April 16, sponsored by NIMH and other NIH institutes, 8:30 a.m.–5:45 p.m. (breakfast from 7:30), Wilson Hall, Building 1. No advance registration required.

A national "DNA Day," April 25, on which high schools throughout the country celebrate the 50th anniversary of the description of the DNA double helix. NHGRI scientists, many of whom are part of the mentors network of the American Society of Human Genetics, are being encouraged to consider speaking at a local school to mark this day. For more information, contact Susan Vasquez at (301) 402-2205 or by e-mail.

In addition to these specific events, NHGRI is also planning a long series of scientific, educational, cultural, and celebratory events across the United States, including:

Activities at science museums across the country. Items available to museums include a program guide of genomics-related events, a training workshop for museum staff, a kit of materials and equipment, and advertising graphics to call attention to the events. For more information, contact Kris Wetterstrand at (301) 435-5543 or by e-mail.

Public outreach through television, radio, and print features on genetics and genomics.

Classroom outreach—Lesson plans, challenging activities, and curriculum supplements regarding the Human Genome Project, genomic science, and the basics of human genetics will be developed and made available online. More information is available on the NHGRI website or contact Susan Vasquez at (301) 402-2205; e-mail.

For more details about the NHGRI-sponsored events, visit this website.








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