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2003 Scientist of the Year

Wed, 11/12/2003 - 7:43am

 

Eric Lander has a very simple goal in lifeall he wants is to know everything there is to know about the human genome. And he believes he can do it.

Eric Lander is director of the MIT Center for Genome Research at the Whitehead Institute in Cambridge, Massachusetts. A little more than three years ago he was involved in what was termed at the time as a racea term Lander dislikes since his group was posting daily sequencing data on a public Web siteto see who would be the first to produce the preliminary draft of the human genome. Would it be an international public group headed by the National Human Genome Research Institute (NHGRI, an Institute of the National Institutes of Health in Bethesda, Md.), or a private group led by Celera Genomics Group in Rockville, Md.?

The prize in this competition, which entailed a lot of jockeying back and forth, was ownership of the intellectual property rights to the final sequence data. The end result of all this data collection activity was for all intents, a tie. Both groups initially announced their results on June 26, 2000, in a joint White House ceremony. Celera published its preliminary draft in the February 16th issue of Science and the NHGRI-led group published their preliminary draft in the February 15th issue of Nature .
This past September, Eric Lander and the staff of the Whitehead Institute/ MIT Center for Genome Research hosted the Dalai Lama as he toured the facility.Bottom: Before a committee, Senator Tom Harkin (Iowa) unveils a disk containing the draft sequence of the human genome. (Images: Whitehead Institute and the NHGRI)


On April 14, 2003, the International Human Genome Sequencing Consortium, led in the U.S. by the NHGRI and the U.S. Dept. of Energy, announced the successful completion of the Human Genome Project (HGP) more than two years ahead of their previously forecast 2005 completion schedule. The preliminary draft sequence of the 3 billion DNA letters in the human genome had been replaced by a finished sequence that was 99% documented to an accuracy of 99.99%. For this announcement, there was no White House ceremony and there were no glaring newspaper headlines.

But, oh what a time it was for the two years preceding that June 2000 announcement. The research pace was frenetic, the anticipated rewards were thought by some to be enormous, and the technological breakthroughs came at a rate that really only occurs in these rare types of highly competitive and emotional situations. At the time, the media focused on Francis Collins as the head of the NHGRI and
J. Craig Venter as the head of Celera Genomics. (Venter was R&D Magazine's 1998 Scientist of the Year.)

Eric Lander, as head of the MIT Center for Genome Research, also caught much of that media attention in 2000, especially from the technical community since it was his lab's 125-person sequencing team that produced 28% of the public-sector sequence data and produced many of the data collection breakthroughs. These efforts kept the public sequencing program, even with the much more heavily financed private effort that ran on masses of distributed computer systems.

The Center for Genome Research actually produced six times as much DNA code as they initially had planned to produce. Much of this was due to Lander's aggressive approach to the program, to ensure that the public sector program came out better than the private sector program. To do this, Lander's lab was upgraded with 125 sequencing machines, more than those at all the other centers combined.

Evolving Centers of Genomic Research

The Whitehead Institute for Biomedical Research was founded in 1982 through the second largest gift, at the time, made by a living person: businessman and philanthropist, Edwin "Jack" Whitehead. David Baltimore, a 1975 Nobel Laureate and MIT biology faculty member was subsequently appointed its founding director.

Jack Whitehead created the Institute as independent of the financial and legal control of a university, yet offering the benefits of a university environment and academic relationships. By 1990, the Institute was recognized as a major force for change and innovation in biomedical science and the MIT Center for Genome Research was founded as an integral part of the Institute with Eric Lander, a Whitehead Institute fellow at the time, as its founding director. Other components of the Whitehead Institute include the Whitehead Library, the Center for Microarray Technology, the W.M. Keck Biological Imaging Facility, and various biocomputing functions.

In its 13 years, the Center for Genome Research has become one of the largest genome centers in the world, recognized for its research programs in structural genomics, medical and population genetics, and clinical medicine. It was one of the key centers in the Human Genome Project, spearheading a coalition of 20 genome centers around the world and by itself sequencing nearly a third of the total genome. The Center also created a novel industry-academia consortium to collect and map single nucleotide polymorphisms (SNPs). Today, the Center has an annual operating budget of $80 million, and employs 250 scientists and medical researchers.

This past summer, Los Angeles philanthropists Eli and Edythe Broad announced their plans to create a new type of biomedical research institute-the Broad Institute a collaboration of MIT, Harvard Univ., and the Whitehead Institute aimed at realizing the promise of human genome data to revolutionize clinical medicine. The Broads donation of $100 million over 10 years and plans by MIT and Harvard to raise up to $200 million more in private support over the next decade, along with an unannounced amount of federal research support promise to make the Broad Institute the leading genomic research center in the world. Eric Lander was named as the founding director of the Broad Institute. The Center for Genome Research is expected to become the foundation of the Broad Institute, bridging the gap between genomics and clinical medicine. When operational early next year, the Broad Institute is expected to support 12 core faculty and about 30 associated faculty from MIT, Harvard, and Whitehead.




One of the breakthroughs in the public sector side of the Human Genome Project came when Lander needed to find a way to computationally sort through the data from the 20 centers worldwide that were involved in the public sequencing effort. In December 1999, Lander contacted David Haussler at the Univ. of California, Santa Cruz, to ask if he could assemble a team to develop the software that could sort through the masses of data to identify sequencing information. Haussler, R&D Magazine's 2001 Scientist of the Year, agreed and with UCSC grad student Jim Kent created the GigAssembler software to sequence the data. Numerous advances in sample prep, automation, image analysis, and microarraying that pushed state of the art were also made during this time.

Researchers and technicians-such as Pierre Tchuinga, Shawn O'Bryan, Tsering Wangchuk, Casey Stone, and Tina Goode -comprise the staff of nearly 250 at the MIT Center for Genome Research. (Photo: Marc Berlow)


But, as exciting a time as that period was, "the human genome sequence was not and is not the answer to biomedical researchit is the foundation," says Eric Lander. The sequence is now finalized, and the procedures for getting it are established. Now is the time that researchers can begin to determine what those sequences actually do.

And this is where Eric Lander can now take center stage.

Biomedical research

Eric Lander has been selected as R&D Magazine's 38th Scientist of the Year. Lander was selected for this honor for a number of reasons. One reason is that he is the founding director of the MIT Center for Genome Research, which he has established as one of the premier genomic research centers in the world.
Click on image to enlarge

The history of the human genome project outlined in an elegant timetable shows the progression of discoveries and important events. (Source: NHGRI)


Another reason is that he is an educator, who continues to teach introductory biology at MIT, even when it would be very simple for him to just say 'there isn't enough time from my other responsibilities.'

Another reason is that he was probably the single largest technical force in actually making the sequencing of the human genome happen when it didyes, someone else could also have directed the research, but few became so successfully and personally involved in it.

And finally, Eric Lander has been selected as our Scientist of the Year because of his vision. Lander's vision is that he sits in a corner of the world where the confluence of technology, medicine, and genomic research is uniquely supreme. The Massachusetts Institute of Technology is recognized as one of the best, if not the best, centers of technical education in the world. Just down the Charles River from MIT, and in the same city of Cambridge, are Harvard Univ. and its world-renown Harvard Hospitals, known for their clinical research and medical breakthroughs. Add to this mix, Lander's very own Center for Genome Research and the other Whitehead Institute staff and facilities, and you have a "marriage made in heaven" with the potential capability to create medical knowledge out of genomic information.

For a year and a half, Lander had this vision of tying these parts together. It all came together this past summer as billionaire philanthropists Eli and Edythe Broad donated $100 million to create the Broad Institute, a very unique technical collaboration of MIT, Harvard, and the Whitehead Institute for the extensive investigation of genomic-based biomedical research.

From math to genomics

Eric Lander was recognized in October by Scientist of the Year-sponsor National Instruments' VP of marketing Ray Almgren, who presented Lander with a trophy and monetary grant to The Broad Institute.

Lander was born in Brooklyn, N.Y., in 1957. "I really focused on math as a kid," he says. He attended Stuyvesant High School in lower Manhattan, a specialized high school for mathematics, science, and technology. "I hung out with the math team and eventually became captain of it." He placed second in a national mathematics test and had the highest grades in his class at Stuyvesant. While at Stuyvesant, he wrote a paper on quasi-perfect numbers that won him the Westinghouse Prize.

In college, he once again focused on math. He received an A.B. in mathematics with highest honors from Princeton Univ., N.J., in 1978, which earned him a Rhodes Scholarship.at Oxford Univ., U.K.

"I loved going to Oxford," says Lander. "It's a very relaxed environment. When I was there it was really a pleasure to get away from the rush of American life. It was a wonderful opportunity to withdraw and think and also to travel. They have six-week vacations between their eight-week terms, so you get to travel. There are times now that I think it would be lovely to take a sabbatical there." He received his PhD in mathematics from Oxford in 1981.
"Unfortunately, it was only after that when I realized that I didn't want to do pure mathematics as a career. As much as I loved it, it was not the type of career that I wanted to doat the same time, I had no idea of what I wanted to do at the time."

Educational Benefactor
Eli Broad
Eli Broad is known in this story's context as donating $100 million (with his wife, Edythe) to create the Broad Institute in Cambridge, Mass. But, the breadth of his philanthropy goes far beyond this singular event. Broad is a billionaire making his fortune in the financial services industry. He is an active giver, with about $400 million pledged to education, including $25 million for a new biotech center at CalTech, creation of the Broad College of Business at Michigan State Univ., his alma mater, and support, through the Broad Foundation, of the Broad Institute for School Boards.

This last item is modeled after Harvard University's programs for new mayors, members of Congress, and college presidents. The Broad Institute for School Boards is a national school board training program for newly appointed urban school board members, with the mission that properly trained school boards will foster better school districts. The Broad Foundation also sponsors training sessions for school board candidates to familiarize them with the principles of policy governance and the roles and responsibilities of effective school board members.

Broad also is an avid supporter of contemporary art, having one of the largest personal collections in the world and operating an active "lending library," to more than 400 museums and university galleries worldwide. The Broads also have made major contributions to the Schools of Art and Architecture at UCLA. And not least of all, but in keeping with his other philanthropies, Broad also is vice chairman of the board of trustees of the California State Univ. system.





Returning to the U.S. after getting his doctorate, Lander got a position teaching managerial economics at Harvard Business School through a series of recommendations based on his mathematical prowess in statistics. He admits that he didn't know any economics when he started, but knew that he could learn it. He wound up teaching managerial economics at Harvard for about eight years. At some point along this path, he decided that what he really wanted to do was learn about biology. "So I started moonlighting," he says. "I moonlighted for a number of years, learning how to do molecular biology. I would teach managerial economics by day and clone fruit flies by night at the Harvard biology labs."

He got started in this by first sitting in on a biology course. "The graduate student who was the teaching assistant took me back to meet his advisor, then his advisor and his wife, who ran the lab together, offered to teach me molecular biology," he continues. "They gave me a bench and I just moonlighted. Following that, a fly geneticist down the hall took me under his wing and I learned about fly genomics."

This work became so intriguing that Lander decided to take a year's sabbatical from Harvard Business School to take some biology courses at MIT. Some of the coursework Lander took was with Robert Horvitz, one of the world's preeminent specialists on worm genetics (Horvitz won the Nobel Prize for Medicine in 2002, along with two British scientists, for their work on how genes control the division of the body's cells and the development of organs.)

It was also at this time, that Lander met David Botstein. "Botstein was the person who button-holed me one day in the halls at MIT to talk about human genetics." Botstein spent 20 years at MIT as the Earle A. Griswold Professor of Genetics. He then moved to Genentech, Stanford Univ., and is currently the director of the Institute for Integrative Genomics at Princeton Univ. "Botstein had heard that I was a mathematician who had also learned genetics and he really wanted to talk to me about a problem in human genetics. The next thing I knew I was drawn into the possibility of the human genome project before there was a human genome project," says Lander. "This was about a year before the human genome project came onto the scene. It was all very accidental and all very wonderful."

Botstein was relentless with Lander in his discussions about human genetics. "He came from the Bronx and I came from Brooklyn, so we immediately started arguing about things like how statistics could be used to search for genes in complex human tissues. We had a great time! And I've never looked back," says Lander.

"In retrospect, it looks brilliant to have a background in mathematics, biology, and business for trying to run a large genome center like the Center for Genome Research. But of course, in prospect, it was an utterly random walk," he says. Life Science Mentors
David Botstein (top) and David Baltimore (bottom)

When it comes to genome-based life science, it really is a small world with many of the professional players working with each other or for the same organizations at one time or another. When asked as to who were his mentors during his career, 2004 Scientist of the Year Eric Lander, immediately mentioned David Botstein and David Baltimore, Botstein for his perseverance in educating Lander in genetics and Baltimore for the opportunity to work at Whitehead and the confidence he gave in Lander's capabilities.


Botstein and Lander's paths crossed when Botstein was a professor of genetics at Massachusetts Institute of Technology. Botstein was educated at Harvard, Cambridge, Mass. (A.B. 1963) and the Univ. of Michigan, Ann Arbor (PhD, 1967). He left MIT in 1987 to join Genentech, San Francisco, Calif., as VP/Science before moving to Stanford, Calif., in 1990, where he became professor and chairman of the Dept. of Genetics and created the "Botstein Lab." He moved back to the East coast earlier this year, when he was appointed as the new director of the Lewis-Sigler Institute for Integrative Genomics at Princeton Univ., N.J. Princeton established the genomics institute in 1999, with a new building, the Carl Icahn Laboratory (one of those contemporary Frank Gehry designs), being completed this past May.

Botstein has a long history of genomic research, having proposed a method for mapping genes that laid the groundwork for the Human Genome Project as early as 1980. His paper describing the technique was "the beginning of modern human genetics," according to Shirley Tilghman, president of Princeton Univ.

David Baltimore was the founding director of the Whitehead Institute and crossed paths with Eric Lander when he offered him a Fellowship at the Institute in 1986. Baltimore received his B.A. in chemistry from Swarthmore College, Pa., and went on to study animal virology at the Rockefeller Institute (now Rockefeller Univ.) in New York City, where he received a PhD. He also studied at MIT and worked at the Salk Institute, La Jolla, Calif., studying the polio virus. Baltimore won the Nobel Prize in Medicine or Physiology in 1975 for his work in virology. He then became the founding director of the Whitehead Institute in 1983, being personally selected by Jack Whitehead.

Baltimore left Whitehead in 1990 to become president of Rockefeller Univ., and in 1997 left there to become president of California Institute of Technology, Pasadena. Baltimore was called by Gordon Moore, founder of Intel and chair of the Caltech Board of Trustees as "the most influential living biologist, and one of the most accomplished."


Goals and heroes

Lander recognizes Botstein and David Baltimore as the two people who have had the greatest impact on his careerhis mentors, so to speak (see sidebar on pg. 27). David Baltimore was Director of the Whitehead Institute when he met Lander. "Baltimore gave me a position as a Whitehead Fellow, despite the little detail that I had never published a paper in biology, which took some real chutzpah on his part. But David was confident in his judgments and bet on people," says Lander. Lander reassured Baltimore's judgment by receiving a $250,000 MacArthur Foundation Fellowship in 1987 for his work in genetics.

"I cannot imagine what I would be doing if I had not met either David Botstein or David Baltimore, but I am sure it would not be what I am doing now."

The people that Lander respects the most are Gregor Mendel and Francis Crick for their extraordinary ability to see important things in data. Gregor Mendel is recognized as the "father of genetics." Working in the mid-nineteenth century, long before the discovery of genes and chromosomes, he laboriously recorded the results of his experiments with peas. Using new statistical methods, never before used in biology, he formulated the Laws of Segregation and Independent Assortment. The genetic terms "recessive" and "dominant" are attributable to Mendel.

Francis Crick is best known for his discovery of the DNA double helix and its replication scheme in 1953. Surprisingly, in 1947, Crick knew no biology or organic chemistry or crystallography. However, in those six intervening years, he learned the elements of these technologies to such a degree that he was able to develop a general theory of x-ray diffraction by a helix.

Regarding goals, "I want to extract all of the information on the human genome," says Lander. "We've got information on the nucleotides, I want to figure out what they mean. I want to identify every feature in the human genome. I want to figure out every variation in the human genome. And I want to find the meaning of the features, And of the variations."

"That's a reasonable goal," he says seriously. "And I don't even think that it's an impossible goal." These goals also include what some may define as proteomics. "It's all genomics," he says. "To me, the word genomics means taking global views of biological systems. And so one way is to look at DNA, one way is to look at RNA, and one way is to look at proteinsI use the word genomics as an umbrella word to mean all of that."

Research manager

Lander's biggest challenge over the past ten years has been to "build an organization where biologists and non-biologists (computational engineers and others) view themselves as complete partners and forget about themselves." This was relatively easy during the highly competitive, emotionally driven "race" to create the preliminary draft of the human genome. Those episodes are rare, however, and the more normal operating environment is much less emotional.

Organizations with these traits must be established as cultural environments. "Computer scientists should not ask what the biologist needs to do his or her job they must view the job as a biologist," says Lander. "Once you obtain this, it allows for real fulfillment."

With potential solutions to various diseases, human genome research requires a collaborative effort from MIT scientists like Andrea Horn. (Photo: Marc Berlow)


As with most good managers, Lander is a good communicator. Good at communicating ideas and good at communicating your work to others who should know about it, according to his students. Lander is very much the academic, preferring to meet with students one-on-one or in small groups. He has taught undergraduate introductory biology at MIT for the past ten years and does not see that ending anytime soon. He was rewarded for his teaching enthusiasm by winning the Baker Memorial Award for Undergraduate Teaching. "Of all the honors I've received, this is the one that I most value, because it's nominated by the undergraduate students. And they're a very demanding audience," he says.

The MIT Everett Moore Baker Memorial Award for Excellence in Undergraduate Teaching is presented to faculty members in recognition of exceptional interest and ability in undergraduate instruction. This is the only teaching award in which the nomination and selection of the recipients is done entirely by the students. The award is given in memory of Everett Moore Baker, Dean of Students at MIT from 1947-50.

Lander is impressed with the creative and innovative capabilities of today's current college graduates, compared to those of just a few years ago. "The incredible energy they have seems to be only getting better. I don't know how it can be but each generation seems to be even more creative. Maybe because they have more tools." While this situation is valid for American students, it is not as relevant in other countries. "The U.S. invests so heavily in research and education that, while the students are every bit as smart, the opportunities in the U.S. are extraordinarily larger."HGP Revisited
The Center for Genome Research was a leading center involved in sequencing of the preliminary draft of the human genome, which was announced in February 2001. The International Human Genome Sequencing Consortium, led in the U.S. by the National Human Genome Research Institute and the Dept. of Energy announced this past April that 99% of the human genome's gene-containing regions had been sequenced to an accuracy of 99.99%-basically saying that the human genome sequencing effort is now complete, about two years ahead of the original schedule.

Sequencing work at the Center for Genome Research continues in other areas. This year alone, researchers working at the Center generated and published high-quality draft sequences of the genomes of three of the Saccharomyces yeast species, the Ustilago maydis corn smut, and the chimpanzee genome (Pan troglodytes), along with starting to sequence the domestic dog (Canis familiaris). The dog sequence is expected to be completed by June 2004.

The dog genome will be sequenced using the Whole Genome Shotgun Approach, in which the sequence from the entire genome is generated and reassembled by recognizing identical segments using an assembler developed at the Center for Genome Research.

"Being able to read the evolutionary notebook and compare genomic information across species allows us to glean important information about ourselves," says Eric Lander, director of the Center for Genome Research.


The future

Andrew Barry's work at MIT advances human genome research, helping scientists form a complete picture. (Photo: Marc Berlow)

What are the current and long-term plans for the Broad Institute? "The goal is to really help bring together a community of scientists to create comprehensive tools for genomic medicine," he says. "My job is to identify all of the synergies across this extraordinary community (Harvard, MIT, and Whitehead) and help people identify ambitious and audacious projects to take on and help them figure out how to get them accomplished. My responsibility is mostly scientific and not administrative."

The future relationship of the Broad Institute to the Center for Genome Research is that the Center becomes the foundation for the Broad Institute. The Center will 'morph' into the Broad Institute, according to Lander.

The most important technology for Lander right now is computational technology. Only with computational technologies will researchers be able to pick out the hidden signals from evolutionary data about what evolution cares about, he says. "The coolest technology is that evolution has been doing experiments and it's the computational technologies that are now available to read them."

Lander also notes that the nanoscaling of technologies offer lots of possibilities for better detection limits and better modulation of biological systems. "I can see all of that converging," he says. "Exactly how this will occur, I don't know, but we're not close to being done with the detection and modulation problems that we have in biology and I'm hoping that computational sciences and nanotechnology will all provide better tools for that."

When asked after the announcement of the Broad's $100 million donation to create the Broad Institute about why the average man on the street should care about the Broad Institute, Lander responded, "I'd explain they should be interested for the same reason that I'm interested. I have kids." Lander then pointed to his three children in the audience, Jessica, 15, Daniel, 12, and David, 8, and said "I'm hoping by the time that they grow up and they need medical attention for some of the common diseases that afflict us all, that they will be able to have access to a medicine that is based on an understanding of actual causes. Medicine that is based on understanding what's really wrong in a disease and where the Achilles' heel of the disease process may lie, will indeed be much more powerful."Genomic Resources
Broad Foundation, www.broadfoundation.org
Genome Database, www.gdb.org
Harvard Medical School, www.hms.harvard.edu/research.html
Lewis-Sigler Institute for Integrative Genomics, www.genomics.princeton.edu
MIT Department of Biology, web.mit.edu/biology/www
National Center for Biotechnology Information, www.ncbi.nlm.nih.gov
National Center for Genome Resources, www.ncgr.org
National Human Genome Research Institute, www.genome.gov
National Institutes of Health, Science Resources, www.nih.gov/science
Stanford Genome Resources, genome-www.stanford.edu
The Institute for Genomic Research, www.tigr.org
U.S. Dept. of Energy, Office of Science, www.doegenomes.org
Whitehead Institute, www.wi.mit.edu

--Tim Studt

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