Eric Lander: The great amplifier

Audacious thinking may help crack the code of cancer

Bill Snyder
Published: February, 2007

Eric Lander
Photo by Maria Nemchuk, Broad Institute of MIT and Harvard
Eric Lander, Ph.D., strides down a sun-drenched hallway to yet another research meeting in the genome center he directs, his face beaming with purpose and excitement.

His bear-like handshake radiates strength; his patience is easily taxed by the pedestrian and the hesitant. But he is anything but intimidating. On the contrary, his sparkling blue eyes and easy smile convey a warmth and vitality that are often described as infectious.

A driving force behind the sequencing of the human genome, Lander is now tackling the “cancer genome.” He and his colleagues around the country are out to redefine tumors by the genetic changes that trigger their malignant growth, rather than by where in the body they strike.

Within 15 years, he predicts, “every patient in the clinic (will) have a complete genomic workup… for a couple of hundred dollars per patient.” Their doctors will be able to determine the precise genetic characteristics of their illnesses, and therefore which treatments are most likely to be successful.

“I don’t want to pretend that having such a comprehensive description of human disease automatically gives us therapies,” says Lander, the dynamic founding director of the Broad (pronounced “Brode”) Institute of the Massachusetts Institute of Technology (MIT) and Harvard University. “There’s still a tremendous amount of work.

“But I can’t imagine how we’re ever going to make therapies for these diseases without actually knowing what’s wrong.”

In 2005 a panel led by Lander and Nobel laureate Leland Hartwell, Ph.D., president and director of the Fred Hutchinson Cancer Research Center in Seattle, proposed a 10-year, $1.5 billion effort, called The Cancer Genome Atlas project, to identify the major mutations in human cancer. A three-year, $100 million pilot to test the project’s feasibility is currently underway.

While federal health officials hail the initiative as the beginning of a new era in cancer diagnosis and treatment, others complain that it will divert limited research funds from equally important cancer projects (See “Bonanza or boondoggle?”).

Those who know Lander, however, are hesitant to doubt him.

“People will say, ‘Oh well, Eric says this is going to happen, but you know… (it) doesn’t,’” says Oxford University geneticist Kay Davies, D.Phil., who has made key contributions to understanding Duchenne muscular dystrophy. “But then three years later, it does happen.”

Tom Sawyer approach

Lander, who turned 50 in 2007, is perhaps the world’s best known mathematician-turned-geneticist.

The former Rhodes Scholar and MacArthur Fellow established and directed one of the five centers primarily responsible for completing the Human Genome Project.

While hundreds of scientists contributed to this landmark achievement, “he certainly was one of the leaders in… starting to turn out the sequence on a large scale,” says Philip Green, Ph.D., professor of Genome Sciences at the University of Washington in Seattle, who worked with Lander in the late 1980s.

“That took a lot of organizational skill and fairly aggressive approaches,” Green continued, “to really acquire the resources and motivate the people in his group to get going on that.”

“You know Tom Sawyer getting everybody together to paint the fence? That’s Eric,” says Lander’s younger brother Arthur, laughing. “He can get groups of people to do enormous amounts of work and thank him for it.”

The ability to inspire others actually may be Lander’s greatest talent, and his most enduring legacy.

Eight hundred scientists actively contribute to the Broad Institute’s projects, of which the cancer genome is one of a dozen. When they congregate for coffee, they’re more likely to discuss a colleague’s latest paper in Nature Genetics than the sports pages of the Boston Globe.

“This is the truly important work for our generation in science,” enthuses Mark Daly, Ph.D., an assistant professor of Medicine at Harvard Medical School who has worked with Lander since he was a freshman at MIT 20 years ago. “We have an unswerving belief that this is the work that is going to make a difference in medicine in the future.”

Lander’s “big science” approach to cancer has its share of critics, among them Nobel laureate Sydney Brenner, D.Phil.

Even though he was an early proponent of what would become the Human Genome Project, Brenner worries that investment in expensive technology is now driving the research agenda, rather than the other way ’round.

During a lecture at Vanderbilt University in 2006, the Oxford-trained geneticist joked that he would like to buy Lander’s gene sequencers “and throw them into the sea. That would be the inverse of the Boston Tea Party.”

Yet for Lander, big science is not about the machines.

“It’s about taking on the responsibility of creating datasets of tools, and then putting them in the hands of thousands of young scientists who make them 50 times more efficient,” he says.

“So it’s always ‘big science’ in the service of the individual investigator. That was what the Human Genome Project was about… And that’s what the projects going on here on inherited genetic variation of disease, on cancer, on evolution, on infectious disease—all of them share that role.

“We’re playing a great amplifier… We’re trying to empower a generation of remarkable scientists who really want to take on the important problems in disease.”

Productive collisions

Empowering remarkable people has been a hallmark of Lander’s life, at least as far back as high school.

Lander and his brother—now chair of the Department of Developmental and Cell Biology at the University of California, Irvine—grew up in the Flatlands section of Brooklyn.

Their parents were lawyers, but their father, Harold, became disabled from multiple sclerosis and died when Eric was 11 and Arthur was 10. Pitching in to help with housework and home repairs, the boys early on developed a strong sense of initiative.

Eric Lander (third from left) poses with other members of the Stuyvesant High School math team in 1974.  To Lander's right are Jesse Deutsch and teacher Irene Finkel; to his left are Francis Barany, Kelly Pan and Paul Zeitz.
Photo by James Hamilton
Their mother, Rhoda, who died two years ago, told the Boston Globe Magazine in 1999 that she was mystified by her sons’ achievements. “They did their thing, and then I paid the bills,” she said.

Pursuing an early interest in mathematics, Eric enrolled in Stuyvesant, one of New York’s premier math and science high schools, and became a leader of Stuyvesant’s celebrated math team.

At age 17, he won the Westinghouse Science Talent Search prize for a paper on “quasi-perfect” numbers, but he was much more than a math whiz, recalls former math teammate Kelly Pan.

“Eric has what is probably unusual in the field of math, a very outgoing personality,” says Pan, who went on to earn an MBA and who now runs an investment management firm, Pantheon Capital Management, in Manhattan. “He reaches out to people and is always very willing to share what he knows.”

In 1974, Lander enrolled at Princeton University, where he earned his bachelor’s degree in math with highest honors. He also met his future wife, Lori, in a constitutional law class their sophomore year. Married since 1981, the Landers have three children: Jessica, 18, Daniel, 15, and David, 11.

Lander describes his life as if he were an atomic particle, bouncing randomly into key people. Not knowing what he wanted to do after earning his doctorate in mathematics from Oxford, he went to Boston, he says, “because the probability of productive collisions was higher.”

He joined the faculty of the Harvard Business School, where he taught courses in business management and negotiation. Meanwhile his brother, who at the time was earning his M.D. and Ph.D. degrees at the University of California, San Francisco (UCSF), urged him to switch to the life sciences.

“Even in high school, he’d had an affinity for genetics,” Arthur Lander recalls. “Lots of mathematicians like genetics. It really fits with the mathematical view of the world.”

Lander took a few courses, and learned fruit fly genetics at Harvard. He also worked with MIT biologist Robert Horvitz, Ph.D., who would share the 2002 Nobel Prize with Brenner and John Sulston, Ph.D., for their ground-breaking studies of organ development and programmed cell death in the round worm, C. elegans.

Then in 1985, in one of those productive collisions, Lander bumped into MIT geneticist David Botstein, Ph.D.

Up to the task

Five years earlier, in a pivotal paper, Botstein and his colleagues Ronald Davis, Ph.D., of Stanford and Mark Skolnick, Ph.D., and Ray White, Ph.D., of the University of Utah had proposed a method to map the entire human genome using restriction fragment length polymorphisms or RFLPs.

RFLPs are pieces of DNA that have been sliced apart by restriction enzymes. In 1978, researchers at UCSF discovered that one of the restriction fragments from patients with sickle-cell anemia differed in length from normal fragments from people without the disease.

Botstein and his colleagues reasoned there were many such genetic differences between individuals. Most were probably innocuous, but theoretically they could be used as markers to create a map of the entire human genome.

Mathematical methods available at the time, however, were not up to the task of unraveling the intricate web of genetic interactions that contribute to complex disorders like cancer or diabetes.

“It became clear that what was needed was somebody to think about this problem who had mathematical tools beyond what I knew,” says Botstein, now director of Princeton’s Lewis-Sigler Institute for Integrative Genomics.

So he asked around and eventually was directed to Lander. Within a week of their meeting, “we had a lot of stuff worked out,” Botstein recalls.

Thus began what Lander happily describes as his “chaotic career path.”

In 1986, on Botstein’s recommendation, Nobel Prize-winning virologist David Baltimore, Ph.D., invited Lander to become a fellow of the Whitehead Institute for Biomedical Research in Cambridge.

“When I met Eric, I knew immediately that he had enormous potential,” says Baltimore, the institute’s founding director, who went on to become president of the California Institute of Technology (Caltech).

The next year, Lander received a five-year MacArthur Foundation “genius grant” to support his innovative application of statistics to the study of genetics.

Meanwhile, he and Botstein churned out half a dozen papers detailing their methods for mapping complex genetic traits. With the help of Philip Green, Ph.D., who, like Lander, was a mathematician-turned-molecular biologist, they put those methods to work at a Massachusetts biotechnology company called Collaborative Research Inc.

“What the company was trying to do was to identify lots of these RFLP markers and then determine where they were on the chromosomes by finding their locations relative to each other,” Green recalls. This approach was called genetic linkage mapping.

At the time, researchers could map only three or four markers at a time. Green and Lander met frequently to discuss ways to construct maps with many more markers, and independently developed software programs to implement their ideas.

In 1987, the team, led by Collaborative Research senior researcher Helen Donis-Keller, Ph.D., published the first genetic linkage map of the human genome.

“He certainly is competitive,” Green says his former collaborator. “That can create a tension because you’re both collaborating and competing in a sense at the same time, trying to come up with ideas first. But overall, you get past that, and I actually think competition really drives science.”

In 1990, the National Institutes of Health (NIH) and Department of Energy (DOE) officially launched an ambitious international effort—dubbed the Human Genome Project—to determine the sequence of every human gene.

That year Lander, a recipient of one of the project’s first grants, founded the Whitehead Institute/MIT Center for Genome Research to exploit recent advances.

Among them: automated DNA sequencing machines, and “shotgun” sequencing, in which randomly sliced up fragments of DNA are cloned and sequenced, and—with the help of powerful computer programs—pieced back together in proper order.

Others were racing to embrace the new technology. In 1998, former NIH scientist Craig Venter, Ph.D., shocked the scientific world when he announced that his new company, Celera, would sequence the human genome by 2001—several years earlier than the target date set by the Human Genome Project.

Urged by Lander, among others, the public effort reorganized its priorities to produce a rough draft sequence first and a final finished product later.

Lander’s center became the largest of the project’s top five gene-sequencing operations. The others were Washington University in St. Louis, Baylor College of Medicine in Houston, the DOE Joint Genome Institute and the Wellcome Trust Sanger Institute near Cambridge, England.

In June 2000, the race ended in a “tie:” Celera and the Human Genome Project jointly announced working drafts of the human genome sequence. The public genome project went on to complete a final sequence three years later.

Blown away

In October 2001, Lander and his colleagues were filling in the gaps in the sequence when Eli Broad called him up, and asked if he and his wife Edythe could visit his lab during a visit to Cambridge.

Broad, founder of two Fortune 500 companies and a Caltech trustee, previously had been introduced to Lander by Baltimore. Through their foundations, Broad and his wife had made major contributions to the arts and education, and recently had begun to support medical research.

Family man
Eric Lander shows photos he's taken of Masai children during a trip to Kenya (top left); he and his son Daniel prepare to feast on chili crabs in Singapore (below left); and he shares a quiet moment with his daughter Jessica, now college-age (right).
 
Photos courtesy of the Lander family
“This was Saturday,” Broad recalls. “So my wife and I go to see his lab and we’re blown away by 140,000 square feet of robotics and computers working 24 hours a day decoding the human genome.

“And (Lander’s) here with all these young very bright people from Harvard Medical School and MIT who don’t want to go home they’re so excited.”

Asked what he wanted to do once the sequence was completed, Lander said he’d like to apply the new knowledge to help patients. “That whole notion appealed to me,” says Broad, who began talking to officials at Harvard and MIT.

In June 2003, Broad and his wife announced a $100 million gift to establish the institute that bears their name. Eighteen months later, they doubled their philanthropy to $200 million.

Within their sparkling labs near the MIT campus, institute researchers are applying genomic tools to better understand a wide range of ailments, from malaria and tuberculosis to psychiatric disorders, diabetes—and cancer.

Cancer lends itself to genomic investigations because it’s a genomic disease, Lander explains.

“We’re not talking about common, pre-existing genetic variations,” he said. “We’re talking about new mutations that arise in each tumor.

“So once you have a sequence of the human genome, you can then ask, ‘How does (this tumor) differ amongst 400 lung cancers?’ And in each case you are comparing it to the normal genome that the person started with.

“There’s background noise; there are (random) changes that occur. But… if you see a gene mutated 10 percent of the time, that’s no accident,” Lander says. “It must be playing an important, causal role. So by simply collecting enough data, the genome should be willing to tell us which genes matter.”

Lander shrugs off criticism that The Cancer Genome Atlas project is too expensive or simply can’t be done. The proposed cost would be less than 3 percent of National Cancer Institute’s budget, he notes. And, the technological hurdles will be overcome. The important thing is to nurture visions of what might be.

“What’s the biggest product of this place? It’s scores of people who have come out of the genome center and the Broad Institute who… (are) willing to work together, to do the heavy lifting necessary to change the world,” Lander says.

“It’s faith, a confidence that the way to change the world is to get information and tools into the hands of as many people as rapidly as possible.”

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