UW lures Leroy Hood to help break the human genetic code

As France fell during the 1940 Nazi blitzkrieg, a group of brilliant British mathematicians made a breakthrough in their quest to crack Germany’s top-secret war codes. Named Ultra, the undertaking used primitive computer-like decoders to unravel the seemingly random sequences of German cyphers.

Ultra’s success would give advance warning of air raids, troop movements and U-Boat maneuvers. With its crucial information, British air marshals could prepare for the bombing runs of the blitz. Winston Churchill was able to warn Stalin of the Nazis’ 1941 invasion (a warning Stalin ignored) and the Allies could confidently plan the D-Day invasion. Of the cryptologists, linguists and mathematicians who broke the code, Churchill said, “They were the geese that laid the golden eggs.”

Today biologists, mathematicians and computer scientists are trying to break an even more complex code. If they solve this cypher, they might be able to wage war within the human cell, blitzing defective genes that could lead to diabetes, multiple sclerosis or Alzheimer’s disease. But some warn that breaking the code might lead to a Nazi-like nightmare—the genetic engineering of the human species.

In a 15-year, $3-billion project, scientists are trying to map the chemical sequence of every gene in the human being, what they call the human genome.

Nature has encoded all its information about the human species in 23 pairs of chromosomes, not just obvious traits like hair color, but the essence of our biology. These chromosomes contain between 50,000 and 100,000 genes that tell our body’s cells how to grow and when to do it.

Once the human genome is decoded, scientists will be well on their way to a comprehensive understanding of genetically based disease. But beyond that lie the real “goodies”: elimination of a tremendous amount of misery through disease prevention or gene “therapy,” where doctors could repair the genes of an unborn child.

But these benefits to health, happiness and economic vitality won’t come without a cost—in job and insurance discrimination, in genetically based social selection, in a fundamental loss of privacy—and in a host of agonizing decisions by the carriers of genes that put them—and their offspring—at risk.

Just as the Ultra project had its brilliant cast of characters, such as the eccentric mathematician Alan Turing, the Human Genome Project has its visionaries, such as Leroy Hood, head of the University of Washington’s newly created Department of Molecular Biotechnology. With Hood’s recruitment from the California Institute of Technology last year, UW scientists hope to take the lead in unlocking the door to this microworld of genetic inheritance.

On the morning of Oct. 7, 1991, UW President William P. Gerberding announced the largest single gift to the UW ever made by an individual: $12 million from Microsoft Chairman and CEO William Gates III to establish the Department of Molecular Biotechnology. While the money was of tremendous importance, the real news that morning was that Gates had helped recruit “Lee” Hood, a supernova among the stars of this most ambitious and well-funded biology project ever.

Side by side at the podium, the young wizard of the world’s most successful computer software company and the guru of molecular genetic technology spoke of a new way of attacking the problems of biology. They suggested a marriage of classical laboratory approaches with technology and computation. Such a marriage could transcend the barriers choking back the acceleration of biomedical progress.

Hood’s recruitment and the founding of a new discipline further enhanced the prestige of the UW School of Medicine, already the leader in NIH grants to public universities. The new department allowed Hood to assemble a world-class faculty, which would have been impossible at Caltech, which has a small faculty and no medical school. As a sign of the department’s promise, applications from some of the world’s brightest students immediately came flooding in.

But grants and glory didn’t motivate Dr. Lee Huntsman when he first suggested to Gates that he consider helping recruit Hood.

“We didn’t hire Lee Hood just because he was famous. And we didn’t hire him because he has an incredible record of attracting money,” says Huntsman, director of the UW Center for Bioengineering. “We really hired him because he is a legitimate visionary in an important area of biomedicine and he has the leadership abilities to pull it off.”

That leadership had become apparent in 1973, when the Montana-born Hood was promoted to associate professor of biology at Caltech. Trained in immunology and medicine, Hood had authored or co-authored 30 articles on genetics and immunology by the end of the year. In 1975, Hood formed a team of Caltech researchers that would eventually build a revolutionary machine, an Ultra-like code breaker that would automate the chemical analysis of proteins.

All the while, Hood found time for hiking and mountaineering with his wife, Valerie, and a small cluster of friends from his student years. The closest of them, Eric Adelberger and Ted Young, now are on the faculty at the UW. Adelberger, a professor of physics, and Young, a professor of biochemistry, recall that Hood always had a knack for asking the right questions and attacking problems at the critical point that would yield real results.

By the late 1970s, scientists at Harvard and Cambridge universities had devised technologies to sequence the base pairs in a segment of DNA. But it was a tedious process and one that was largely unsuited to the demands of commercialization.

That changed in the early 1980s, when Hood’s group of scientists gave biology a huge push by inventing new technology for automating and speeding up DNA sequencing. Before the invention of his sequencer, it could take weeks to get enough pure material—genes, proteins or amino acids—to conduct an experiment. It used to take a good graduate student one year to decode 12,000 DNA base pairs; with Hood’s machine it now takes one technician about half a day.

Frustrated by existing companies’ unwillingness to take a risk with the new technology, Hood helped form Applied Biosystems Inc. to manufacture and market the revolutionary machines. Thousands of those devices still form the technological backbone for much of the biotechnology industry and molecular biology research.

Despite that leap ahead, Hood never seriously contemplated cataloging the human genome until 1985 when he was one of a dozen scientists invited to the first conference on the subject at the University of California at Santa Cruz.

“I went to the meeting with enormous skepticism,” recalls Hood. “But as a consequence of that meeting I became intrigued with the notion that it was a feasible endeavor—if one was willing to make a major commitment to develop technology to map and sequence the genome at rates that were much greater than anyone could imagine at the time.”

As before, instead of talking about the problem, Hood applied the methods for which he has become famous. He attacked it with technology and leadership.

In 1986, Hood and his Caltech colleagues invented an automated sequencing process that uses fluorescent dyes to color code the four DNA bases and reads and analyzes their sequences at a rate of 12,000 to 30,000 base pairs per day.

That is more than 350 times the rate possible in 1980 but still far too slow to satisfy Hood or accomplish the goal of a full genome blueprint within 15 years.

Now Hood hopes to increase the speed of automated DNA sequencing to allow one technician to analyze more than one million base pairs per day by early in the next decade.

In addition to developing technology, Hood has been tireless in developing and selling a vision for the project to scientists, Congress and federal agencies.

Early on he and a few other pioneers got involved with the Department of Energy to push the human genome. As a result of the energy department’s enthusiasm and worldwide interest, Congress and the National Institutes of Health committed to the project.

Hood says he sees his role in the Human Genome Initiative as threefold. “I have helped formulate the current vision of the genome. I certainly have pushed to get the two major agencies, who now support the project, to fund it. And I have really attempted to inculcate the vision that technology should be the primary objective for the first five to 10 years. In that endeavor, I must say that I have been a lot less successful than I would have liked.”

In fact, the program, as originally proposed, has taken several hits.

First, its $3-billion price tag is immense, and other scientists complain loudly that it is stealing funding from critical research they believe promises more tangible results. Others protest that it is an impractical waste of resources.

UW Nobel Prize-winner Edmond Fischer is concerned about a general diversion of funding for so-called targeted research. The genome initiative is “no doubt a very important project,” he says. “The question is: How much will it divert from other research?”

Worried about their research funding, in 1990 dispossessed scientific groups “began to behave like postal unions,” hiring lobbyists, wrote Nobel Prize-winning scientist James Watson, the first genome project director.

“Hate letters have made the rounds, including the rounds of Congress, contending that the project is ‘bad science’—not only bad but sort of wicked,” wrote Watson in The Code of Codes, a book on the Human Genome Initiative co-edited by Hood and Daniel Kevles and released earlier this year by Harvard University Press.

Congress has pushed for some immediate returns to justify the program’s cost. One result, says Hood, has been “a temptation to just get out and get started mapping the genome on a large scale, perhaps prematurely.”

Achieving the ultimate goal of cracking the code will be extraordinarily challenging. Unless the speed of sample preparation, sequencing and analysis can be dramatically improved, completing the project on time and on budget is extremely improbable.

The project has created a philosophical chasm between those who believe the genome money would be better applied to such things as preventing infant mortality and strengthening Alzheimer’s disease research and those who believe the genome is the key to finally understanding and preventing disease.

Then there are the ethicists, who have raised all kinds of troubling issues.

The ultimate fear is of attempts to engineer the DNA in human sperm and egg cells to create a “superhuman.” Detractors cite a long history of discrimination based on eugenics, a discredited scientific discipline that flourished in the early 20th century and inspired many of the Nazi race laws. Many people fear eugenics is resurfacing in attempts to link criminality and violence to genetic flaws.

Despite fear about the manipulation of germ cell DNA, most molecular biologists believe that level of genetic tinkering will be impossible until the middle of the 21st century. But many people still worry about less technologically challenging efforts to purge “disease genes” and “undesirable traits” from the gene pool.

Albert Jonsen

The most troubling issue is that the genome initiative will let individuals glimpse their future before it’s possible to do much about it, says UW Medical History and Ethics Chair Albert Jonsen.

Imagine your entire genetic code rests in a single CD. Physicians put your CD into a computer and out comes a list of odds, kind of like a bookmaker’s sheet. It says the odds are 3 to 1 that you will develop atherosclerosis and have a life-threatening heart attack by age 40.

But the printout also notes that if you follow a strict diet, exercise and medication program, you would have a 1-in-3 chance of delaying serious consequences of the disease by 10 years. And the sheet indicates a 1-in-8 chance that the disease might never happen. What would you do? How would you feel? Would you want to know the odds at that level of uncertainty?

On the other hand, if your genetic blueprint indicated your children might be predisposed to manic depression, schizophrenia or early onset Alzheimer’s disease, would it affect your decision to have children?

These kinds of questions are basic to the debate about the genome initiative, because the ability to diagnose genetic defects will far precede viable therapies. Jonsen predicts this knowledge of the genome will turn many of our children into “unpatients.”

“They are not going to be patients because there is nothing you can do for them,” says Jonsen. “They ar: not really ‘not-patients’ because (inevitably) they are going to be part of the health care system.”

He predicts a crisis in genetic counseling when we are able to carry a CD containing our genetic encyclopedias. The result, he says, will be “mass misinformation.”

A fundamental problem is that in most cases, predicting disease based on genetic information is an exercise in probability and not a sure thing. But our culture has become almost obsessed with the notion that our lives are genetically predetermined, says Philip Bereano, a UW professor of women’s studies and technical communication.

Bereano is one of the country’s most vocal critics of the genome project. He believes it should be halted until reasonable safeguards are built to protect privacy and avoid discrimination due to “bad genes,” that is, indications the person could develop a catastrophic disease.

“Technology is not an inevitable conveyor belt of progress from which we are free to sample the goodies that the benevolent scientific establishment will bring to us,” says Bereano, whose specialty is technology assessment and the relationship between technology and social values. “Technologies are a result of purposeful human choices, and the choices which led to the Human Genome Initiative were made by a small elite, powerful group of scientists in connection with certain politicians.”

Jonsen, however, believes attempts to slow the pace of this technology are bound to fail. “I think these things happening in molecular medicine are an essential part of moving ahead,” says Jonsen.

Despite the criticisms, the project is forging ahead, buoyed by the vision of scientists such as Hood, who believes the potential for preventing disease far outweighs what he considers solvable ethical problems.

Part of Hood’s vision, seconded by genome pioneer Dr. Maynard Olson, is that too little emphasis has been placed on fundamental research, while too much has gone into sequencing genes and crunching out DNA maps.

“It is my belief that if we are to take seriously sequencing the human genome on a reasonable cost basis,” Hood says, “we are probably going to have to do sequencing 100 times faster, maybe even 500 times faster.”

Olson left his position at Washington University in St. Louis earlier this year for a faculty position in the new UW department. Hood, Olson and others in the department plan to create what Hood calls a “unique ecological niche” in biology research.

“Part of the reason this department was born was the frustration that there isn’t any place that is trying to attack, in deep and fundamental ways, the whole question of technology development in biology,” says Hood.

Indeed, Hood and his colleagues have set their horizons well beyond the genome project. Within five years, Hood hopes to have pushed the technology far enough that the grunt work of sequencing the genome might be contracted out to industry.

Then he hopes to shift his focus to furthering the understanding of complex biological systems, such as the brain, auto-immune disorders, and how hormones control development. He also wants to develop “nanotechnology” for gene sequencing—machines the size of a fingernail that will do 100 times the work of today’s machines, which are half the size of a conference table.

Just as the work on high-level mathematics in the Ultra project helped spur the post-war development of the computer, the new department’s work, Hood believes, will force a shift in life sciences education. “I think we have a unique opportunity with these kinds of ideas to really change over the next 10 years how people think about biology and do biology.”

Scientists trained in the Department of Molecular Bio­technology will combine education in biology with other disciplines such as computation, engineering and computer science. Hood also hopes his faculty and students will be able to collaborate with Microsoft CEO Gates in a software institute for attacking complex biological systems.

Hood says, “We would like to catalyze … changes in biology and medicine and make them happen here. But it is more important to train the leaders who are going to make them happen. It is our feeling that these students will become the leaders in biology in the next century.”

Climbing to the top: Why Hood came to the UW

When University of Washington officials announced last year that they had recruited Leroy Hood from Caltech to head a new Department of Molecular Biotechnology, few people knew such a move had been on his agenda for years. Born in Missoula, Mont., Hood had longed for an academic position that would satisfy him scientifically while allowing him to escape easily to the mountains to hike and climb. He satisfied those urges once or twice a year during his career in Pasadena, by escaping with his wife, Valerie, and friends to challenge peaks from Alaska to Switzerland.

As a scientist Hood, too, was becoming restless. He became increasingly frustrated with the narrowness of focus that was ingrained in university graduate training, and he yearned for an academic environment that would support his vision of multidisciplinary doctoral programs.

Despite his own productivity and the excellence of Caltech’s programs, its small, contained campus never was able to support a new paradigm for research he believed would be necessary to tackle the truly difficult questions facing biologists.

Where other scientists might be satisfied with what they had, Hood was driven to excel. He looked north to where his perennial companions, Eric Adelberger and Ted Young, had moved in their academic careers. Both at the University of Washington, Adelberger (Hood’s undergraduate roommate at Caltech) was a professor of nuclear physics and Young was a professor of biochemistry.

Young and Hood had discovered their mutual affinity for vertical surfaces during graduate school at Caltech. They began climbing together late at night during breaks in their biology experiments—on exteriors of the university’s buildings. On the weekends and during term breaks, the trio headed to the Sierra Madre range with their wives and children, taking turns babysitting at camp while the others ascended the peaks.

Ted Young

Young says he always feels comfortable climbing with Hood. “You always feel that Lee is in control of his environment when you are with him,” says Young, who still competes in triathlons.

Hood, 54, keeps very fit by running several times a week and tailoring his conditioning to the challenges of specific climbs.

While sitting around a campfire or huddling in a tent on the side of a windswept mountain, Hood and his friends have always found plenty of time to talk—about their personal lives, science, the meaning of life, the ideal academic atmosphere.

Over the years, Hood began to wonder if the UW might not be that place. Its first-rate medical school was very attractive, as was the cross-discipline collaboration he witnessed in areas from computers to medicine and engineering.

Hood adds that he and his wife had been attracted personally to Seattle, where they had more friends than in Pasadena.

The UW seemed to be a place that might embrace his ideas of multi-disciplinary Ph.D. programs, and for a number of years he talked with his friends about the ideal circumstances for coming to the UW.

But none of those imagined circumstances included the kind of endorsement for his pioneering work that came last year through Bill Gates’ $12-million gift to the University.

Though Hood had turned down many offers to leave Caltech, the promise he saw at UW made the decision an easy one to make.

The University offered him a new department, with a new franchise for multi-disciplinary education and research he believed would support his vision and allow him to recruit a world-class faculty. A fervent believer in transferring research technology to industry, UW’s Washington Technology Center and Seattle’s healthy biotechnology industry made the move even more attractive, he says.

And then, there was the “personal equation”—good friends, weekend trips to the mountains, a return to the Northwest.

When it came right down to it, Hood says, “We got almost everything we wanted.”