2001 Nobel laureate Leland Hartwell ’61 displays a culture of yeast cells—his research subject for three decades at the University of Washington. His discoveries about how the genes that govern cell division in yeast function and malfunction have produced new insights into the nature of cancer and other diseases.

A magnified image taken in a lab at Seattle’s Fred Hutchinson Cancer Research Center, which Hartwell now heads, shows yeast undergoing stages of cell division.

Hartwell Rising

Nobel Prize-winning yeast researcher finds new challenges leading a cancer research center

By Rhonda Hillbery

As a boy growing up in Glendale, California, where wildlife spills out of the Verdugo Mountains that envelop the foothill neighborhoods, Leland Hartwell ’61, without any particular encouragement, collected butterflies. Then he headed to the library to read up on them.

“None of my friends was doing that,” says the cowinner of the 2001 Nobel Prize in physiology or medicine, which he received for basic discoveries about the universal mechanisms controlling cell division in organisms. “I really didn’t understand that I was sort of an inborn scientist. I didn’t realize I was weird.”

Hartwell met kindred spirits at Caltech, where opportunity serendipi-tously led him. During his freshman year at Glendale Community College, a guidance counselor hooked him up with a Caltech recruiter, who rightly gambled that the intellectually curious Hartwell would soak up the Institute’s coursework like a dry sponge.

At Caltech, Hartwell considered physics as a major before tumbling headlong into biology. Plant physiologist James Bonner, PhD ’35, was one of his role models.

“He made biology sound just terribly exciting,” says Hartwell. Around the same time, a bacteriophage genetics course captivated him, showing that biology could be quantitative, as well as exciting. “I think I immediately changed my major.”

He adds, “Caltech is a very special place, because as an undergraduate you can participate in research. I did research the entire time I was there. I really learned what science was about and it was very seductive.”

After completing his PhD at MIT, Hartwell spent more than 30 years as a bench scientist in the lonely study of yeast cells. “I was sort of alone in the woods because it wasn’t at all clear to me that yeast cells were related to human cells,” says Hartwell, who chose yeast mostly because it could be studied at a level then impossible with human cells.

The biologist (who shares the prize with Timothy Hunt and Paul Nurse, both of the Imperial Cancer Research Fund in London) carried out most of his groundbreaking work as a faculty member at the University of Washington. His research has revealed that humans have a lot more in common with the backbone of bread and beer than had been previously imagined, and that the process of cell division is fundamentally the same in all organisms.

“We are essentially all made out of the same Erector set,” Hartwell sums up colloquially.

Just a few years before being awarded the Nobel Prize, Hartwell became head of the Fred Hutchinson Cancer Research Center in Seattle. The “Hutch,” where his earlier research is now being used to help develop anticancer drugs, is internationally known for pioneering bone-marrow transplantation. Also known for its cancer-prevention research, the Fred Hutchinson program is among the world’s largest. Transplantation is now recognized as one of the leading life-saving therapies for cancer, blood disorders, genetic diseases, and autoimmune disorders.

Hartwell maintains a laboratory on the Hutch campus, but admits that the demands of his administrative job leave him little time for work there.

His job also keeps him from traveling widely, even though becoming a Nobel laureate confers a blizzard of invitations to speak and write from all over the world. Suddenly, everyone wants to know what you are thinking.

And there’s no question that Hartwell has a lot on his mind.

“I’m interested in seeing public-health science move into genomic areas where it may be possible to identify people at risk for disease very early and manage disease risk before people become seriously ill,” he says. “The whole area is very promising.” Mapping of the genome is expected to lead to revolutionary discoveries about the relationship between genes and disease—
insights that scientists expect will lead to new treatments for a wide range of diseases.

But as biomedicine’s promise grows, says Hartwell, a growing threat looms over clinical research. As a scientist who heads one of the country’s leading biomedical centers, Hartwell worries about public ignorance of science, and society’s growing mistrust of clinical research trials.

“On the public-policy side, I think the most critical medical issue in our country right now is the increased oversight, regulation, and criticism of the clinical trial process,” he says. “There have been a lot of articles written about how clinical trials endanger people. There’s a negative mood in the country now on clinical trials.”

Most damaging may have been the 1999 death of Jesse Gelsinger, an 18-year-old whose volunteer participation in a gene-therapy trial at the University of Pennsylvania went fatally wrong. The lead researcher was found to have an interest in the company whose treatment substance was being tested. After looking into the case, the Food and Drug Administration temporarily shut down all human gene-therapy experiments at the university. And public scrutiny intensified with the recent highly publicized death of a healthy volunteer who died during an asthma-drug treatment experiment at Johns Hopkins Medical Center.

Fred Hutchinson itself has been on the receiving end of negative coverage.

A 2001 series of articles in the Seattle Times alleged that patients weren’t properly informed of the treatment risks and stated that Fred Hutchinson and some doctors held financial interests in the drugs being used.

Says Hartwell, who became the facility’s director in 1997, “It was a very distorted and inaccurate series to begin with, about research trials carried out 20 years ago.”

Dealing with the controversy has been time-consuming and not the type of leadership responsibility that Hartwell likely had in mind when he signed on for the job.

In letters to the editor of the Seattle Times, on the Hutch Web site at www.fhcrc.org, and through other avenues, the Hutchinson emphatically rebuts the articles’ conclusions. Following publication, an internal investigation by the Hutch concluded that the central themes of the articles were “false and unsupportable.” Hartwell adds that the issues were investigated and put to rest nearly 10 years ago by the federal Office of Protection from Research Risks, part of the National Institutes of Health. And in an attempt to assure patients and the public that the Fred Hutchinson is taking a leadership role on this evolving issue, the center recently outlined an 11-point course of action intended to strengthen practices and policies in the conduct of clinical trials.

Among the changes, the Hutchinson has centralized its trial-monitoring procedures and now uses an outside contractor to monitor safety and ethical issues. The facility has hired a regulatory compliance officer, and tightened its conflict of interest policy governing clinical researchers.

Hartwell believes the measures will foster increased confidence among patients. “Those of us who conduct the medical research necessary to alleviate disease and suffering recognize the importance of ensuring that the clinical trials system meets strict safety and ethical standards. We all need clinical research and clinical trials to improve the outcomes and quality of life of the critically ill because any one of us might at some time be a patient with a life-threatening disease.”

An often-overlooked larger issue, in Hartwell’s view, is a growing public ignorance of biology and science, which is fed by negative, often overblown media accounts. Fear of litigation and concerns over ever-increasing regulatory requirements are leading some researchers to leave the field altogether. He says the worsening environment for clinicians makes it harder to identify appropriate patients to enroll in tests and may ultimately make it harder to test new drugs that may save lives and cure disease.

“It’s very dangerous, because at a time when science has the ability to translate a lot of its findings to benefit people, that translation will be impossible if there is not a robust clinical-trial process.”
At best, he says, the new scrutiny will help the nation come to terms with the risks and benefits associated with clinical trials. “We need to educate the public, to take advantage of opportunities to speak and write.”

At a recent retreat representing 60 cancer advocacy organizations, he says, he reminded his audience, “When people are talking about patients’ rights, they are frequently meaning that we need more oversight. But they are forgetting that what patients really want is the right to the fruits of the research that, as taxpayers, they’ve been paying for over the past few decades.”

Although Hartwell often misses carrying out the research for which he was honored in Stockholm, he is philosophical about this new stage in his life.

“It takes a while to get used to a change, and it is no different when you become an administrator.

I’ve been a bench scientist for a long time. I took this job because I really felt an enormous opportunity to apply basic research findings to medical science. It’s just doing science at another level.”

In its citation, the Nobel Committee recognized Hartwell for his discoveries of a specific class of genes that govern the cell cycle—the process by which cell division is initiated and regulated in organisms. At the heart of his research is learning when and how genetic errors can cause the cell cycle to go awry, often leading to the runaway, uncontrolled cell division that is characteristic of cancer.

“In an elegant series of experiments” in 1970–71, the committee noted, “he isolated yeast cells in which genes controlling the cell cycle were altered (mutated). By this approach he succeeded to identify more than one hundred genes specifically involved in cell cycle control,” which are known as cell division cycle genes. One of these genes, known in the trade as “start,” was found to have a central role in controlling the first step of each cell cycle. Hartwell also introduced the concept of “checkpoint” genes.

The discoveries by Hartwell, Hunt, and Nurse have led to new avenues of research that, as the Nobel citation said, “may in the long term open new possibilities for cancer treatment.”

Says Hartwell, “It turned out that the same genes we found in yeast were found in human cells and all other higher organisms. This common evolutionary heritage that has come out of so many simple organisms—yeast, and fruit flies, and nematodes—has resulted in a tremendous amount of information that is very fundamental to medical science. It really has confirmed that we all share one biology.”

When the former butterfly enthusiast looks at his beloved dog, Emma, he is reminded how seemingly little genetic material separates one species from
another.

“I think I do have a sort of Buddhist feeling about the sacredness of life of any type—a sense that affinity rather than separateness characterizes all forms of life. It’s that unity that means a lot to me.”