Bioscience

Genetics pioneer aims to transform global healthcare—from Arizona

January 30, 2008

By Flinn Foundation

Lee Hartwell
Nobel Laureate Lee Hartwell, president and director of the Fred Hutchinson Cancer Research Center in Seattle, and executive chair of a new Arizona-based initiative, the Partnership for Personalized Medicine

Over the past several decades, scientific inquiry has produced a flood of new knowledge about cell biology, advancing the field rapidly from discoveries such as th
e structure of DNA to achievements like the sequencing of the human genome.

Lee Hartwell, president and director of the Fred Hutchinson Cancer Research Center in Seattle, and executive chair of a new Arizona-based initiative, the Partnership for Personalized Medicine, has been responsible for several of the most important breakthroughs in the field over the past 40 years, most famously through his pioneering investigations of the cell cycle.

Dr. Hartwell’s discovery of the “checkpoint” genes that control cell division constituted a major leap forward, not only toward understanding the cell cycle, but also toward unlocking the mechanisms of cancer. In 2001, his achievements were recognized with the Nobel Prize in Physiology or Medicine.

The research community’s accomplishments are satisfying and impressive, Dr. Hartwell says, but “what we all want is for this knowledge to have an impact on medicine, and it hasn’t had as much of an impact as I feel it should. Our medical interventions are still pretty primitive,” he argues, “given the incredible knowledge we have about cell biology.”

Consider, for example, the case of a patient who reports a sore throat and fever to her doctor. A physician might prescribe an antibiotic—wagering on the basis of outward symptoms that the patient is more likely to have a bacterial infection than a virus, which would be unfazed by the antibiotic.

Dr. Hartwell has a different vision of how to conduct medicine.

“I’ve come to a particular point of view in terms of what the problem is: We don’t have enough things we can measure about people,” he asserts. “We depend upon vague amounts of information for diagnosing disease, but medicine should be based upon high-resolution information.”

That conviction, made firm over the course of Dr. Hartwell’s 40-year career, underlies his current work at the Hutchinson Center. It will also guide the Partnership for Personalized Medicine, unveiled in Phoenix in October 2007 by Dr. Hartwell and his colleagues on the Partnership’s executive council—Jeffrey Trent, president and scientific director of the Translational Genomics Research Institute (TGen), and George Poste, director of the Biodesign Institute at Arizona State University.

“What we really need are markers of disease that reveal a person’s dynamic, real-time state of health,” Dr. Hartwell says. “The answer to that need is proteins. They respond to the state of the organism and reflect what’s really going on.”

Thus, the Partnership for Personalized Medicine will develop, test, and validate new molecular diagnostic tools—instruments and tests that can precisely measure for particular disease-indicative proteins—and will work toward approval and distribution of these tools for widespread clinical use.

In Dr. Hartwell’s vision of the future for medicine, when a patient complains of a sore throat and a fever, his physician would be able to administer a simple blood test that would both accurately indentify the patient’s ailment and indicate what treatment regimen to follow.

From Baker’s Yeast to Proteomics

Dr. Hartwell, born in Los Angeles in 1939, was the first member of his family to go to college. After a year at a Glendale Junior College, he transferred to the California Institute of Technology, which he entered as a physics major, but where he was soon captivated by the emerging discoveries of genetics, especially in gene regulation—the genetic means by which cells control their structure and function.

He graduated in 1961 and completed a doctoral program in genetics at the Massachusetts Institute of Technology in 1964, then spent 18 months doing post-doctoral research at the Salk Institute for Biological Studies in San Diego. At the Salk Institute, Dr. Hartwell worked in the lab of virologist Renato Dulbecco (who would win the Nobel Prize a decade later) and was mentored by Marguerite Vogt, Dr. Dulbecco’s collaborator in the study of polio and cancer-causing viruses. In 1965, Dr. Hartwell took a position as an assistant professor at the University of California, Irvine, where he began his own research on the genetic basis for cell growth.

The model organism Dr. Hartwell selected for study was Saccharomyces cerevisiae, baker’s yeast. A single-celled fungus that grows relatively easily in the lab setting, it shares traits with more complex eukaryotic organisms—those whose cells contain internal structures like nuclei—and Dr. Hartwell reasoned that his research might, therefore, yield insights even about human cellular biology. Three years later, he joined the genetics faculty at the University of Washington, where he continued his research in the company of Herschel Roman, Donald Hawthorne, and other pioneers in yeast genetics.

Over the next several years, Dr. Hartwell produced a set of cell cycle mutants, examples of yeast that failed to progress normally through the process of cell growth and division; by studying these mutants’ genetic properties, Dr. Hartwell and others were able to identify many of the specific genes, also present in higher eukaryotes, that control the cell cycle. He established the concept of cell cycle “START,” when intercellular and extracellular signals trigger cell proliferation, identified the gene that controls START, and ultimately showed that eukaryotes use checkpoints at multiple junctures during the cell cycle to assess whether a cell is healthy and should continue toward division, or whether damage needs to be repaired before subsequent steps in the cell cycle occur. His recognition that cancer cells circumvent cell-cycle checkpoints provided a critical insight into cancer biology and a toehold for researchers hunting for cancer vulnerabilities.

Dr. Hartwell received the Nobel Prize in Physiology or Medicine in 2001 with R. Timothy Hunt and Paul M. Nurse, “for their discoveries of key regulators of the cell cycle.” In his Prize presentation speech, Anders Zetterberg, of the Nobel Committee at the Karolinska Intitutet, said to the three researchers, “Your fundamental discoveries have profoundly increased our understanding of how the cell cycle is controlled. This new knowledge has a huge impact on cell biology with broad applications in many fields of biology and medicine.”

By the time he won the Nobel Prize, Dr. Hartwell had already assumed leadership of the Hutchinson Center. Several years earlier, his desire to strengthen the practice of medicine had led him to shift his attention toward medical research from the kind of fundamental inquiry about cell biology and genetics that built his research career. In 1996, he joined the faculty of the Hutchinson Center, and in 1997 became its president and director.

“I took the position as a chance to immerse myself in the challenges of translating basic science into medical knowledge,” Dr. Hartwell explains.

While the Hutchinson Center includes a robust basic-science research program, its 2,300 scientists and staff also conduct clinical investigations on many kinds of cancer, as well as HIV/AIDS and several autoimmune diseases. Its public-health arm works to develop scientific, environmental, and public-policy strategies for reducing disease incidence and mortality.

Most recently, Dr. Hartwell has directed his attention to proteomics—the study of proteins’ structure and function in organisms—and molecular diagnostics. The knowledge amassed by genetics researchers, as well as advances in mass spectrometry and computing, have made extraordinarily complex analyses of an organism’s proteome—all of the proteins that an individual produces during its life—conceivable for the first time.

“Five years ago,” Dr. Hartwell says, “I began working to promote this field of proteomics. We built up our proteomics capability at the Hutchinson Center, and I also worked with the National Cancer Institute to develop a program in clinical proteomics. We started an international consortium of biomarker-discovery teams, more than a dozen teams that work on different disease sites.”

(Biomarkers are substances whose detection indicates particular biologic states, such as an antibody that indicates infection with a particular disease.)

Dr. Hartwell believed that an opportunity had arrived to advance the new field of proteomics even further, but he saw a major unmet technological requirement. “What I felt was necessary to make this push,” he says “was an industrial-style proteomics production facility. Most academic institutions don’t work at the necessary factory scale,” he explains.

“There are, though,” he says, “two places in the United States that have genome centers and already have become places that can do high-throughput research,” which employs powerful computing resources to conduct rapidly millions of biochemical and genetic tests. “One of those sites is TGen.”

Global Collaboration, with Headquarters in Arizona

The Partnership for Personalized Medicine, launched last October with a $35 million contribution from the Virginia G. Piper Charitable Trust and $10 million from the Flinn Foundation, brings together resources from the Hutchinson Center, TGen, and the Biodesign Institute to develop personal molecular diagnostics.

The Virginia G. Piper Center for Personalized Diagnostics (PCPD) is the Partnership’s discovery and development engine. Drawing on TGen and Biodesign expertise, the PCPD will include state-of-the-art proteomics laboratory facilities that enable protein biomarker discovery and validation.

The Flinn Fund for Arizona Proteomics Research will promote collaborative proteomics research among top scientists around the state, support proteomics-capacity development and the collection and storage of biospecimens for research, and drive the Partnership’s Arizona-based demonstration projects.

“What makes Arizona such an appealing place to do this is its entrepreneurial spirit,” Dr. Hartwell says, “as well as the desire people have to do translational medicine” that delivers basic science directly into clinical settings. “It’s characteristic of what’s going on at Biodesign,” he notes, “which is why they’re a partner in this. It’s also going on at the University of Arizona and at its medical school and pharmacology department.”

The demonstration projects it conducts, Dr. Hartwell explains, will allow the Partnership to prove the value of its proteomics study not just to the research and medical communities, but also to pharmaceutical and insurance industries, as well as regulatory agencies and legislative bodies around the world.

“A problem we face,” under the current healthcare system, he continues, “is that even if we discovered diagnostics tomorrow, they wouldn’t get into patient care. What drives healthcare now is expensive therapeutics and an emphasis on late-stage diseases.”

The U.S. healthcare system’s regulatory and financial structure is not designed to support the development and validation of diagnostics, despite the long-term cost savings they would yield by keeping more people in better health.

Consequently, some of the Partnership’s first demonstration projects will involve collaborations with healthcare systems in other nations. The Hutchinson Center has been a key participant in the annual Pacific Health Summit, which brings together 300 world leaders from business, healthcare, and government who are concerned about science and health.

“The Pacific Health Summit has been our forum to develop partnerships,” Dr. Hartwell says. “I rolled out this model last year at the meeting, and already we’ve met with minister-level people from one European nation, and more are to come.”

Countries with single-payer healthcare systems, Dr. Hartwell believes, will have great incentive to support research that can reduce costs, since those costs are borne by the government. Collaborating nations will both underwrite some of the costs of the demonstration projects and secure the information Partnership researchers will require.

“What is really important is that we have a committed partnership,” he says. “People need to have skin in the game to be committed. We’re asking the [national] payer to participate in the research and to use their influence to bring together researchers and to collect patient information and outcomes.”

The outcome of the Partnership itself, Dr. Hartwell predicts, will be fundamentally better—and less costly—healthcare. “That’s the real incentive,” he says. “In any country, it’s a multi-billion industry, and there’s a huge incentive to contain this avalanche [of healthcare cost increases] that’s occurring.”