Vol. 33, No. 1     Winter 2010
Download the PDF

Genomic Medicine at the
University of Washington

Megan Jensen shows genetic counselor Robin Bennett her new engagement ring.

Before an appointment at the Seattle Cancer Care Alliance in December, Megan Jensen shows genetic counselor Robin Bennett her new engagement ring. When Jensen found a lump in her breast last summer, Bennett provided invaluable advice about getting a genetic test. “We discussed the BRCA1 mutation, what it means if you have it, what preventative options are available, the likelihood of developing cancer with the mutation,” says Jensen. “I decided to have the test done in the first meeting.”

No one would envy Megan Jensen her family history. Jensen’s father carries a BRCA1 gene mutation that significantly increases the risk for breast cancer, and her paternal grandmother and many other family members died of cancer. When Jensen found a lump in her breast last August, she was more than a little rattled. Thankfully, it wasn’t cancer. But after hearing about Jensen’s father, her doctor recommended she visit the University of Washington’s Genetic Medicine Clinic.

There, Jensen met Robin Bennett, the clinic’s senior genetic counselor and co-director, and Jensen took the test for the BRCA1 mutation. Unfortunately, Jensen, like her father, carries the mutated gene. “I knew I had a 50-50 chance of having the mutation since my dad was positive,” she says. But she’s not frightened. “By knowing I have it, I can be proactive and take the necessary precautions,” Jensen says.

Jensen is one of approximately 1,600 people who visit the Genetic Medicine Clinic each year for genetic testing, advice and reassurance. And with advances in genomic sciences at UW Medicine and other institutions, that number is likely to grow by leaps and bounds.

UW Medicine: all about the genome

Jensen’s experience is an example of the power of medicine in translation: where discoveries made in the laboratory translate into direct benefits for patients, such as a test for a disease, a new medication or a cure. (The initial mapping of BRCA1, for instance, was carried out by UW Medicine faculty member Mary-Claire King, professor of medicine.)

Like any other successful enterprise, translational genomic medicine requires expertise and leadership. It also requires investment. Over the past two years, UW Medicine faculty in genome sciences, medical genetics and pediatric genetic medicine received six grants that helped advance their fields.

“I knew I had a 50-50 chance of having the mutation since my dad was positive. By knowing I have it, I can be proactive and take the necessary precautions."

– Megan Jensen

One grant, called SeattleSeq, was made by the National Institutes of Health to support exome analysis: looking at the parts of the human genome that contain the code to create proteins. Proteins are the workhorses of living organisms, responsible for many functions in the body, including structure, communication, protection and more.

Although the exome only makes up about 1 percent of the genome, explains Jay Shendure, assistant professor of genome sciences, focusing solely on exome analysis poses a challenge. “It is technically hard because the protein-coding portion is not all in one place, but scattered all over the place in hundreds of thousands of very short segments,” he says. With exome sequencing, however, scientists now have a tool that is much less expensive and more efficient than sequencing the entire human genome.

A second instrumental grant was made by the Washington State Life Sciences Discovery Fund. This grant created the Northwest Institute of Genetic Medicine, which supports faculty working on projects or grant proposals that involve translational medicine.

“There are so many challenges to translational research, and each of us brings some expertise to the table: sample collection, informatics, analysis or technology,” says Gail P. Jarvik, Fel. ’91, professor and head of the Division of Medical Genetics. The need to combine these elements can make projects and proposals quite complicated. Over the past year, the institute has helped to put these pieces together for researchers — including a senior fellow investigating the genetic basis of a rare and lethal surgical complication and a kidney researcher developing a new research area. “We feel like our work cuts across a lot of different places at UW Medicine,” she says.

genomic sequencer/equipment photogenomic sequencer/equipment photogenomic sequencer/equipment photo

With the help of federal and state grants, Professor of Genome Sciences Debbie Nickerson is helping develop a new genomics center, complete with new genomic sequencers, pictured at left. The work supported by the grants will have far-reaching effects on medicine as well as on the local economy. “A number of businesses have laid off really talented technologists, and we hired some of them,” says Nickerson. “We also hired some new young people, and they now think they have the coolest job on the planet. They’re working on a cutting-edge science project that they never would’ve thought possible in this kind of economy.”

The big grant and human variation

These two grants laid the groundwork for investment from four additional awards. In October 2009, UW Medicine received a large-scale DNA sequencing project award from the National Heart, Lung, and Blood Institute (NHLBI), made under the auspices of the American Recovery and Reinvestment Act (ARRA) of 2009.

The lion’s share, $25 million, has been used to launch the Northwest Genomics Center at UW Medicine. An additional $2 million grant from the state’s Life Sciences Discovery Fund is supporting the new center’s infrastructure. Deborah A. Nickerson, professor of genome sciences and one of the center’s principal investigators, says the grant recognizes UW Medicine’s expertise in genomics. “We’ve been working in the area of medical sequencing for quite some time, particularly in cardiovascular disease,” says Nickerson.

The lion’s share, $25 million, has been used to launch the Northwest Genomics Center at UW Medicine. An additional $2 million grant from the state’s Life Sciences Discovery Fund is supporting the new center’s infrastructure. Deborah A. Nickerson, professor of genome sciences and one of the center’s principal investigators, says the grant recognizes UW Medicine’s expertise in genomics. “We’ve been working in the area of medical sequencing for quite some time, particularly in cardiovascular disease,” says Nickerson.

Cardiovascular disease is the leading cause of death worldwide, claiming 17.1 million lives each year. But the genetic variations that predispose people to heart disease are largely unknown, says Nickerson, despite genomic mapping studies. “[Such studies] don’t typically explain more than a few percent of the risks for heart disease,” she says. “So, common DNA variations in the population may not be responsible for the underlying disease.” That’s why Nickerson, Shendure and the study’s other principal investigators, Philip P. Green III, professor of genome sciences, and Mark J. Rieder, research associate professor in genome sciences, will use the grant to look at a different set of people: those on the extremes of the heart-disease spectrum.

“We’ll be looking at the genetic underpinnings of early-onset heart attacks, people who have very low and very high levels of cholesterol and blood pressure,” says Nickerson. “Many of these traits may give us insights into how to treat these diseases and develop new drug targets, in addition to new understandings of why people have heart attacks or strokes.”

In addition to cardiovascular diseases, the center also will explore the genetics of lung disease through a newly funded grant to Michael J. Bamshad, professor of pediatrics in the Division of Genetic Medicine. Bamshad received $5.2 million from the NHLBI’s ARRA grant to study lung diseases by exome sequencing. With it, he and his colleagues will identify and investigate genetic variants that influence cystic fibrosis, asthma, pulmonary hypertension and chronic obstructive pulmonary disease — in an effort to determine why people who contract the same diseases have very different outcomes.

The power of exome sequencing

The work being done by Shendure, Nickerson and Bamshad throws the importance of exome sequencing into sharp relief.

For 30 years, says Shendure, scientists used electrophoretic sequencing, the technology that powered the Human Genome Project. “In the wake of the project,” says Shendure, “we realized that everything had already been optimized.” He and his colleagues then developed a process that allowed the sequencing of millions of templates in parallel. With this technology, the cost of sequencing a human genome drops dramatically. When the new technology is combined with the focus provided by exome sequencing, the cost falls again. And fewer patients need to be screened— a definite benefit if you’re investigating a rare disorder.

“It’s that variation in outcome that is so important — why do some of these kids fly and some of them sink? — we need to understand that. We’d like to help all of them to fly.”

– Gail Jarvik

Using the exome improves the speed of sequencing as well as the cost. “It took us literally 10 years to identify the Freeman-Sheldon syndrome gene using conventional strategies,” says Bamshad. (Freeman-Sheldon is a rare genetic condition which involves problems with joints, among other symptoms. “[With exome sequencing], we demonstrated that we could do it with just a small number of individuals in months instead of years.”

Shendure, Bamshad, Nickerson and Wendy H. Raskind, M.D. ’78, Res. ’81, Fel. ’83, professor of medicine, also received an ARRA grant from the National Human Genome Research Institute to use exome sequencing to scale up the discovery of the genetic bases of rare diseases such as Freeman-Sheldon.

“This effort between genome sciences and medical genetics is bringing our efforts full circle,” says Jarvik. Exome technology will identify mutations that cause rare lipid disorders, she says. It also will be part of investigations into the genetic underpinnings that sometimes lead to intellectual impairments in children born with severe congenital heart defects.

“It’s that variation in outcome that is so important — why do some of these kids fly and some of them sink? — we need to understand that,” says Jarvik. “We’d like to help all of them to fly.”

Technology changes everything

In conducting genetics research, Bamshad, Nickerson and their colleagues have come to rely on bioethicist Holly Tabor, assistant professor of pediatrics and researcher at Seattle Children’s. Ethical issues abound at the intersection of patient care and genetic studies. One hot topic, says Tabor, is reporting on research results. Most studies don’t return information about results to participants — it’s not part of the traditional arrangement. Still, this is becoming more of an issue as sequencing technology has become better and cheaper.

“As a result, you’re able to get more information about the DNA sequence of an individual than you would have done in regular practice,” Tabor says. “You can imagine that there might be some scenarios where you might think a research result was important [to a patient].”

A close-up image of DNA molecules being scanned to determine the sequence of an exome.

Photo courtesy of the Department of Genome Sciences

A close-up image of DNA molecules being scanned to determine the sequence of an exome. Assistant Professor Jay Shendure, a faculty member in UW Medicine’s Department of Genome Sciences, is one of the pioneers of next- generation sequencing technology.

Informing study participants, though, isn’t a straightforward process. Studies are so different that no standard set of rules applies, says Tabor. Then there’s the human factor: what information will participants want? And will that information be useful or simply stressful?

Robin Bennett, who has been a genetic counselor at UW Medicine for 25 years, assesses similar issues in her job. “The future of genetic medicine is exciting, but it needs to be approached cautiously,” says Bennett. “Just because the test exists doesn’t mean that everyone should take it.” Tests are often expensive, she says, and when patients do take them, there’s a good chance that they’ll learn about a genetic variant that may not even be significant. Such results can provoke unnecessary anxiety, Bennett says. At the same time, genetic testing can allow patients like Megan Jensen to take control of their health care. And for some patients, a genetic test provides peace of mind.

Bennett remembers a patient whose mother died of breast cancer. “She was convinced she was going to need a mastectomy some day,” Bennett says. After being persuaded to take a genetic test, the patient found she did not possess the risk factors for breast cancer.

“She was able to go on with her life,” says Bennett.

Personalized medicine: low-hanging fruit, high aspirations

Gail Jarvik has a number of expectations for patients, genetics and health care in the years ahead.

“The low-hanging fruit for personalized medicine is medication,” says Jarvik. If a patient genome could be sequenced to identify adverse side effects from drugs, she says, “that would be enormously helpful to the patient and also cost-saving to medical care. I believe that we will be doing that within 10 years.”

“If we could find the genes with the variants that create that protection, we could develop a new drug to target those genes in the way we target bad cholesterol with statins.”

– Debbie Nickerson

For her part, Debbie Nickerson hopes that these new grants will allow her to take a look at a novel part of the disease process: disease resistance.

“I think that we often look at what leads to disease, but many people — who have the same environmental exposure — don’t get disease,” Nickerson says. For instance, people who have very high levels of “good” cholesterol are practically resistant to heart disease, and scientists don’t understand why.

“If we could find the genes with the variants that create that protection, we could develop a new drug to target those genes in the way we target bad cholesterol with statins,” Nickerson says. And in making medical advances, Nickerson wants to demonstrate what large-scale medical investments mean to human health.

“I think every scientist funded under ARRA wants to make a big impact,” Nickerson says. “Billions of dollars are being spent, and we want to show that this could really make a difference in our health care and in our understanding of human biology.”

Table of Contents|Past Issues

Features

Special This Issue

Report to Donors 2008–2009
Your contributions to our mission

Legacy Gifts ad
Help us go green

Help us go green
Update your email address

Send a ClassNote

Send a ClassNote
Send an update

Write the editor

Write the editor
Tell us what you think

Mission ad