Next in the Sequence
“One thing we have to do is prove to the scientific community and to funding agencies that studying disease on a gene-by-gene basis is good activity—that if you have some gene candidates for particular diseases it makes sense to get patient samples together, to start resequencing and look for mutations.”
RICHARD K. WILSON, PHD
NEW ERA OF MEDICINE IS UNDER WAY.
The Human Genome Project, completed 50 years after the discovery of DNA, is arguably one of mankind’s greatest achievements, and scientists at the School of Medicine were at the project’s forefront. Today, those researchers, in conjunction with physician-scientists from many departments across the university, are leading the way toward reaping the potential of this powerful genetic database.
Already, the genome sequencing effort has helped to spur discoveries about breast, colon and prostate cancers, cystic fibrosis, Huntington’s disease and Parkinson’s disease. And while mapping the complete genomes of organisms remains the focus of the Genome Sequencing Center, it is the next step—the application of the genetic code—that holds the potential to change medicine. Using the map of the human genome, physician-scientists can “finger” the genes that cause disease. Now, the detective work that may someday change, and even save, lives begins.
The Genome Sequencing Center (GSC) at Washington University in St. Louis, one of the three largest such centers in the world, remains a gene-sequencing powerhouse. It specializes in large-scale, high-throughput genome sequencing, with 155 state-of-the-art sequencing machines churning out up to 1.2 billion bases, the building blocks of DNA, each month.
Current GSC projects include sequencing the genomes of the chimpanzee, the chicken and the mouse. Data from these projects—like that from the Human Genome Project—are added to public databases; information gathered is made immediately and freely available to the international scientific community via the Internet to facilitate developments in genetic research.
The challenge that remains in de novo sequencing lies mainly in improving the process, says Wilson, who works routinely with GSC colleagues to improve processing technology and software and to better manage data. Today, it is the application of the information gleaned from sequencing that holds exciting future promise. This new field of study—called applied or functional genomics—has given the Genome Sequencing Center’s leadership an opportunity to redefine its mission and its goals.
Working with colleagues across the university, investigators at the GSC are applying genomics to better understand illnesses ranging from neonatal lung disease to cancer. The genome encyclopedia that sequencing the human genome provides allows researchers to “look up” genes of interest and study them in detail. “The human genome sequence provides a place for researchers to begin if they are interested in correlating specific genes to specific disease,” says Wilson.
The infrastructure—the machines and people of the GSC that can manage the volume of data applied genomics will require—is in place and, according to Wilson, will grow even better and faster in the future. How much or how fast the new field of applied genomics will expand is less easy to predict.
“One thing we have to do is prove to the scientific community and to funding agencies that studying disease on a gene-by-gene basis is good activity—that if you have some gene candidates for particular diseases it makes sense to get patient samples together, to start resequencing and look for mutations,” says Wilson.
The GSC already is working with a handful of investigators Wilson labels as “visionary” in their attempts to incorporate genomics into their research. His goal for the GSC is to connect with as many like-minded School of Medicine physician-scientists as possible.
One such researcher is Timothy J. Ley, MD, the Alan A. and Edith L. Wolff Professor in Medicine and professor of genetics, who is leading a study designed to identify genetic changes associated with adult acute myeloid leukemia (AML). Ley began assembling a team more than two years ago to study specific genes found in patients with AML, with the ultimate goal of looking at every gene in the map to find all those involved in causing leukemia.
Ley, who also is associate director of basic research at the Alvin J. Siteman Cancer Center, along with colleagues Wilson and GSC co-director Elaine Mardis, PhD, from the Genome Sequencing Center, and John F. DiPersio, MD, PhD, Daniel C. Link, MD, Michael Tomasson, MD, Timothy A. Graubert, MD, Howard L. McLeod, PharmD, Hanna J. Khoury, MD, Kathryn M. Trinkaus, PhD, Mark A. Watson, MD, PhD, William D. Shannon, PhD, and Jeffrey D. Milbrandt, MD, PhD, all from the Siteman Cancer Center, designed an initial study that examined a dozen genes in 47 AML patients. Data generated in that pilot study showed interesting sequence changes—possible mutations—that warranted further research. On the basis of that work, Ley, Wilson and colleagues recently received a four-year, $11 million program project grant from the National Cancer Institute that will allow the research team to scale up, eventually looking at thousands of genes from 140 AML patients.
According to Ley, functional genomics research is not so much a collaboration between researchers as it is a joint agreement among many people who share the same powerful vision. “It doesn’t just take a sequencing center to do this research, it takes a group of people who understand the disease they are studying and the nuances of treatment,” Ley says. “We have the critical mass at Washington University to launch these projects.”
That “mass” includes the expertise of the GSC, physician-scientists, human and experimental geneticists, computational biologists, pathologists, cell biologists, mouse modelers, clinical data managers and statisticians. “It takes a mix of people to do a project correctly—it can’t be done in one lab,” says Ley. “We all pull together to solve problems.”
The potential benefits of such collaboration are enormous.
“Getting to the genetic roots of disease one patient at a time will
rewrite how we deal with disease,” says Ley. “Even thinking
about getting at the molecular roots of disease will change our understanding
and approach to individual therapy and give us new drug targets. It’s
revolutionary and will affect how we ultimately treat patients.”
Jeffrey D. Milbrandt, MD, PhD, professor of pathology and immunology and of medicine, and a multidisciplinary team of researchers have received funding from the CapCURE Foundation to survey all of the kinase genes for mutations in prostate tumors from nearly 100 patients.
The first study of its kind, Milbrandt believes it will identify new drug targets in prostate cancer cells and thereby speed development of innovative treatments for the disease. The work also may identify patterns of mutations that could improve diagnosis and help doctors predict the course of the disease and the best therapy for individual patients. “The Human Genome Project has made studies like this possible; having the Genome Sequencing Center on campus enables us to do our work here and now,” says Milbrandt, who also directs the Bioinformatics Core at the Siteman Cancer Center.
Jeffrey I. Gordon, MD, the Dr. Robert J. Glaser Distinguished University Professor and head of molecular biology and pharmacology, agrees. His study underway with the GSC examines the stem cells that fuel the renewal of the stomach and intestinal lining throughout life. The study will provide a molecular description of these gastrointestinal stem cells and determine how they compare with other stem cells in the body. That information, Gordon says, should provide new insights that will help doctors diagnose and treat many gastrointestinal diseases.
Other investigators utilizing the GSC’s capabilities include F. Sessions Cole, MD, who is studying a gene for a lung protein that is essential for breathing at birth, and Scott J. Hultgren, PhD, who has a five-year Specialized Centers of Research (SCOR) grant to detail bacterial-host interactions during urinary tract infections.
Looking to the future, two key initiatives will alter the
way the GSC does business, by bringing physician-scientists together and
by securing funding earmarked for applied genomics research.
“We have always thought it important to be surrounded by more people who are actually doing genomics and who are using the information and technology in an applied way,” says Wilson. “By having these researchers in close proximity to the technology, the data and the people generating it will create a real synergy.”
And, because preliminary research results are critical in the competition for federal research dollars, Wilson and his GSC colleagues hope to secure funding for that purpose, as well as to put in place a review group for preliminary research applications.
“The School of Medicine is uniquely positioned to participate in the transformation of medicine that is occurring with the application of genomic sciences to the solution of clinical problems,” says Larry J. Shapiro, MD, dean and executive vice chancellor for medical affairs. “The Genome Sequencing Center is an exceptional resource; in addition, the focus on collaborative efforts between basic scientists and clinicians insures that we will be leaders in this exciting new area.”
How will the new field of applied genomics affect the health and life of the average person? Most likely, genetic data will lead to a precise personalization of individual health care. Today’s scientists are just beginning to explore where such knowledge may lead.
While beneficial, some people may find the prospect of such detailed genetic analysis unsettling. “Any technology that we humans inflict on ourselves carries its risks along with its benefits,” says Wilson. “This is one technology where, applied the right way, the benefits far outweigh the risks.”