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CONTENTS SAN FRANCISCO MEDICINE September 2008 Volume 81, Number 7 The Mystery of DNA FEATURE ARTICLES
MONTHLY COLUMNS
10 Science and the Mysteries of DNA Mike Denney, MD, PhD
4 On Your Behalf 5 Upcoming SFMS Events
12 Epigenetics Victoria Lunyak, PhD 14 The Genetics of Mental Disorders Steven P. Hamilton, MD, PhD 16 Genetics and Drug Response Jaekyu Shin, MS, PharmD; and Robert L. Naussbaum, MD 18 Understanding a Patient’s Genes Kati Malabed, MS, CGC 20 Cancer in the Family Kathleen McCowin, JD, MS; and Marcia McCowin, MD
7 President’s Message Steven Fugaro, MD 9 Editorial Mike Denney, MD, PhD 28 Hospital News 30 Classified Ads 30 In Memoriam
22 Coming of Age Patricia Kelly, PhD 24 Unlocking the Genetic Mystery Eisha Zaid 26 Darwin and Literature Steve Heilig, MPH 27 Breast Cancer Risk: An Expert Speaks Erica Goode, MD, MPH
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and software bring evaluation and measurement tools to the Physician to use in the clinical setting. we also have a full time physician on staff.
Mon - Saturday 8-5 + Editorial and Advertising Offices 1003 A O’Reilly Ave, San Francisco, CA 94129 Phone: 415.561.0850 ext.261 Fax: 415.561.0833 Email: adenz@sfms.org Web: www.sfms.org Subscriptions: $45 per year; $5 per issue Advertising information is available on our website, www.sfms.org, or can be sent upon request. Printing: Sundance Press P.O. Box 26605 Tuscon, AZ 85726-6605
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September 2008 San Francisco Medicine The width is 3.5 by 4” high CALL Kae with any questions or concerns 415-567-5888
ON YOUR BEHALF
September 2008 Volume 81, Number 7
A sampling of activities and actions of interest to SFMS members Editor Mike Denney Managing Editor Amanda Denz Copy Editor Mary VanClay Cover Artist Amanda Denz Editorial Board Chairman Mike Denney Obituarist Nancy Thomson Stephen Askin
Shieva Khayam-Bashi
Toni Brayer
Arthur Lyons
Linda Hawes Clever
Terri Pickering
Gordon Fung
Ricki Pollycove
Erica Goode
Kathleen Unger
Gretchen Gooding
Stephen Walsh
SFMS Officers President Steven H. Fugaro President-Elect Charles J. Wibbelsman Secretary Gary L. Chan Treasurer Michael Rokeach
AMA Helps Defeat Medicare Payment Reduction Despite a presidential veto, H.R. 6331, the “Medicare Improvements for Patients and Providers Act of 2008,” passed with wide, bipartisan majorities in both the U.S. House of Representatives and the U.S. Senate. The AMA and many other medical groups pushed very hard for defeat of the proposed reimbursement cuts. This legislation replaces the 10.6% payment cut that went into effect on July 1 with a 0.5% update extension through December 31, 2008. For calendar year 2009, the update will be 1.1%. Other important provisions such as extending the GPCI floor on physician work were also included. This 18-month reprieve will also provide time for Congress to work with physicians on developing a long-term solution to a payment system that all agree is fatally flawed.
Editor Mike Denney Immediate Past President Stephen E. Follansbee
Judge Blocks State’s Cut in MediCal Fees
SFMS Executive Staff
A federal judge has blocked California’s 10 percent cut in Medi-Cal fees for doctors, dentists, and pharmacies, saying the moneysaving measures appear to violate federal law and would worsen medical care for millions of poor people. In her ruling, U.S. District Judge Christina Snyder of Los Angeles said she was aware of California’s gaping deficit, but said the state has accepted federal funds for Medi-Cal and is bound to use them to provide quality health care to low-income residents. Medical groups such as the CMA presented evidence that many physicians had previously stopped treating Medi-Cal patients because of the state’s low reimbursement rates, and many more would refuse to accept new Medi-Cal patients because of the 10 percent cuts. This injunction halts the 10 percent fee reductions for doctors, dentists, pharmacies, adult day health centers, and clinics receiving Medi-Cal funds. State officials are planning to appeal the decision.
Executive Director Mary Lou Licwinko Director of Public Health & Education Steve Heilig Director of Administration Posi Lyon Director of Membership Therese Porter Director of Communications Amanda Denz Board of Directors Term: Jan 2008-Dec 2010
Jordan Shlain
George A. Fouras
Lily M. Tan
Keith Loring
Shannon Udovic-
William Miller
Constant
Jeffrey Newman
Term:
Thomas J. Peitz
Jan 2006-Dec 2008
Daniel M. Raybin
Mei-Ling E. Fong
Michael H. Siu
Thomas H. Lee
Term:
Carolyn D. Mar
Jan 2007-Dec 2009
Rodman S. Rogers
Brian T. Andrews
John B. Sikorski
Lucy S. Crain
Peter W. Sullivan
Jane M. Hightower
John I. Umekubo
Donald C. Kitt
Candidates’ Night
CMA Trustee Robert J. Margolin
You are cordially invited to participate in a San Francisco Board of Supervisors Candidates’ Interview Night on Wednesday, September 24, 2008, starting at 5:15 p.m. at the SFMS offices at
AMA Representatives H. Hugh Vincent, Delegate Robert J. Margolin, Alternate Delegate
San Francisco Medicine September 2008
1003A O’Reilly Avenue in the Presidio. RSVP required. As many of you know, this is a great way to get to know the candidates early on in their political careers. The format for this event will be a series of informal interviews with each of the invited candidates. Candidates will be interviewed by small groups of physicians. We have prepared a list of interview questions which will be sent in advance to the candidates. If you are interested in attending, please RSVP to Posi Lyon by phone at (415) 561-0850 extension 260 or by e-mail at pylon@sfms.org no later than September 18. Make sure to include your phone number and e-mail address so we can provide you with directions to the event.
Membership Updates The 2008–2009 Membership Directory has been mailed to all active members. If you have not received this important member resource, or if you are interested in obtaining extra copies, contact the Membership Department. The entire membership should have received the SFMS annual database update forms in August. If you have any changes, updates, or corrections to your information of record, please be sure to respond to the mailing at your earliest convenience if you have not already done so. Have you paid your dues online yet? Starting with the 2009 billing, members are able to pay their dues by visiting the SFMS website. Details on this new and convenient way to renew your membership will be provided on the 2009 dues statements throughout the renewal period.
An Opportunity to Reach out to the Next Generation of Medicine On Thursday, September 25, members of the San Francisco Medical Society are invited to a pizza party mixer with first- and second-year medical students at the UCSF campus. Check the website or contact the Membership Department for the exact time and location. This event will be sponsored by Epocrates and will be a wonderful chance to meet and talk with the next generation of doctors, who are equally eager to meet those already established in the profession. Don’t miss it! For more information, or to RSVP, www.sfms.org
contact Therese Porter at (415) 561-0850 extension 268 or tporter@sfms.org.
September 27, 2008 CMA Foundation’s Obesity Prevention Cultural Competency Training Symposium 9:00 a.m. to 12:00 p.m. at the Airport Hilton in Oakland, California This training will provide physicians and health care providers with comprehensive tools, resources, and tips to provide culturally competent obesity prevention education and services for their patients. If you would like more information about the project, please visit www.calmedfoundation.org/projects/obesityProject.aspx. or contact Jennifer Caulfield, Obesity Prevention Project Assistant, at (916) 779-6631 or by e-mail at jcaulfield@thecmafoundation.org.
California Debates Direct to Consumer Genetic Testing
Whether or not individuals should have access to their genetic information is Advance registration is required for all a topic currently up for debate in CaliforSFMS seminars. Please contact Posi Lyon at nia. In June laboratory testing regulators plyon@sfms.org or (415) 561-0850 extenin the state sent thirteen companies that sion 260 for more information. All seminars offer genetic testing directly to consumers take place at the SFMS offices, located in the “cease and desist” letters. In late August, Presidio in San Francisco. however, the tides turned when Navigenics and Google backed 23andMe were granted licenses to do business in the state. October 3, 2008 Customer Service/Front Office Telephone The cease and desist letters said that Techniques companies could not solicit customers from This half-day practice management seminar will California without receiving a license from provide valuable staff training to handle phone the state to operate as a laboratory and calls and scheduling professionally and efficiently. October 2–3, 2008 that doctors had to be involved in ordering 9:00 a.m. to 12:00 p.m. (8:40 a.m. registration/ California Primary Care Association Annual genetic tests. continental breakfast) Conference According to an article in the New $120 for SFMS/CMA members and their staff DoubleTree Hotel Ontario Airport, Ontario York Times, the companies argued that they ($99 each for additional attendees from the same Contact Carole Loeb at (916) 440-8170 exten- were not offering medical testing but rather office); $159 each for nonmembers sion 206 or cloeb@cpca.org, or visit www.cpca. personal genetic information services, and org for more information. that consumers had a right to information November 4, 2008 from their own DNA. The companies also October 4, 2008 “MBA” for Physicians and Office Managers said they did not need a license because 9:00 a.m. to 5:00 p.m. (8:40 a.m. registration/ Headache Cooperative of the Pacific Fall the actual testing of the DNA samples was continental breakfast) Colloquium being done by outside laboratories that did This one-day seminar is designed to pro- Mission Bay Conference Center at UCSF have licenses. vide critical business skills in the areas of fi- 1675 Owens St., San Francisco “I think we’re very satisfied that they nance, operations, and personnel management. This conference will highlight very recent have met the California requirements for $250 for SFMS/CMA members and their staff advances in headache medicine in an intimate, licensure,” Kathleen J. Billingsley, a senior ($225 each for additional attendees from same casual, and creative setting where health care official in the California public health deprofessionals can expand their collective knowl- partment, told the New York Times. office); $325 for nonmembers edge bases by sharing experiences, observations, Four of the other companies targeted and ideas. For more information, please visit by the state have agreed to stop selling tests Other Local Events www.hcop.com or e-mail Don Primack at dpri- in the state, while the rest, including the September 25, 2008 mack@aol.com. genomic testing company DeCode GenetIn the Heart of the Mission Gala ics, remain in limbo. Cathedral of Saint Mary of the Assumption, 11 October 23, 2008 For the full story, see the New York Times Gough St., San Francisco Hope for the Uninsured: Operation Access 15 website, www.nytimes.com/2008/08/20/ Celebrate the fortieth anniversary of the Mission Year Anniversary and Volunteer Celebration business/20gene.html.
SFMS Seminar Schedule
Neighborhood Health Center with champagne, sangria, and a Latino food festival. This fundraiser will honor Dolores Huerta, cofounder of United Farmworkers, and Antonia Sacchetti, MD, retiring medical director of thirty-eight years. Please call (415) 552-3870 for more information, to buy tickets, or to reserve a table for ten.
www.sfms.org
For medical professionals who volunteer with Operation Access (OA), a San Francisco-based nonprofit that provides donated outpatient surgical and specialty care to uninsured, low-income Bay Area residents. Drinks, dinner and a program with keynote speakers and OA surgeon co-founders Drs. Doug Grey and William Schecter. At the San Francisco presidio between 6 – 8 pm. Invitation only. For more information please contact communications@operationaccess.org
For Local Events of Interest Please Visit Our Website, www.sfms.org.
September 2008 San Francisco Medicine
The Best Care -The Best Career Veterans Affairs Medical Center San Francisco
PRIMARY CARE PHYSICIAN/BOARD CERTIFIED INTERNIST The Department of Veterans Affairs is searching for a Primary Care Physician/Board Certified Internist for the Ukiah VA Outpatient Clinic located 100 miles north of SF on Hwy 101. The clinic serves Mendocino and Lake Counties where affordable living meets outstanding recreation with easy access to the spectacular coastline. Responsibilities include: building a manageable panel size across the adult age continuum; some administrative duties, and no call. Great supportive staff and potential for growth await the enthusiastic, self starter who values team spirit and cooperation. Full time position available. Interested candidates please contact Linda Mulligan, MD at (707) 468-7704 and send a CV c/o Ken Browne, Ukiah Outpatient Clinic, 630 Kings Court, Ukiah, CA 95482. Fax (707) 468-7733. US Citizenship required. Selected applicant is subject to random drug testing. Equal Opportunity Employer.
Welcome New Members! The San Francisco Medical Society would like to welcome the following new members:
Pamela Chan, MD, Permanente Medical Group Louise Greenspan , MD, Permanente Medical Group, Referred by Charles Wibbelsman, MD Josephine (Josie) Howard , MD, Referred by Ricki Pollycove, MD Gary Huang , MD, Permanente Medical Group Wen Jing , MD, Permanente Medical Group, Referred by Sid Boriak, MD Kristine Lee , MD, Permanente Medical Group, Referred by Charles Wibbelsman, MD Carolyn Y. Li , MD, Permanente Medical Group, Referred by Wen Jin, MD STUDENTS (UCSF) Nancy Hsu, Mara E, Horwitz, and Lacey R. Whitmire
president’s Message Steven Fugaro, MD
Discovering DNA
T
his issue of San Francisco Medicine focuses on the most dramatic story in biology of the last sixty years—the discovery of DNA and the rapid progress made over the past decades in understanding the complex interaction of our genome and disease. When I was a college student in the 1970s, the breakthrough by Watson and Crick in identifying the structure of DNA was barely twenty years old. Research on recombinant DNA and biotechnology was just beginning. Since then, enormous strides have been made in understanding the exact structure and function of DNA in our genome. Indeed, the completion of the sequence of the human genome has been the start of the genomics “revolution,” with promises of numerous direct applications to patient care. One of the most powerful technologies in this field is the DNA microarray. DNA probes have been miniaturized to allow thousands of specific DNA or RNA sequences to be detected simultaneously on a small slide just one or two centimeters square. These DNA microarrays offer unprecedented opportunities for analyzing gene expression and understanding gene function. There are several major applications of microarrays, one of which is gene expression profiling. The ability to detect the expression level of thousands of genes allows exploration of gene function on a scale previously impossible. In clinical practice, more precise diagnosis and risk assessment based on expression profiles are very promising. Already there is the microarray technology to reclassify patients with diffuse large B cell lymphoma as being in prognostic subgroups with fiveyear survivals ranging from 40 to 80 percent. An equally exciting clinical application is genotyping, in which mutations and polymorphisms can be detected that underlie susceptibility to a range of common diseases. This “genetic fingerprint,” obtained via DNA microarrays, will hopefully enable clinicians to assess the risk of patients of developing single gene disorders or more common complex diseases such as diabetes, hypertension, and coronary artery disease. One application of genotyping has already been approved by the FDA for general clinical use. Vitamin K epoxide reductase (VKORC1) is the therapeutic target of warfarin. Those patients with two copies of the variant allele for VKORC1 reach a therapeutic level of anticoagulation twice as quickly (seven days versus fifteen days) compared to those patients with two copies of the nonvariant allele. This finding confirms the importance of genetic variation in www.sfms.org
influencing drug metabolism and is an example of the burgeoning field of pharmacogenomics. Another finding, using genotyping technology, has some very interesting connections with the Middle Ages. In the late 1990s, Samson identified the cc-chemokine receptor-5 protein (CCR5), a transmembrane G protein receptor that mediates the internalization of HIV in macrophages and monocytes. Studies of individuals who have been multiply exposed to HIV and yet remain disease-free led to the identification of a gene mutation. the CCR5D32 allele with multiple base pair deletion. This shortened protein is consequently not integrated into the cell membrane. The homozygous state of the CCR5D32 allele is associated with a high degree of protection against HIV infection. The CCR5D32 allele is common in Europe, with a frequency of 10 to 20 percent in Caucasians. There is evidence that this mutation first arose more than 3,000 years ago, but how did it become so prevalent across Europe in an age before the HIV epidemic? Could this allele also have boosted resistance to an earlier epidemic, such as smallpox or the bubonic plague? Answers to these questions, using medieval DNA, may come from one of the most ambitious archeological projects in the Netherlands. Since 2002, anthropologists and archeologists have been working on a massive excavation of a 600-year-old cemetery in Eindhoven at St. Catherine’s Church. The team has unearthed the skeletons of more than 750 residents from the Middle Ages with the express purpose of obtaining their DNA and creating a medieval Eindhoven DNA bank. Studies of this ancient DNA will be used to answer questions about the CCR5D32 allele and its putative role in enabling resistance to the Black Death. By studying genetic variations over time, researchers hope to advance knowledge of the genetic factors that increase the risk of disease or that boost immunity to infection. Obviously, it is intriguing to look both backward and forward as we begin to reap the benefits of unraveling the mysteries of DNA. Genomics now routinely uses microarrays for gene expression profiling, mutation detection, genotyping, and gene discovery. It will be fascinating to follow this field in the coming years as we gain insights into the function of thousands of genes previously known only by their gene sequence.
September 2008 San Francisco Medicine
2008 Northern California Conference on
Transgender Health & Wellness Jointly presented by Sutter Medical Center of Santa Rosa and the Sonoma County Academic Foundation for Excellence in Medicine
October 10 - 11, 2008 Friday program 12:30pm-5:30pm Friday reception 5:30pm-7:00pm Saturday program 7:30am-5:30pm
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Conference Faculty (partial list) Michael L. Brownstein, MD, FACS Jennifer A. Burnett, MD, Assistant Professor of Community Medicine, UCSF Nicholas DeMara, PhD, Clinical Psychologist Randall Ehrbar, PsyD, Clinical Psychologist Leah M. Kelley, MD, Ob/Gyn Lori Kohler, MD, Professor, UCSF Judy D. Lively, MD, Physician-in-Chief Carol F. Milazzo, MD, FAAP Suegee Tamar-Mattis, DO Lucy Watkins, PhD, Clinical Psychologist
Editorial Mike Denney, MD, PhD
Key to an Unknown Lock
A
fter my ninety-six-year-old mother died a few years ago, I began the tedious job of sifting through drawers and boxes, sorting out hundreds of small items she had squirreled away over the years—old postcards and letters, rusty paper clips, canceled checks, outdated receipts, frazzled spools of thread, and the like. My favorite piece of all sits here on my desk. I discovered it in a small cardboard box that contained many keys of different shapes and sizes, each carefully identified in writing on a round white tag attached by a string. Some of the keys were for doors to long-since vacated houses; one was for a discarded toolbox; others were for abandoned cabinets, storerooms, and garages; and still other small ones were for padlocks, jewelry boxes, and tiny strap-locks on books and diaries. One key is very special, and I keep here on my desk because it seems to have deep meaning. It is a gold key, and there on the round white tag, in Mother’s distinctive hand, the writing says, “Key to an unknown lock.” Mother is now an ancestor, and, as in this issue of San Francisco Medicine we ponder the mysteries of DNA, perhaps we should think of her writing on that white tag attached to that gold key as a kind of posthumous oracular message. Indeed, we might do well to view the recent identification of the 30,000 genes of the human genome and the 3.1 billion base pairs to be as far-reaching as the paradigmshifting discoveries of sixteenth-century Copernicus who taught us that we are not the center of the universe, nineteenth-century Darwin who demonstrated that we are only one form of a whole living web of life, and twentieth-century Freud who showed that our cognitive awareness is only a fraction of the irrational unconscious images and motivations that guide our lives. Are we in this twenty-first century ready to accept the reality that all of our bodily and personal characteristics can be precisely identified, and possibly altered, on a specific double-helix DNA molecule that is the secret of life itself—each of us with our own unique genome? As a headline in a recent issue of The New York Times asked, “DNA Changed the World. Now What?” Following the meticulous mapping of the human genome, we already have forensic genomics, diagnostic genomics, nutrigenomics, and pharmacogenomics. We even have epigenetics, through which researchers can determine how the external and the internal www.sfms.org
environment can alter DNA so as to change phenotypes within one generation. Looking back, we can discover our ancestry by having tested our mitochondrial DNA through our mother’s lineage, and men can have the Y chromosome DNA traced through their father’s lineage. Such data can give us accurate data about our propensity to develop certain diseases, some of them lethal. This information can then lead to decisions about childbearing and such profound questions as whether to have preventative measures, including major surgery for removal of susceptible organs. Looking forward, some scientists predict that with genetic engineering we may be able to construct more “perfect” humans, not just by modifying susceptibility to disease, but by predetermining such characteristics as IQ, height, appearance, and even personality. Not only that, germ-line genetic engineering might enable such altered genomes to be passed on to future generations through egg and sperm. Other scientists, however, urge caution when manipulating such complexity. They focus on the mysteries of DNA, warning that every cell that exists arose from a cell that preceded it, admonishing that we are just learning how genes interact with one another, warning about the complexity of the interactions of genes with their environment, and dreading the monstrous individuals and traits that could result from genetic engineering gone awry. Noting that neuroscientists are beginning to understand how particular DNA combinations can determine personality traits, psychopathologies, mood changes, and addiction propensities, ethicists point out that defense lawyers might soon blame their clients’ crimes on DNA. Acknowledging these complex permutations of the mysteries of DNA, Stanford anthropologist and geneticist Kenneth Weiss was recently quoted as saying, “I think we should really temper making genetics the established religion of our country.” In view of both these phenomenal opportunities and possible dire consequences, what will we learn about human genetics in the future? As for me, I shall dwell upon the mysteries of DNA, remembering the wonderful oracular message of dear Mother, who donated to, nurtured, and gave birth to my genome. Mother would say that DNA is a key to an unknown lock.
September 2008 San Francisco Medicine
The Mystery of DNA
Science and the Mysteries of DNA From Gregor Mendel to J. Craig Venter Mike Denney, MD, PhD
I
n the year 1865, science was not ready for an article published in Proceedings of the Scientific Society of Brno by the Austrian botanist and monk Gregor Mendel. After working for more than ten years in the gardens of the Augustinian monastery in Bohemia, studying hybrid Pisum sativum—common garden peas—Mendel observed that physical traits were not passed on from generation to generation in mixed or blended forms but appeared or did not appear in the offspring independently. Furthermore, he noted that the numeric count of traits appeared in the next generation in nearly whole-number ratios and could thereby be expressed as “dominant” or “recessive.” This was too much for a world that was already reeling in an uproar from the scientific, cultural, and religious implications of Charles Darwin’s book Origin of Species, with its law of natural selection, which had been published six years earlier in 1859. The ecclesiastical establishment, including Calvinist conservatives, high Anglican churchmen, and the Bishop of Oxford, sided against a science that seemed to disagree with the teachings of “creationism” as recorded in Genesis. On the other hand, philosophers such as Herbert Spencer and Julian Huxley used the findings to attack the church and promote their own theories of secular social progress. This apparent dispute of science versus religion, of evolution versus creationism, continues to the present day. Meanwhile, Mendel’s laws of inheritance were denounced by a few scientists, such as the reigning leader in botany, Karl Naegeli, but simply ignored by most others, including Darwin himself. Little did any of them know that Mendel’s work was the key to understanding Darwin’s notion of natural selection by providing the missing
element to explain how mutations could continue to manifest themselves in succeeding generations. It was in the year 1900, thirty-five years after Mendel’s publication and fifteen years after his death, that the scientific community finally was ready to embrace the laws of inheritance. It was in that same year of 1900 that Bertrand Russell discovered the error in his Principia Mathematica, an error that undermined the foundations of mathematics and logic, that later was confirmed by Godel’s Incompleteness Theorem and resulted in chaos and complexity theory, all of which demonstrated that mathematics and science were forever incomplete descriptions of reality, caught in a recursive, self-referential paradox that undermined the positivistic, empirical consistencies of logic itself. In that paradoxical year of 1900, Hugo de Vries, professor of botany at the University of Amsterdam, completed his own studies on hybridization using Oenothera lamarckiana—the evening primrose—named after an earlier biologist, Jean-Baptiste Lamarck, who was the first to offer a coherent theory of evolution. In his publication, de Vries postulated discrete heredity entities called “pangenes,” and the data from his research on the primrose clearly confirmed Mendel’s work. Meanwhile, two other botanists, Carl Correns, at the University of Tübingen, and Erich Tschermak, at University of Agricultural Sciences in Vienna, also
10 San Francisco Medicine September 2008
confirmed Mendel’s findings in their own hybridization experiments. Finally, the world of science was ready to embrace Mendel’s law of inheritance and to see its vital place in the theory of evolution. But Lamarckian and Mendelian theories of evolution were fundamentally opposed. Whereas Lamarckians proposed that the genetic changes in species were “acquired,” the result of environment acting upon them, Mendelian thought considered the changes to be spontaneous mutations, which then were tested in the environment by “survival of the fittest.” These two theories reached their oppositional peak in Russia during the 1940s and 1950s when agronomist Trofim Lysenko, promising abundant crop yields through Lamarckian genetics, became director of the Institute of Genetics and promptly instituted a ruthless campaign, declaring Mendelian ideas to be “decadent.” Opposition to Lysenko was formally outlawed in 1948, and scientists who did oppose were called “enemies of the Soviet people.” They fled the country, were sent to the gulags, or mysteriously disappeared. By 1964, however, when the abundant crop yields www.sfms.org
failed to materialize, Lysenko was discredited and Russia joined the rest of the civilized world in recognizing the validity, indeed the brilliance, of Mendel’s work. However, science was not finished with Jean-Baptiste Lamarck. The identification during the first half of the twentieth century of the nature of genes and their specific regions on chromosomes, the mapping of the chromosomes of Drosophila fruit fly, the demonstration that DNA is what transmits the gene’s information, and the elucidation of the double-helix structure of DNA by Watson and Crick all paved the way to a deeper understanding of just how genes function. Newer observations revealed that grandchildren of women subjected to famine had low birth rates and were susceptible to certain diseases, and that offspring of birds who survived droughts had longer beaks. These observations added spice to Mendel’s genetics. Then, laboratory research on mice who were fed large doses of folic acid demonstrated that, by a chemical process of methylation, new inheritable traits, such as the color of hair, could be passed on by changing the cellular chemical environment without changing the DNA itself. Thus a whole new science of epigenetics evolved, validating Lamarck’s theory that environmental factors could produce inheritable changes in genetic traits. Nowadays, understanding the laws of heredity may require both Lamarckian and Mendelian constructs. Medical research now focuses upon this phenomenon of epigenetics and its influence upon many diseases, including work by Victoria Lunyak, PhD, at the Buck Institute in Marin County, California. (See her article on page 12). But such a combination of heredity and environment brings a high level of complexity, some of which is not measurable by ordinary science. Following the report in 2007 of the complete sequencing of the human genome by James Watson and J. Craig Venter, the relationship between DNA and science is heralding new horizons that may even begin to include the recursive paradox in mathematics and logic that Bertrand Russell discovered in 1900. Indeed, the illogical paradox of chaos and complexity theory, which thus far has been shunned, perhaps feared, by the logical scientific community, www.sfms.org
may be finding its way into a new science through the mysteries of DNA. In addition to cooperating and competing with James Watson in the race to map the human genome, J. Craig Venter has been a leader in the use of supercomputers to explore the complexities of human genetics. He and his team members were the first to decode the genome of a whole organism, the bacterium Haemophilis influenzae, and later sequenced the fruit fly and the mouse genomes. When he successfully completed the sequencing of the human genome it was with his own DNA, using a new technique called “shotgun sequencing,” which requires supercomputers that can process new mathematical algorithms upon massive amounts of data with memory storage measured in petabytes (one quadrillion bytes). Using this technique now in even more complex ways, he is collecting air and ocean specimens and running the randomly harvested DNA sequences through supercomputers. He has now discovered DNA of life forms that have yet to be identified by phenotype. Venter says, “We have since discovered tens of thousand of new species, many of them strange and exotic. In all we discovered more than 1.3 million new genes in only 200 liters of water. To put this number in context, the first samples analyzed doubled the number of known genes on the planet.” This new kind of scientific approach represents a paradigm shift, a methodology capable of processing data in highly complex systems that is beginning to reveal some order in the paradox of chaos. In highly complex systems, such as the weather, formation of sand dunes in the wind, and the ecosystems of the planet, spontaneous emergence of phenomena occur that are beyond the predictability of ordinary empirical science. In genetics, such emergent phenomena can be thought of as mutations. When emergent phenomena occur in relationship to the complexity of the healing of the human body, we call them “miracles” or “spontaneous remission of incurable disease.” And we can surmise that such spontaneously occurring events might be present in all disease, including heart disease, immune deficiency syndromes, and cancer. With massive amounts of data in
supercomputers, we may begin to identify these emergent phenomena. Chris Anderson, editor-in-chief of Wired magazine, notes that the petabyte age represents a new science. Instead of establishing hypotheses, then setting out to prove them by quantitative and objective data, the new science, with the aid of supercomputers, simply gathers massive amounts of data, crunches them, and then identifies what emerges from the complexity and chaos of possibilities. Speaking of Venter and the petabyte age, Anderson says, “The opportunity is great. The new availability of huge amounts of data, along with the statistical tools to crunch these numbers, offers a whole new way of understanding the world. Correlation supersedes causation, and science can advance even without coherent models, unified theories, or really any mechanistic explanation at all.” In this year 2008, is medical science ready to accept the reality of the recursive paradox inherent in mathematics and logic? Are medical researchers ready to explore the miracle of spontaneous remission of incurable disease? Indeed, are we ready to include in all of healing the notion of phenomena emerging from the highly complex system of the human mind and body, phenomena that are not explainable by ordinary science? What might be the far-reaching implications of shotgun sequencing, petabyte technology, and a whole new scientific approach? And, as a philosophical and spiritual afterthought, what might this new paradoxical science offer to the old yet ongoing controversy about science versus religion, evolution versus creationism? We might notice that the recursive paradox in spontaneous emergence out of complexity, as the driving force of evolution, leads us beyond ordinary science to the ineffable mystery of existence itself. Additionally, we might observe that in Genesis, and its resulting belief in creationism, language itself contains the recursive paradox in the form of metaphor, allegory, and the imaginal. Thus, looking through the lens of the complexities, paradoxes, and unfathomable mysteries of DNA, some of us may even imagine evolution and creationism to be one and the same.
September 2008 San Francisco Medicine 11
The Mystery of DNA
Epigenetics New Frontiers for DNA Victoria Lunyak, PhD
D
NA is an elegant molecule with mind-blowing properties and an amazing information storage medium. A single cubic centimeter of DNA holds more information than a trillion CDs. Living systems must squeeze their identity into what the physicist Erwin Schrödinger called a “code script.” The history of DNA (deoxyribonucleic acid) research begins with Friedrich Miescher, a Swiss biologist who, in 1868, carried out the first carefully considered chemical studies on the nuclei of cells. Using the nuclei of pus cells obtained from discarded surgical bandages, Miescher detected a phosphorus-containing substance that he named nuclein. He showed that nuclein consists of an acidic portion, which we know today as DNA, and a basic protein portion now recognized as histones, a class of proteins responsible for the packaging of DNA. Although Miescher separated the nucleic acid and studied its properties, the structure of DNA did not become known with certainty until the late 1940s. Using information derived from a number of other scientists working on various aspects of the chemistry and structure of DNA, in 1953 James Watson, an American geneticist, and Francis Crick, an English physicist, were able to assemble the information-like pieces of a jigsaw puzzle, producing a structural model of DNA—the double-stranded helix. This assembly was possible due to the elegant and comprehensive X-ray diffraction studies of Rosalind Franklin and Maurice Wilkins. The double helix electrified the emerging discipline of molecular biology. It electrified the world as well. For their outstanding work in the discovery of the double-helical structure of DNA, Watson and Crick shared the 1962 Nobel Prize for physiology and medi-
cine with Maurice Wilkins. Sadly, Rosalind Franklin, whose work greatly contributed to this key discovery, died before this date, and the rules do not allow a Nobel Prize to be awarded posthumously. Since Watson and Crick started the molecular biology revolution in the 1950s, culminating in cataloging the human genome, thousands of commercial tools have been created and marketed for manipulating DNA molecules. Details on the nucleotide sequences for every human chromosome have been accumulated, but the secret remains a secret. DNA was introduced originally as a code script of four nucleotides, A, T, G, C, and it has enjoyed successive incarnations as a “blueprint,” “design,” “template,” or “computer program.” Yet the DNA paradigm has so far failed to explain cell-type and tissue variations during organism development, given that every cell has the same genetic information yet follows a different developmental pathway. The Sixty-Eighth Symposium on the Genome of Homo sapiens at Cold Spring Harbor, New
12 San Francisco Medicine September 2008
York, was an important landmark in genetics; and although there is still much genetic work to be done, the complete sequencing of this and other genomes signified that it was time to move “above genetics”—a literal meaning of epigenetics. Over the years we have leaned that DNA encodes for proteins (the basic building blocks of every living system), but something else is involved in the command, control, and coordination of their expression. Whatever the message contained in DNA, it must somehow be conveyed into a variety of tissues in living organisms and it must be heritable upon cellular division. Cumulative research suggests that something remarkable has taken place to produce a multitude of phenotypes with the same genetic content. The emerging field of epigenetic studies promises to take up the story where The Double Helix ends. Well, what is epigenetics? Besides being a fashionable word intensively used in almost every other NIH grant application, what kind of science is it, and, most importantly, what does it have to offer? The history of epigenetics is linked with the study of evolution and development. This concept had its origins in late nineteenth-century developmental studies that laid the groundwork for our present conceptual framework of developmental-specific gene regulation. The meaning of the term “epigenetics” has itself evolved with our dramatic progress in deciphering the molecular mechanisms underlying regulation of gene expression in eukaryotes. The present-day definition stands thus: Epigenetics is a study of any inheritable influence on gene activity that does not involve a change in DNA sequence. How is epigenetic information mainwww.sfms.org
tained and propagated? Is it true that epigenetics thrives on the idea that there is a code above the code embedded in the DNA itself? In humans, DNA is organized into 23 pairs consisting of approximately 25,000 genes coding for proteins. When summed across all chromosomes, the DNA molecular in high eukaryotes is about 2 meters long and therefore needs to be condensed to fit into the cell’s nucleus. This packaging is achieved by wrapping DNA around repeating protein units (nucleosomes). This “beads-on-a-string” template, known as “chromatin fiber,” is a dynamic polymer existing in many configurations, prone to remodeling and restructuring as it receives physiologically relevant input from development-specific, cell-type specific or environmental signaling pathways. In simplistic terms, chromatin dictates when, where, and on what level the genes within our genome are transcribed to provide for protein products. Thus chromatin should be viewed as major source of epigenetic information, providing an elegant solution to the DNA packaging problem, influencing genome plasticity and defining a source for the cellular memory to transmit the regulatory information. Chromatin packaging designs can be altered through the introduction of unusual histone proteins (known as histone variants), local changes in chromatin structure (known as chromatin remodeling), and the addition of chemical tags to the histone proteins themselves (known as covalent modifications). All of these alterations expand the repertoire of the epigenetic codes to govern epigenetic influences. Moreover, the addition of a methyl-group directly to a cytosine (C) base in the DNA template (known as DNA methylation) can provide docking sites for proteins to alter the chromatin state or affect the covalent modifications of resident histones. The DNA methylation represents an important epigenetic strategy with numerous applications to cancer biology and regenerative medicine. Recent evidence suggests other epigenetic mechanisms, postulating that nonprotein-coding RNAs can “guide” specialized regions of a genome into more compacted chromatin states or “bookmark” chromosomal domains of differential gene www.sfms.org
function. New studies indicate a critical, and probably primary, role for noncoding RNAs in triggering epigenetic transitions and heritably maintaining specific chromatin states of the chromatin template. Largely transcribed from endogenous transposons and other repetitive sequences, the noncoding RNAs have once again reminded us there is no such thing as “useless genomic junk DNA.”
“DNA is an elegant molecule with mindblowing properties and an amazing information storage medium. A single cubic centimeter of DNA holds more information than a trillion CDs.” We now know of countless examples of epigenetic mechanisms at work in organisms. Although presented separately, all aforementioned epigenetic mechanisms should more properly be viewed as a series of parallel and interrelated processes aimed to define and explain epigenetic phenomena. Despite the fact that contemporary epigenetics is a relatively young discipline, it still addresses the century-old, fundamental questions about mechanisms of development. Through the elegant genetic and biochemical studies to the recent genomewide analysis and resolutions at the molecular level, this fast-paced discipline is full of surprises: Accounts of new and unexpected phenomena always hold our imagination. The popular press portrays epigenetics as an antidote to the subjects classic genetics stumble over as “unexplainable.” Researchers are assigning full responsibility for altruism and depression, aggression and eating disorders to epigenetics. Some of them depart for “epigenetic shores” with what seems a rare urgency, promising “the epigenetic drugs” to cure devastating diseases. Others enter the field like quick sunbursts and then leave the study of epigenetics dazzled but disappointed when their
research yields more questions than answers. But epigenetic research continues to move forward, attracting tremendous attention from scientists and clinicians in almost all areas of biology and medicine. More than one thousand reviews on epigenetics written in the past five years are scholarly milestones and have delivered new paradigms. It is now fifty years since Watson and Crick initiated “the DNA paradigm” and, understandably, claimed that in discovering DNA they had really discovered the secret of life. And as so often happens in the sciences, molecular biology has not resolved the mysteries of the elegant molecule just yet. Epigenetic language of the “book of life” is unparalleled, and the truth is that we are only scratching the tip of the iceberg in understanding its complexity. Victoria Lunyak, PhD, currently works on the faculty at the Buck Institute for Age Research. She received her PhD in Molecular Biology from the St. Petersburg Nuclear Physics Institute, Russian Academy of Science in St. Petersburg, Russia. In addition to her position at the UCSD Department of Medicine, she has also held posts in the lab of MG Rosenfeld, a principle investigator at the Howard Hughes Medical Institute in La Jolla, CA, and in the Department of Molecular Biology, Cell Biology and Biochemistry at Brown University in Providence, RI.
Send Your Message to 2,500 Health Care Professionals The San Francisco Medical Society offers multiple advertising opportunities ranging from full-page, 4-color display ads to classified ads with discounted rates for members. Please contact Ashley Skabar for more information, (415) 561-0850 extension 240 or askabar@ sfms.org.
September 2008 San Francisco Medicine 13
The Mystery of DNA
The Genetics of Mental Disorders An Update of Recent Progress in Understanding the Link Steven P. Hamilton, MD, PhD
I
t has been five years since the announcement of the completion of the human genome sequence by the National Human Genome Research Institute of the NIH. This work, which provides the elemental instruction manual for building a human being, is already contributing to a remarkable understanding of human evolution, human biology, and human disease. A number of spin-off projects from the Human Genome Project are extending our understanding even further. With names like the HapMap Project, the ENCODE Project, and Cancer Genome Anatomy Project, researchers are using genomic research to examine DNA variation between individuals, determine the variety of functional roles that all DNA sequences may encode, and elucidate the genetic basis of cancer at the DNA sequence level. Many additional organisms have had their genomes sequenced in parallel, including our closest primate relatives as well as model organisms (mouse, rat, dog, zebra fish), economically important organisms (rice, honey bee, chicken, cow, pig, horse), and disease vectors (the mosquito A. gambiae). These projects afford us an opportunity to directly compare the results of hundreds of millions of years of vertebrate evolution, as well as to understand the inner working of organisms that inflict widespread disease.
The GWAS Era Has the hype from this monumental foray into Big Science told us much about human disease, and more specifically about psychiatric illnesses? To answer this, one has to know of three convergent events: First, the International HapMap Project enabled the cataloguing of millions of DNA variants called SNPs, or single nucleo-
tide polymorphisms, AGTGCTGATG CCATACG GTAC that occur across the genome (Figure 1). These SNPs explain a major fraction of the genetic differences among humans. The project provided greatly detailed information about these variants, especially how their frequencies AGTGCTGATG CCG TACGG TAC differ among representative populations of Europe, Africa, and Eastern Asia, facilitating their use as markers or probes of DNA variation among individuals. Figure 1 The second developA single nucleotide polymorphism (SNP) is a substitution of a ment was the design single base in a DNA sequence. This leads to the presence of alternate and manufacture of alleles. In the figure, a homologous region of a chromosome is depicted, microarrays by bio- with the upper and lower chromosomes coming from the mother and technology compa- father, respectively. In this case, the mother transmitted an “A” allele nies that would allow at the highlighted position (in green), while the father transmitted a researchers to simul- “G” allele at the same position (in red). Thus this person is heterozytaneously examine gous at this SNP (“A/G”), having both possible alleles. from 300,000 to 1 million SNPs on a single chip, facilitating 2). For example, regarding type 2 diabetes, a genomewide assessment of variation at investigators from a number of teams having the individual level. Finally, scientists and more than 30,000 cases and controls found funding agencies realized that cooperative DNA variants in some ten genes or gene rearrangements were required that led to the gions that were reliably associated with the agglomeration of thousands, or even tens of presence of type 2 diabetes. Interestingly, thousands, of cases and controls for diseases the genes uncovered were not previously such as type 2 diabetes, Crohn’s disease, connected to any understanding of diabetes, breast and prostate cancer, obesity, and opening the field to new research directions. psychiatric disorders. The confluence of Unfortunately, these risk-increasing SNPs all three factors has resulted in the prolif- were found to have small individual effects. eration of genomewide association studies Each variant increases the risk by less than (GWAS) over the past two years (Figure 20 percent. In a very large collaborative
14 San Francisco Medicine September 2008
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effort, many of the world’s type 2 diabetes geneticists teamed up for a meta-analysis of more than 10,000 subjects, followed by additional replication in almost 80,000 subjects, and they reported at least six additional gene variants that are correlated with the presence of this disease. Similar undertakings have been carried out with Crohn’s disease, where about thirty novel genes or gene regions have been identified. Early indications from these types of studies suggest that knowledge of a person’s complement of risk variants may not explain enough of the susceptibility risk for a practical, predictive laboratory test. Nonetheless, knowledge of completely novel genes opens numerous doors for understanding pathophysiology and drug development.
Progress in Psychiatric Genetics, Too? Given the relative success for finding common disease risk alleles for common complex traits such as type 2 diabetes, it is reasonable to presume it might work for psychiatric disorders, which, similarly, are partly determined by genetic factors and are at high prevalence in the population. There are number of studies that suggest this might be the case, as described below. Additionally, a number of observations coming from genetic analyses of psychiatric disorders raise the possibility that some cases of schizophrenia and autism may actually involve dramatic large-scale genomic events, many of which are not transmitted from parental genomes. Schizophrenia: The first reported GWAS in a psychiatric disorder was for schizophrenia, in which a relatively small set of schizophrenia cases and matched controls were genotyped for more than 500,000 SNPs, leading to a novel association to a region common to the X and Y chromosomes, termed a “pseudoautosomal” region. This curious finding, which has not been seen by others, was in a region surrounding genes encoding receptors for colony-stimulating factor and interleukin 3. The potential involvement of cytokinerelated genes in schizophrenia may lead to additional attention to inflammatory processes in the etiology of this disease, for example in utero viral infection. A second www.sfms.org
CASES
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Figure 2 The design of a case-control association study is depicted. Cases and controls are genotyped for between one to one million SNPs, and the frequencies of alleles (e.g., A versus G) or genotypes (AA, AG, or GG) is tabulated. A statistical test is performed to determine if the distribution of alleles or genotypes are significantly different between the two groups. If the statistic is significant, the SNP can be said to be “associated” with the phenotype.
GWAS involved a large sample comprised of cases from Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). The top finding generated an association p-value of 0.0000017, which was determined to be insignificant in that such a result is highly likely to result by chance given that the authors carried out some 492,000 statistical tests. Although disappointing, this study did have a number of intriguing findings of even lesser statistical significance that will be pursued in other samples. It was reassuring to see that this study found some support for the previously described schizophrenia risk genes DISC1 and NRG1. The most recent GWAS identified twelve DNA variants of interest in a modest set of about 480 cases and 2,900 controls but then sought to replicate the findings in an additional 16,800 subjects. Three regions maintained some support, with one containing a novel gene called ZNF804A, which is an unstudied gene with unknown function, although its sequence suggests that it binds to DNA and zinc ions, making it a potential regulator of transcription of other genes. Interestingly, the two other supported regions lie within regions in which there are no known genes, raising the possibility that these intervals contain undiscovered genes or sequences that are involved with long-range regulation of yet other genes. Bipolar Disorder: A series of
GWAS experiments involving several thousand bipolar disorder cases has been published since 2007. The first, a study of 2,000 British cases and 3,000 controls, was sponsored by the Wellcome Trust. This study reported an association between bipolar disorder and a SNP within a gene called PALB2, which encodes a protein whose function appears to be to partner with the protein produced by BRCA2, a gene previously linked to highly heritable breast cancer. If this finding is indeed true, it may raise questions about the connection between bipolar disorder and important cellular functions. A smaller genomewide SNP scan of North American and German bipolar disorder cases identified a gene (DGKH) that encodes diacylglycerol kinase eta, a component of the lithium-sensitive phosphatidyl inositol pathway. Investigators from both of these studies looked at genomic regions that scored highly in both experiments. Interestingly, they report that the top findings were not replicated in both studies but that other regions that were modest in both “rose to the top” when data were combined. Two such genes include a zinc transporter and JAM3, whose protein product appears to be involved in cellular junctions, for example between the myelin-forming cells of the peripheral nervous system. A third GWAS of bipolar disorder, focusing primarily on
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September 2008 San Francisco Medicine 15
The Mystery of DNA
Genetics and Drug Response Pharmacogenomics and Warfarin Therapy Jaekyu Shin, MS, PharmD; and Robert L. Naussbaum, MD
C
linicians have wondered why some patients have good responses to a particular drug and why some either do not respond to the drug or develop toxicity or other adverse reactions. Many factors play a role in causing this variability, and genetic factors are certainly among them. Pharmacogenomics is the study of how genetic differences among individuals influence responses to a drug. Pharmacogenomic studies have discovered genetic variants that contribute to causing variable responses to drugs that are commonly used in clinical practice. In fact, there are more than fifty drugs that have pharmacogenomic information on the label, as required by Food and Drug Administration (FDA) packaging regulations. The agency requires a genetic test to be performed before prescribing certain drugs, such as trastuzumab (Herceptin) and maraviroc (Selzentry); the FDA recommends genetic testing for others. Warfarin is one of the drugs for which genetic testing is recommended by the FDA prior to starting therapy. The anticoagulant warfarin is a drug that is used to reduce the risk of systemic embolism due to cardiac arrhythmia, ventricular dysfunction, and the use of mechanical heart valves, as well as to prevent venous thrombosis and thromboembolism in deep veins. Though warfarin is an old drug that was first introduced as a medication in the 1950s, the drug is still widely used. Nearly 31 million outpatient prescriptions for warfarin were dispensed in 2004, up from 21 million in 1998. The drug has a narrow therapeutic window and has been associated with a high incidence of adverse drug reactions, particularly bleeding. Warfarin is among the top ten drugs with the largest number of serious adverse event reports submitted to
the FDA’s Adverse Event Reporting System during the past twenty years. Anticoagulants ranked first in 2003 and 2004 in U.S. death certificates for drugs causing “adverse effects in therapeutic use.” Warfarin was associ-
“Pharmacogenomics is the study of how genetic differences among individuals influence responses to a drug. Pharmacogenomic studies have discovered genetic variants that contribute to causing variable responses to drugs that are commonly used in clinical practice.” ated with about 29,000 visits for bleeding complications per year, and it was among the drugs with the most visits. These wellknown aspects of warfarin therapy led the FDA to require a “black box” warning about warfarin’s bleeding risk to be added to the U.S. product labeling in 2006. One of the main reasons of the high incidence of adverse events by warfarin is its unpredictable dose requirements among patients. There is up to a sixteenfold difference in dose requirements, from as low as 1 mg/day to as high as 16 mg/day, among patients. This is why the use of warfarin requires careful monitoring of the degree of anticoagulation by frequent INRs during the induction phase of anticoagulation, with repeated dose adjustments when the INR is found to be out of range. This unpredict-
16 San Francisco Medicine September 2008
ability increases the risk of bleeding complications or treatment failure associated with warfarin therapy. Studies have shown that genetic variability in two genes called CYP2C9 and VKORC1 accounts for about 40 percent of total variability of warfarin dose requirement among patients. Based on this information, the FDA recently revised the warfarin label by recommending a lower initial dose of warfarin for patients with certain genetic variants of CYP2C9 and/or VKORC1. Warfarin is mainly metabolized in the liver by the cytochrome P450 enzyme 2C9 (CYP2C9). The CYP2C9 gene has two common genetic variants: CYP2C9*2 and CYP2C9*3 (* is used to denote a genetic variant compared with wild type, which is usually denoted as *1 for the cytochrome P450 genes). Both of the variants produce a CYP2C9 enzyme with reduced enzymatic activity compared with wild type (CYP2C9*1). Because of the reduced enzyme activity, patients with either of these variants may need smaller amounts of warfarin in order to achieve a therapeutic INR, compared with patients with a wild type CYP2C9 gene. As with all genes (except those on the X chromosome in a male), every person has two copies of the CYP2C9 gene and therefore can have one wild type and one *2 or *3 variant, or they can even have two copies of the *2 or *3 variant and require even less warfarin to achieve therapeutic anticoagulation. In fact, studies have shown that patients who carry one CYP2C9*3 variant required 1.5 to 3 mg/day of warfarin. In contrast, the average dose of warfarin in patients who do not carry any CYP2C9 variant was 5.5 mg/day. The frequency of CYP2C9 genetic variants differs by racial background. The two CYP2C9 www.sfms.org
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variants are more common in Caucasians than in the others (see Table). A second gene, VKORC1, plays an important role in variability in warfarin therapy. This gene specifies the production of vitamin K epoxide reductase, an enzyme involved in regenerating vitamin K required for the synthesis of the coagulation factors II, VII, IX, and X. Vitamin K epoxide reductase inhibition is the major mode of action of warfarin. DNA variation in the sequences that regulate the expression of the VKORC1 gene cause variation in the amount of VKORC1 that is made, resulting in variability in sensitivity to a given dose of warfarin. There are a number of DNA variants that are usually found together in the VKORC1 gene, and we refer to them all as a variant “haplotype.” We only need to genotype one of the variants in the haplotype to know what the other variants are and, therefore, to predict warfarin dose requirements. For example, VKORC1 -1639G/A, a G to A nucleotide change at nucleotide position -1639 in the VKORC1 gene, is the site that is most commonly genotyped for VKORC1 genetic variability. The variant VKORC1—for instance, VKORC1-1639A—has been shown to produce a smaller amount of mRNA of the gene compared with wild type (VKORC1 -1639G). Compared to individuals with two normal VKORC1 genes, who need 6 mg/day of warfarin to attain a therapeutic INR, individuals with one or two variant haplotypes require 5 mg/day and 3 mg/day of warfarin, respectively. This makes sense because VKORC1 variant carriers make less of the warfarin target protein due to a reduced amount of VKORC1 mRNA and, as a result, www.sfms.org
they need smaller amount of warfarin. The VKORC1 variant haplotype is much more common in Asians than in other ethnicities. It is well known that Asians need smaller dose of warfarin compared with other races. The frequency differences in the VKORC1 variant among races may explain this clinical observation (see Table). There are two warfarin pharmacogenomic tests that have been approved by the FDA. In addition, many clinical laboratories such as the UCSF clinical laboratory, Quest Diagnostics, and Laboratory Corporation offer CYP2C9 and VKORC1 testing. The cost is about $300 to $500, with a turnaround of one to several days. By incorporating the genetic test results with the patient’s age, weight, and gender into a dosing algorithm, the test results should improve our ability to estimate what the ultimate correct maintenance dose of warfarin will be and, therefore, help guide the initial dosing during induction of anticoagulation. There are many published dosing algorithms available that take both genetic and nongenetic variables (age, weight, smoking status, interacting drugs, etc.) into account to predict an individualized warfarin dose. One such, www.warfarindosing.org, is a publicly available warfarin dosing algorithm developed by Washington University at St. Louis. The dosing algorithm seems to be accurate and accounts for 60 to 80 percent of warfarin dose variability. Regular monitoring of INR is still important in warfarin therapy even when genetic information is used to predict dose, since the genetic information and other variables do not account for the remaining 20 to 40 percent of the variability in dosage. It should also be noted
that genetic information will be most useful when it is applied to predicting warfarin dose for patients who are starting on warfarin therapy and not for patients who are already stabilized on a dose of warfarin. Robert L. Nussbaum, MD, is the Holly Smith Distinguished Professor in Medicine and the Chief of the Division of Medical Genetics at UCSF. He is a board-certified internist and medical geneticist and has served on the American College of Medical Genetics Working Group on Pharmacogenetic Testing for Warfarin Use and on a working group on Personalized Medicine for the Institute of Medicine as well as an advisory committee on this subject for the Secretary of Health and Human Services. Prior to coming to UCSF, he was the Chief of the Genetic Disease Research Branch at the National Human Genome Research Institute of the NIH. Dr. Nussbaum has particular interests in translational research efforts to assess the value of “personalized medicine,” the application of genetic and genomic approaches to improving patient care. Dr. Nussbaum seeks to evaluate whether individuals’ genetic and genomic information can be used effectively to improve health care by improving outcomes, reducing adverse reactions, lowering costs, and promoting health through risk education. Jaekyu Shin, MS, PharmD, is an Assistant Professor of Clinical Pharmacy at UCSF and will serve as Research Coordinator of this study. He completed a three-year fellowship in Cardiovascular Pharmacogenomics under the mentorship of Dr. Julie Johnson, a leading researcher in warfarin pharmacogenetics. Along with Drs. Nussbaum, Wu, and Kayser, he is a member of the Warfarin Pharmacogenetic Consultation Service Team, which provides warfarin dosing service based on an individual patient’s CYP2C9 and VKORC1 genotype for inpatients who are receiving heart valve replacement surgery and are newly starting on warfarin.
September 2008 San Francisco Medicine 17
The Mystery of DNA
Understanding a Patient’s Genes Genetic Counseling for the Twenty-First Century Kati Malabed, MS, CGC
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f you have never worked with a genetic counselor before, it’s likely that you don’t know much about what we do. For centuries, people have observed that certain conditions tend to run in families and “medical genetics” has been practiced on some level. But the formal discipline of genetic counseling began merely forty years ago. The first organized training program was started in 1969 and was formed in part by happenstance. Since then, many more programs have sprung up and others have folded. The National Society of Genetic Counselors (NSGC) website currently lists thirty programs in the United States and an additional six in Canada, the U.K., and Australia. In the Bay Area, new genetic counseling programs at California State University and Stanford University are each preparing to start their first year of course work this fall. The American Board of Medical Genetics (ABMG) offered its first examinations to certify genetic counselors, as well as the other medical genetics specialties, in 1984. Seven years later, in 1991, the American Medical Association recognized medical genetics as its own subspecialty. As a result, genetic counselors formed their own accreditation group, the American Board of Genetic Counseling (ABGC). Despite having separated their governing bodies, genetic counselors continue to work very closely with other medical genetics specialists in clinical genetics (including dysmorphology and metabolic genetics) and laboratory genetics (cytogenetics and molecular and biochemical genetics). So what do we do? According the NSGC, genetic counselors are health professionals with specialized graduate degrees and experience in the areas of medical genetics
and counseling. They work as members of a health care team, providing information and support to families who have members with birth defects or genetic disorders and to families who may be at risk for a variety of inherited conditions. They identify families at risk, investigate the problem present in the family, interpret information about the disorder, and analyze inheritance patterns and risks of recurrence and review available options with the family. Genetic counselors also provide supportive counseling to families, serve as patient advocates, and refer individuals and families to community or state support services. They serve as educators and resource people for other health care professionals and for the general public. A fairly simple description of genetic counseling would be that I meet with people to discuss their family history and provide education and informed consent around genetic testing. It doesn’t really do justice to our profession, but it works for casual conversation. Pressed for more detail, I would add that genetic counseling melds the art
18 San Francisco Medicine September 2008
and science of understanding genetic information and making sense of it for others, bringing medical and scientific knowledge about genetic disease—its diagnosis, natural history, and management—together with counseling skills to help individuals and families digest and adapt the information to their own circumstances. As a group, genetic counselors are innately curious and enjoy the sleuthing process. Eliciting pertinent family and health history is the typical starting point. Tracking down and obtaining medical records that are often thought unattainable is sometimes necessary. Evaluating, interpreting, and explaining information and shepherding an individual or family through the process are the ultimate goals. The genetic counselor most commonly works in a medical center, and a little more than half of genetic counselors work in prenatal diagnosis. This has remained fairly constant over the years. Adult and pediatric genetics as well as cancer genetics follow closely. Numerous specialty clinics, ranging from biochemical genetics to skeletal dysplasias, cancer to neurogenetics, are also run by many centers. Many counselors see patients in more than a single setting. Depending upon the clinical setting, patient encounters can last a single visit or span several years. In prenatal diagnosis, many interactions are one-time encounters and fairly straightforward. Many women come for a prenatal screening test that is normal and requires no further visits. Fortunately, uneventful encounters are the most likely kind in the prenatal clinic. A family history of a genetic problem or a fetus identified with a malformation, however, can lead to numerous visits over the course of a pregnancy and may involve fetal diagnostic procedures and complex www.sfms.org
genetic testing. Genetic counselors are usually involved at each step to provide case management by coordinating appointments and testing and by conveying results. Often, genetic counselors are able to provide more continuity of care than other team members and interact with the family to the greatest extent. In pediatric and adult clinics, the referring indication generally necessitates multiple visits over a period of months or even years. Again, the genetic counselor often coordinates visits and testing and as acts as communication liaison, while providing supportive counseling throughout this time. In multispecialty clinics, which focus on a single condition such as Marfan syndrome, or on a group of conditions such as familial cancer syndromes, genetic counselors work as part of a team that provides multiple facets of care. One example is a craniofacial clinic, where a day’s visit could include appointments with a genetic counselor, clinical geneticist, nurse, oromaxillofacial and/or plastic surgeon, dentist, speech pathologist, and social worker. A neurometabolic clinic might include visits with a counselor, geneticist, neurologist, and dietician. In cancer risk, counselors help identify patients who are at risk for hereditary cancers and collaborate with oncologists and surgeons to provide the best care. Because genetic counselors are not trained to provide long-term psychological counseling, we must also know our limitations and refer to other counseling professionals as part of our ethical and professional responsibilities. In the last few years, the media has highlighted the development of directto-consumer genetic testing. Testing at home provides a person access to his or her genetic information without necessitating the involvement of a doctor or insurance company. Individuals might choose this route for maximum confidentiality and lower expense. Some direct-to-consumer companies offer testing for single gene disorders, such as cystic fibrosis and hemochromatosis, to determine an individual’s status regarding a trait or disease known to run in the family. In the last year a number of companies, such as Navigenics and 23&Me, have emerged and are offering genomewide scans to aswww.sfms.org
sess susceptibility risks for common disease, complex disease, single gene traits, ethnic heritage, or some combination of these factors. The information might be sought for the opportunity to modify one’s lifestyle and to prevent, diagnose, and thereby reduce the risk of developing specific diseases. Or one might pursue testing out of simple curiosity. But concerns about this model have surfaced. The states of New York and California
“For centuries, people have observed that certain conditions tend to run in families and ‘medical genetics’ has been practiced on some level. But the formal discipline of genetic counseling began merely forty years ago.” have filed cease-and-desist orders regarding offering direct-to-consumer testing due to concerns about how the services will be provided. The current position of the American College of Medical Genetics (ACMG) is that genetic testing should be provided only through licensed and trained professionals and that minimum requirements should be met for such services to be rendered. The story of direct-to-consumer testing is just now unfolding. The explosion of information that continues to come from sequencing of the human genome consistently leads to the development of new genetic tests. Understanding and explaining the nuances of the various tests can be daunting. Many health professionals are capable of such interpretation and explanation, and they provide some level of genetic counseling to their patients. Genetic counselors, however, train specially for this purpose and take time with families to insure their understanding. Naturally, I am biased in favor of genetic counseling and the multidisciplinary setting in which it is most often practiced. The services offered can provide invaluable information in a unique fashion. Genetic
counseling has historically been nondirective, which distinguishes it from the traditional physician model of care. The supportive environment provided during genetic counseling is aimed at allowing individuals to explore their feelings and choose the best individual course of action. This may or may not mean having genetic testing/screening, continuing or terminating a pregnancy with known abnormalities, or choosing prophylactic surgery or medication for an inherited predisposition or disease. I am reassured that I do my job well whenever someone understands all pertinent information and chooses no further testing. It tells me they understood all their options and decided their best choice was no more investigation. For those who do choose further genetic testing, we can serve as guides through a complex landscape. Genetic counseling may not be useful for everyone, but it is an invaluable instrument for many. Now that the Genetic Information Nondiscrimination Act of 2008 (GINA) has been signed, federal law prohibits discrimination based on genetic information when it comes to establishing health insurance eligibility or premiums. It also prohibits employers from hiring, firing, promoting, or placing employees on the basis of genetic information. After thirteen years of debate in Congress, its passage is exciting and overdue. Hopefully, it will remove barriers to genetic testing that will benefit individuals, as well as simplify the process for providers to refer patients for services. Genetic counseling services are available in San Francisco through the University of California, San Francisco, and through California Pacific Medical Center and Kaiser Permanente. Kati Malabed graduated from the genetic counseling program at U.C. Berkeley in 1996. She has been a genetic counselor at UCSF for eleven years, starting in the Sickle Cell Center at San Francisco General Hospital. She ran a quarterly pediatric genetics outreach clinic in Santa Rosa until this year. She has been with the Prenatal Diagnostic Center since 1999 and currently acts as the liaison to the Fetal Treatment Center. For a full list of references, visit www. sfms.org.
September 2008 San Francisco Medicine 19
The Mystery of DNA
Cancer in the Family A Personal Tale of Genetic Testing Kathleen McCowin, JD, MS; and Marcia McCowin, MD
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unt Mae was sixty-seven when she was diagnosed with advanced stage III ovarian cancer. In her twenties, she had survived a highly aggressive thyroid cancer, likely caused by thymic irradiation as a child as a result of an unfortunate episode in medical history when children with thymic “enlargement” were given high doses of radiation. Although Aunt Mae had cheated death before, it seemed unlikely she would survive this time. And it seemed unfair that she was hit twice with cancer when the rest of her voluminous family was healthy. She is the oldest of eleven brothers and sisters, with more than sixty offspring in the next generation. Amazingly, after extensive treatment, Aunt Mae survived this brush with death. Was this cancer a combination of bad luck and unnecessary childhood radiation rather than genetic predisposition? Probably, since more than 90 percent of ovarian cancers are sporadic. Later, Aunt Mae’s three sisters had their ovaries and tubes removed during other pelvic surgeries. When one of her scores of cousins died of pancreatic cancer, that also seemed sporadic. Several years later, two of her sisters each developed postmenopausal stage II breast cancer. Both did well with lumpectomies and prophylactic chemotherapy. We are two of Aunt Mae’s nieces: Kathleen (a licensing officer with a master’s in human genetics) and Marcia (a diagnostic radiologist) were beginning to ponder the genetic odds. Although breast cancer affects one in seven women in the U.S., postmenopausal breast cancer in the two of four sisters appeared to be borderline excessive. When Mae’s nephew developed colon cancer in his early forties, it was time to see a genetic counselor, and a review of family cancer
history was begun. Cousins were found with breast cancer (a few premenopausal and bilateral) and, in at least two cases, ovarian cancer. There were also cousins and a brother with older-age prostate cancer and
“Contemplating this apparently simple next step led us to numerous questions. First of all, who should be tested— and would they want to be tested? If we found something, what would that mean? ... Would family members who tested negative have peace of mind and those who tested positive be living with an early death sentence?” a few cousins with colon cancer. By now, many of Aunt Mae’s siblings, nieces, and nephews had had colonoscopies, and several had colonic adenomas, the precursor to colon cancer.
Deciding Whether or Not to Undergo Genetic Testing Three genetic syndromes seemed the most likely: BRCA1, BRCA2, and Lynch syndrome II. BRCA1 and 2 are linked to ovarian, breast, and prostate cancers; BRCA2 is also associated with pancreatic cancers; and Lynch syndrome II hereditary nonpolyposis colorectal cancer (often
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diagnosed in patients in their mid-forties) is associated with increased endometrial, ovarian, prostate, and other cancers. At first it seemed straightforward to proceed with genetic testing, now that the family data appeared to justify it. However, contemplating this apparently simple next step led us to numerous questions. First of all, who should be tested—and would they want to be tested? If we found something, what would that mean? Would that set some family members up to be uninsurable or unmarriageable? Would family members who tested negative have peace of mind and those who tested positive be living with an early death sentence? Thinking further, would identifying a genetic marker be useful to the family? If it were an issue of colon cancer only, it might not. We don’t need genetic testing to know we should get colon cancer screening, although we might start screening at an earlier age and screen more frequently if we knew our genetic status. Ovarian cancer screening, however, is not very effective, and the effectiveness of breast cancer screening is good but not great. A risk for ovarian cancer would pose a prophylactic salpingo-oophorectomy, which these days can be done with laparoscopy. A significant risk for breast cancer would up the ante on screening and bring up the possibility of bilateral prophylactic mastectomies, a much bigger and riskier surgery.
Going through with It We proceeded with genetic testing. Some family members were happy we were doing this, and others were nervous or just plain against it, particularly because of potential discrimination by life and health insurers against those found to be affected. Our www.sfms.org
genetic counselor determined that Aunt Mae was the key person to test, since ovarian cancer was the common denominator of the syndromes, and the most significant. Even Aunt Mae’s thyroid cancer could be related, since most people of her generation with childhood irradiation did not develop thyroid cancer, suggesting that her genetic makeup may have set her up for cancer in general. Since Aunt May was the most likely to be a carrier of whatever offending gene we might find, we asked for her participation. Being the oldest of a very large family, Aunt Mae took this decision very seriously. She decided it was in the best interest of the family for her to get tested since, on balance, lives could be saved. Now we had yet another reason to be grateful that Aunt Mae had survived her cancers and was alive and well! The initial testing was not covered by insurance and was very expensive because there were so many gene abnormalities that needed to be evaluated. However, if a genetic defect was found, other family members could be tested relatively inexpensively, since just one gene needs to be tested. Either you’re negative and don’t need to worry, or you test positive and can start screening procedures and thinking about possible prophylactic surgery.
Getting the Results And the verdict was . . . inconclusive. Testing found one genetic abnormality— one that was not associated with known cancers. For many who hoped this would provide an opportunity to rule in or out their susceptibility, this was a serious disappointment. However, since the inconclusive information was known, our mother, Aunt Mae’s sister and one of the breast cancer survivors, was tested and found not to carry that gene. So what was the outcome of all this genetic counseling and testing? Probably the most important result was the increased knowledge and awareness in the family of the possibility of inheritable cancers. As CBS news anchor Katie Couric knows, the lifetime risk for colon cancer in the general population is at least 5 percent; therefore screening for colon cancer is a good thing, www.sfms.org
and hopefully we won’t have another case in the family. And we have a heightened awareness about other screening procedures, such as mammography. Even though we don’t know whether specific individuals in our family have an increased risk of ovarian cancer, Marcia decided—based on the likelihood that we as a group are more prone than the average person—to get a laparoscopic salpingooophorectomy, which reduces her chances for ovarian cancer by at least 80 percent. She made this decision after weighing the fact that screening techniques (biannual exams, ultrasound, and CA-125 blood tests) are not very effective, the mortality rate from ovarian cancer is extremely high, and laparoscopic bilateral salpingo-oophorectomy is a safe procedure with minimal recovery time. She continues to be screened for colon cancer with colonoscopy alternating with CT colonography, and for breast cancer with biannual physical examinations and annual mammography. Kathleen was concerned that her family could be in serious jeopardy were she to develop cancer at the age that her mother and aunts were diagnosed. Her children would still be in high school and college when their mom, the sole breadwinner of the family, was facing major surgery and chemotherapy. So she chose prophylactic bilateral mastectomies in addition to a salpingo-oophorectomy performed during the “tummy-tuck” DIEP (deep inferior epigastric artery perforator) flap breast reconstruction procedure. Although mammography screening is more effective than ovarian cancer screening, and the mortality rate for breast cancer is significantly better, her reasoning was that one in seven women in the general population will get breast cancer, while the surgery would reduce her chances to almost nothing. Although she could have relied on mammography as a worthwhile but imperfect screening procedure, with prophylactic surgery up front she won’t worry about breast cancer and its associated issues, such as radiation, chemotherapy, arm lymphedema postnode dissection, and so on. She continues to be screened for colon cancer. The journey from awareness of a possible genetic cancer predisposition in our
family to genetic testing and deciding on the appropriate actions based on the information has been eye-opening. Even though the testing in our case has been inconclusive, it provided us useful information so that various family members could take action based on their personal preferences. Our family was spared the difficult decisions of what to do with a known genetic defect in terms of possibly becoming uninsurable or deciding not to have children. We were comforted knowing that the decisions each of us made were based on the best current knowledge available. Kathleen McCowin, JD, MS, studied genetics and is a licensing officer at the University of California, Berkeley. Marcia McCowin, MD, is a clinical professor of radiology at the University of California, San Francisco.
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September 2008 San Francisco Medicine 21
The Mystery of DNA
Coming of Age Cancer Risk Assessment and Genetic Testing for Hereditary Cancer Risk Patricia Kelly, PhD
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enetic testing for hereditary cancer risk is available for an increasing number of cancers and cancer syndromes. Risk assessment, in conjunction with genetic testing, provides specific and relevant information to help physicians formulate more precise follow-up care and treatment. For example, a man who carries a mutation increasing colon cancer risk can be followed very differently from his sibling who is not a carrier. Patients benefit from cancer risk assessment by learning about hereditary and nonhereditary risk factors, how cancer cells arise, age-specific cancer risks, the origin of cancer cells, and early detection modalities. With more precise information, patients often find that cancer’s mystique and their concerns about cancer risk are diminished, giving them increased confidence in surveillance and treatment, which leads to improved compliance. Cancer risk assessment is designed to determine the likelihood that genetic testing will benefit a given family and patient, the types of genetic testing that might be useful, the appropriate tests to order for patients, and the best ways to fully explain the ramifications of test results to patients. Not all mutations that increase cancer risk can be detected at present, so test results are not always informative, even in the presence of a strong family history. Only when a mutation has been detected in a family can a negative result be regarded as conclusive. Therefore, whenever possible, geneticists prefer to first test an individual in the family who was at some point diagnosed with cancer. Information about cancer risk and genetic testing is complex and must be tailored to meet the very different interests, educational levels, and emotional needs of each patient. At the completion of the consultations, a comprehensive report is sent to
patients’ physicians. Age-specific risks are an important component of the cancer risk assessment service. For example, a recent study found that female BRCA1 mutation carriers had a 46 percent chance of developing breast cancer by age seventy (Chen et al 2006). The risk from age fifty to sixty was far lower—13 percent. The most relevant risks are often those for the next ten years, since within this time new treatments and early detection techniques will be developed and more precise information about risks at older ages will become available. Unfortunately, many patients make decisions based on lifetime instead of age-specific risks, not realizing that they cannot be at risk for ages through which they have already passed. In addition to relevant information about hereditary and nonhereditary risks, patients benefit by learning about cancer etiology and recent advances in detecting and treating cancer. Some have questions about lifestyle and other factors purported to increase cancer risk. Others benefit by learning how to talk effectively with family and friends about their cancer diagnosis or increased cancer risk. Patients most likely to benefit from cancer risk assessment include those with: • questions about nonhereditary risks, early detection, cancer etiology, or risk of a second cancer; or those wondering how to discuss a cancer diagnosis, genetic test results, or increased cancer risk with relatives. • a cancer diagnosis, particularly at a young age. Caution: A sizeable proportion of strongly inherited breast cancer is diagnosed at older ages. For example, in one study, more than 20 percent of BRCA mutation carriers’ breast cancers were diagnosed at age fifty or older (Brekelmans et al 2007). • two or more primary cancers. • a family history of cancer, including:
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1) cancer diagnosed in two or more generations. Caution: Only a single individual may be affected in small families or in other instances. For example, individuals who inherit an MYH gene mutation from both parents have a significantly increased colon cancer risk. Parents are not at significantly increased risk, so only a single individual or a single generation may be affected. Each sibling of a mutation carrier has a 25 percent chance of having a significantly increased colon cancer risk. 2) two or more relatives diagnosed with cancer. Caution: Some FAP gene mutations result in the attenuated familial adenomatous polyposis colon cancer syndrome (AFAP). Mutation carriers have significantly increased colon cancer risks and are often diagnosed at older ages. About one-third are due to a new mutation, so a family history of cancer may be absent. Each child of an individual with AFAP has a 50 percent chance of inheriting a mutation that significantly increases risk. 3) relative(s) diagnosed with cancer at age fifty or younger. Caution: Hereditary cancers are not infrequently diagnosed after age fifty. 4) a relative with two or more primary cancers. As these guidelines and caveats suggest, a thorough risk assessment, with or without genetic testing, may be needed to accurately determine cancer risk. Increasingly, cancer risk assessment and genetic testing are covered by insurance. California law and a just-signed federal law prohibit genetic discrimination by medical insurance carriers. Dr. Kelly is a diplomat of the American Board of Medical Genetics and a founding fellow of the American College of Medical Genetics. She has authored several books, including the most recent, Assess Your True Risk of Breast Cancer (H. Holt, NY). Her website is www.ptkelly.com. www.sfms.org
The Genetics of Mental Disorders Continued from Page 15... the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, identified the genes encoding a type of myosin (MYO5B) and a transmembrane protein that may be involved in cell signaling (TSPAN8) as potential risk genes for bipolar disorder. These genes did not confer the same risk in a British bipolar disorder replication sample. When these researchers combined their results with that of the Wellcome Trust experiment, DNA variants in the gene encoding an L-type voltagedependent calcium channel (CACNA1C), whose broad functions involve mediating neuronal calcium-dependent events and avidly binding dihydropyridine drugs such as verapamil. The lessons from these studies in schizophrenia and bipolar disorder are that the expected “usual suspects,” such as genes encoding components of serotonin or catecholamine pathways, are likely not going to be prominent contributors to the genetic risk, and that more progress will be made when large, well-characterized sample are jointly analyzed. One move that will facilitate the latter is the formation of the Psychiatric GWAS Consortium, which is working to carry out a joint analysis of genomewide studies of five disorders, including ADHD, autism, major depressive disorder, schizophrenia, and bipolar disorder. This project will lead to a joint analysis of some 9,500 schizophrenia cases and 13,500 controls, providing a powerful sample for identifying genes exerting small but potentially meaningful effects. Similarly, analysis of some 2,800 ADHD cases, 5,200 autism cases, 7,100 bipolar disorder cases, and 13,000 depression cases will be carried out.
Rare Genomic Alterations in Schizophrenia and Autism A relatively new approach for identifying genetic determinants of psychiatric disorders has been to assume that a small number of cases may be largely due to large-scale genomic events in which regions of tens or hundreds of thousands of DNA base-pairs are deleted from the genome, or www.sfms.org
even duplicated in multiple copies. Technological advances have facilitated this research, which is still in the stage of development. Nevertheless, the first attempts at carrying out this type of analysis suggest that a small percentage of autism cases are correlated with such genomic changes, also called “structural variants” or “copy number variants”. Similar studies in schizophrenia suggest that up to 15 percent of cases harbor rare genomic deletions or duplications, compared to 5 percent of control individuals. Two collaborative studies involving almost 4,800 cases combined found more subtle evidence for large-scale genomic events that appear to occur at higher rates in cases than in controls in four separate regions on three different chromosomes. These studies are sure to spark future investigation into the functional relevance of genes in these regions of structural differences, with the idea that having fewer or more than the usual number of copies of the gene or genes in the regions contributes to the pathophysiology of the disease.
Horizons Given that major psychiatric disorders such as schizophrenia, autism, and bipolar disorder are highly heritable, it is not surprising that we are beginning to see the identification of genetic elements that contribute to the development of these diseases. Knowledge of novel risk genes for mental disorders results in greater understanding of the biology of these disorders. We will learn how these genes are regulated, the function that the protein products of these genes perform, and how their dysfunction leads to mental illness. A practical application will involve the development of novel treatments targeting these dysfunctional proteins. Dr. Steven Hamilton is a psychiatrist and geneticist at the University of California, San Francisco. He received his PhD in biological chemistry and his MD from the University of California, Los Angeles. He was a psychiatry resident and research fellow at Columbia University. Dr. Hamilton’s research focuses on identifying the genetic determinants of behavior. A full list of references is available online at www.sfms.org.
Contribute to “The Greatest History Book Ever Written” National Geographic Wants Your Genetic Information From the National Geographic Web site
Where do you really come from? And how did you get to where you live today? DNA studies suggest that all humans today descend from a group of African ancestors who—about 60,000 years ago—began a remarkable journey. The National Geographic Society, IBM, geneticist Spencer Wells, and the Waitt Family Foundation have launched the Genographic Project, a five-year effort to understand the human journey—where we came from and how we got to where we live today. This unprecedented effort will map humanity’s genetic journey through the ages. Our genes allow us to chart the ancient human migrations from Africa across the continents. Through one path, we can see living evidence of an ancient African trek, through India, to populate even isolated Australia. “The greatest history book ever written,” Wells says, “is the one hidden in our DNA.” But to fully complete the picture we must greatly expand the pool of genetic samples available from around the world. The Genographic Project has established ten research laboratories around the globe and are hoping to get samples from as many people as possible. If you choose to participate and add your data to the global research database, you’ll help to delineate our common genetic tree, giving detailed shape to its many twigs and branches. Together we can tell the ancient story of our shared human journey. Visit www3.nationalgeographic.com/ genographic to find out more and to learn how you can participate.
September 2008 San Francisco Medicine 23
The Mystery of DNA
Unlocking the Genetic Mystery DNA Use in Criminal Investigations Eisha Zaid
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NA, deoxyribonucleic acid, has been viewed as the blueprint containing the instructions to life. The color of our eyes, our predisposition to developing certain diseases, our physical appearance, and our genes—these are just a few of the things dictated by the sequence of A, T, C, and G in our DNA. After the Human Genome Project sequenced the bases in the genome, scientists determined that there are 3 billion base pairs in our genetic code. Interestingly, any two individuals are more than 99 percent genetically identical, meaning that the sequences in their bases match perfectly more than 99 percent of the time. It is a difference of 3 million bases in our 3 billion base pairs of genes that defines the diversity we see between any two human beings. The variation in our DNA has been used for practical purposes, including tracing ancestry, understanding disease pathogenesis, and performing criminal investigations. Technological advancements and scientific discoveries have enabled DNA to emerge into the forefront, expanding the use of DNA beyond the lab. Having transformed to an essential forensic tool, DNA testing has become a part of a growing arsenal of criminal investigation instruments currently employed by law enforcement officials. With DNA testing, investigations are becoming more definitive, moving away from simply relying on an eyewitness account to extracting DNA to identify suspects. While the use of DNA testing can potentially take investigators one step closer to proving or disproving guilt, DNA use in criminal investigations represents a controversial topic that has several practical and ethical implications that must be carefully considered. ***
DNA testing is involved in identifying suspects involved in a crime, or the victims left at a crime scene. DNA testing has also been used to vindicate individuals who have wrongfully convicted. For the purpose
“Having transformed to an essential forensic tool, DNA testing has become a part of a growing arsenal of criminal investigation instruments currently employed by law enforcement officials.” of an investigation, DNA can be extracted from the crime scene from samples of blood, bone, hair, and other tissues, including semen from rape kits. From these tissues, the DNA is extracted and studied for the presence of particular markers. For a frame of reference, DNA from the suspect must also be acquired. The San Francisco Police Department crime lab, located in the Hunters Point Naval Shipyard, is a state-of-the-art facility equipped with the technology required to handle increased DNA testing. The Forensic Services Division performs the DNA testing, including processing DNA samples from blood, semen, hair, and saliva, on a case-bycase basis as well as analyzing DNA to type sex offenders and other criminals. If a drop of blood is left at a murder scene, investigators can use the blood sample to develop a DNA fingerprint to determine if the blood belonged to the victim or to someone else. To do so, investigators rely on the existence of stretches of DNA in
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human genome that are unique and variable between any two individuals. In processing samples for DNA testing, investigators use thirteen regions of DNA that are distinct in humans to create an individual DNA fingerprint. To create a genetic fingerprint, investigators develop a series of probes that are composed of small fragments of DNA. The probes are unique, because they are complementary to specific DNA sequences in the genome. Once the probes are created, a DNA fingerprint can be developed for the unknown DNA, based on how much the probes bind to the DNA acquired from the crime scene. The DNA profile can then be compared to the profile of a suspected perpetrator. The more DNA regions that match, the higher chance that the DNA extracted from the crime scene belongs to the suspect in question. To increase the odds, more probes can be used to scan more DNA regions. In the case of DNA left a crime scene, a positive match can only confirm that the suspected individual’s DNA was present at the crime scene. Ultimately, the combination of further investigation and a jury will determine a suspect’s fate; the DNA test will become another piece of evidence. Nationally, DNA forensic evidence is catalogued on a database called the Combined DNA Index System (CODIS). The database contains DNA profiles of individuals who have been convicted of violent crimes and sex offenses. DNA recovered from crime scenes can be compared to DNA profiles catalogued in the CODIS system. If a match is found, the suspect can then be identified. With the passage of the DNA Identification Act of 1994, all fifty states passed laws www.sfms.org
requiring that DNA profiles of convicted felons be catalogued in CODIS. As of April 2008, Congress passed legislation to require foreign detainees to provide DNA samples, regardless of whether or not they were charged of a crime. Essentially, these acts allow investigators to collect DNA from any individual who is arrested. *** As criminal investigations move toward using DNA testing, a number of ethical and practical issues emerge. The question becomes whether the pros of DNA testing outweigh the cons in criminal investigations. Aside from providing a type of scientific proof that a suspect was present at the crime scene, the advantages of DNA testing include ease of identifying repeat offenders, whose DNA is stored in the database. And if DNA is stored and can be easily accessed, investigation time and cost can be reduced. In addition, postconviction DNA testing can be used to exonerate the wrongfully accused, providing an additional route of proving innocence. Postconviction DNA testing has been used by the Innocence Project, an independent nonprofit organization affiliated with the Cardozo School of Law at Yeshiva University. The organization, which was founded in 1992, reports that “218 people in the United States have been exonerated by DNA testing, including 16 who served time on death row.” The organization reports that the wrongfully accused will typically serve an average of twelve years in prison before being exonerated and released. Although the Innocence Project aims to use postconviction DNA testing to exonerate the wrongfully accused, the organization understands the implications of DNA testing in reaffirming guilt. Clients are advised that the DNA results become part of public record, even if the results reaffirm a guilty verdict. Clients turn to the Innocence Project after exhausting most other routes of legal appeals. The demand for the services is high; thousands of prisoners await review of their cases. For those whose cases are reviewed, clients undergo an extensive screening process to determine if DNA evidence exists and if it can be used to prove innocence. www.sfms.org
The organization attributes wrongful convictions to a variety of factors, including eyewitness misidentification, unreliable or limited science, false confessions, forensic science fraud or misconduct, government misconduct, and ineffective lawyering. With increased use of DNA technology and a growing number of exonerations, the organization is alarmed by the inherent problems in the justice system. In addition to helping exonerate prisoners using DNA technology, the organization aims to introduce reform in the criminal justice system by partnering with legislators and law enforcement officials on the state, local, and federal levels. To address issues relating to wrongful convictions and reform the criminal justice system, the Innocence Project works with states to develop reform commissions that address issues surrounding wrongful convictions. A number of states have implemented reform commissions, which are charged with making key recommendations geared at addressing concerns surrounding investigations, lab operations, defense, prosecution, and judicial review. Although the Innocence Project, one of the forerunners that champions the rights of the wrongfully accused, has used DNA testing to correct injustices that have been committed against the innocent, a number of ethical issues must be considered when using DNA testing. The biggest concern revolves around privacy of the individuals whose DNA is stored in CODIS, including the convicted and individuals who were suspected, even if they were later proved to be innocent. *** Our DNA represents more than just a series of A, T, C, and G; our DNA holds the key to sensitive health information, including family history and disease susceptibility. We take such great efforts to protect our personal identity; how do we ensure the same for protecting our genetic identity? A number of concerns emerge when considering who gains access to genetic information and what would happen if the database was hacked and sensitive health information was sold to insurance companies or employers. If a suspected criminal has to provide DNA and it is later determined that he or she is innocent, his or her DNA will
be kept on record. And once an individual’s DNA is on record, law enforcement officials can access the information without an individual’s consent. Does such an act violate an individual’s rights? Search warrants are required to enter into a suspected individual’s property. Should the same rules apply before an investigator trespasses into someone’s genetic code? Another consideration we must make revolves around the limitations of DNA technology, including concerns of contamination or mishandling evidence. Proper oversight will be needed to ensure DNA samples are processed properly, especially as the DNA technology advances to prevent false positives and wrongful convictions. In addition, analyzing DNA results has its limitations. For example, does a positive DNA match, or partial DNA match, mean an individual committed a crime? What if someone’s DNA was left at the crime scene because they had visited the scene earlier? DNA testing only says that the DNA at the scene matches that of an individual. But further investigation would be required to link the crime to that or any individual. Despite the myriad of disadvantages, DNA testing has advanced criminal investigations by opening an entire new frontier of forensic technology to convict felons and exonerate the wrongfully accused. The double-edged sword that is DNA testing requires careful consideration when DNA results come into question during an investigation. As much as DNA testing provides scientific proof, the matter of innocence or guilt will ultimately come down to a human process, including investigators who must process the DNA and a jury who must unravel the mystery behind the evidence and determine how it fits in the puzzle that determines the fate of someone’s life. Eisha Zaid is a secondyear medical student at UCSF.
September 2008 San Francisco Medicine 25
Book Review Steve Heilig, MPH
Darwin and Literature Madame Bovary’s Ovaries: A Darwinian Look at Literature By David P. Barash and Nanelle R. Barash Delacorte (2005), 262 pp.
W
hat if Charles Darwin wrote a novel? What if he wrote them all? Well, maybe he did, in a sense; the thesis of Madame Bovary’s Ovaries is that Darwin, or rather the forces of evolution and natural selection that Darwin did write about, underlie the plot and behavior of all human characters in literature. David Barash is a well-known zoologist at the University of Washington, and his daughter Nanelle is a student at Swarthmore. They call their perspective that of evolutionary psychology. Almost thirty years ago, a massive tome bearing that title by famed Harvard biologist E. O. Wilson posited that human behavior has a strong genetic component, thus setting off a firestorm of criticism, both scientific and, especially, political. A number of subsequent books, such as Richard Dawkins’s The Selfish Gene, have explored this perspective with similarly controversial results. Not so fast, reply the Barashes. They proceed to survey the best of literature—Western, anyway—for evidence of our Darwinian urges. And those, it would appear, largely come down to doing whatever we can to ensure that our genes live on after our bodies. “Whether bat or bird, seal or spider, living things reproduce because this is the major way their genes propagate themselves,” the Barashes write. “It is also the major reason for love, including love of adults for each other and of parents for children.” Apparently, even love is a genetic adaptation. Thus, from the works of Homer through Shakespeare to Tolstoy, Dostoevsky, Dickens, Twain, Faulkner, Austen, Joyce, Nabokov, Steinbeck, and right up to Kundera, Márquez, Alice Walker, and even Charles Bukowski, the storylines, however poetic, convoluted, steamy, or spiritual, are really about the rules of the jungle—or desert or boardroom or bedroom or anywhere the struggle for survival takes place—even though most authors have been largely unaware they are being guided to some degree by the “evolutionary bottom line.” The primary theme is, apparently unavoidably, sex. Men want to spread their genes far and wide and can easily do so, at least physically; women must be more careful. Men look for women who appear to be good potential childbearers but who will not cuckold them; women 26 San Francisco Medicine September 2008
look for providers, from ancient Greek myth up to Bridget Jones. A peacock’s feathers or a Porsche are similar male displays. Othello is a “dominant bull elk,” driven to murder and madness by male sexual jealousy—a common dynamic the Barashes then trace through many of Shakespeare’s other plays and onward to The Great Gatsby. In Flaubert’s famous novel, which provides the title for the Barashes’ book, poor Emma Bovary herself, a bit “loose” for her times, was merely yielding to deep-set desires for a better “catch” and the possibility of “marrying up,” looking for someone who would ensure reproductive success. The mobsters in The Godfather put family above all else for the same nepotistic reasons that a pride of lions on the savannah would. On the other hand, the Joads and other desperate farmworkers in The Grapes of Wrath cleave to one another outside of family ties due to “reciprocal altruism,” at bottom expecting some sort of payoff from helping others. Thus even friendship, wherein reproduction should not be an issue, is underneath it all a game of mutual back-scratching, rooted in needs for food and protection. The Barashes have read widely, thought hard, and produced an engrossing, provocative work of literary speculation. If some of their interpretations seem too cynical in the end, they remind us, as Katherine Hepburn’s character in the movie adaptation of C.S. Forster’s The African Queen argued, “Nature, Mr. Allnut, is what we are put on earth to rise above.” Though, as many classic novels show, doing so is not always easy and sometimes not so entertaining. This review originally appeared in the San Francisco Chronicle.
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Book Review Erica Goode, MD, MPH
Breast Cancer Risk: An Expert Speaks Assess Your True Risk of Breast Cancer Patricia Kelly, PhD Henry Holt and Co. (2000), 253 pp.
D
r. Patricia Kelly, specialist in cancer risk assessment and counseling, states that many women with a family history of a cancer have come to her feeling that the “other shoe will drop.” However, Dr. Kelly points out, the opposite is the case. Typically, an unexamined risk is overblown and daughters are seeking bilateral mastectomies and oophorectomies without adequate information of risk. This book gives examples of peoples’ issues and ways to find answers to an array of questions. Dr. Kelly decodes the language of genes, oncogenes, and what is known of hereditary cancers, and she discusses BRCA genetics, CA-125, and genetic testing issues. A few chapters are devoted to discussing benign breast disease, ductal cancer in situ, and lobular carcinoma in situ. Another covers the limited change in breast cancer risk associated with hormone replacement therapy. Yet another discusses other factors thought to increase risk, such as age at pregnancy, alcohol, and diet. The book then shifts to arming the reader with a clear method of navigating the medical system to best advantage, proceeding through a series of best steps. One needs a primary physician who is open to spending time on a topic and who knows and will refer patients to appropriate specialists and second-opinion sources as needed. Dr. Kelly provides an insert regarding the Women’s Health Initiative study, the results having been released after the book’s publication. As originally reported, the WHI study “conclusively”
showed an increased risk of breast cancer in those taking Prempro. However, Dr. Kelly shows (as I and a number of physicians, notably Ricki Pollycove, have thought all along) that in fact the WHI study does not demonstrate a statistically significant increase in breast cancer risk in women taking Prempro. The difference between those treated and those untreated was 8/10,000 women/year. And since the study was stopped after five years, despite our knowledge that a breast cancer takes more than eight years to reach even a small size, and despite intense objections to the conclusions released to the media by one of the primary investigators, the results, from Dr. Kelly’s analysis, are not what they seem. Each chapter is summarized with a list of key points to remember, and Dr. Kelly completes the directive with a chapter entitled “Living at Ease with Uncertainty,” which is the ultimate key point. The appendix includes a glossary and screening questionnaires for women to use to decide if they should seek cancer risk assessment. Because this book is infinitely readable and provides a road map to this highly charged issue in women’s lives, it would be advisable for any primary care or oncology office to provide several loaner copies for the benefit of all concerned. To order these, contact Patricia T. Kelly at ( 510) 527-8938 or ptkelly@ptkelly.com. This book is a wise and practical guide for anyone trying to weigh the statements they have heard from doctors, read in the lay press, and gleaned from other media, friends, and relatives.
2008-2009 SFMS Member Directory Available Now! Directories are now available! All SFMS members receive one copy of this valuable resource as part of their memberships. Please watch for your copy in the mail. If you are interested in ordering additional copies please contact Carol Nolan at (415) 561-0850 extension 0 or cnolan@sfms.org for information.
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September 2008 San Francisco Medicine 27
hospital news Chinese
Joseph Woo, MD
The Chinese Community Health Plan’s colorectal screening program has continued to receive national attention. In fact, it has received finalist recognition for the 2008 Community Leadership Award at the June meeting of the American Health Insurance Plan Institute from its board of directors; its poster presentation was displayed in the reception hall later that evening at its opening reception. This program will also be presented at the National Cancer Institute’s conference on disparities in Washington, D.C., in July as part of a presentation on colorectal cancer by the Asian American Network for Cancer Research and Training (AANCART). AANCART is an NCI special-needs grant, and the San Francisco AANCART Chinese Council is one of two AANCART regional sites in San Francisco. Our esteemed CCHP Medical Director/IPA Executive Director, Dr. Edward Chow, serves as the principal regional investigator, and Dr. Justin Quock is the clinical director for our site. In November, Dr. Chow will be presenting his experience on colorectal screening at the annual meeting of the Chinese American Medical Association in New York City. Our thanks to Drs. Chow and Quock for the excellent community work they have been doing. Chinese Hospital medical staff and our IPA are members of the Federation of Chinese American and Chinese Canadian Medical Societies (FCMS) and, as such, will be supporting the Fourteenth Conference on Health Care of the Chinese in North America September 28–29 in Toronto. This conference occurs every two years and rotates host sites across North America. This year’s topic is “Emerging Health Issues among North American Chinese” and there will be an inaugural Dr. Harry Lee Memorial Lecture. FCMS is dedicated to promoting the health of Chinese in North America through education, advocacy, and communication. Check out the website at www.fcmsdocs.org. The current president of FCMS is our own Dr. Randall Low, and we are proud of the great job he is doing!
Kaiser
Robert Mithun, MD
The history of the Kaiser Permanente Northern California Regional Genetics Program parallels the history of medical genetics. It was in the 1950s, a decade before our genetics program had its beginnings, that Watson and Crick described the structure of DNA. In the 1960s, when our program was launched, Nierenberg had just “cracked the genetic code” at the National Institutes of Health. By the time the human genome project was completed in 2003, the Kaiser Permanente Regional Genetics Program had expanded to become the largest and most comprehensive clinical and laboratory genetics program in the country. The regional genetics program at Kaiser Permanente offers cutting-edge services in all areas of medical genetics, including genetic evaluation and diagnosis, counseling, testing, and treatment. A full range of genetic testing, including molecular DNA, cytogenetics, and cancer genetics, is available through a regional laboratory. Multispecialty clinics provide ongoing care for many common genetic conditions: craniofacial problems, spina bifida, metabolic disorders, skeletal disorders, neurofibromatosis, and neurogenetic problems. Kaiser Permanente also has extensive genetic screening services including newborn screening, hemoglobinopathy screening, ethnicity-based genetic carrier screening, breast cancer screening and tracking, and infectious disease screening. The Regional Genetics Education Program is a new addition that reflects the increasing demand for genetic information. The mission of the regional genetics program is to provide genetics education to Kaiser Permanente providers and health plan members, and to help both groups understand the contribution of genetics to overall health and wellness. The San Francisco Genetics Department was founded in 1982 and covers a service area ranging from Santa Rosa to Daly City. The department includes two medical geneticists, eight genetic counselors, and a genetics nurse available to address the genetic needs of health plan members and provide consultative services.
28 San Francisco Medicine September 2008
Saint Francis
Wade Aubry, MD
Saint Francis has had an interest in issues related to the human genome for several years, which has been led by medical geneticist Patricia Kelly, PhD. Dr. Kelly is recognized as one of the nation’s leading experts in medical genetics and cancer risk assessment. She is a diplomate of the American Board of Medical Genetics and a founding fellow of the American College of Medical Genetics. Dr. Kelly has been on the Saint Francis staff for almost ten years, in addition to providing counseling and educational programs for the community over the past several years, and she now maintains a private practice in cancer risk assessment and counseling in the Bay Area. One of her key areas of interest has been the use of genetic testing for BRCA-1 and -2 in the management of familial breast cancer and ovarian cancer. President and CEO Tom Hennessy recently announced the appointment of new Chief Operating Officer Tony Jackson. Mr. Jackson has a doctorate of pharmacy from Florida A&M University and a master’s in business administration from UCLA. He started in his new position on July 28 and brings a wealth of experience in operations, strategic planning, and contract negotiations to the hospital. He will work closely with Robert Vautrain, MD, VPMA, and the medical staff leadership to build on the success shown by our favorable Joint Commission Survey in June. And finally, congratulations to John Meyer, MD, on the publication of the book he edited, IMRT, IGRT, SBRT: Advances in the Treatment, Planning, and Delivery of Radiotherapy. The volume is a comprehensive guidebook to new technologies in radiation oncology and the many clinical treatment programs that bring them into practical use, and it provides essential treatment guidelines for clinical and technical practitioners. www.sfms.org
hospital News St. Luke’s
Jerome Franz, MD
With the Blue Ribbon Panel’s July report on the future of St. Luke’s, there has been noticeably more hope in the lunchroom, corridors, and offices of our campus. We will have a new hospital meeting seismic safety standards. It will be adjacent to the west side of the 1970 tower and designed for sixty acute-care patients. Outpatient services will also be expanded. We will continue our excellent programs in obstetrics and cardiology and plan a new center of excellence for geriatrics, which will be multidisciplinary. We await details and the approval of the CPMC Board. We commend and thank the members of the Blue Ribbon Panel for their commitment to this community and its health care. On July 2, the chaplaincy provided a memorial service for two longtime St. Luke’s doctors. Pedro Pinto practiced family medicine at 16th and Mission for forty years and served as Chair of Family Practice. Born in Ecuador, he came to San Francisco in 1952 and always maintained close ties with his home country. He was a model of dress and deportment, revered by his patients. He retired some years ago to spend more time with his family. He passed away in May. Stanley Baer recently retired from forty years of orthopedic practice at St. Luke’s. He also served as chair of his department. He is remembered for his excellent care and his willingness to work with underinsured as well as private patients. He kept many of us entertained with stories about his family, and he always seemed to be available for consultation. He died in June.
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St. Mary’s
UCSF
Richard Podolin, MD
Elena Gates, MD
Complex traumatic injuries requiring multiple procedures from several specialty surgeons can present medical and care management issues for both the patient and the physician. Last fall, St. Mary’s Medical Center responded to the need for a more efficient care setting by opening an outpatient Plastic, Reconstructive, and Orthopedic Surgery (PROS) Center with a team of top surgeons from St. Mary’s, UCSF, and the Orthopedic Trauma Institute at San Francisco General Hospital. Working collaboratively, surgeons are able to perform even the most complex reconstructive procedures more proficiently and with fewer procedures. Patients recover more quickly and have improved outcomes. Orthopedic and plastic surgeons work together from the very beginning to develop individualized treatment plans that take into account all aspects of a case, whether it is a leg crushed in an accident, a wound that fails to heal, a severed finger, or any other injury that would benefit from this multispecialty team approach. One young man, who had lost his thumb in a woodworking accident, underwent a toe-to-thumb transplant and now has a working thumb with full motion. In another case, a man who had experienced a tibia fracture with subsequent infection had been told he was going to lose his leg. PROS Center surgeons cleaned out the infection in his bone and performed a skin graft—saving the leg of the very grateful patient. The PROS Center team of orthopedic and plastic surgeons specializes in the treatment of traumatic injuries and posttraumatic complications, including acute bone and soft tissue injuries; brachial plexus injuries; trauma complications; limb salvage surgery; pelvic and acetabular fracture surgery; complex hand, wrist, and elbow surgery; flap reconstruction of the extremities, face, and breast; chronic wound problems; and osteomyelitis. The development of the surgically innovative PROS Center exemplifies the mission and pioneering spirit of St. Mary’s Medical Center.
We were pleased to learn recently that UCSF Medical Center has retained its ranking as the seventh best hospital in the country, and the best in the Bay Area, according to the new 2008 “America’s Best Hospitals” survey conducted by U.S. News & World Report. This year UCSF earns a spot on the survey’s “honor roll,” which recognizes a breadth of excellence across specialties. UCSF placed among the top ten medical centers in endocrinology, neurology and neurosurgery, gynecology, urology, cancer, respiratory disorders, rheumatology, and ophthalmology. “We are proud to consistently rank among the top ten hospitals in the nation,” said UCSF Medical Center CEO Mark Laret. Human genetics is playing an increasingly important role across the range of specialty services at UCSF. In the Helen Diller Family Cancer Center, the Cancer Risk Program provides counseling and testing as well as prevention and screening strategies. Genetic profiling of individual cancers now guides treatment choice. The Program in Cardiovascular Genetics evaluates and treats patients with a variety of genetic heart disorders, including arrhythmia and cardiomyopathy. In the neurosciences, genetic knowledge is improving the care of children with neurometabolic conditions in the Metabolic Disease Center, and families affected by neurodegenerative diseases such as Alzheimer’s, in the Memory and Aging Center. UCSF’s Prenatal Diagnosis Center collaborates with specialists across the institution in helping families with inherited diseases make decisions about childbearing. Throughout UCSF, genetic knowledge is being used to improve health.
September 2008 San Francisco Medicine 29
hospital News In Memoriam Veterans
Diana Nicoll, MD, PhD, MPA
Representative David Obey (D - WI), Chair of the House Appropriations Committee, recently visited the San Francisco V.A. Medical Center. He was accompanied by House Speaker Nancy Pelosi (D - CA), a longtime supporter of the Medical Center. Mr. Obey and Speaker Pelosi received briefings on clinical and research activities. Charles Marmar, MD, chief of Mental Health, and Thomas Neylan, MD, director of the Posttraumatic Stress Disorder (PTSD) Program, reviewed clinical and research initiatives in the diagnosis and treatment of PTSD. Chief of Medicine Paul Volberding, MD, discussed AIDS research at SFVAMC, noting that the V.A. system is the largest provider of HIV/AIDS care in the U.S. Speaker Pelosi commended the high quality of health care for veterans being provided at SFVAMC and observed that the San Francisco V.A. Medical Center’s prominent position as a research center “can be attributed to the high caliber of clinicians and scientists here, which is a result of the strength of the collaboration between SFVAMC and UCSF.” Following the briefings, they toured the new 3-D Imaging Laboratory and heard about the latest radiologic and neurologic advances from Senior Scientist Norbert Schuff, PhD; Parkinson’s Center Director William Marks, MD; and Chief of Radiology Judy Yee, MD. They concluded their tour by visiting several hospitalized patients, including a patient referred from American Samoa. Obey was “very impressed by all the great work” being done at the San Francisco V.A. Medical Center. “This is why we’ve made veterans’ health our first priority in Congress,” he said. “I’ve been a fan of this place for many years,” responded Speaker Pelosi.
Robert Louis Marvin, MD Robert (Bob) Marvin, MD, was born in Los Angeles on June 30, 1925, and died at home in San Francisco on June 26, 2008. He became a long-term resident of Marin County after growing up in Southern California and completing his psychiatric training at the Harvard Services of Boston Psychopathic and Massachusetts Memorial Hospitals. Toward the end of a highly productive clinical and community-oriented medical career, Bob specialized in workers’ compensation and Social Security disability psychiatric assessments and services. He served as clinical professor of psychiatry at the University of California, San Francisco School of Medicine until he retired. As a young boy in Los Angeles, Bob Marvin performed a number of times on stage as a child actor. He was a member of the professional actors’ union, AFTA. From his youthful career issued a lifelong enthusiasm for theatrical performances and musical events. During World War II he joined the Navy, and at war’s end he entered UCLA, where he earned a Phi Beta Kappa key as a junior and qualified for medical school at UCSF. Interning at St. Elizabeth’s Hospital, Washington, D.C., he went on to train in general psychiatry in Boston. He became a diplomate of the American Board of Psychiatry and Neurology in 1958, two years after his ultimate move to Northern California. Since 1956, he has been
a staff member at Mt. Zion Hospital, San Francisco, McAuley Psychiatric Clinic of St. Mary’s Hospital, and St. Francis Hospital Department of Psychiatry. From 1982 to 1985, he served as chairman of the psychiatry department at St. Francis. He also functioned as a president of the Northern California Psychiatric Society. Throughout this time, he taught and supervised medical students and resident physicians at UCSF. He also took part in teaching psychologists-in-training at both Mt. Zion Hospital and UCSF. Bob served on the Editorial Board for San Francisco Medicine. He chaired the SFMS Committee on Mental Health and was a member of Professional Relations and the Impaired Physician committee. Bob never gave up his special affection for music and the theater. He loved travel, art, and reading. He will be remembered for the love and care he gave his family, friends, and profession; for his boundless energy; his energized smile; his attention to details; and a willingness to take risks. He loved life. Bob Marvin died of pancreatic cancer following a prolonged and brave fight against the disease. He is survived by his wife of twenty-three years, Connie, his brother Frederick, and by his children, Jody and Jonathan.
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30 San Francisco Medicine September 2008
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..They seem happy now, but... can you identify the one who may sue you for: ...Wrongful termination? ...Discrimination? ...Sexual harassment by a fellow employee?
Is that in my job description? .How was I supposed to know I wasn’t supposed to say that?z
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