Volume 17 Number 3 FALL 2000

’scope

A QUICK LOOK AT THE LATEST DEVELOPMENTS FROM STANFORD UNIVERSITY MEDICAL CENTER

Bio-X moves into high gear

HOW CLOSE ARE WE TO THE DAY WHEN "SCIENCE FICTION" MEDICINE BECOMES REALITY -- THE DAY WHEN DAMAGED SYNAPSES IN YOUR NERVOUS SYSTEM WILL BE REPLACED BY ELECTRONIC CHIPS AND PERSONAL VACCINES TO FIGHT CANCER WILL BE STANDARD TREATMENT?

Such medical breakthroughs may be closer than expected, thanks to a decision this October by the Bio-X program, which awarded 19 grants to Stanford faculty members, amounting to nearly $3.03 million for innovative biological research.

* Bio-X, a faculty-run program designed to promote interdepartmental bioscience research, became a reality one year ago following a $150 million donation from former engineering professor Jim Clark -- the largest single gift to Stanford since the founding grant in 1885.

The first round of awards took place this spring when Bio-X committed $7 million in grants to build and upgrade research facilities and laboratories. At the same time, the newly formed Bio-X Interdisciplinary Initiatives Program Committee sent out a request to faculty members for proposals for imaginative new interdisciplinary, interactive research and educational projects in biology, medicine, computer science, engineering and other disciplines.

* This October, the committee announced that of the 85 proposals submitted, 19 will receive seed grants, averaging $158,000 over a two-year period. After that, researchers are expected to obtain independent funding.

"One of the key criteria in our decision-making process was that a proposal had to be truly interdisciplinary," says committee chair Harvey Cohen, MD, PhD, a professor of pediatrics in the School of Medicine.

A good example of that approach, he notes, is a proposal submitted by computer scientist Carlo Tomasi, PhD, and radiologists Christopher Beaulieu, MD, PhD, and Sandy Napel, PhD. Their project, one of the 19 grant recipients, combines diagnostic radiology with state-of-the-art computer imaging.

Over the past few years, Tomasi and his colleagues note in their proposal, medical imaging devices such as CAT scans and MRIs used to take pictures of the inside of the human body have been markedly improved compared with earlier devices. As a result, diagnostic radiologists who interpret the pictures often review as many as 1,000 separate images of a single patient in a few minutes.

"Trying to interpret such a large amount of information accurately and thoroughly is unquestionably beyond human capacity," add the authors. "Fortunately, the information contained in medical images can be 'seen' by tireless and ever more powerful computers if they are appropriately programmed. Going beyond simple programming, we will develop tools that will enable our computer programs to 'learn' more about human anatomy and the differences between normal and abnormal."

Interdisciplinary education is another major component of Bio-X, explains Cohen, which is why one group received a grant to create a new course for graduate students in biological and engineering sciences called "Introduction to Medical Sciences."

The goal of the class will be to equip biomedical scientists/engineers with an understanding of disease sufficient to allow them to understand and pursue areas of medical research in which they can apply their more specialized training to clinical problems, says Jane Parnes, MD, a professor of medicine and one of the coordinators of the course. The 3-unit course may be offered to graduate students as early as spring 2001.

"The committee really feels that these 19 grants will help define where Bio-X is going," says Cohen, "because all of the proposals came straight from our faculty."

And, adds Cohen, faculty who had no project funded in this round can look forward to another request for proposals -- if all goes well -- in the not too distant future. -- MS

Virtual colonoscopy

THE LATEST IN VIRTUAL REALITY TECHNOLOGY HAS MOVED OUT OF THE ARCADE AND INTO EXAM ROOMS AT STANFORD UNIVERSITY MEDICAL CENTER. But the radiologists using the technology are playing a serious game -- attempting to accurately diagnose precancerous masses in the colon and rectum using a new, noninvasive technique to scan the interior of the digestive tract.

If the new method passes muster, it will allow thousands of people to avoid a more invasive test that can be somewhat uncomfortable and embarrassing. Aversion to such procedures causes many people to put off recommended screening tests for colorectal cancer, even though such tests offer a real chance of saving their lives.

Colorectal cancer is the second leading cause of cancer-related deaths in this country. About 150,000 people will be diagnosed with colorectal cancer this year, and more than 50,000 people will die of the disease.

Colorectal cancers almost always begin as abnormal growths, or polyps, springing from the lining of the large intestine or rectum. If the polyps are detected and removed before they become malignant (the chance of malignancy increases significantly as the polyp grows), the patient escapes this deadly cancer.

"Many of these cases are totally preventable if adequate screening is done," says R. Brooke Jeffrey Jr., MD, a professor of radiology and member of the gastrointestinal multidisciplinary tumor board at Stanford's Clinical Cancer Center. Jeffrey is a member of the Stanford team working to develop a virtual method reliable enough to replace the current gold standard of colorectal screening, the colonoscopy.

* During traditional colonoscopy, a flexible fiber-optic tube is inserted into the rectum and threaded up through the colon, giving the physician an unobstructed view of the interior of this part of the digestive tract. Any unusual growths can be immediately removed and biopsied.

Although its effectiveness for preventing and detecting colorectal cancer is unquestioned, many patients shy away from the test, which in addition to being uncomfortable requires sedation and a day off from work.

* In contrast, the virtual colonoscopy test being developed at Stanford and other academic centers uses a machine that spirals around their body to generate multiple computerized tomography (or CT) scans -- a series of about 400 images of the patient's abdomen and pelvis. The entire scan takes less than a minute and requires no recovery period. About 70 patients have undergone the procedure at Stanford since the study began four years ago.

The images, each an incremental "slice" of the patient's torso, are assembled by computer into a three-dimensional representation of the patient's colon. Sophisticated software takes physicians on a virtual tour of the interior of the large intestine, allowing them to zoom back and forth at will, occasionally pausing to rotate the image for a better view. The overall effect is somewhat like watching a bobsled race from the hood of the sled. Small bumps in the track may indicate the presence of polyps that should be removed.

* So far the results have been promising, says research team member Sandy Napel, PhD, associate professor of radiology.

But until the new technique is perfected, say Napel and Jeffrey, it's important to use available methods to prevent colorectal cancer. The American Cancer Society recommends that every American get a traditional colonoscopy at age 50, and every 10 years thereafter. Other screening tests, including collecting stool samples to check for the presence of blood or having a digital rectal exam by your physician, are also important and should be conducted regularly. If colorectal cancer is discovered before it has spread, the five-year survival rate is greater than 90 percent.

If you are concerned that you may be suffering from symptoms of colorectal cancer, such as bloody stool, a change in bowel habits, abdominal discomfort, unexplained weight loss, vomiting or tiredness, talk to your doctor. -- KC

Stanford launches first startup

ON MAY 9TH, STANFORD'S NEWEST GRADUATE WAS NOT SPORTING A PHD OR AN MD, BUT A NEW SET OF LETTERS -- DOT COM. The launch of e-SKOLAR, Stanford's first Internet spin-off, represents an extension of the University's core mission, to promote knowledge and enhance learning, says the School of Medicine's dean, Eugene Bauer, MD.

The company's first product, Stanford SKOLAR, MD, is based on the School of Medicine's computerized reference tool known as SHINE (the Stanford Health Information Network for Education), which was created over the past four years by professor of medicine (emeritus) Ken Melmon, MD, and a team of students and faculty from the schools of computer science and medicine.

The company's second major enterprise, announced this fall, is SKOLAR, RN -- a joint project with Yale University to provide a similar information resource for nurses.

For several years, SHINE has allowed Stanford students, physicians and researchers to perform quick integrated searches of multiple medical reference sources -- including textbooks, medical journals, drug databases and clinical guidelines. By entering an unstructured query, users can find disease or symptom information ranging from basic definitions to drug dosage schedules for patients with complicating factors such as pregnancy or a secondary illness. Stanford physicians currently use the service to supplement their clinical decision making.

Now, through SKOLAR, MD, clinicians across the country can use the tool as well. Any physician or medical group can subscribe to the service for an annual fee of $240 per user. Agilent Technologies Inc. (a subsidiary of Hewlett-Packard) is e-SKOLAR's first distribution partner and is incorporating SKOLAR, MD in a new generation of Internet-enabled medical product devices. The company plans to incorporate SKOLAR, RN as well. -- KC

Preserving fertility through egg-freezing

CANCER PATIENTS AND OTHER WOMEN AT RISK OF LOSING THEIR FERTILITY BECAUSE OF MEDICAL TREATMENTS CAN HELP PRESERVE THEIR CHILDBEARING OPTIONS THROUGH A NEW EGG-FREEZING PROGRAM.

* Under the Stanford program, women ages 18 to 40 who are undergoing chemotherapy, radiation or surgical removal of the ovaries can choose to have their eggs retrieved before treatment and then stored indefinitely in a freezer for possible future fertilization.

"A lot of people don't realize that there are things we can do that may help future fertility," says Lynn Westphal, MD, director of the Medical Center's donor oocyte program and a Stanford assistant professor of gynecology and obstetrics."It's something women should know about and have a discussion about before they have chemotherapy or other treatment for their disease. Later on, we may not be able to reverse any damage that occurs to the ovaries."

* Fewer than 100 women worldwide reportedly have become pregnant as a result of the experimental process in which their eggs were frozen, thawed and then fertilized in the laboratory, says Barry Behr, PhD, assistant professor of gynecology and obstetrics and director of Stanford's In Vitro Fertilization (IVF) and Assisted Reproductive Technologies laboratories. Few medical centers in the country offer this option, and Stanford has the only program in the Bay Area with an approved research protocol, he says.

Frozen sperm have been used for many years for preservation of future fertility as sperm are much smaller cells than eggs, making it more likely that they would survive a freezing and thawing process. But the use of frozen eggs in IVF treatment became a viable option in the mid-1990s with the introduction of a technique called intracytoplasmic sperm injection (ICSI). ICSI involves injection of a single sperm into a single egg in order to achieve fertilization. With ICSI, the chance of success is much higher, with reported fertilization rates approaching 65 percent, Westphal says.

* IVF treatment using frozen eggs, however, is still considered experimental and is reserved only for women undergoing medical treatments that directly affect their fertility, Westphal says.

"This is meant to help women who are going to have their fertility cut short because of a medical treatment and not for women who are going to delay fertility because of timing," Westphal says. "These women do have a choice, and I would hate for them to delay their childbearing when there are no guarantees that pregnancy will result from their frozen eggs."

* Women who are interested in the egg-freezing program can contact IVF nurse coordinator Andrea Speck-Zulak, RN, at (650) 498-4721. -- RR

Now open

THE NEW CENTER FOR CLINICAL SCIENCES RESEARCH (CCSR) WAS DEDICATED MAY 18 AT A CEREMONY ATTENDED BY ABOUT 225 FACULTY, ALUMNI, STUDENTS AND STAFF. The building, located next to the Beckman Center,

is designed to encourage intellectual exchange and collaboration among scientists in a variety of basic science and clinical disciplines.

Research specialties of the new neighbors include anatomy, bone marrow transplantation, dermatology, genetics, immunology, molecular pharmacology and oncology. The building's inhabitants will also include representatives from the departments of pathology, radiation oncology and surgery.

The mix-and-match atmosphere is intended to shake things up a bit, inspiring the basic scientists to realize additional potential clinical applications of their research and enabling the clinical researchers of the group to preview new findings that may soon be coming their way. -- KC

Researchers solve structure of "most important protein in biology"

STANFORD RESEARCHERS HAVE ASCERTAINED THE STRUCTURE OF THE RNA POLYMERASE PROTEIN, ONE OF THE PIVOTAL MOLECULES IN BIOLOGY. The polymerase protein is an enzyme that copies genes from DNA to RNA -- an essential step in the transfer of information from gene to protein.

* "It is arguably the most important protein in biology," says Roger Kornberg, PhD, professor of structural biology. "The structure provides the basis for understanding all gene activity in eukaryotic cells," says Kornberg, whose group's findings were published in the April 28, 2000, issue of Science magazine.

RNA polymerase II is the first apparatus in the production line from gene to protein. Its task is to faithfully copy regions of gene-containing DNA into strands of messenger RNA (mRNA) -- a process called transcription. Later the protein-making machinery -- the ribosome -- uses the mRNA as a template to make proteins.

* As the human genome project nears completion, soon the entire DNA sequence of a human being will be revealed. "But on its own, this information is silent," says Kornberg. "RNA polymerase gives it voice." That is because every cell of the human body contains the same DNA. What makes varied cells -- such as blood, nerve and liver cells -- differ is the selection of which genes are to be copied by RNA polymerase into mRNA for the eventual production of different proteins in each cell type.

"Transcription of some genes but not others by RNA polymerase is the basis for development of a single cell, the fertilized egg, into a human with many cell types. The solution of the RNA polymerase structure is necessary to understand this process," he explains.

* The RNA polymerase enzyme actually consists of 12 separate protein subunits. Using data collected via X-ray crystallography, researchers in Kornberg's lab made a model of how the subunits fit together to form the enzyme complex. "Jaws," "clamp" and "funnel" are the names he and his collaborators have given to the complex's individual parts. Regions of three subunits combine to form a pair of pincer-like jaws that trap the DNA near the gene that will be transcribed. The clamp portion of the molecule then swings over the DNA and locks closed, ensuring a tight coupling between the RNA and DNA. Components for the growing mRNA strand enter the machinery through a central pore and funnel. The opening also serves as a waste portal for incorrectly transcribed mRNA.

* Members of the Kornberg lab crystallized the RNA polymerase molecule from yeast; but previous studies have shown the genetic makeup of the yeast and human proteins to be very similar, leading the scientists to believe that the shape of the two proteins is the same. Yeast and humans are eukaryotic organisms, which carry their DNA packaged in chromosomes inside the cell nucleus. This key feature separates fungi (the group that includes yeast), animals and plants from bacteria, which have no cell nucleus. The team worked with yeast because biochemical and genetic studies can easily be done in yeast to confirm and supplement their results.

Though microscopic, the RNA polymerase (at 500 kilodaltons) is unusually large for an enzyme. It is the largest protein structure ever determined and was seen as a great technical challenge. It took at least five years for the researchers to master the skills to produce crystals of the enormous protein complex, but their troubles did not end with the crystallization. Postdoctoral fellows Patrick Cramer, PhD; Jianhua Fu, PhD; and David Bushnell, PhD, worked on the crystals for another five years, learning how to modify traditional methods to cope with the large size of the complex, before the structure was finally revealed. It was December 17, Kornberg remembers, when Cramer computed the final data showing that the problem was solved.

The RNA polymerase enzyme is the focal point of an even larger protein complex that initiates mRNA transcription. Researchers in Kornberg's lab are now busy solving the structure of the additional 50 proteins that form the larger complex. -- KW

Brown named VP of development, alumni affairs

JACQUELYN BROWN, WHO HAS SERVED AS THE PRINCIPAL STRATEGIST AND AUTHOR OF VIRTUALLY ALL MAJOR FUND-RAISING PROPOSALS FOR THE MEDICAL CENTER OVER THE PAST FIVE YEARS, BECAME THE SCHOOL OF MEDICINE'S NEW ASSOCIATE VICE PRESIDENT FOR MEDICAL DEVELOPMENT AND ALUMNI AFFAIRS IN MARCH.

Regarding her new position, Brown says, "This is a time of unprecedented promise for biomedical research, education and patient care at Stanford.

"I look forward to working with colleagues at the Medical Center and the University, as well as patients, their families and friends of Stanford, to help make sure we live up to that promise," she adds.

Brown joined Stanford University Medical Center in 1987 as director of development communications and held that position until 1994. During that time, the publications under her direction won three gold medals and two silver medals from the Council for Advancement and Support of Education. In 1994 Brown became deputy director of the Office of Medical Development and director of major gifts.

Since 1997, Brown has served as director of the Office of Medical Development, overseeing the Medical Center's fund-raising program. With key faculty and volunteers, she spearheaded the successful $75 million campaign for Stanford's Center for Clinical Sciences Research. -- JT

Home pesticide use linked to Parkinson's Disease

A STUDY OF OVER 475 PEOPLE NEWLY DIAGNOSED WITH PARKINSON'S DISEASE HAS FOUND THAT EXPOSURE TO PESTICIDES AT HOME MAY BE ASSOCIATED WITH AN INCREASED RISK OF DEVELOPING THE DISEASE.

"This study is the largest yet of newly diagnosed individuals with Parkinson's disease and it is the first study to show a significant association between home pesticide use and the risk of developing Parkinson's disease," says neuroepidemiologist Lorene Nelson, PhD, associate professor of health research and policy and co-author of the study.

* The researchers interviewed 496 people who were diagnosed with Parkinson's disease in 1994 or 1995 about pesticide use in their homes. The researchers wanted to know if patients had handled or applied herbicides (to kill weeds), insecticides (to kill insects) or fungicides (to control mold or mildew) in the home or garden. The researchers then asked detailed questions about past pesticide use, including when patients first were exposed and how frequently they came into contact with such chemicals. The researchers also queried the respondents on lifestyle factors such as cigarette, alcohol and coffee consumption. An age- and gender-matched control group of 541 people without Parkinson's disease answered the same questions.

* When the researchers compared the lifetime histories of the patients and members of the control group, they found that people who had handled or applied pesticides in the home or garden were more likely to develop Parkinson's disease than were those who had not been exposed.

* People exposed to in-home insecticides were 70 percent more likely to develop the disease than those who had not been exposed. The average amount of exposure in this category was 77 days. Exposure to garden insecticides carried a 50 percent increased risk of disease. Among herbicide users, risk of developing Parkinson's disease increased as the number of days that people were in contact with herbicides accumulated. Respondents who reported handling or applying these products for up to 30 days were 40 percent more likely to develop disease whereas respondents who reported higher levels of exposure (an average of 160 days) had a 70 percent increased risk of developing Parkinson's disease. Interestingly, exposure to fungicides was not found to be a risk factor.

* Nelson's study is believed to be the first investigation to specifically examine the link between Parkinson's disease and domestic exposure to pesticides. She and her collaborators Stephen Van Den Eeden, PhD, from the Kaiser Permanente Medical Care Program of Northern California and Caroline Tanner, MD, PhD, from the Parkinson's Institute in Sunnyvale presented their findings in May 2000 at the annual meeting of the American Academy of Neurology. -- KW