12/07/06 News Release

STANFORD, Calif. — Medicine is always advancing, but somehow the pace of the change seemed just a little faster this past year. The promise of genetics seemed to become ever more tangible. Awareness of the intricacies of DNA replication suddenly became a leading story as two Nobel Prize winners, both from the Stanford University School of Medicine, were recognized because of their work with RNA. And suddenly stem cells were no longer a winning political issue in just California, but in elections across the country.

The new developments were happening at institutions nationwide and globally, but you could have stayed on the Stanford campus and gotten a front-row seat to see some of the most intriguing trends and discoveries. Below are some of the biggest medical science stories of 2006.

• Now the center of attention, DNA’s little sister
• Stem cells’ newfound popularity
• Big Pharma told to stop influence peddling
• Minds over matter
• He’s looked at science from both sides now
• Help wanted! Genetic counselors
• Funding troubles for NIH

Now the center of attention, DNA’s little sister

For years RNA received second billing to its flashier big sister, DNA. But this was the year that it got asked to the prom: Two Nobel Prizes were awarded for basic research involving RNA.

	L.A. Cicero
	Andrew Fire (right) congratulates med school colleague Roger Kornberg (left).

The central dogma of genetics holds that double-stranded DNA makes single-stranded messenger RNA, which in turn makes protein. While there has been much hoopla for decades about research focusing on the DNA gene rather than the RNA message, this year RNA became the hot ticket, with two members of the medical school faculty winning separate Nobel Prizes for their complementary work in this area. One was awarded for work elucidating how RNA turns genes on, while the other was for an explanation of a mechanism to turn them off.

The Nobel Prize in Chemistry was for work that showed how DNA is converted into RNA through a process known as transcription, using the enzyme RNA polymerase. The winner, professor of structural biology Roger Kornberg, PhD, was recognized for his success in charting the complex arrangement of the 30,000 atoms in the RNA polymerase. "This allows us for the first time to see the chemical details of transcription," Lars Thelander, a Nobel panel member, told National Geographic. "It has many implications for human diseases, antibiotics, stem cells and so on."

The Nobel Prize in Physiology or Medicine went to pathology professor Andrew Fire, PhD, and Craig Mello, PhD, of University of Massachusetts, for explaining an oddity—double-stranded RNA. They showed that it can destroy a messenger RNA with a matching sequence, halting the orderly progression of DNA to RNA to protein. The process is now known as RNA interference, or RNAi. "It was like opening the blinds in the morning," Erna Moller, another Nobel committee member, told the Associated Press. "Suddenly you can see everything clearly."

These RNA discoveries have yet to produce any direct clinical benefits for patients. But researchers are captivated by their enormous potential, and their enthusiasm has begun to filter into the public's general knowledge of science. And there's reason to believe that the discoveries will eventually have a direct effect on medical care. Indeed, in only eight years since the RNAi gene-silencing mechanism was first announced, therapeutics based on it have entered clinical trials, including treatments for macular degeneration, respiratory syncytial virus and hepatitis C.

And at least one big pharmaceutical company is betting on RNAi's prospects: At the end of October, Merck spent $1.1 billion to acquire San Francisco-based Sirna Therapeutics, one of the leading developers of RNAi-based therapies.

Stem cells’ newfound popularity

For embryonic stem cells, 2006 could be the tale of two faces: Hwang Woo Suk and Michael J. Fox.

	Julie Baker

The year began with front-page revelations about how Hwang, one of the star researchers in the field, had essentially fabricated claims of creating new stem cell lines from cloned embryos. But while some scientists feared that this would be a blot on the field's promise, hope inspired by stem cells seemed to grow.

Indeed, when Fox, the actor who suffers from Parkinson's disease, appeared in commercials in the fall urging people to vote for candidates who called for ending federal restrictions on stem cell research, it appeared to turn the tide in several races, most notably in the election to the Senate of Claire McKaskill (D-Mo.).

"The year ended with a thundering note of support," said Christopher Scott, executive director of the Stanford Program on Stem Cells in Society, noting that it sets the stage for lawmakers to try to overcome President Bush's denial of federal funds for creating new embryonic stem cell lines.

Of course, what was behind the rising popular tide was a stream of scientific advances. "We are all making significant progress in the fields of adult tissue stem cell research, embryonic stem cell research and cancer/leukemia stem cell research," said Irving Weissman, MD, director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine.

At Stanford alone, in spite of the lack of federal funds, six new stem cell lines were created. Researchers also made progress toward using embryonic stem cells to replace lost pancreatic cells and to repair damage in the brain. And with scientists at Stanford taking major strides in the understanding of cancer stem cells, the medical school was awarded a $20 million gift to establish the Ludwig Center for Cancer Stem Cell Research and Regenerative Medicine.

Remarkably, the stem cell work at Stanford and elsewhere has put the shock over Hwang's fraud in perspective. "If you look at the timeline of scientific research, that was a microdot," said Scott. Meanwhile, scientists have kept working to achieve what Hwang failed to do. "My feeling is that it's just a matter of time before we get that one licked for real," he added.

Big Pharma told to stop influence peddling

The era of the free lunch appears to be nearing its end, as several leading academic medical centers, including Stanford, moved to enact new policies to ensure that the pharmaceutical industry is not influencing medical decisions by giving free meals, gifts and other perks to doctors and scientists.

	Phillip Pizzo

In September, Stanford medical center announced its new policy that bans all gifts from sales reps to physicians; eliminates industry funding of meals at many medical center events, and restricts visits to the medical center by company representatives.

The policy is modeled in part after one approved in 2005 by the Yale Medical Group. The Hospital of the University of Pennsylvania, among others, approved guidelines this year for interactions with the pharmaceutical industry. But Stanford's policy is broader than those of its counterparts in that it not only regulates the pharmaceutical industry, but also the device, biotech, hospital and research equipment and supply industries, throughout the medical center.

"It is essential that medical professionals and scientists reclaim the moral high ground and avoid the appearances of conflict of interest that can otherwise cloud or alter the trust of the American public," said Philip Pizzo, MD, dean of the School of Medicine.

Response to the new policy, which went into effect Oct. 1, has been "overwhelmingly positive," said Kathy Gillam, the dean's senior advisor and leader of the policy implementation group. Although some people had complained about the ban on free drug samples to physicians—they said that the perk benefited patients who couldn't otherwise afford them—the new policy allows pharmaceutical firms to give drug samples directly to pharmacies at the two hospitals, which can distribute them to clinics for needy patients.

The policy also prohibits companies from paying for meals for faculty and trainees except under strict guidelines. In the past, industry had paid directly for food at lunchtime educational programs, typically pizza or sandwiches, for interns and residents; sales and marketing representatives were often present. Now such funding from companies must come as unrestricted gifts to the departments, and the sales and marketing representatives generally no longer attend. To make up for lost funds, the school is looking at new approaches for raising money to support its educational programs.

Minds over matter

The term "mind control" has an ominous, Orwellian ring to it. But when it's the owner of the mind at the controls, the benefits can be tremendous, as two groups of researchers showed this past year.

	David Plunkert

Sean Mackey, MD, PhD, assistant professor of anesthesia, used the power of a new technology called real-time functional magnetic resonance imaging, or rtfMRI, to help patients learn to reduce their own pain.

Subjects were placed inside an MRI scanner where they were able to watch their brain activity. They were then shown "live action" images of an area of the brain responsible for processing pain, and given various mental strategies to try to alter their brain activity.

"As an example, we asked them to think about changing the meaning of the pain," Mackey said. "Instead of thinking of it as a terrible experience, to think of it as something relatively pleasant. Over time, subjects showed an increased ability to change their brain and by doing so to modulate their pain."

Mackey said more studies still have to be done to see if the method holds up.

Another brainy advance came from Krishna Shenoy, PhD, assistant professor of electrical engineering and of neuroscience. His work brought a long-standing science fiction concept—the idea of a disembodied brain linked to a computer apparatus by which it controls the world—one step closer to reality.

Actually, Shenoy has a more humanitarian aim: helping paralyzed people interact with the world around them. He and his team of researchers worked with a prosthesis called a brain-computer interface—consisting of electrodes attached to a subject's head—to record brain waves. The device then sends the signals to a computer, which translates them into commands to control the prosthesis.

A big barrier to making such prostheses practical has been the slowness of translating signals into action. Shenoy's team developed a new algorithm that quadrupled the processing speed and published the results this year. Shenoy said that his team's work—done with rhesus macaque monkeys—coupled with advances from other researchers working with human subjects, shows it will be possible to devise a truly functional prosthesis for the paralyzed.

He’s looked at science from both sides now

The resignation in February of Harvard president Larry Summers ended months of turmoil in Cambridge, but the issue that triggered his stepping down remained very much in the limelight.

	Timothy Archibald for Newsweek
	In 2006, Ben Barres emerged as a leading champion for equality for women in science.

Summers' suggestion—that biological differences may help explain why men are more likely to reach the highest ranks of science—was rebuked in September by a National Academy of Sciences report, which attributed the glass ceiling to bias and "outmoded institutional structures'' in academia. And that report followed a stinging commentary in the July issue of Nature by professor of neurobiology Ben Barres, PhD, who is in a position to know something about the topic: He's done science as both a man and a woman.

Barres argued that it's easier to get ahead as Ben than as Barbara, referring to his personal experience as a female-to-male transgendered person. But he drew not only on his own experiences but also on extensive research, showing that even the most fair-minded people have inherent gender biases. He cited studies, for instance, that found that women applicants for grants had to be three times more productive than male peers to be considered equally competent.

In the five months since his piece appeared, Barres has received more than 3,000 e-mails, eight book offers and countless speaking requests. Among those who applauded Barres was medical school dean Philip Pizzo, MD, who reprinted the essay in his July newsletter, writing, "Change only occurs when individuals speak up and lend their voice and reputation to important issues."

Change, in this case, came in the form of two programs aimed at preventing bias at the medical school. The first, announced Oct. 23, was a recommitment to policies already in place allowing extended time off for child care and a delay in the tenure deadline for people who take extended leaves. That was followed by a Nov. 6 announcement of the formation of the Faculty Searches Task Force, which includes Barres. The task force is charged with eliminating inherent biases in the faculty selection process, with the end goal of increasing faculty diversity.

Help wanted! Genetic counselors

A little knowledge can be a dangerous thing. Just ask Golda Bradfield's descendants. All they had to do was look at the family photo from 1942 and the toll that stomach cancer had taken would hit them like a brick. Not only did the disease kill Golda, but also six of her eight children.

	Courtesy of Linda Bradfield
	Six of the Bradfield cousins gathered for a mini-reunion at Stanford on Feb. 13, 2005, the day before two of them, Mike Slabaugh (far left) and Mark Allen (far right), had surgery to remove their stomachs.

When one of Golda's grandchildren died of stomach cancer in 1960, the remaining grandchildren concluded, rightfully, that the condition was genetic. What to do about it was another matter.

"I felt like this big cloud was hovering over me since I was 13, when my mother was diagnosed," said one of Golda's grandsons, Mike Slabaugh, whose concerns about cancer kept him from marrying or having children of his own.

But sometimes a little more knowledge can make a dangerous thing less dangerous.

In 2003, it became possible to detect the responsible gene, and the 17 cousins turned for advice to what has become an increasingly necessary medical specialty: genetic counseling. "Internists are not trained to do complex genetics," said James Ford, MD, assistant professor of medicine and director of the Stanford Cancer Genetics Clinic. "We need people to interpret the information."

There's a growing demand for people who can translate genetics into English, and a national effort is under way to increase the number of genetic counselors. The School of Medicine, for instance, announced in July that it was launching a new master's degree program in genetic counseling—a collaboration between the departments of genetics and pediatrics. Louanne Hudgins, MD, Lucile Packard Children's Hospital's director of perinatal genetics, will serve as medical director of the two-year program, which in the fall of 2007 will begin training six new counselors each year.

In the case of Slabaugh and his cousins, the information they received from the genetic counselors at Stanford and elsewhere was life saving. After learning that those with the gene ran a 70-80 percent chance of developing stomach cancer, all 11 of the cousins who tested positive chose to have their stomachs removed. Six of them had the operation at Stanford.

Although the procedure was drastic (many people who have inherited a predisposition to certain conditions can get by with more frequent or more thorough screenings), it was the correct one for this family. When the physicians examined removed tissue, they found that nine of the cousins had already developed potentially fatal early tumors that screens failed to detect.

"Now, when I wake up in the morning," said Slabaugh, "it's a day I wouldn't have had."

Funding troubles for NIH

Funding for the National Institutes of Health was cut in 2006 for the first time in more than 30 years—and the administration's budget proposal for the next year would freeze the NIH budget at that level.

	©iStockphoto.com/Tom Grill

That would make three years running that NIH funding didn't keep up with inflation, raising concerns among scientists about the future of basic research in the United States and its role as a worldwide leader in biomedical research and innovation.

"Given the current fiscal challenges of the nation, I am not optimistic that we will see significant increases in the NIH budget for the near future," said Phillip Pizzo, MD, dean of the School of Medicine, who has warned that the trend could have disastrous effects on the ability to make basic science discoveries and tranlate them into beneficial therapies for patients.

Stanford isn't alone in its concern about budgetary cutbacks. The NIH is the principal federal source of funding for medical research. It funds nearly 50,000 competitive grants at more than 2,800 U.S. research institutions. "As I talk to scientists and administrators throughout the country, the anxiety is palpable," NIH director Elias A. Zerhouni wrote in November in the journal Science.

The need for consistent NIH funding for research is demonstrated clearly by the two 2006 Nobel Prize winners on the medical school faculty. Both Roger Kornberg, PhD, the laureate in chemistry, and Andrew Fire, PhD, the laureate in physiology or medicine, said their work could not have happened without years of support from the NIH.

Despite their proven track record, a number of leading faculty have not had their NIH grants renewed in the last year. Stanford researchers suffered a $1.1 million decline in NIH grants in fiscal year 2005, the latest available data.

Pizzo has played a leading role in efforts to persuade Congress to sustain funding. "We will certainly do everything we can to advocate improved support for the NIH," he said. "The nation's global leadership in biomedical research and innovation are closely linked to support from the NIH."

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