stanford medicine




The secret life of genes

Certain small stretches of seemingly useless DNA harbor a big secret, say researchers at the School of Medicine. Though laboratory animals live happily even if researchers snip the sequences out, they must be important. The proof is their staying power: They’ve hung on through eons of evolution.

Illustration by Terry Allen
secret life of genes

“The true function of these regions remains a mystery, but it’s clear that the genome really does need and use them,” says Gill Bejerano, PhD, assistant professor of developmental biology and of computer science. In fact, these so-called “ultraconserved” regions are about 300 times less likely than other regions of the genome to be lost during mammalian evolution, according to research published in the November 2008 issue of Genome Research.

Although some of the ultraconserved regions are involved in the regulation of the expression of neighboring genes, previous research has shown that mice missing each of four regions seem perfectly normal.

This lack of effect is usually taken as a strong argument against an important functional role for the missing segments of DNA — either because they don’t do much or because other bits of DNA serve as understudies when the primary actors are missing. But when the researchers tried to determine whether similar deletions occur in the wild, “We found that this is almost never seen in nature,” Bejerano says.

To analyze the evolutionary pressure against losing ultraconserved sequences, the researchers quantified the extent to which rodents have lost sequences that are strongly conserved by mammals far away on the family tree — in this case humans, macaques and dogs. They found that the rodents were missing less than one-tenth of 1 percent of segments that were identical among the primates and dogs. In contrast, the rodents lacked about 25 percent of nonconserved segments.

It’s not that ultraconserved regions are somehow protected against change: They are mutated in about one in 200 healthy humans. Rather, these changes seem to be swept away over time by the tides of evolution in a process called “purifying selection.” The researchers believe that something similar may be happening in the laboratory mice on a scale too subtle to be seen in the controlled experimental conditions.

Oldies but goodies

The researchers went on to examine the staying power of sequences found in animals even further away from human on the family tree: opossum, platypus, chicken, frog and fish. Scientists reason that sequences such as these, which are shared among many distantly related species, are older than sequences shared only by closely related species.

The analysis revealed that “old” sequences found in humans’ distant relatives are more likely to occur in humans than sequences appearing only in the genomes of humans’ closer cousins. In other words, the greater a sequence’s evolutionary age, the more likely it is found in humans.

“The longer the sequence has been in us, the less likely it is to be lost,” Bejerano says. “It’s almost like the bricks in the foundation of a building, which hold up the rest of the structure.” —Krista Conger

The research was supported by a Stanford Bio-X graduate fellowship and an Edward Mallinckrodt Jr. Foundation junior faculty grant.


Illustration by Terry Allen

Marauding molecules cause the tissue damage that underlies heart attacks, sunburn, Alzheimer’s and hangovers. But scientists at the School of Medicine say they may have found ways to combat the carnage after discovering an important cog in the body’s molecular detoxification machinery.

The culprit molecules are oxygen byproducts called free radicals. These highly unstable molecules start chain reactions of cellular damage — an escalating storm that ravages healthy tissue.

“We’ve found a totally new pathway for reducing the damage caused by free radicals, such as the damage that happens during a heart attack,” says Daria Mochly-Rosen, PhD, professor of chemical and systems biology and senior author of the study that appeared in the Sept. 12, 2008, issue of Science.

The research builds on evidence that heart muscle can be preconditioned with alcohol to resist heart attack damage — for instance, moderate drinkers tend to have smaller, less severe heart attacks than teetotalers. But researchers didn’t understand how preconditioning worked.

To figure out how alcohol protects heart muscle from free-radical damage, Mochly-Rosen’s team tested alcohol pretreatment in a rat heart-attack model. They compared the enzymes activated during the attacks with those switched on without alcohol. Enzymes are the “doers” of the cellular machinery, catalyzing all of the biochemical reactions that form the basis of life.

Surprisingly, the treatment activated aldehyde dehydrogenase 2, an obscure alcohol-processing enzyme. Alcohol pretreatment increased the enzyme’s activity during heart attack by 20 percent, leading to a 27 percent drop in associated damage.

“We’ve found a totally new pathway for reducing the damage caused by free radicals, such as the damage that happens during a heart attack.”

ALDH2 isn’t one of the well-studied antioxidant players. It neutralizes an aldehyde molecule, a toxic byproduct of the ethanol in alcoholic beverages. But aldehydes are also formed in the body when free radicals react with fat molecules. The body’s cells contain a lot of fat, Mochly-Rosen notes.

Inside cells, the accumulating aldehydes permanently bind and damage cellular machinery and DNA. Such damage occurs in many diseases, from heart attack and Parkinson’s to sun-induced aging of the skin.

After learning of ALDH2’s novel role in reducing the damage, the researchers searched for a molecule that could make the enzyme function even better. The winner was the tiny molecule Alda-1 that reduced heart attack damage by 60 percent in the rat model.

Because Alda-1 is small, it should be easy to adapt for pharmacological use, Mochly-Rosen says. She expects the new molecule to have many possible drug applications. — Erin Digitale

The research was funded by the National Institute on Alcohol Abuse and Alcoholism and received support from Stanford’s SPARK program.

New outpatient clinics

A wide array of Stanford outpatient clinics, from orthopaedic surgery and sports medicine, to pain management and sleep medicine, are now accessible through one main door. The Stanford Medicine Outpatient Center, which opened Feb. 17 in Redwood City, is the new home of many specialized services that previously were located on the main campus at Stanford Medical Center.

Photograph by Norbert von der Groeben
new outpatient clinic
Stanford Hospitalís new outpatient center, located in Redwood City, opened in February. It offers easy access to clinics and imaging facilities.

With space scarce on the main campus, the medical center has moved multiple academic and related clinical activities to the new off-campus center — the first such move since 1959, when the medical school moved to Stanford from San Francisco.

The new site also includes outpatient services for hands and upper extremities, joint replacement and spine.

“The creation of the campus, for our patients, was truly a multidisciplinary effort,” says Helen Wilmot, vice president for ambulatory care. “The four-year planning and construction project involved feedback from patients about what they expect from an outpatient experience, direction from doctors about the latest clinical technology and input from staff about creating an environment that enables them to be their best for our patients. The building and the environment at the Stanford Medicine Outpatient Campus capture the best of all three.”

better care

The facility holds six operating rooms, which surround a central “clean core” where sterile supplies are stored. With some 630 square feet — the new industry standard for accommodating new technologies — the ORs are organized for efficiency and the latest in care. Anesthesia booms can be moved to accommodate operating teams and high-intensity surgical lights spotlight procedures that are visible from multiple angles on four display screens in each operating suite.

“The idea was to create a center where we will have all of our outpatient clinics, and all of our imaging and diagnostic capabilities,” says Bill Maloney, MD, chair of the department of orthopaedic surgery. “It’s not crowded, it’s easy to find, right off Highway 101, and there’s free parking.” — Diane Rogers

Bye-bye, pharmaceutical pie

The School of Medicine no longer accepts support from pharmaceutical or device companies for specific programs in continuing medical education. The policy, which took effect Sept. 1, 2008, builds on a 2006 policy that banned gifts, including free meals, and industry marketing at the medical center.

Both policies address the concerns of the school’s leaders that industry-directed funding may compromise the integrity of education programs for practicing physicians.

Stanford is one of few U.S. medical schools to enact such restrictions. The school implemented the new policy as part of an ongoing review of its interactions with industry in education and clinical work.

“I want to be able to honor the public trust. We want CME to be unbiased and science-driven, and we don’t want it to be influenced by marketing.”

Continuing medical education programs are designed to help physicians stay current in their fields. Physicians are legally required to take CME courses to remain licensed to practice medicine. Under the new guidelines, the school may accept commercial support for CME only if it is provided for broad areas, such as medical, pediatric and surgical specialties; diagnostic and imaging technologies; and health policy and disease prevention. Funding must not be linked to a specific course, topic or program. In addition, commercial exhibits will no longer be permitted at Stanford-sponsored CME activities on or off campus.

Dean Philip Pizzo, MD, says he believes CME programs can be true to the School of Medicine’s goal of improving quality and clinical outcomes only if they are free of commercial influence.

“I want to be able to honor the public trust,” Pizzo says. “We want CME to be unbiased and science-driven, and we don’t want it to be influenced by marketing.”

The pharmaceutical and medical-device industries have been a growing source of funding for CME programs. Between 1998 and 2006, industry funding for CME activities nationwide rose from $302 million to $1.2 billion, according to the Accreditation Council for Continuing Medical Education.

In fiscal 2006-07, about 38 percent of Stanford’s budget for CME, or $1.87 million, came from industry sources.

Teaching, not marketing

Robert Jackler, MD, the school’s associate dean for CME, said that under the old system, CME events were often held only if an outside sponsor was willing to cover the costs. “This leads to a CME curriculum which is, at least in part, designed to address market needs rather than being entirely focused on improving the performance of practicing physicians,” he says.

Under the new policy, any funds received will be channeled through the school’s CME office, which will work with the faculty to determine how best to use the money to meet the needs of physician-learners. — Ruthann Richter

Stem cell powerhouse

The School of Medicine broke ground Oct. 27, 2008, for the Lorry I. Lokey Stem Cell Research Building, which will be the nation’s largest stem cell research facility.

The 200,000-sqare-foot building will bring together some 600 scientists now working in scattered locations in a unified effort to capitalize on the power of stem cells in treating human disease. The $200-million building is scheduled to open in the summer of 2010.

“The Lokey Building will have a transforming impact on stem cell biology and regenerative medicine,” says Dean Philip Pizzo, MD.

Scientists in the building will be involved in the full spectrum of stem cell programs, including research in embryonic and adult stem cells, cancer stem cells and the development of disease-specific stem cell lines.

“What is important is that it will give people the opportunity to apply stem cell thinking to different problems, including regeneration, aging and cancer,” says Irving Weissman, MD, director of the Stanford Stem Cell Biology and Regenerative Medicine Institute, which will be housed in the new building.

The four-story facility along Campus Drive will be designed to echo Stanford’s main quad, with its limestone exterior and red-highlighted roof. The building has an open design to encourage collaboration. Two major wings, which will lead off the lobby, will offer private areas for focused research. Within these “neighborhoods,” there will be small, parklike areas to encourage scientists to intermingle.

The building will be financed through a mix of public and private funds. The California Institute for Regenerative Medicine, the state stem cell agency, has provided a grant of $43.6 million to help pay for construction. In addition, at least $130 million will come from philanthropic contributions, including a $75 million gift from Lorry I. Lokey, the Business Wire founder for whom the building is named.

The architecture firm for the building is Zimmer Gunsul Frasca Architects LLP.
— Ruthann Richter

The patient is no dummy

Mr. Overton? Mr. Overton?!”

Nurse Rusty DeGuzman’s patient in Stanford Hospital’s intensive care unit was moaning, vomiting blood and responding erratically at 10:01 p.m. DeGuzman ordered six units of blood. One minute later a pulmonary critical-care fellow arrived and ordered a “massive transfusion protocol” from the blood bank.

Illustration by Terry Allen
the patient is no dummy

Within minutes, an anesthesiologist came in as the fellow prepared to put in a central line to deliver medication. By 10:12 p.m. a respiratory therapist was hand-bagging Mr. Overton, and eight other professionals monitored his pulse, blood pressure and breathing.

“OK, that’s it,” Geoff Lighthall, MD, PhD, announced at 10:14 p.m. To his colleagues running the event with him, he said, “That was a high-performing crew.”

On this busy night, ICU staff had interrupted whatever they were doing to care for Mr. Overton. They knew he wasn’t a typical patient — his plastic torso was a giveaway — but no one cracked a grin. As far as they were concerned, it was the real deal.

The mobile simulation exercise was part of a pilot program to test the hospital’s response to critical, life-threatening events, says Jeff Driver, the hospital’s chief risk management officer.

“The idea is to allow ourselves to make errors in a lab environment so that we’re not making them when we’re caring for patients,” Driver says.

In the past, simulation mannequins have been used primarily to teach new procedures. But by hoisting mannequins onto gurneys and sending them into patient rooms, Stanford is taking simulation in a new direction.

Lighthall and his team program a mannequin for the kind of critical event being tested (hemorrhage, allergic reaction, respiratory distress) then give the nurse manager the patient’s clinical history. “We say, ‘The mannequin is going to experience some problems — we can’t tell you just what, but take it seriously,’” Lighthall explains.

Initial findings indicate great variability in how well high-risk events are managed. Lighthall thinks some improvements can be made in the availability of key sets of information. For instance, physicians already carry printed cards that spell out the protocols for cardiac arrests; they could use similar aids for other life-threatening events, such as rescuing a hemorrhaging patient.

As Lighthall and his colleagues debriefed the team that had cared for “Mr. Overton,” nurse DeGuzman had one final question: “Did he survive?”

Thumbs up. Mr. Overton would be back to bleed another day. — Diane Rogers







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