Doctors fighting HIV/AIDS have a new strategy working for them: Use the treatment of the disease as a way to prevent it – a strategy borne of the growing effectiveness of that treatment in the three decades since the disease first emerged.

“Treatment revolutionized AIDS,” says Diane Havlir, MD, professor of Medicine at UCSF and chief of the AIDS program at San Francisco General Hospital and Trauma Center. “Treatment changed AIDS from a uniformly fatal disease to a chronic disease.”

And now, Havlir says, “today’s treatment is also prevention.” Timely treatment can stop the spread of HIV/AIDS in many ways. In patients, it stops the virus from progressing into AIDS, and it prevents damage to organs such as the heart, liver and kidneys, which occurs in untreated AIDS. Treatment also greatly reduces the risk of HIV transmission.

Havlir cites the most encouraging news to date, the National Institute of Allergy and Infectious Diseases – HPTN 052 study, released in May 2011, which reported a 97 percent reduction in HIV transmission among discordant couples – couples in which one partner is HIV-infected and the other is HIV-negative – when the HIV-infected partner is treated with antiretroviral therapy relatively early in the course of HIV infection.

The so-called 052 study – conducted by the HIV Prevention Trials Network (HPTN) – released its results four years early because the prevention effectiveness of the antiretroviral drugs now commonly used to treat HIV infections was so clear-cut.

That news put one more arrow in the quiver of scientists and doctors looking not only to attack HIV, but to stop it.

“Certainly we’re hoping that the next 30 years of HIV can be the last 30 years, especially in San Francisco, where we have the community resources and knowledge to put an end to the epidemic,” says Grant Colfax, MD, director of the HIV Prevention and Research Section in the San Francisco Department of Public Health AIDS Office. Colfax, who trained at UCSF, is adjunct faculty at the university today.

“We have very good data now that show that when you know your HIV status, and you get treatment if you’re HIV positive, combined with psychosocial supports that decrease stigma, there’s a dramatic decrease in HIV as a result of testing and treatment,” Colfax says.

Employing New Tools, Tactics

Preventing transmission is key to the epidemic in the U.S., where 50,000 new infections per year are still reported. Some of the exciting new tools and tactics employed in the war on HIV and AIDS include:

• Pre-exposure prophylaxis (PrEP). The National Institutes of Health announced in November 2010 that high-risk gay men who take retroviral medication (tenofovir) before they’re infected can prevent HIV infection. While such a strategy is costly, and could be difficult to sustain depending on whether people consistently take the medicine, Colfax hails the study results as “momentous” and says San Francisco is moving forward to test the practicality of this approach.
• CAPRISA microbicides. CAPRISA (the Centre for the AIDS Program of Research in South Africa) announced in July 2010 that when women used an antiretroviral microbicide (tenofovir gel) before intercourse, they significantly reduced their chances of getting HIV. The study was particularly significant because 60 percent of new HIV infections in Africa occur in women and girls. “Microbicide has particular potential among women who may not necessarily be empowered to negotiate condom use with a partner,” Colfax says.
• 052. In the 1990s, when Highly Active Antiretroviral Therapy, or HAART, came into use, the side effects of the drugs was so severe that they weren’t given to people unless they were very ill or had a low level of immunosuppression, as measured by low CD4 count or viral load. The drugs have improved so that now they can be given to people much earlier in the course of the virus. The new HPTN 052 study showed the drugs can also be effective when given to infected people while their immune systems are still relatively healthy. The study was the first randomized study to find that giving antiretrovirals to someone can reduce the risk of sexual transmission of HIV to an uninfected partner.
• Male circumcision. In Africa, as governments begin to promote male circumcision, infection rates are starting to drop, according to Craig R. Cohen, MD, MPH, a UCSF professor and director of Family AIDS Care and Education Services (FACES), an HIV/AIDS care and treatment program in Kenya. Several trials of male circumcision “demonstrated a 60 percent reduction in the number of new infections in men,” Cohen says. World Health Organization guidelines promote voluntary male medical circumcision, and Kenya encourages it as well.

Condoms Cornerstone of Protection

Despite the new tools, some of the best forms of prevention remain the tried and true: Use a condom, and don’t share needles. “Condoms remain a cornerstone of HIV prevention,” Colfax says. “The goal is to provide people with as many prevention options as possible.”

Even people participating in PrEP and other prevention trials receive condoms and risk reduction messages, he says.

Additional prevention strategies include frequent HIV testing, and if found to be positive, early treatment.

As the stigma associated with AIDS lifts in many regions, more people are willing to take those steps. But in some places, from rural America to Africa, the stigma persists. Many HIV-positive patients show up at the doctor’s office or clinic with late-stage disease, which severely limits the efficacy of treatment.

In San Francisco, “we started a universal HIV treatment program,” says Havlir, whose many hats include director of the AIDS Services, Prevention, Intervention, Research and Education (ASPIRE) Program at UCSF. “We were the first in the world to do this. As soon as an individual is identified with HIV, we are offering treatment for the individual’s benefit.”

Models by UCSF investigators Edwin Charlebois, Moupali Das, Travis Porco and Havlir show that more than just the individual will potentially benefit. “If we treated all persons with HIV currently in care in San Francisco, we’d have a 50 percent reduction in new infections in five years,” Havlir says.

The strategy can have impact well beyond San Francisco.

“African countries struggling with high rates of untreated AIDS stand to benefit enormously from universal treatment,” she says. “Untreated AIDS has massive social and economic collateral damage. People drop out of the workforce, and kids drop out of school to work and support the family. We see all these damages of AIDS and HIV, which our group is postulating can be reversed with universal use of antiretroviral therapies.”

“Everyone says, ‘Oh, antiretroviral therapy is so expensive,’” Havlir says. “Our hypothesis is that it may be the least expensive option, because you get all these benefits. We are working on that with the World Bank, the World Health Organization and others.”

Cohen sees the same thing. “There was a large trial in Uganda, Kenya and Tanzania testing people for HIV – the whole community,” he says. “Once someone tested positive, they immediately started treatment, and did not wait for their CD4 (white blood cell) count to go down. If you bring down a community’s viral load, you can decrease the rate down to almost zero.”

Tests like that show such a strategy may be feasible as well as cost-effective, he says. “You can prevent not just HIV, but potentially other diseases like TB and malaria. And it could improve economic performance in a community where, if someone is infected with HIV, the economic performance goes down.”

The rapid pace of new strategies emerging inspires the researchers to believe that progress will continue, perhaps even pick up speed. “Treatment is prevention,” Havlir says. “We’ve seen it work and it’s a critical part of the strategy to end the AIDS epidemic.”

The science of biology is undergoing a historic transformation, from one based on observation to one based on creation, and UCSF is in the forefront of driving that change. The move to a New Biology promises to accelerate an era of astounding discovery and achievement, in which science will not only cure many diseases and offer new therapies, but will also provide new breakthroughs in energy, agriculture, the environment and other fields in which biology plays a role.

New Biology follows in the footsteps of earlier revolutions in its sister sciences of physics in the 16th and 17th centuries and chemistry in the 19th. New telescopes allowed astronomers to move physics from observation to analysis, ultimately enabling Newton to confirm the truth of his universal principles. Similarly, the development of the periodic table of elements in the 1860s helped establish the principles of chemical structure, and the growth of synthetic chemistry that followed helped propel the Industrial Revolution.

Advances in technology and new discovery are now leading to New Biology, both through the mapping of the human genome and in the use of increasingly powerful microscopes and other instruments. Instead of merely describing what exists, New Biology explores what is possible, leading to broader, more systematic applications.

“How we think of the role of biology is changing,” said Wendell Lim, PhD, professor in UCSF’s Department of Cellular and Molecular Pharmacology and investigator with the Howard Hughes Medical Institute. “We’ve got so much data from the genomic and the proteomic revolutions that we can start to see how biological systems work together.”

“New Biology has two main streams,” Lim says. “We are working to understand biology at a deeper, mechanistic level, and to apply biology to solve a broader swath of problems.”

Lim and Keith Yamamoto, PhD, UCSF’s vice chancellor of research and executive vice dean in the UCSF School of Medicine, have been leading the push for New Biology.Yamamoto testified in Congress to gain support for additional funding, and he and Lim co-authored a National Academy of Sciences report as part of the Committee on a New Biology for the 21st Century.

“Biology is at an inflection point, poised on the brink of major advances that could address urgent societal problems,” Yamamoto told Congress. He described four areas of “urgent need — food, energy, the environment and health” — and said biological research could help bring new advances in each. “It no longer makes sense to talk about biomedical research as if it is unrelated to biofuel or agricultural research; advances made in any of these areas are directly applicable in the others, and all rely on the same foundational technologies and sciences.”

UCSF researchers are already applying the principles of New Biology in their work. In one key aspect of New Biology, “we need to be effective at bringing people from different fields together, breaking down barriers and creating a culture of cooperation,” Lim says. “UCSF has always been a place that is historically not dominated by departments. Turf over ideas doesn’t exist here. It’s the perfect environment to be open to thinking about using different approaches to solving different classes of problems.”

The Team Challenge organized by the Cell Propulsion Lab (an NIH sponsored Nanomedicine Development Center at UCSF) in 2009 was a good example of New Biology in action. In that exercise, Dan Fletcher, a bioengineering professor at UC Berkeley, joined with a team of UCSF and UC Berkeley scientists from different disciplines to conceptualize how to create a vesicle that could deliver therapies to cells. “If you had a blank sheet of paper, and the ability to put together any components you wanted, what would you want?” Fletcher asked. That notion was put to bright people with diverse backgrounds, such as cell biology, pharmacology, bioengineering and chemistry, from UCSF, UC Berkeley and Lawrence Berkeley Laboratory.

“It’s an attractive idea to engineer a new process and find the defining rules of a system, like past engineers and physicists have done for other systems,” says Jessica Walter, PhD, a biology/biophysics postdoc who participated in the vesicle challenge. Walter remembers the inspiring nature of the project. “You could see ideas that at first sounded totally insane, but when people took them to their logical limits, they got something that might be feasible,” Walter says. “It’s counter-intuitive, but crazy ideas could become practical.”

For instance, researcher Aynur Tasdemir, a former postdoc in the Lim lab, proposed a “kamikaze cell,” Walter says, and “everybody laughed at the idea.” But they went ahead and brainstormed, and actually figured out a way it might make sense to give the vesicles something toxic, send them somewhere such as a cancer cell, and then have them release their payload. Jason Park, an MD/PhD graduate student in the Cell Propulsion Lab, continues to pursue this approach.

“We thought 20 years ago, we could attack cancer with a magic bullet, like radiation or chemotherapy,” Walter says. “But determining which cells are bad or good requires more computation than a single marker. It’s the kind of problem where an engineer might come in handy.”

Fletcher says the tools that have developed in the intervening years have made this kind of thinking possible. “Rebuilding parts of cellular processes to harness them as therapeutics is not something that was realistic years ago,” he says. “Now it has become a real opportunity, because we have new technology to control the assembly of new materials, together with increased knowledge of what the molecules do and how they do it.”

Cancer was the target in the spring of 2011, when Wallace Marshall, PhD, an associate professor of biophysics and biochemistry at UCSF, organized a meeting of cancer biologists and physicists. Recognizing the complex ways cancer operates, Wallace considered the notion that many problems that arise in cancer biology are similar to those faced by physicists in understanding the behavior of complex systems. His symposium studied whether the approaches used for understanding physical systems — conceptual, experimental, and computational — might provide useful insights into the behavior of cancer cells and tumors.

“The basic idea is to try to put some more general principles into biology to make it more of an engineering discipline than just a collection of facts,” Marshall says. “I’m an engineer by training so that works for me. I’m trying to figure out how cells solve their own engineering problems. If a cell wants to change its structure, how does it do that?”

One sure sign that science is heading in this direction, Marshall says, is that students arrive at UCSF “wanting to do this.” When he was a student, he had a “weird double major” of electrical engineering and biochemistry, with the goal of finding out, “how do I build things inside of cells?” Now universities are encouraging this sort of cross-fertilization, and he says it’s essential for moving science forward.

Talk to Marshall and others in the field, and a theme emerges — a search for the big picture, for the same sort of principles underlying biology that Newton found when he studied physics 400 years ago. Some examples:

* Zev Gartner, PhD, an assistant professor in pharmaceutical chemistry, is studying the body’s building blocks – from molecules to cells to organs – to better understand biological processes relating to tissue structure and its breakdown during disease. “At its core, we are trying to understand the way different systems and modules fit together in the complex task of maintaining homeostasis,” (the body’s ability to remain stable) Gartner says. “We’re not looking at, ‘How does this one little piece work?’ It’s only recently become possible to think about things in this way.”

* Michael Fischbach, PhD, an assistant professor in bioengineering and therapeutic sciences, also works with the principles of modularity, but his lab’s approach is to build things and then study how they work. “When we build something, we have the potential to create something that we can actually understand in all of its complexity,” Fischbach says. And then, when scientists “perturb,” or disrupt the system, they can see the results of that single action reverberate throughout.

“Think of synthetic ecology,” Fischbach says. “How do we construct a community of bacterial cells that I can put into the gut of a human being and get them to perform functions that are beneficial to the host? How is it that a community of hundreds of thousands of bacteria interacts? How are they structured physically? How do they alter one another’s behavior? And how does that play a role in how microbes interact with the host? That’s a great example of where you can take the lessons from old fashioned ecology, and the new fashioned studies that have revealed a wide range of organisms, and try to construct synthetic communities of bacteria to study.”

* Hana El-Samad, PhD, an assistant professor in biochemistry and biophysics, is like Marshall an engineer by training who is deep into the search for sweeping biological principles. Instead of studying cruise controls and autopilots and other human engineered systems, El-Samad is studying the “homeostatic feedback systems that nature has evolved.” “There are so many similarities between complex biological systems and the technological systems we were so successful at designing.’

“the challenge,” she says, “is that there are also differences between engineering and biological systems. In engineering, people can build a laptop to such precise specifications that millions will roll off an assembly line, and each will perform in exactly the same fashion. Natural systems don’t work that way, instead exhibiting stochastic, or unpredictable, behavior. Cells could all be cloned from each other, and yet each behaves differently. But now scientists have the ability to run 1 million tests on those cells, get a distribution of outcomes, and we can quantify probability. That’s a good first step towards finding the principles that biological systems use to tune their fidelity and precision.”

“We’ve gotten very good at collecting data we can analyze,” El-Samad says. “But we don’t know how to extract principles out of the data. Once we know those laws, the sky’s the limit.”

The Mets of the Mill Valley Little League's Minors Division (Photo for NY Times by Penni Gladstone)

Youths who had never played the game suddenly saw themselves as Cody Ross or Tim Lincecum, and local leagues have had to scramble to find enough coaches and fields to accommodate the interest.

“We knew we were reaching capacity, and then the Giants had to do something stupid like win the World Series and add to the fervor,” Mike Singer, the president of San Francisco Little League, said jokingly. San Francisco has about 1,100 players this year, up 100 players, or 10 percent, over last year. The league started a waiting list and had to place some players in suburban Mill Valley, 12 miles north of the city.

Yet Mill Valley felt its own squeeze, with an increase of 181 players in leagues of 750 kids, according to the league president, Chris Kearney.

Ned White, the district administrator who oversees the leagues in San Francisco and its northern neighbor Marin County, which includes Mill Valley, said he had never seen such an increase among so many leagues. “It was really a big jolt into the system to have that many kids coming out,” he said.

The leagues are struggling to find enough fields for games and practices. San Francisco Little League controls three fields on Treasure Island, a windswept former Navy base in San Francisco Bay just off the Bay Bridge, and is seeking more from the city’s parks department. In addition, more players mean a need for more coaches.

“We had to twist some arms,” said Bill Johnston, the commissioner of Mill Valley Little League’s minors division.

And coaches are particularly needed because some of the new players are truly new to baseball. “We had a couple of kids who didn’t know which end of the bat to hold,” Johnston said. “They’re going to be real challenges for the coaches.”

White, who said he had been involved in Little League for 38 years, said he had to write 200 waivers to receive permission for Little Leaguers to cross boundary lines. The most he had to write in a previous year was 20, he said.

Dave Wetmore, administrator for the Little League district east of San Francisco that includes Danville, San Ramon and other cities, said his enrollment was up more than 8 percent, to about 7,500 from 6,924. “Having a local champion is huge,” Wetmore said. “What little T-baller doesn’t want to be on the Giants this year? All of those players were Little League players at one time.”

The Little League’s national Web site last week featured a story about Ross, a Giants postseason star in 2010, and his formative years playing Little League in Allen, Tex. Whether there is another Ross who will emerge from the flood of Little Leaguers in the Bay Area remains to be seen.

Some, clearly, are ahead of others. Oliver Zink, age 9, of Mill Valley, had never been a big baseball fan, said his father, Andy. But when the Giants made the playoffs last October, Oliver and his grandfather began watching the games, and the schoolyard buzzed with Giants fever.

“Buster Posey and Tim Lincecum became almost mythological figures,” Andy Zink said of his son.

Spring arrived, and his son decided to try out, although his father, a biology professor, admitted Oliver did not know “what a batting stance was, or how to catch a pop fly.”

Andy Zink admitted he was not much help, either — “I had never played baseball in my life,” he said — but a friend’s dad stepped in and taught Oliver the basics, and now he is a Little Leaguer.

Then there is 11-year-old Caroline Olesky, who drew inspiration from the fact that the 2010 Giants were filled with position players not really wanted by their former teams. Out she went for Little League and now she is playing a range of positions for the Mets, a team in the Mill Valley Little League minors.

“Nobody thought I would actually make it, but I did,” she said.

Giants fever has manifested itself in many ways around the Bay Area since October. An estimated one million people turned out for a parade to celebrate the World Series championship, the team’s first since it arrived in San Francisco from New York in 1958. Fans wore black beards in honor of Brian Wilson, who is part closer and part performance artist. The Giants took their championship trophy on tour, routinely drawing lines of 1,000 people or more waiting to be photographed with it. And the Giants also sent the trophy to the San Francisco Little League’s kickoff parade, where each team got to pose with it.

A fan festival that the team hosted at AT&T Park in February drew more than the 40,000 the Giants expected, with fans waiting two hours in lines for autographs. Fans also flocked to spring training in Arizona in record numbers. And now come the Little League registration numbers.

“The characters on the team are cool characters to youth,” said the Giants’ president, Larry Baer, citing Wilson and Lincecum, who looks more like a surfer than a pitcher, and others. “We’re really fortunate to have a team with personality. It’s what baseball needs to bring the younger kids back.”

The resurgence has taken Mill Valley’s Little League up to a level it had not been at for 15 years.

“It’s really great to see the popularity of baseball get stronger, because it’s been falling for the last decade or so,” said Ron Campbell, who is on the board of San Francisco Little League.

But just how much the Giants’ championship might be inspiring minority youngsters to play baseball is not clear. White, the Little League district administrator, said that the organization did not specifically track minority numbers, but that local districts with a substantial minority population seemed to be receiving the same boost as other districts.

That the Bay Area has a lot of youngsters with baseball fever as the result of a championship is hardly unique.

“We occasionally see spikes in Little League participation in areas where a major league team has won the World Series,” said Steve Barr, the director of media relations for Little League International in Williamsport, Pa.

In Massachusetts, the Boston Red Sox’ World Series championship in 2004, their first in 86 years, led to about an 8 percent increase in Little League enrollment the next spring, according to John Berardi, the information officer for Massachusetts Little League. In other years, he said, the increase is about 1 percent. However, Massachusetts did not see a second surge in registration after the Red Sox won another title in 2007.

But that was one side of country, and this is the other. If the Giants win it all again, who knows? Bay Area baseball could spill over onto football fields.

Whenever I characterize the religious differences between my non-Jewish wife and me, I often think of Woody Allen’s line: “I did not marry the first girl that I fell in love with, because there was a tremendous religious conflict. She was an atheist, and I was an agnostic, and we didn’t know which religion not to bring the children up in.” Our technological differences have proved more significant than religion — what I think of as the digital divide. As a journalist who has covered technology since the 1990s, I’ve been an early adopter of e-mail, Facebook, Twitter, the iPhone, you name it.

My wife? She doesn’t have a personal e-mail account. She doesn’t text, much less tweet. She’s appalled at the mere notion of Facebook. She uses an old brick of a Nokia cell phone, with various buttons rendered unusable by age, and she doesn’t give the number out to anyone but close friends or family.

So when Reboot proposed a National Day of Unplugging last year, it was one Shabbat event that was easy to get my wife to buy into. The idea is simple enough. For one day a year, keep the computer off. Keep the phone off. Let the email go unanswered. And instead, do the things that the sages who came up with Shabbat originally envisioned: Go outside. Connect with loved ones. Eat bread. Nurture your health.

And try to take the mindfulness that comes from that annual exercise into a weekly ritual.

The other day, I took my 11-year-old son to his first Little League practice of the season. It was Saturday morning. We were running late, as usual. And as we drove down the street, I realized: I forgot my cell phone. This is often a recipe for disaster. My wife would not be able to reach me. I had not yet checked email that day. I wanted to let friends know I was going to stop by their house to pick something up.

When I told my son, he said, “If you need to make a call, there’s a gas station near the ballpark.” I appreciated the wisdom. I relaxed. I actually was mentally present for his practice, helping the other parents out, playing ball with the kids. I wasn’t constantly checking my pocket, listening for a ring, or the beep of a text, or the vibration of an email. We stopped at our friends’ house, and they didn’t mind that we hadn’t called first. When I got home, I saw I had missed three calls from my wife, but it was nothing that couldn’t wait.

We have deluded ourselves into thinking that we need to answer the phone every time it rings, and respond to the email whenever it comes in. But in turning things off occasionally, we see that we can actually enjoy the preciousness of life’s ordinary moments. We allow ourselves to let go a little.

I have increasingly stopped answering the phone in many situations — usually when I’m with my son. Or when I’m having lunch with a friend. Or when I’m driving. I have also started using more analog devices, like a Moleskine journal, because I like the way my brain focuses when it’s just me, a pen and paper — and not another window open in my browser, silently beckoning me to surf to one more page.

My wife, my son and I follow many of the tenets of the Sabbath Manifesto. We often use the weekend as a chance to take a big hike and to cook a big meal. We play board games; Clue has been a favorite, but Risk proved difficult, as some of us got a little too aggressive. We get together with friends, and we make time for each other.

I have found my connection to those wise ancient rabbis who gave us the concept of the Sabbath. And I have converted to my wife’s religion. I have unplugged.

Sometimes, the rarest diseases provide the most critical insights. Pediatrician David Rowitch, MD, PhD, is leading a stem cell trial designed to treat children with connatal Pelizaeus-Merzbacher disease (PMD), an uncommon but fatal brain disorder.

It is UCSF’s first stem cell clinical trial in humans, and Rowitch has high hopes that his work will not only help those patients with severe PMD, a disease so rare that he estimates there are only 10 cases in the United States, but also that it will improve understanding of more common disorders like multiple sclerosis (MS) and cerebral palsy – and how they might be cured.

Both multiple sclerosis and PMD are myelin disorders. Myelin, made by oligodendrocyte cells in the brain, coats nerve fibers, allowing communication among neurons, which forms the basis of all activity in the brain. In MS, some oligodendrocytes are damaged and die; in PMD, they are defective and can’t make myelin at all.

In the trial, Rowitch is working with StemCells, Inc. of Palo Alto, whose proprietary neural stem cell precursors are being transplanted into four boys’ brains. In animal trials, these cells became oligodendrocytes. In the current trial, Rowitch said, scientists are asking questions regarding their safety.

“If you put neural stem cells into the brains of children with PMD, what will happen?” Rowitch asks. “Will it make them worse? Will it cause a tumor? What about the burden of immunosuppression? This is a five-year study to see if PMD patients will be adversely impacted by implanted cells. If the answer is no, then what is the efficacy? Is it helping?” Rowitch believes the answers to these questions will be answered, allowing the field to progress to the next level.

Several departments at UCSF together recruited Rowitch, a Howard Hughes Medical Institute investigator, from Harvard University four years ago. “David Rowitch is a world expert in myelinating oligodendrocytes, with an interest in the diseases such as multiple sclerosis in which they are affected, as well as the tumors [brain cancer] that they can give rise to,” says Arnold Kriegstein, MD, PhD, director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.

Kriegstein wanted Rowitch to fill a key role in stem cell research. At the same time, Mitchel S. Berger, MD, chairman of the UCSF Department of Neurological Surgery, wanted him for brain cancer research, and Sam Hawgood, MBBS, now dean of the UCSF School of Medicine, recruited Rowitch to lead the Division of Neonatology and the Intensive Care Nursery.

The heart cannot adequately regenerate damaged tissue after a heart attack. But could stem cells help it along that path? Doctors and researchers at UCSF with a wide range of expertise are exploring this possibility together, working to see whether stem cell therapies might pump some regenerative power into the heart.

Working within a so-called pipeline designed to move basic research discoveries into studies in animals and, eventually, in humans, the scientists and clinicians work with all sorts of patients, and on all rungs of the research ladder, in the hope of reaching a cure faster.

The effort starts in early-stage labs like those of developmental biologist Deepak Srivastava, MD, and cell biologist Harold Bernstein, MD, PhD. It extends to clinicians like Yerem Yeghiazarians, MD, who can look at how the cells interact once they’re in the body.

Srivastava, director of the Gladstone Institute of Cardiovascular Disease, brings expertise as a pediatric cardiologist to his leadership of the cardiology pipeline. The other leader, Yeghiazarians, as co-director of the Adult Cardiac Catheterization Laboratory, works with adults.

“We are always looking for areas of synergy where expertise from one group can be leveraged by the other groups,” Srivastava says.

Srivastava’s lab looks at the way a stem cell can differentiate and become a cardiac muscle cell. Bernstein’s lab focuses on later stages of the differentiation process, often applying what he’s learned from Srivastava’s findings to his own study of how different types of heart muscle cells develop.

The simple worm piqued the budding young scientist’s interest in developmental biology. “I loved it,” he says.

Robert Blelloch, MD, PhD, followed that passion through fellowships and into work with blood stem cells. “It was so exciting to see how many different ways blood stem cells were being used to treat patients,” he says.

Stem cells also proved to be his route into UCSF, where, although his specialty was pathology, he ended up with an appointment in urology as well, tackling prostate cancer. That’s life at UCSF, where it seems that nearly every department works with every other department.

“Nothing happens here through a single program,” Blelloch says, seated at his desk in the new Ray and Dagmar Dolby Regeneration Medicine Building. “Every principal investigator in this building has a second appointment” in another department, he says.

Blelloch works with colleagues in many different fields:

• He published a paper with the bioinformatics group at UCSF’s Helen Diller Family Comprehensive Cancer Center, profiling small RNAs. “One of the biggest growth areas in cancer research is being able to follow a patient’s disease,” he says. “Is the disease progressing? Do we treat it aggressively or not?” The scientists developed an assay to look for signatures of small RNAs in the blood that indicate disease severity and response to treatment, and they’re looking to study it in patients.
• He is publishing a paper with Marco Conti, MD, director of UCSF’s Center for Reproductive Sciences, studying how certain genes disrupt the development of the oocyte, or unfertilized egg, which should provide insights into infertility.

Researchers at the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF are tackling monumental problems – cures for diseases as pernicious as Parkinson’s disease and brain tumors. Yet a vexing barrier to those would-be cures doesn’t get as much limelight: how to put the cells into people as efficiently as possible.

Given the significance of this translational problem, one UCSF clinician-scientist felt compelled to develop a pet project to address the issue. He began by partnering with an engineering class across the bay.

Daniel Lim, MD, PhD, a neurosurgeon and stem cell researcher, realized that current surgical tools do not adequately deliver stem cells to the human brain, with its large size and irregular shape with twists and turns. He called it “a gap in the pipeline to our therapies, a bottleneck to translation.”

“I assure you, we risk clinical trial failures unless we develop that tool,” Lim says.

Lim hit an early roadblock when he approached medical device manufacturers, who didn’t see commercial potential. Undeterred, he moved on to work with a team of UC Berkeley engineering students, who designed and produced an improved cell injector prototype that can deploy and turn like a periscope to target the delivery of cells.

“This first prototype is already a great improvement over current devices, but my goal is to bring together a team that can innovate something even more novel, perhaps even unexpected,” he said.

Stem cells have an innate attraction to tumor cells. If genetically engineered to produce proteins with anti-tumor activity, they could serve as tumor-killing assassins.

At UCSF, a team of scientists led by Mitchel S. Berger, MD, chair of the Department of Neurological Surgery, is exploring this strategy in the fight against glioblastoma – the most common and lethal brain tumor.

Under a $19 million grant from the California Institute for Regenerative Medicine (CIRM), the work involves an even bigger team, one that extends outside of UCSF to four other California institutions. The goal is to be ready for a clinical trial in four years.

“We needed to assemble a team of investigators having all the necessary skill sets to accomplish this very ambitious and very timeline-driven project,” says UCSF Professor David James, PhD, coordinator of the CIRM project.

Progress has been quick, James says. Researchers started in early 2010 by looking at 12 possible options involving different combinations of three potential stem cell hosts, two therapeutic genes and two routes of delivery. They hope to identify the single most efficacious therapeutic stem cell host and route of delivery approach. In nine months, they’ve narrowed the possibilities to four options.

Currently, the research team continues to investigate fetal neural stem cells and mesenchymal stem cells, derived from bone marrow, as candidate host cells, and have concluded that administration of therapeutic stem cells directly into the tumor is the approach to be used in a clinical trial.