Reflection: 30 years of top NIH funding for UCSF School of Pharmacy

Reflection: 30 years of top NIH funding for UCSF School of Pharmacy

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The last fiscal year marks the 30th in a row that the UCSF School of Pharmacy has received more research funding from the National Institutes of Health (NIH) than any pharmacy school in the US.

“As we end this 2010 calendar year and look back, our NIH contracts and grants award record for the past fiscal year heads our list of accomplishments,” comments Mary Anne Koda-Kimble, PharmD, the School’s dean.

This uninterrupted preeminence in securing prestigious and highly competitive U.S. federal research grants stretches back to 1979 — when Jimmy Carter was president and disco ruled the airwaves.

The achievement reflects the pharmacy school’s tradition of basic science research, especially in its Department of Pharmaceutical Chemistry (PC) and the former Department of Biopharmaceutical Sciences, which evolved in 2009 into the Department of Bioengineering and Therapeutic Sciences (BTS).

In the late 1970s and early 1980s the School was a leader in pharmacy education, physical chemistry, and pharmaceutical sciences. Since that time, the School has established fresh directions—both in basic science and also in training more clinical scientists, which is a focus of the School’s Department of Clinical Pharmacy.

“In total, these moves over the past 30 years have positioned us to continue our leading levels of NIH funding in years to come,” says Koda-Kimble.

Indeed, the six largest individual NIH research awards in fiscal year 2009 reflect the School’s research strength across its three departments, as well as the relatively new orientation by the NIH toward funding more clinical and translational science. (See: Top Six Grants)

And the impact of this funding success?

“We see a world in which every patient benefits from medicines that are targeted to the patient’s unique genetic needs, are safe, effective, and side-effect free,” says Koda-Kimble. “That kind of moxie demands that our science—across the board—continue to move ahead in new directions.”

Those new directions include research not only related to pharmaceuticals but research on diagnostic tests, medical devices, health policy, and better ways to deliver pharmaceutical care.

Budget significance

The School’s long-term leadership in winning NIH contracts and grants is significant in ways that go beyond support for specific research projects and maintaining the School’s international reputation for excellence.

Over the past decade, federal contracts and grants to the UCSF School of Pharmacy have grown 54%, while California state funding has fallen by 16%.

Indeed, federal contracts and grants are the largest component of the School’s operating budget, and NIH grants consistently comprise three-quarters or more of that category.

All told, funds from NIH grants currently account for about 23% of the School’s U.S.$71 million operating budget, according to Michael Nordberg, MPA/HSA, the School’s interim associate dean of administration and finance.

Reasons for past success

Why has the School been so dominant in drawing that sought-after support for so long?

  • The School is part of a graduate campus. The School’s location on a graduate campus means that faculty members have both the mandate and the time to do research as well as teach graduate students.
  • The School is physically integrated with other disciplines. The School’s research takes place in a famously collaborative and cross-disciplinary setting. “We don’t have a School-of-Pharmacy-only building, and so we have been immersed within the UCSF campus community,” says BTS department Co-chair Kathy Giacomini, PhD. “We integrate physically while maintaining our School identity.”
  • The School made the pharmacy connection early on. The School’s leadership in the 1970s saw the need to connect pharmacy with basic research science, and this connection jump-started the School’s NIH funding success. For example, back then the School made a commitment to computational biology, a field that:
    • uses computers to visualize key structures inside cells such as disease- related proteins,
    • analyzes with applied physics how those proteins interacted with drugs, and
    • runs mathematical procedures, called algorithms, to rapidly search large databases of compounds for potential drug molecules to counteract the proteins.

    Computational biology was on the periphery of pharmacy at the time. This and other decades-old decisions about basic research direction continue to pay dividends in federal funding today.

    Key forefathers of the field established the School as a leading force. These trailblazers included Robert Langridge, PhD (founder of the UCSF Computer Graphics Laboratory), Peter Kollman, PhD (creator of the widely used AMBER molecular simulation software), and Irwin “Tack” Kuntz, PhD (whose DOCK algorithm is now regularly used in drug discovery by the pharmaceutical industry).

Today the School continues to receive major NIH funding in computational biology. Indeed, that heritage is clearly evident in fiscal year 2009 funding. Department of Pharmaceutical Chemistry faculty member Thomas Ferrin, PhD, who was once a graduate student of Langridge and Kuntz and is now director of UCSF’s Resource for Biocomputing, Visualization and Informatics, received a $1.2 million grant. (See: Top Six Grants)

It is only the latest installment in 40 consecutive years of federal support for what Ferrin notes is “the longest running National Center for Research Resources-funded national resource center in existence.”

The Resource is the current-day incarnation of Langridge’s laboratory with an expanded emphasis beyond biomolecular structures.

Likewise, in the latest funding round:

  • Department of Pharmaceutical Chemistry faculty member Matt Jacobson, PhD, received a U.S.$250,000 grant to develop computer programs that “predict the ability of compounds to enter cells.”
  • BTS department colleague Andrej Sali, PhD, received U.S.$278,000 to design a computer program that will help describe the three-dimensional shapes of large macromolecular “machines” within cells, such as nuclear pore complexes and ribosomes, to better understand how they work both under normal and disease conditions.

As an aside, in a classic case of NIH-funded School of Pharmacy collaboration, Ferrin’s Resource provides the computer visualization for researchers in Sali’s lab who model and analyze those large molecular complexes, which are comprised of dozens or even hundreds of proteins.

A decade of funding for bioinformatics

Another evolutionary branch of this traditional School strength is bioinformatics. In this field, scientists are using computing power and developing software tools to mine the enormous amount of information coming out of the genome projects for proteins and other molecular structures that are conserved in different organisms and over the course of evolution. The goal is to infer their functions. This information might eventually be used for therapeutic interventions.

For example, BTS faculty member Patricia Babbitt, PhD, who has received NIH support in this area for more than a decade, is exploring conserved protein structures—“the ancestral scaffold”—to infer the functions of otherwise diverse enzymes. Her lab is building a Structure-Function Linkage Database, as well as identifying small molecules that are likely to bind to the enzymes as substrates or inhibitors of their chemical reactions, providing useful information for future drug design.

New drug discovery directions attract support

While the computational biology trail has long since become a standard path to drug discovery in the pharmaceutical industry, the School’s ongoing NIH funding leadership reflects fresh frameworks for drug discovery.

This includes Department of Pharmaceutical Chemistry Chair James Wells’ work in chemical biology. He is building molecules block-by-biological-building-block (via a process he co-invented, called “tethering”) that are then used to probe cells and trigger their processes.

In fiscal year 2009, Wells received NIH grants totaling U.S.$1.5 million for everything from new equipment for the Small Molecule Discovery Center he directs to finding the molecular leads that might activate enzymes that destroy cancer cells or block others involved in inflammatory and autoimmune diseases.

In the same department, Brian Shoichet, who earned his PhD at UCSF under Kuntz in 1991, has also made major contributions to drug discovery, combining computational with experimental research to generate unexpected findings. These include the observation that many apparently promising "drug leads" behave as colloids, not unlike milk, that sequester proteins and lead to unwanted side effects. That research has attracted ongoing attention among pharmaceutical companies.

With major NIH support, Shoichet's lab continues to work on the computational methods first pioneered at UCSF for predicting drug action and design and, recently, applying them to discovering new leads for an adrenergic receptor (the target for asthma drugs), the adenosine receptor (a target for Parkinson's Disease), and for predicting drug side effects.

Research stalwarts draw funding for decades

Some progenitors of pharmacological research have continued to draw NIH support to the School for decades, despite an ever-shifting landscape of competition and new biomedical technology. Here are but a few examples.

  • Szoka and drug delivery. BTS department faculty member Francis Szoka, PhD, helped pioneer the engineering of nano-sized drug delivery ”vehicles“ back in the 1980s, using tiny bubbles made from cell membrane materials such as liposomes

    In fiscal year 2009, his ongoing work was awarded more than U.S. $700,000 to design and test the latest generation of his laboratory’s tree-shaped macromolecule-sized biodegradable-polyester drug delivery vehicles to better target anti-cancer drugs (including delivering two drugs at once and/or with different release rates) or to provide for diagnostic imaging.

  • Burlingame and mass spectrometry. Alma Burlingame, PhD, faculty member in the Department of Pharmaceutical Chemistry, first received NIH funding for developing his National Bio-Organic Biomedical Mass Spectrometry Resource Center in 1973, before bringing the center and its subsequent decades of continuous federal funding to UCSF in 1978.

    “The technological pace in [mass spectrometry] has been astounding—almost a revolution every two to three years, literally,” notes Burlingame. “Probing deeper into the molecular nature of human and other cell biology opens new vistas almost constantly. There is a continuing flow of new biological questions, from researchers locally and nationally, that we meet with new methodological capabilities and developments on a daily basis. What we are doing now was not possible some five years ago.” (See: Top Six Grants)

  • Ortiz de Montellano and the P450 enzyme family. Again in the Department of Pharmaceutical Chemistry, Paul Ortiz de Montellano, PhD, has likewise spent decades researching the cytochrome P450 enzyme family, both for the key role it plays in drug metabolism and toxicity and as drug targets in bacterial and other diseases. He has written the seminal text on the subject and won pharmacology’s highest honor, the Bernard B. Brodie Award in Drug Metabolism, for his work in the area.

    He continues to win NIH grants, which totaled nearly U.S. $800,000 in fiscal year 2009, for his ongoing exploration and manipulation of those enzymes as well as for specific analysis of those involved in tuberculosis in order to develop better treatments for the disease, especially during its latent state.

New directions in translational research attract support

Beyond such traditional and ongoing strengths, the School’s continued funding leadership has been fueled by scientific leaps forward in areas such as translational therapeutics.

For example, current BTS department faculty member and former longtime chair of the Department of Biopharmaceutical Sciences, Leslie Benet, PhD, co-pioneered in the early 1970s the now-standard concept of individualized drug clearance in pharmacokinetics with colleagues Malcolm Rowland, PhD, and Gary Graham, PhD. They were also the first to consider the effects of proteins that transport drugs in and out of cells, thus determining their bioavailability and excretion rates.

Benet recruited current BTS department Co-chair Giacomini in 1981, and she started a new line of inquiry, which focused on those membrane transporters and thus, as she explains, “understanding the mechanisms responsible for pharmacokinetic phenomena such as drug absorption and disposition.”

While Giacomini notes that the NIH stopped funding much pharmacokinetic research, her laboratory’s pioneering work in the pharmacogenomics of drug transporters—how genetic differences alter the structure, action, and concentration of membrane transporters, and thus the clinical drug responses of individuals—gained U.S. $25 million in funding over the past 10 years and has received a total of more than U.S. $14 million in program expansion funds from the NIH over the next 5 years starting July 1, 2010.

Expansion of the School’s research agenda brings support

Meanwhile, the BTS department has expanded the School’s therapeutic work beyond drugs and attracted distinctive cross-disciplinary researchers such as faculty member Shuvo Roy, PhD. Last year, Roy relocated his work on a bioartificial kidney and its associated U.S.$1 million in fiscal year 2009 NIH funding from the Cleveland Clinic. (See: Top Six Grants)

The project, which Roy has been honing for about a decade, combines microelectromechanical systems (MEMS), a filtration membrane (employing microchip fabrication technology to create its pores) and human renal cells into a surgically implantable device the size of a coffee cup that provides the health benefits of a kidney transplant, while addressing the limited number of kidney donors. The device is being designed to filter toxins from the blood, while also providing other biological functions of a healthy kidney. Roy is now successfully concluding research meant to tackle key technical challenges and assess feasibility.

New roads to continued funding leadership

Looking farther down the road, Giacomini and Wells see increasing NIH funding flowing to nascent areas where School researchers have unique expertise:

  • Systems biology. This line of inquiry is being pursued at the School by, among others, Chao Tang, PhD, and C. Anthony Hunt, PhD, in the BTS department. Systems biology approaches look at sub-cellular bio-networks and seek to prioritize key nodes for intervention in disease processes.
  • Protein-protein interactions. BTS department faculty member Tanja Kortemme, PhD, is exploring this area in order to, among other things, better inhibit so-called “undruggable” proteins that lack typical nook-and-cranny binding sites for small molecules.
  • Human microbiomics. Michael Fischbach, PhD, who is also in the BTS department, is an emerging leader in the infant field studying microorganisms that are found in the human body, their interactions with each other and their host, and characterizing small molecules from them.
  • Genomics of non-coding regions. The BTS department’s Nadav Ahituv, PhD, is a leader in exploring the role that areas of the human genome that do not encode proteins play in health and disease.

Clinical department focuses on research

Given the traditionally basic science orientation of NIH funding, the School’s Department of Clinical Pharmacy, while internationally renowned for innovations in doctor of pharmacy (PharmD) education and pharmacy practice models, was not a magnet for such federal research grants.

“Clinical science has struggled to get its foot in the door, but this is changing,” says department Chair B. Joseph Guglielmo, PharmD.

The change began in the first decade of the 21st century as both the NIH, in its 2003 Road Map initiatives, and the School, in a shift codified by its 2007-2012 strategic plan, cited the need for more translational science and more clinical scientists to bring that about.

As defined by the NIH Road Map, this means more funding “to accelerate the movement of scientific discoveries from the bench to the bedside.” And as the School’s strategic plan notes: “To succeed in translating basic drug research into patient care, we must prepare more doctors of pharmacy with the skills they need to conduct the essential clinical research that falls between the development of a potential drug and the use of that product in patients.”

Indeed, Guglielmo asserts, “We have a fraction of the pharmacist clinical scientists we need.” Thus, a newly increased area of NIH funding at the School is for just such training.

Shortage of clinical scientists addressed. In fiscal year 2009 alone, Department of Clinical Pharmacy faculty member Ruth Greenblatt, MD, received a nearly U.S. $500,000 NIH grant to extend a previous program training junior faculty in clinical or translational science to treat chronic diseases in women—and, in turn, to create a national model for such training programs.

The School’s clinical scientist ranks have been further bolstered by pharmacy candidates’ successes in UCSF-wide competition for the NIH-funded K12 career development grants, Guglielmo reports. These grants provide several years of financial support and yield master’s degrees in clinical research.

NIH funding for the training of clinical scientists has also flowed to the School via faculty placement in the Training in Clinical Research program administered by UCSF’s medical school, which can also lead to master’s degrees in the field. Guglielmo notes that recent department faculty hires have typically held post-PharmD clinical science fellowships or earned concurrent PhDs.

The result is a department that is increasingly primed to compete for the more clinical grants the NIH is now distributing.

“My department’s the little kid. We’re new to it,” says Guglielmo. “But we’re looking pretty good … We’ve taken the need to develop clinical scientists seriously. We have a bunch of young faculty who are set to carry the torch.”

Significant successes. A blaze of that non-traditional NIH funding was already highly visible in fiscal year 2009 in multi-million dollar support for Department of Clinical Pharmacy faculty members Greenblatt and Kathryn Phillips, PhD.

Greenblatt, a physician who founded the Women’s HIV Program at UCSF, heads the Northern California node of the NIH-supported Women’s Interagency HIV Study. The latter tracks and treats thousands of women nationwide. (See: Top Six Grants) She also received NIH grants totaling nearly U.S.$580,000 for another clinical study—analyzing whether levels of antiretroviral drugs present in small samples of study subjects’ hair correlated with the bioavailability and effectiveness of such medications. This could yield “an inexpensive, noninvasive, field-friendly method” for determining levels of drug exposure for patient treatment or further research.

Phillips, a professor of health economics and health services research, pushed that NIH-funded research envelope even further. She received a U.S.$1.8 million grant to study how and if so-called personal medicine (i.e., pharmacogenetics) can be made cost-effective in the diagnosis and treatment of certain types of breast and colorectal cancers, thereby creating a model for such genetically based cancer treatment evaluation. (See: Top Six Grants) It is a study that goes beyond matters of clinical efficacy to establish evidence-based information for future health care regulations and socioeconomic policies.

Getting that initial grant

“These kinds of NIH funding successes do not happen overnight and are not expected of new, junior faculty members,” explains Koda-Kimble. What is required is usually initial funding from other sources and research success, which leads to the possibility of NIH support.

A good example, notes Koda-Kimble, is the funding history of now senior scientist Charles Craik, PhD, a member of the Department of Pharmaceutical Chemistry. Craik began his protein engineering research at UCSF with a grant from the National Science Foundation (NSF), which funded both his work and a much-needed renovation of his laboratory space into a state-of-the-art protein engineering center. From there, Craik shifted his research emphasis to structure-based drug design and began 20 years of funding support from the NIH on the structural biology of HIV. This work grew into a current NIH center grant on HIV directed by Craik’s School of Medicine colleague Alan Frankel, PhD. Subsequent success led to a 10-year project supported by NIH’s National Cancer Institute and recent support for Craik’s work in infectious diseases and cancer nanotechnology. The NIH also supports, with a training grant, the Chemistry and Chemical Biology PhD Graduate program that Craik directs. “NIH funding success in turn has also helped attract collaboration with industry,” explains Craik.

Great science is the goal

The growth over the years in NIH support also reflects the growth in the number of the School’s basic science faculty. Many of these new faculty members are young and are now building their portfolios to be able to contend for the highly competitive and shrinking NIH research dollars.

“We are here for the duration,” says Koda-Kimble. “Our focus remains on great science to improve human health. We’ve always delivered on this and we continue to amaze even ourselves.”

UCSF School of Pharmacy top 6 NIH grants for fiscal year 2009

  1. U.S. $1.2 million to Thomas Ferrin, PhD, Department of Pharmaceutical Chemistry, to support the UCSF Resource for Biocomputing, Visualization, and Informatics (RBVI).
  2. More than U.S.$1 million to Alma Burlingame, PhD, Department of Pharmaceutical Chemistry, to continue his pioneering multi-decade work directing the National Bio-Organic Biomedical Mass Spectrometry Resource Center.
  3. U.S.$1 million to Shuvo Roy, PhD, Department of Bioengineering and Therapeutic Sciences, to further the development of an implantable bioartifical kidney.
  4. U.S. $15 million over the next 5 years to Kathy Giacomini, PhD, Department of Bioengineering and Therapeutic Sciences to continue her previous 10-year NIH-funded study of the pharmacogenomics of membrane transporters.
  5. U.S. $2.7 million to Ruth Greenblatt, MD, Department of Clinical Pharmacy, for the Northern California node of the ongoing Women’s HIV Study, the largest U.S. study of women living with or at risk of HIV disease.
  6. U.S. $1.8 million to Kathryn Phillips, PhD, Department of Clinical Pharmacy, to study how personalized medicine (i.e., pharmacogenetics) can be made cost-effective in the diagnosis and treatment of certain types of breast and colorectal cancers.

About the School: The UCSF School of Pharmacy is a premier graduate-level academic organization dedicated to improving health through precise therapeutics. It succeeds through innovative research, by educating PharmD health professional and PhD science students, and by caring for the therapeutics needs of patients while exploring innovative new models of patient care. The School was founded in 1872 as the first pharmacy school west of the Mississippi River. It is an integral part of UC San Francisco, a leading university dedicated to promoting health worldwide.