Mary Anne Koda-Kimble, PharmD

Mary Anne Koda-Kimble, PharmD, dean of the UCSF School of Pharmacy, was honored by the UCSF Medical Center on May 4, 2012 for her “exceptional vision as a leader, commitment to patients, compassion as a human being, and dedication to UCSF Medical Center and UCSF Benioff Children’s Hospital.”

The leadership award is especially significant, according to Koda-Kimble, “because the Medical Center is at the heart of my career as a pharmacist.”

Harry W. Hind, 1915-2012

Harry W. Hind, a 1939 graduate of the UCSF School of Pharmacy who invented solutions that revolutionized contact lens use, as well as a topical patch to treat pain from shingles, died on April 12 at age 96.

Hind co-founded Barnes-Hind Pharmaceuticals Inc., which developed drugs to treat tuberculosis and glaucoma. He was a trustee of the UCSF Foundation and a major benefactor of the School of Pharmacy.

Hind and his wife, Diana, who passed away in 2011, gave a total of $5.3 million to establish the School’s first two distinguished professorships.

Speaking on a White House panel discussing President Obama's just-released Bioeconomy Blueprint, UCSF Vice Chancellor for Research Keith Yamamoto, PhD, cited the implantable bioartificial kidney project led by UCSF bioengineer Shuvo Roy, PhD, as a prime example of biomedical collaboration with potentially major social and economic impact.

Image credit: The Front of the White House by Ben | Smith on Flickr

Al Burlingame, PhD

From the start of his illustrious half-century career in mass spectrometry, Al Burlingame, PhD, has been part of a scientific sea change.

In his first lab at UC Berkeley, complete with a dirt floor and leaky roof, he looked for signs of extraterrestrial life in meteorites. He compares an earlier mass spectrometry technique to “throwing a rock at a mud puddle and looking at the splash.” Nowadays, Burlingame’s laboratory is housed in 21st century digs at UCSF’s Mission Bay campus where he pries apart molecules using electrons, analyzing the most daunting sub-microscopic complexities of health and disease inside human cells.

—David Jacobson

Image credit: © majedphoto.com

Precisely targeting malaria parasites with drugs

Adam Renslo, PhD

• Associate director of chemistry for the department-housed Small Molecule Discovery Center
• Awarded $207,625 from the National Institute of Allergy and Infectious Diseases as part of a two-year $442,688 research grant

Adam Renslo, PhD

Renslo is developing a new drug delivery technology to more precisely target the parasites that cause malaria, which is responsible for close to a million preventable deaths worldwide each year.

In malaria, parasites invade red blood cells and digest hemoglobin, the protein that carries oxygen through the body, thus generating significant concentrations of ferrous iron in the form of unbound heme in their digestive compartments. Renslo’s delivery system specifically targets that type of iron, which is extremely rare in healthy cells.

The system uses a derivative of a new class of synthetic anti-malarial drugs (now in late-stage clinical trials) with a chemical structure that breaks apart in the presence of the free heme. This fragmentation yields anti-malarial effects of its own, but in Renslo’s system it also severs a chemical linkage, which only then releases and activates a second drug inside the parasite.

Using this NIH funding, the approach was successfully demonstrated in mice. The selective drug delivery cured the infection and also reduced the animal’s overall exposure to the partner drug, notably improving its safety and reducing side effects.

The research team, which includes Matthew Bogyo, PhD, faculty member at Stanford University School of Medicine, is now seeking to refine the delivery system, including chemically simplifying it to make it cheaper to produce, with the goal of eventually testing it in humans.

Renslo’s work on targeted drug delivery potentially enables the use of effective drugs that would otherwise be too toxic.

Directed protein-chopping to dissect cellular self-destruction

James Wells, PhD

• Professor and chair
• Awarded $285,442 by the National Institute of General Medical Sciences as part of a four-year $1.1 million research grant

James Wells, PhD

Wells’ latest NIH-funded project augments his lab’s focus on apoptosis, which is the healthy self-destruction of damaged cells that fails to occur in cancers. He is applying technologies developed or co-developed by his lab to dissect the process.

Normally, a sub-group of protein-cleaving protease enzymes called caspases spur the final steps of cell demolition by cutting apart as many as 1,000 different types of proteins.

To determine which targets or networks of targets are most important amid this implosion of simultaneous protein-chopping, Wells developed methods to cleave specific targets using an engineered enzyme called the SNIPer. Another technique tags and identifies the products of those chopping events.

Wells will isolate and analyze the effect of caspase cleavage on three cellular sub-systems:

• Enzymes that cleave and repair DNA
• Enzymes that promote and halt cell replication
• The proteasome, a complex in the cell that normally destroys caspases and other selected cellular proteins, thus acting as a brake on caspase-induced apoptosis

Wells’ precise dissection of apoptosis should help scientists identify weak points in the cell to design new drugs to treat the uncontrolled proliferation of cancer cells.

—David Jacobson

Image credit (Wells): © majedphoto.com

Malaria treatment for HIV-positive children and pregnant women

Francesca Aweeka, PharmD

• Professor in residence
• Awarded $579,350 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development as part of a five-year $2.7 million research grant

Francesca Aweeka, PharmD

Aweeka is researching the interactions between drug treatments for malaria and HIV in a region of eastern Uganda that has high rates of both infections.

She will examine the most widely used treatments for malaria in pregnant women and children under age five who are also being treated with combination antiretrovirals for HIV infection. Her study aims to evaluate their proper dosing, effects on the body and the disease (pharmacodynamics), and how individuals process the drugs (pharmacokinetics).

In particular, she will determine if the standard dosing of antimalarial drugs, derived from adult studies, is:

• Appropriate and effective for young children or pregnant women.
• Safe and effective when used in combination with HIV antiretrovirals.
• Causing neutropenia (decreases in the immune system’s key white blood cells) in those patients who are also HIV infected and being treated with antiretrovirals.

Aweeka’s findings will help establish drug-dosing guidelines based on age, pregnancy, and co-use with antiretroviral therapy for the most widely used anti-malarial medications.

Conflicts of interest and nonclinical research

Lisa Bero, PhD

• Professor and vice-chair for research
• Awarded $231,750 from National Institute of Environmental Health Science as part of a two-year $424,875 research grant

Lisa Bero, PhD

Bero is examining the impact of conflicts of interest on the design, conduct, and reporting of nonclinical pharmaceutical and toxicological research—laboratory and animal studies conducted to determine if a drug should go on to be tested in humans.

Specifically, she will look at whether researchers receiving industry funding, or with financial ties to companies, are more likely to design studies and/or selectively publish outcomes (i.e., reporting bias) that favor those sponsors.

In order to assess methodological bias, Bero will review and select the best tools to evaluate methods used in animal studies, then compare study quality, financial ties, and the extent of favorable results.

If Bero finds evidence of bias it would provide the basis for new conflict of interest policies, which would help to yield more accurate results and thus safer and more appropriate clinical trials.

—David Jacobson

Image credit (Aweeka): © majedphoto.com

Image credit (Bero): Cindy Chew

Genetic mutations and liver cancer

Xin Chen, PhD

• Associate adjunct professor
• Awarded two new grants totaling $351,488 from the National Institute of Alcohol Abuse and Alcoholism (part of a two-year $405,563 grant) and the National Cancer Institute (part of a two-year $369,642 grant)

In the first of the two new studies, Chen focuses on how alcohol contributes to liver cancer development. Increased alcohol consumption leads to liver diseases and eventually liver cancer. In this study, Chen is investigating genetic mutations that contribute to alcohol-induced liver cancer development in mice.

In the second new study, Chen is focusing just on hepatitis B (HBV) and hepatitis C (HBV) infections, the major risk factors for liver cancer. While it is known that HBV and HBV play direct roles, the resulting cancer takes a long time to develop and often does not occur at all. She seeks to determine what additional or on-going genetic mutations are occurring in the virally damaged liver cells.

Chen aims to precisely determine which changes to key liver cell genes lead to cancer, providing the basis for better ways to prevent and treat the disease.

New devices to treat retinal diseases

Tejal Desai, PhD

• Professor and vice-chair for education
• Awarded $379,264 from the National Eye Institute as part of a four-year $1.5 million research grant

Tejal Desai, PhD

Desai is developing a nanoporous thin-film device that can be used to treat eye disease. It will be as thin as a strand of hair with pores about 25 nanometers in diameter. Once deployed into the back of the eye, the device will deliver sustained doses of medications that can effectively fight the wet form of macular degeneration, a disease that damages sharp, central vision.

The new drug diffusion device would have multiple advantages over current treatments, which call for monthly injections of drugs into the eyeball with large-bore needles. Beyond the daunting discomfort, the injection method is neither pharmacologically optimal nor cost efficient due to the drugs’ rapid breakdown and clearance from the body.

By contrast, the new device would protect the drugs from degradation and deliver a sustained dose over several months. This study will develop and test prototypes in in vitro and animal eye models.

Desai’s research seeks to create new and improved tools for treating retinal diseases.

Biosensors that detect and respond to small molecules inside cells

Tanja Kortemme, PhD

• Associate professor
• Awarded $231,750 from the National Institute of Biomedical Imaging and Bioengineering as part of a two-year $424,875 research grant

Tanja Kortemme, PhD

Kortemme seeks to create a new type of modular sensor made from biological materials; in this case, protein molecules inside cells. Such sensors would allow real-time detection of small molecules such as intracellular signals, metabolites, and drugs inside living cells and organisms.

The biosensors will be made by reengineering heterodimeric proteins, which are pairs of proteins that normally interact to fulfill their biological roles. For the sensors, they will be altered so that they can only come together when a particular small molecule is present. This will be done by transplanting binding sites for the small molecules into the protein-protein interface.

The reengineered proteins will also each be linked to half of a so-called reporter, such as green fluorescent protein, that has been split in two. The reporter will only glow when the reengineered proteins combine, thus signaling the presence of the small molecules.

That split reporter can also be an enzyme, which is a protein molecule that affects the rates of chemical reactions and thus controls biological processes. In that case, when the heterodimeric proteins combine in the presence of the small molecules, the enzyme will be rejoined and activated.

Thus, Kortemme’s biosensors may go beyond detecting small molecules. If the reporter proteins she uses are enzymes, the biosensors could also control biological processes, such as activating cellular events that make more of the target molecules or metabolize them if, for example, they are toxic.

Kortemme is making new tools to detect and respond to many molecular targets. The biosensors could be used for probing cellular processes or for new medical diagnostics and treatments.

Inducing antibodies to neutralize HIV

Francis Szoka, PhD

• Professor
• Awarded $193,125 from the National Institute of Allergy and Infectious Diseases as part of a two-year $424,875 research grant

Francis Szoka, PhD

Szoka is making molecules known as immunogens designed to stimulate a virus-neutralizing immune system response against a region of an HIV protein called GP41.

GP41 is part of a protein complex embedded in and protruding from HIV’s viral envelope. The complex allows the virus to attach to and enter T-cells via a surface receptor called CD4.

The region of GP41 that Szoka is focusing on is the target of ongoing HIV vaccine development aimed at triggering the response of antibodies that would neutralize the virus before it enters cells.

Szoka’s unique approach is to stimulate that immune response with immunogens (linked amino acids called peptides) that mimic the targeted GP41 region but include specific chemical alterations (post-translational modifications) that may occur in that part of the protein during HIV infection.

Szoka hypothesizes that it is those modifications that induce the neutralizing antibodies to recognize the GP41 region.

His lab has synthesized chemically modified peptides that mimic the protein region and incorporated the immunogens into lipid nanocapsules. He thinks this will maximize the immune response and generate neutralizing antibodies to HIV.

Szoka will ultimately use the most effective immunogens in a vaccine meant to induce HIV-neutralizing antibodies, which could be a precursor to a vaccine to prevent AIDS.

Modeling and probing the cell cycle

Chao Tang, PhD

Chao Tang, PhD

• Adjunct professor
• Awarded $410,793 from the National Institute of General Medical Sciences, part of a four-year $1.6 million research grant

Tang is developing mathematical models of how cell division and replication (cell cyle) are regulated. The cell cycle is one of the most fundamental and complex biological processes, and one that goes awry in cancer’s cellular proliferation.

In this project, Tang is building and validating computer models of the entire cell cycle system in yeast, which share similar cell cycle processes and proteins with human cells. He is focusing on key checkpoints and switches that ensure the process, including the accurate and complete replication of DNA, is occurring correctly.

Tang plans to use his computer models to identify the effects of different disturbances on the entire cell cycle regulation system and at key checkpoints. He will use experiments in actual yeast cells to test his mathematical model’s predictions.

Tang expects that simulating disturbances of the cell division process will help explain why certain gene mutations can lead to cancer and may suggest new treatments.

—David Jacobson

Image credit (Tang, Szoka, & Desai): © majedphoto.com

Improving computer programs to yield better drug candidates

Ryan Coleman, PhD

• Post-doctoral fellow in the laboratory of Brian Shoichet, PhD
• Awarded an NIH fellowship of $48,398 in fiscal 2011, with an additional $52,190 of support in 2012

Ryan Coleman, PhD

Coleman’s research seeks to improve the predictive accuracy of molecular docking computer programs. The programs virtually screen and score small molecules (ligands) for the relative strength with which they bind to proteins, thus changing their activity (e.g., inhibiting those involved in disease processes). The technology, first developed at the UCSF School of Pharmacy, is the basis of much modern drug discovery.

Specifically, Coleman is examining computer-simulated bindings at increasing levels of detail to more efficiently determine the best scoring ligand-protein combination.

He is putting the refined technique to work by screening ligands for a key protein, called dopamine receptor D3. While the receptor has been targeted for decades by drugs that treat conditions such as schizophrenia and addiction, many of those medications bind to other protein receptors as well. Such off-target binding is the molecular basis of medication side effects.

Coleman’s efforts to improve docking may yield better ligands with fewer off-target effects.

Regulating an enzyme’s action

Adam Steeves, PhD

• Postdoctoral fellow in the laboratory of Matthew Jacobson, PhD, jointly advised by John Gross, PhD, and David Morgan, PhD
• Awarded an NIH fellowship of $48,398 in fiscal 2011, with an additional $52,190 of support in 2012

Adam Steeves, PhD

Steeves’ work analyzes a process called allostery. The enzymes in our bodies have active sites where they bind to other molecules and catalyze biochemical reactions. Enzymes also have allosteric sites where molecules can bind to them and alter their activity—activating or inhibiting it. Steeves is looking at how a “signal” from a binding event at an allosteric site causes a change at an active site.

As a model, he is examining how allostery works in ubiquitination. In this process a group of enzymes work together to tag unnecessary proteins in the cell with a protein called ubiquitin. Once tagged, the proteins are targeted for destruction. A key hand-off of ubiquitin from one enzyme to another during the tagging of the condemned protein is apparently allosterically activated.

Steeves’ work to better understand allostery should help to develop new drugs that target allosteric sites, thus allowing more specific effects. For example, different enzymes with similar active sites could be more precisely targeted via allostery.

—David Jacobson

School of Pharmacy NIH funding by fiscal year in millions (see below for full chart)

For the 32nd consecutive year, the UCSF School of Pharmacy received more research funding from the National Institutes of Health (NIH) than any other pharmacy school in the United States.

Total grants and contracts awarded to School of Pharmacy researchers during the NIH fiscal year 2011 (running from October 1, 2010 to September 31, 2011) totaled $29.1 million, according to Michael Nordberg, MPA/HSA, associate dean of administration and finance.

Such preeminence in securing highly competitive U.S. federal research funds reflects the School’s strengths in advancing long-standing national technology centers in mass spectrometry and biocomputing, as well as on-going major research projects within the School’s three departments, including areas such as:

• Women and HIV, Department of Clinical Pharmacy.
• Pharmacogenomics of membrane transporters, Department of Bioengineering and Therapeutic Sciences.
• Key enzymes in apoptosis and inflammation, Department of Pharmaceutical Chemistry.

But the School’s continuing leadership also reflects first-time NIH support for new faculty projects as well as for new researchers, including two post-doctoral fellows.

—David Jacobson

More on new NIH funding:

• Postdoctoral Fellows
• Department of Bioengineering and Therapeutic Sciences
• Department of Clinical Pharmacy
• Department of Pharmaceutical Chemistry

School of Pharmacy NIH funding:

Source: American Association of Colleges of Pharmacy (2002-2010),
internal (2011)

Tejal Desai, PhD

UCSF bioengineer Tejal Desai, PhD, will receive the 2012 Paul R. Dawson Biotechnology Award from the American Association of Colleges of Pharmacy (AACP) at the group’s annual meeting in July.

The award honors Desai for her contributions to contemporary teaching and scholarship in biotechnology. She is a faculty member and vice chair for education of the Department of Bioengineering and Therapeutic Sciences (BTS), a joint department of the UCSF Schools of Pharmacy and Medicine

Image credit: © majedphoto.com

Shuvo Roy, PhD with a model of the device

The effort led by UCSF bioengineer Shuvo Roy, PhD, to create an implantable artificial kidney for dialysis patients has been selected as one of the first projects to undergo more timely and collaborative review at the U.S. Food and Drug Administration (FDA).

The FDA announced on April 9, 2012 that it had chosen three renal device projects to pilot a new regulatory approval program called Innovation Pathway 2.0, intended to bring breakthrough medical device technologies to patients faster and more efficiently.

Image credit: © majedphoto.com

Tina Brock, BSPharm, MSPH, EdD

UCSF School of Pharmacy Associate Dean of Teaching and Learning Tina Brock, BSPharm, MSPH, EdD, became president of the national pharmacy leadership society, Phi Lambda Sigma (PLS), at the March 2012 meeting of the American Pharmacists Association in New Orleans.

Brock was voted president-elect by the society’s delegates, who represent 102 U.S. pharmacy schools, in 2011. The position includes a three-year term on the group’s eight-member executive committee. She has been a member of the society since being inducted as an undergraduate in 1989.

Phi Lambda Sigma—Beta Beta chapter cabinet

The UCSF School of Pharmacy student chapter of the national pharmacy leadership society, Phi Lambda Sigma (PLS), has won the organization’s 2012 Charles Thomas Leadership Challenge Grant to support a campus project.

Student pharmacist Caroline Lindsay, president of the School’s Beta Beta Chapter, accepted the award on the chapter’s behalf on March 10 at the PLS Awards Reception at the annual meeting of the American Pharmacists Association in New Orleans.

Brian Shoichet, PhD

Computational chemist Brian Shoichet, PhD, a faculty member in the Department of Pharmaceutical Chemistry, UCSF School of Pharmacy, is the new director of the California Institute for Quantitative Biosciences (QB3) at UCSF.

QB3, with research facilities at UC campuses in San Francisco, Berkeley, and Santa Cruz, has an academic director at each site, as well as a director who oversees operations as a whole.

Conan MacDougall, PharmD

UCSF School of Pharmacy faculty member, clinical antibiotics expert, and prize-winning teacher Conan MacDougall, PharmD, is the 2012 recipient of the Albert B. Prescott / Glaxo SmithKline Pharmacy Leadership Award.

The national award is given annually to a young pharmacist who has “demonstrated exemplary leadership qualities … indicative of someone likely to emerge as a major leader” in the field. It is selected by the Pharmacy Leadership & Education Institute and several prior recipients.

—David Jacobson

Image credit: © majedphoto.com

The UCSF School of Pharmacy continues to rank number 1 among Doctor of Pharmacy (PharmD) programs in the United States, according to a new, 2012 survey published by U.S. News & World Report.

The survey results appear in the magazine’s 2013 issue of “American Best Graduate Schools,” which appeared online today at the U.S. News & World Report website and will be available at newsstands on April 3.

The 2012 ranking of doctor of pharmacy programs accredited by the Accreditation Council for Pharmacy Education is based on peer assessment surveys sent in the fall of 2011 to deans, administrators, and faculty at other pharmacy schools or accredited degree programs.

In her latest appearance on The Dr. Oz Show, Nancy Nkansah, PharmD, discussed the dangers of mixing alcohol and certain medications, including prescription anti-anxiety drugs as well as some over-the-counter painkillers, antihistamines, and cough suppressants.

In a segment titled “When Safe Drugs Turn Deadly,” Nkansah, a faculty member in the Department of Clinical Pharmacy, UCSF School of Pharmacy, noted that about quarter of emergency room visits are due to combinations of medications and alcohol.

Nkansah advised Oz’s millions of viewers to to follow all drug package warnings, and also to help avoid such interactions by waiting to take medications for “about an hour to an hour-and-half, to at least allow the alcohol to begin to clear your system. And that is per drink, assuming you are having some wine or just a small mixed drink.”

“Also, pay attention to your body, if you still are feeling the effects of the alcohol, then of course do not take the medicine with it,” she said in the segment, which was nationally broadcast on March 1, 2012.

—David Jacobson

Watch:

When Safe Drugs Turn Deadly

Pharmacists
in Action

Jennifer Cocohoba, PharmD

How do you convince patients who feel fine to take medicines that can have major side effects?

How can you help them stay on their lifesaving daily medications for years to come despite the obstacle course of everyday life?

How do you help patients and providers choose the best combination of three or more drugs from a selection of more than two dozen that work in multiple ways to fight a virus that can mutate to resist them?

Finding the right answers is the daily work of UCSF School of Pharmacy faculty member and clinical pharmacist Jennifer Cocohoba, PharmD, who specializes in antiretroviral drugs that fight HIV, the virus that—untreated—causes AIDS.

As part of the health care team at the Women’s HIV Program (WHP) at UCSF, Cocohoba’s job is on the front lines of a battle for both personal and public health; a job that demands the medication expertise of the clinical pharmacist, the acuity of a clinical scientist, and the people skills of a counselor and coach.

Following the UCSF website's announcement of School of Pharmacy Dean Mary Anne Koda-Kimble's June 30, 2012 retirement came comments from leaders at UCSF and beyond. Koda-Kimble, whose 46 years at UCSF began as a PharmD student, became (in 1998) the first female dean of the top-ranked pharmacy school in the nation and the first leader from a clinical background. Her deanship carries an impressive legacy—from strengthening and expanding laboratory-based research programs to breaking new ground for programs that move research discoveries closer to clinical application.

Image credit: © majedphoto.com

More:

Colleagues React to Koda-Kimble’s Legacy at UCSF

Recent
Research

Every year U.S. drug regulators approve dozens of new medicines as “safe and effective,” but just how effective are they? How well do they alleviate specific aspects of illness, whether light sensitivity from migraine headaches or itching from eczema?

For answers, many physicians and other health care providers turn to systematic reviews, which combine research about a drug’s efficacy at achieving health outcomes to come up with cumulative estimates. A key tool of these reviews are meta-analyses, which statistically combine the data (e.g., blood pressure measurements, psychiatric test scores, rash cure rates) from multiple studies to seek more accurate answers.

But there is a catch to this effort at making more evidence-based medication decisions. Typically, such combinatorial reviews rely solely on data published in scientific journals. UCSF health policy expert Lisa Bero, PhD, and colleagues find that if nine drugs that were the subjects of such reviews over the past decade had unpublished data added to their meta-analyses, it would change estimates of the extent of their efficacy more than 90% of the time.

Image credit: Cindy Chew