1998–2009: The Giacomini Chairship
In October 1998, Kathy M. Giacomini, PhD, became the fourth chair of the department. During the next 11 years, Giacomini’s departmental goals were to:
- Build an internationally recognized academic program in pharmacogenomics and personalized medicine.
- Create a world-class program in computational and systems biology.
- Maintain and enhance the department’s international reputation in pharmacokinetics and pharmacodynamics.
- Continue to innovate in drug development sciences with an emerging emphasis on regulatory sciences and the FDA.
- Establish an independent PhD graduate program in the pharmaceutical sciences with a focus on pharmacogenomics, pharmacokinetics/dynamics, drug delivery, and bioinformatics.
- Set the stage for the transformation of the department into a joint department between the School of Pharmacy and the School of Medicine.
Giacomini’s leadership was characterized by increased interactions with other departments, programs, and faculty on the campus. Search committees expanded to include relevant faculty members in other departments and graduate programs in addition to faculty members in the department. These expanded committees increased the visibility of the department and allowed access to greater start-up funds, which were critical in recruiting top-tier scientists. To accomplish her first goal, strong collaborative interactions were initiated with the UCSF Program in Human Genetics (predecessor of the Institute for Human Genetics) and its co-directors, Ira Herskowitz, PhD, and Charles J. Epstein, MD, PhD. Pharmacogenomics at UCSF, which started with Giacomini, Sadee, and Kroetz, expanded with the recruitments of Su Guo, PhD; Xin Chen, PhD; and Nadav Ahituv, PhD. Start-up funds for these new pharmacogenomic faculty recruits came from a number of sources: the Program in Human Genetics (and subsequently from the Institute for Human Genetics, under the direction of Neil Risch, PhD); the Program in Biological Sciences (PIBS); and the dean of the School of Pharmacy.
Pharmacogenomics and clinical pharmacology were further strengthened at UCSF by the recruitment of Esteban G. Burchard, MD, MPH, who succeeded Benowitz as Chief of the Division of Clinical Pharmacology and Director of the Training Grant in Clinical Pharmacology, and of Leslie C. Floren, PharmD, who directs the Clinical Pharmacology Fellows bi-weekly seminar program, works with Burchard in administering the program and leads the department’s professional education activities.
Pharmacogenomics research grant
Pharmacogenomics received increasing departmental emphasis. In April of 2000, UCSF was awarded a five-year, $15-million research grant, with Giacomini as the principal investigator. This Cooperative Research Program grant, entitled “Pharmacogenomics of Membrane Transporters,” was an integral part of the NIH’s Pharmacogenomics Research Network (PGRN). The award to Giacomini was the largest among the nine grants awarded by the NIH in the first phase of its new pharmacogenetics research initiative. Over the next 15 years, the Pharmacogenomics of Membrane Transporters (PMT) grant continued to fund more than 20 scientists at UCSF. Pharmacogenomics became an integral part of the Institute for Human Genetics, the School of Pharmacy, and UCSF as a whole. This award—and the new faculty researchers it funded—established the department as a world leader in pharmacogenomics.
Move to Mission Bay
In the 1990s and early 2000s, UCSF began to plan to move to the new Mission Bay campus, which included most of the faculty in the Department of Pharmaceutical Chemistry (and many of the basic science departments in the School of Medicine). Herskowitz and Epstein offered Giacomini, Kroetz, and Guo office and laboratory space on the Human Genetics floor of Rock Hall at Mission Bay, laying the foundation for future growth of the department on the Mission Bay campus.
Computational and systems biology
Through its overall director, Regis Kelly, PhD, and the UCSF director, David A. Agard, PhD, the California Institute for Quantitative Biosciences (QB3) supported the formation of expansive search committees to recruit new faculty members into the department in the fields of computational and systems biology.
The first new member was Andrej Sali, PhD, an internationally acclaimed computational structural biologist, who later became the director of QB3 at UCSF. In the early 2000s, the Sali group began to develop an integrative modeling approach to characterizing structures of macromolecular assemblies—containing from a few to hundreds of proteins and nucleic acids. This effort culminated in an open source software package, Integrative Modeling Platform (IMP), which was instrumental in determining the first structures for a number of macromolecular machines, including the eukaryotic ribosome, mammalian ribosome, the 26S proteasome, and the nuclear pore complex. In addition to IMP, the Sali group is developing MODELLER, a computer program for homology protein structure modeling that has been downloaded by more than 70,000 researchers (as of 2014) and is used widely in the pharmaceutical and biotech industries. Sali’s recruitment was followed by further additions: Tanja Kortemme, PhD; Chao Tang, PhD; Ajay Jain, PhD; and Michael Fischbach, PhD.
Biological and Medical Informatics (BMI)
Concurrent with ongoing faculty recruitments, PhD program in the Biological and Medical Informatics (BMI) began developing strong links to QB3 and other graduate programs on the Mission Bay Campus. The BMI program—co-directed by Babbitt and Thomas Ferrin, PhD, Department of Pharmaceutical Chemistry, and housed in the Department of Biopharmaceutical Sciences—received NIH training grants and was increasingly recognized as a premier graduate program in the computational sciences related to biology. Department faculty collaborated extensively with computational chemists in the Department of Pharmaceutical Chemistry; by 2014, 13 members of Biopharmaceutical Sciences were faculty affiliates of QB3.
Pharmaceutical Sciences and Pharmacogenomics (PSPG)
Until 1999, graduate students carrying out research under faculty members in the Department of Biopharmaceutical Sciences were members of the PhD Program in Pharmaceutical Chemistry at UCSF. The program had three pathways: medicinal chemistry, pharmaceutics, and toxicology.
The pharmaceutics pathway trained students in the basic and translational sciences involved in drug development: drug delivery systems, drug metabolism and transport, pharmacogenomics, pharmacokinetics, and pharmacodynamics. The toxicology pathway was a minor pathway and emphasized training in molecular toxicology.
The great majority of faculty members in the pharmaceutics and toxicology pathways were members of the Department of Biopharmaceutical Sciences. In 1999, the Department of Pharmaceutical Chemistry developed the new PhD program in Chemistry and Chemical Biology, while the Department of Biopharmaceutical Sciences established the PhD program in Pharmaceutical Sciences and Pharmacogenomics (PSPG), with Szoka as the initial program director. The department-based PSPG program swiftly became a new campus-based graduate program and, in 2000, received its first T32 training grant from the NIH.
In the mid-2000s the department continued to expand its entrepreneurial activities, with an emphasis on drug development, clinical pharmacology, and interaction with the FDA. In October 2004, the department took over the Center for Drug Development Science (CDDS) from Georgetown University. The CDDS was established to advance—through research, education, and public policy—the science, strategic planning, and management processes of drug development as a rigorous academic discipline. Located in the University of California Washington Center (UCDC), under the initial leadership of Carl C. Peck, MD, and then of Howard Lee, MD, PhD, the CDDS offered pharmacometric services to UCSF clinical and translational investigators as well as to outside pharmaceutical partners. This was the first UCSF presence at the UCDC. By the end of the decade, the activities of CDDS transformed into other major pathways and the center was closed; still, the department continued to maintain an office on the Washington campus for interactions with the FDA and to provide support for its course in regulatory sciences.
ACDRS and CCDRS
One resounding success of the department’s Washington, DC presence was a CDDS collaboration that led to the creation of the American Course on Drug Development and Regulatory Sciences (ACDRS), modeled on the very successful European Course in Pharmaceutical Medicine taught at the University of Basel, Switzerland. In 2006, CDDS convened a planning committee, drawing participants from department faculty, FDA, professional societies, and pharmaceutical companies. Ellen G. Feigal, MD, a member of the planning committee, was recruited as ACDRS director, with a mandate to develop curriculum, enlist international teaching faculty, and implement the course, which held its first session in 2007. An executive board governs the course, chaired by Louis R. Cantilena, Jr., MD, PhD, who succeeded Feigal as ACDRS director, and including Giacomini, Peck, Benet, and Fritz Bühler, MD, from the European Center for Pharmaceutical Medicine.
The ACDRS consists of 18 teaching days divided into six sections over approximately 15 months (eight hours per day), including learning teams and mentored, case-oriented workshops. Teaching faculty consists of international experts in regulatory sciences, medical product discovery and development, product evaluation, and business practices. Lecturers and mentors are drawn from academia, regulatory agencies (such as the FDA, EMA, MHRA), the pharmaceutical, device, diagnostic and technology industries, coverage and reimbursement organizations, professional societies, and the NIH, in addition to faculty members from the department. The course is taught on alternate (but overlapping) two-year schedules in Washington, DC (at UCDC) and in San Francisco at the Mission Bay Campus. A related recurring conference, the Pacific Coast Statisticians and Pharmacometricians Innovation Conference (PaSiPhIC), was launched in 2009 and co-sponsored by the department and California Polytechnic State University.
The success of ACDRS led to a similar course, the Chinese Course in Drug Development and Regulatory Sciences (CCDRS), founded jointly in 2009 by Peking University, the University of Basel, and the UCSF Department of Biopharmaceutical Sciences, under the leadership of Peck, Benet, and Rae Yuan, PhD. Yuan was then head of the Roche Pharma Development Center in Shanghai, and had earned her doctorate in the UCSF lab of Leslie Benet.
Department of Bioengineering and Therapeutic Sciences (BTS)
Beginning in the fall of 2006, Giacomini led the effort to combine activities of the department and the program in bioengineering to create a new joint department. The UCSF-UC Berkeley Joint Graduate Group in Bioengineering, formed in 1983, expanded dramatically in the 1990s due to the increasing importance of technology in biomedical research. In 2000, the School of Medicine and the Graduate Division took initial steps to create a more formal structure for the discipline by providing funds for three full-time faculty members and start-up financial support to recruit new Bioengineering faculty to UCSF. Sarah Nelson, PhD (School of Medicine, Department of Radiology) was appointed leader of this effort, and was encouraged to reach out to other groups to establish a critical mass of scientists focused on moving in new directions. She assembled an interdisciplinary group of colleagues in the Departments of Radiology, Physiology, Biochemistry and Biophysics, Otolaryngology, Orthopedic Surgery, and Medicine. Giacomini and Nelson recruited leading scientists, including Tejal Desai, PhD, and Shuvo Roy, PhD, to seed development of the field.
With strong support from faculty members and leaders of other departments, School of Pharmacy Dean Mary Anne Koda-Kimble, PharmD, and School of Medicine Dean David Kessler, MD (and later, Dean Sam Hawgood, MBBS), enthusiastically endorsed forming a joint department. The faculty councils of both schools and the Academic Senate were consulted and finally, on April 27, 2009, Chancellor and Nobel laureate J. Michael Bishop, MD, announced:
…the establishment of the first UCSF joint department between schools, the Department of Bioengineering and Therapeutic Sciences…Led by co-chairs Drs. Kathy Giacomini and Sarah Nelson…
Bishop praised the goals and leadership of the unique department:
… the goal of the department is to speed the innovation of sophisticated medicines and medical devices by bringing together scientists with expertise in bioengineering, as well as computing, and scientists with expertise in the pharmaceutical sciences and genetics. Creation of this joint department was a notable achievement in the history of UCSF, and a tribute to the collaborative spirit that we value so highly. I applaud the perseverance and contributions of all faculty and administrators involved, as well as the foresight of School of Pharmacy Dean Mary Anne Koda-Kimble and School of Medicine Dean Sam Hawgood.
Major departmental scientific contributions (1998–2009)
- Established role of polymer architecture in long circulating water soluble polymeric anticancer drugs
- Created the Biopharmaceutics Drug Disposition Classification System (BDDCS) to facilitate prediction of drug disposition of new molecular entities and potential drug-drug interactions in the intestine and liver
- Published first clinical study to demonstrate (with atorvastatin) that an hepatic uptake transporter could dictate elimination characteristics of a highly metabolized drug
- Conducted first pharmacogenetic study of metformin glycemic response, demonstrating that genetic variants in organic cation transporters are determinants of metformin response
- Developed methods for small molecule docking and molecular similarity that rely upon ideas from computer science and robotics, including representation of deformable objects, multiple instance learning, and heuristic non-linear optimization (methods now widely used in industry and academia for rational drug design)
- Established structure of clathrin at crystallographic resolution and molecular mechanisms of its regulation during membrane traffic
- Launched the journal Traffic in 2000
- Identified soluble epoxide hydrolase as key regulator of vascular eicosanoid function
- Identified common naturally occurring genetic variants of P-glycoprotein as key determinants of variation in function of this important transporter
- Using computational methods, elucidated design principle underlying molecular networks that can achieve biochemical adaptation
- Developed integrative structure determination of macromolecular assemblies based on varied experimental datasets, physical principles, and statistical inference
- Suggested the protocoatamer hypothesis that sheds light on the evolution of eukaryotes from prokaryotes by suggesting a common evolutionary origin of coated vesicles and the Nuclear Pore Complex
- Determined the molecular architectures of the Nuclear Pore Complex and the mammalian ribosome
- Developed a suite of popular tools that significantly improve the applicability and accuracy of comparative protein structure modeling
- Developed a large database of annotated comparative structure models for all proteins detectably related to known structures
- Developed a class of methods for annotating functional consequences of single point mutations in proteins
Image credits: Elisabeth Fall for Xin Chen image; © majedphoto for all other images except Kortemme, Fischbach, Jain, ACDRS class, and Koda-Kimble and Bishop.