NIGMS Training in Systems & Integrative Science Peter C. Preusch, Ph.D. Program Director Pharmacological Sciences Training Grant Program, NIGMS, NIH LSRO Meeting Bethesda Marriott Hotel October 20-21, 2002

NIGMS and NIH Predoctoral & Postdoctoral Training in FY2001 PredocNIGMSOther NIHNIH Trainees Fellows Total PostdocNIGMSOther NIHNIH Trainees Fellows Total Total U.S. BiolSci 52,629 Clin Med 15,846 Total U.S. BiolSci 16,093 Clin Med 11,280 OD/NIGMS 11/13/01 NSF-NIH Survey of Graduate Students and Postdocs in Science and Engineering in 2000

GM Other NIH

NIGMS Mechanisms of Training and Research Support  Training Grants  Predoctoral (T32) Institutional NRSA  Postdoctoral (T32) Institutional NRSA  NRSA Fellowships (F32) Postdoctoral  NIH PRAT & ClinPRAT Postdoctoral  Career Development Awards (K08, K23, K25)  Research and Research Supplements  R01, P01, P50, R15, R21, R24, R41-R43, U54  Minority Opportunities in Research

NIGMS Training Programs Predoctoral Trainees (Awards) FY2001 Cellular and Molecular Biology 789 (46) Genetics398 (34) Systems and Integrative Biology247 (30) Pharmacological Sciences202 (25) Molecular Biophysics221 (27) Biotechnology178 (17) Chemistry/Biology Interface113 (15) Joint Training in Neuroscience 17 (1) Bioinformatics and Computational Biol 10 (3) Medical Scientist 927 (39) 3102 (237) NIGMS Active Predoctoral NRSA Trainees 10/30/2001 excludes short-term training awards

NIGMS Training Programs Postdoctoral Trainees FY2001 Anesthesiology21 Clinical Pharmacology31 Medical Genetics39 Trauma and Burn OD/NIGMS 11/13/01

NRSA Postdoctoral Fellowships (F32, F33) Where are the Systems Biologists? FY2001 NIGMS Pharm(P640) Physiol(644) Apps (0.9%) 2 (1.2%) New Awards (1.2%) 1 (0.6%) Active (3.0%) 3 (0.7%) Active RPGs (5.8%) 266 (6.4%) R01,R37,R21,R55,R29,PO1,P50 P140, P141, P142, P143 P144, P145, P146 Source IMPACII QVR search by mechanism and PAC - PCP Fall, 2002

NIH PRAT and CLINPRAT Fellowships  Pharmacology Research Associate Training  Supports Postdoctoral Fellows in NIH Intramural Labs  18 Applications  8 New Awards  15 Active Fellowships  Clinical Pharmacology Res Assoc Training  Supports MD Fellows at NIH Clinical Center  5-6 Applications  1-2 New Awards  4 Active Fellowships Source Program Directors

NIGMS Career Development Awards (FY2001) Applications 29 New Awards 7 Active Grants 21  K08 Mentored Clinical Scientist Award in Anesthesiology, Clinical Pharmacology, and Trauma and Burn Injury  K23 Mentored Patient Oriented RCDA  K25 Mentored Quantitative RCDA Source IMPACII QVR Search by mechanism - PCP Fall, 2002

What is training in the Pharmacological Sciences ?  Pharmacology  Physiology  Toxicology  Pharmaceutical Chemistry  Pharmaceutics  Medicinal Chemistry  Chemistry  Biochemistry, Molecular, and Cell Biology  Structural Biology/Biophysics l Neurobiology l Psychiatry l Immunology l Microbiology l Virology l Pathology l Cancer Biology l Experimental Therapeutics l Medicine l Veterinary Medicine Interdisciplinary training in pharmacology and related disciplines relevant to the discovery and development of therapeutic agents and to the basic understanding of drug targets and mechanisms of action.

What is training in Systems and Integrative Biology?  Physiology  Biomedical Engineering  Neurosciences  Behavioral Sciences  Clinical Sciences  Biochemistry  Cell and Developmental Biology  Organ/Systems Physiology  Complex Biological Problems  Quantitative Approaches  Computational Simulations Interdisciplinary training in the integrative, regulatory, and developmental processes of higher organisms and the functional components of these processes. Integration of approaches from the molecular and cellular to the whole organism and its behaviors.

What are we training Medical Scientists to do?  Biological Sciences  Chemical Sciences  Physical Sciences  Social Sciences  Behavioral Sciences  Computer Sciences  Bioethics  Biostatistics  Bioengineering  Economics  Epidemiology  Public Health The Medical Scientist Training Program (MSTP) supports combined MD/PhD degree training in any area scientific area with the objective of creating scientists who can bridge basic and clinical research.

Distribution of Slots by Program

Distribution of Training Grants by Program

What is meant by Systems &Integrative Pharmacology? l Where is the line? l Human in vivo study? l Animal in vivo study? l Animal in situ preps? l Human subject sample? l Animal tissue samples? l Primary cell cultures? l Cells, genes, proteins? l In silico research? l Do we have a problem? l Which models count? u Primate, rodent, frog, fish, fly, worm, yeast? l What constitutes an integrative response? l Integrated by system or by disease? l Who does the integrating - the system or the pharmacologist?

Fraction of Trainees using Animal Models or Human Subjects Continuing Grants FY2001 Ended New 2001

What counts as research training in drug metabolism?  ADME  Pharmacokinetics  Metabolite Identification  Prodrug Activations  Phase I & II Enzymes  Drug Transporters  Structure/Function  SAR  Expression Levels  Regulation  synthesis and reactivity  chemical models  homogenates, fractions, purified proteins  cell cultures  perfused tissues and intact animal & human  activity & antibody assays  matrix arrays  in silico simulations

NIGMS Predoctoral Training in Pharmacological Sciences N = 26 in FY2002 Slots = 203 Reported students = 358 Drug Metabolism = 41 Drug Metabolism = Ave = 11.5% of trainees Est slots = 1/3 - 1/5 total pool Est total Drug Metabolism predoctoral students = Predoctoral PharmSci Trainees in Drug Metabolism % of trainees reported

Why we held the meeting?  Decline in number of funded PS programs  Loss of program strength in in vivo methods  Loss of program strength in toxicology  Loss of programs in schools of pharmacy  Narrowing scope of research training offered  Changes in medical education landscape  Changes in graduate school admissions  Concerns about balance between old and new  Concerns about overlap with other programs

Goals of the Meeting NIGMS Pharmacological Sciences Training Grant Meeting: What is Training in the Pharmacological Sciences? Goals: 1. Increase scientific diversity of PS program portfolio. a) Balance between molecular/cellular and systems/integrative training b) Inclusion of traditionally allied disciplines c) Inclusion of newly emerging disciplines d) Inclusion of industrial and clinical experiences e) Inclusion of new student pools, e.g., MD, PharmD, DVM 2. Define core knowledge that makes the PS program distinct. 3. Improve communication between potential applicants, reviewers, current trainers, and NIH staff.

Addressing the Issues: Old Schools, New Schools, New Pools  Solution 1: Utilize the existing programs  currently funded PS, SIB, and MSTP grants  Solution 2: Attract new PS programs from existing NIGMS funded schools  33% have PS grants  82% have schools of med, pharm, or vet  Solution 3: Attract new PS programs from currently non-NIGMS funded schools  Wide open field - all your best can be PS  96 Schools of Med, Pharm, or Vet Med  Solution 4: Undergraduate Pharmacology

Hypothesis: The PhD degree experience in a medical school should be different from a non- medical school PhD.  What does your program do to take unique advantage of its affiliation with a medical school?  What are your students doing that they could not be doing in a College of Agriculture or Science?  What are they learning about the interface between basic research and clinical practice?  What opportunities exist for your students to participate in clinical research?

Hypothesis: MD training and PhD training are linked.  How have changes in MD training changed instruction in pharmacology for your MDs and for your PhD students?  What role do MDs play in training your PhD students?  What are you doing to prepare your students for their role in training MDs?

Hypothesis: Pharmacy contributes much to the diversity of PS training  Medicinal Chemistry, Pharmaceutics, and Pharmaceutical Chemistry extend the breadth of PS programs in biophysical, chemical, and physical sciences.  Pharmaceutics and Clinical Pharmacy extend PS programs in the area of drug discovery and drug development.  Pharmacokinetics, pharmacodynamics, drug delivery, drug-drug interactions are of major interest in pharmacy schools.  PharmD students and PharmD/PhD students bring a different set of skills to bear and are more likely to work with human subjects - the ultimate experimental systems and integrative model

Hypothesis: PhD students in a Vet School are more likely to work with animals.  Involving Vet Schools may improve training in Systems & Integrative Pharmacology  What work are your students doing that they would not do, if they were not associated with a Vet School?  What unique contributions can DVMs, PhDs, and DVM/PhDs make to science?

Major Points of Discussion  Pharmacology is the core discipline in which all PS students should receive training.  Pharmacokinetics and Pharmacodynamics remain the core subjects of pharmacology.  Systems and Integrative Pharmacology (in vivo whole animal) is in demand, but in trouble.  State-of-the-art training follows from the research interests of a research active faculty.  New science (e.g., genomics, proteomics, and bioinformatics) needs to be included, but must be connected to old roots.

Major Points (Continued)  Scientific Diversity in research should be a natural outcome of the varied strengths of U.S. institutions.  Scientific Diversity in student pools is desirable and may achieved by reaching out across campus.  Inclusion of a clinical experience in some programs would be an innovation, but is not easy or sufficient.  Inclusion of an industrial experience would be a useful option, but should not be mandatory.  Changes in the medical curriculum have resulted in new separate graduate courses at most institutions.  Changes to umbrella admissions and 1st year core courses have required major changes in programs.

PS Training Outcomes What do academia, industry, and trainees value most? Problem solving, self-learning, communication, collaboration.

What factors determine trends in Graduate Training? l University administration and faculty interests: What's hot? Who's retiring? Who are you hiring? l Industrial and academic job opportunities: What's hot? What's needed? What will be needed in 10 years? l Student application numbers: What's interesting or at least financially rewarding? l Peer reviewer judgments: What constitutes good training? l NIGMS supports only a fraction of the total trainees: NIGMS support leverages other support? NIGMS support affects application numbers, recruitment? NIGMS review process affects university decisions?

What is NIGMS Looking For? Review Criteria: l Strong research faculty Cutting-edge, peer-reviewed, science l Strong student pool Depth, breadth, quality, critical mass l Current trainees and training record l Training Program Courses, rotations, exams, monitoring, mentoring, enrichment, breadth and depth of opportunities. l Recruitment of under-represented minorities l Training in responsible conduct of research

What is NIGMS Looking For? Room for All under the Umbrella l NIGMS supports interdisciplinary training. l Pharmacology is central to the PS Program, but should not be exclusive. l Diversity is good - programs should NOT all look alike! l Potential Strengths: Mol Pharm, Clin Pharm, Med Chem, Toxicol, Pharmacy, Therapeutics l NIGMS would welcome new programs that embrace DVM, PharmD, other new pools.

Will the pendulum return of its own accord? l Transgenic and knock-out rodents? l Pharmacogenetic human phenotyping? l Bioinformatics & Pharmacogenomics? l Behavioral and neurosciences studies? l Chemical biology & drug design? l Imaging methods in drug development? l Human studies vs animal models? l Emphasis on translational research? l Law of supply and demand?

NIGMS Training Grant Information  Pharmacological Sciences Peter C. Preusch  Systems and Integrative Biology Alison E. Cole  Medical Scientist Training Program Bert Shapiro  NIGMS Assistant Director for Training John Norvell