A Medical Research Organization

“People, not Projects”

Transforming discoveries

High risk, high reward research

Few constraints

Generous and flexible funding

Howard Hughes Medical Institute

Howard Hughes Medical Institute $10.6 billion invested in

research and science education since 1985

- $9 billion for research and research support

- $1.6 billion for science education, international research

Endowment of $16 billion* *close of FY 2011

Scientific Leadership Robert Tjian, Ph.D. President, HHMI and Professor of Biochemistry & Molecular Biology University of California-Berkeley Jack Dixon, Ph.D. Vice President and Chief Scientific Officer Science Department, HHMI and Professor of Pharmacology, Cellular & Molecular Medicine, and Chemistry & Biochemistry University of California, San Diego

Gerry Rubin, Ph.D. Vice President and Director, Janelia Farm Research Campus Sean Carroll, Ph.D. Vice President for Scientific Education and Professor of Molecular Biology and Genetics University of Wisconsin, Madison

Medical Advisory Board: A Committee Guiding Scientific Review and Policy

David Baltimore, Ph.D. Nobel laureate President Emeritus and Robert Andrews Millikan Professor of Biology California Institute of Technology J. Michael Bishop, M.D. Nobel laureate Director, G.W. Hooper Foundation and University Professor University of California, San Francisco Michael Botchan, Ph.D. Richard and Rhoda Goldman Distinguished Professor of Biochemistry and Co-Chair of the Department of Molecular and Cell Biology University of California, Berkeley Gerry Fink, Ph.D. Herman and Margaret Sokol Professor Whitehead Institute for Biomedical Research Massachusetts Institute of Technology Carol Greider, Ph.D. Nobel laureate Daniel Nathans Professor & Director Molecular Biology & Genetics Johns Hopkins University School of Medicine Rowena Matthews, Ph.D. G. Robert Greenberg Professor Emeritus of Biological Chemistry and Research Professor Emeritus, Life Sciences Institute University of Michigan

Elizabeth Nabel, M.D. President Brigham and Women's/Faulkner Hospitals, Boston Janet Rossant, Ph.D., F.R.S. University Professor of Molecular Genetics and of Obstetrics and Gynecology, University of Toronto Chief of Research The Hospital for Sick Children, Toronto Phil Sharp, Ph.D. Nobel laureate Institute Professor, Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology Bruce Stillman, Ph.D., F.R.S. President, Cold Spring Harbor Laboratory Marc Tessier-Lavigne, Ph.D. President, The Rockefeller University Craig Thompson, M.D. President, Memorial Sloan-Kettering Cancer Center

HHMI’s Major Programs

HHMI Investigators

Janelia Farm Research Campus

International Research

Science Education

The Science Program at HHMI Seeks

To nurture exceptional scientists at

all career stages

To create a framework for discovery

To connect basic biology and

medicine

The HHMI Science Department

Oversees the flagship Investigator Program 1. 75 host institutions

2. 344 Investigators and 50 Early Career Scientists

3. Conducts investigator reviews for renewal decisions

3. Selects new investigators with open competitions

Oversees the international projects/scholars program

1. K-RITH studying HIV/TB in South Africa

2. International Scholars modeled after the Early Career Scientists program

Oversees Collaborative Innovator Awards program 1. Currently, eight (8) research teams funded

Science Department budget: ~$650M/year Average of $1.4M USD/investigator 344 Investigators 50 Early Career Scientists

HHMI Investigator Program

The HHMI Investigator Life Cycle

Infant

Student

M.D.

Ph.D.

Postdoctoral Training

Faculty Scientist

Publications Recognition

Tenure University Scientific

Leadership

HHMI Review @ 5 Years

Successful Review

Unsuccessful Review

Industry

Chair

Dean

HHMI Investigator

HHMI Investigator Competition

High Risk Research

National Academy (147)

Nobel Prize (13)

Strategies to maximize an investigator’s impact

1. “People, not projects”: Promote freedom to focus on projects driven by passion, incentive to emphasize creativity and a sense of responsibility to harness resources to study risky but high impact questions

2. Minimize non-research requirements

3. Require 75% of time to be spent on “active conduct of research”

4. Provide extensive administrative, legal, operational and scientific assistance, both at Headquarters and at the host institutions

5. Provide salary and benefits for investigators and other lab personnel

6. Enable investigator to manage generous operating budget for personnel and research expenses

7. Enable applications for major equipment purchases during four rounds of capital funding annually

8. Foster critical review and scientific collaborations through annual scientific meetings and workshops

•High Risk Research •Creative, Innovative •Productive, High-Impact •Scientific Meetings •Web Page Updates •Faculty Responsibilities

•Criteria •Review Materials •Research Presentation •Advisors: MAB, SRB, ad hoc •HHMI Final Decision

•Salary •Fringe Benefits •Operating Budget ($600K -

$1.2 million) •Occupancy Payments to

Host Institution

•Success - 5 years support •Non Success - 2 years

support •Rate 80%

Outcome Support

Expectations 5 Year Review

Measures of Success

A Model That Fosters Innovation and Invention

2,477 inventions

1,270 active licenses

1,242 patents

976 pending patent applications

100+ start up companies

Measures of Success

HHMI: A Powerful Model

72 Host Institutions

158 Members of the National Academy of Sciences

12 Lasker Award winners

13 Nobel laureates

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Selecting HHMI Investigators

How can HHMI identify the most transformative scientists?

HHMI Investigator Competitions History

Year Type Selected

1994 General (all levels) 41

1997 General (all levels) 70

2000 Computational Biology (all levels) 12

2000 General (0-7 years experience) 36

2002 Patient Oriented (6-16 years) 12

2005 General (4-10 years) 43

2007 Patient Oriented (4-16 years) 15

2008 General (4-10 years) 55

2009 Early Career (2-6 years) 50

2011 Plant (all levels >4 years) 15

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When the opportunity arises to influence a field or a career stage, HHMI undertakes a

special emphasis competition

Structural biology (~1980’s)

Computational biology (2000)

Physician-scientists in patient-oriented research (2002, 2007)

Hughes Collaborative Innovator Awards (2008 and 2012)

Early career scientists (2008)

Plant Biology (2011), in collaboration with the Gordon and

Betty Moore Foundation

Current Investigator Competition

We invite applications from more than 200 institutions (universities and medical schools, research institutes and independent hospitals)

Individuals apply directly via online system Streamlined applications: CV, Research Description (e.g. 3000

words), Future Plans (e.g. 250 words), self-evaluation of most significant work

Multiple rounds of peer review are used to select new Investigators

This includes experts in the field, Medical Advisory Board (MAB) and Scientific Review Board (SRB) members. In addition, a selected number of HHMI Investigators participate in the early review stage.

Does Our Review Process Retain Only the Best People?

Reviewing the HHMI Investigator

“The most important single task that Jack Dixon and I have at HHMI is to review the reviewers.”

Robert Tjian, President of HHMI

Scientific Review

The Review Process

Reviews take place every 5 years; no review for ECS (a six year appointment)

All reviewer panel votes are counted for each investigator

No progress reports are required between formal reviews

The Reviewers are:

A mixture of experts in a specific field and “knowledgeable generalists”

Especially important to include skilled evaluators of scientific talent

Members of the Scientific Review Board, Medical Advisory Board and ad hoc

distinguished scientists (No HHMI Investigators participate in the review)

“The Howard Hughes Medical Institute expects not only that its investigators be talented and productive scientists, but also that they demonstrate some combination of the following attributes to an extent that clearly distinguishes them from other highly competent researchers in their field: (1) They identify and pursue significant biological questions in a rigorous and deep manner. (2) They push their chosen research field into new areas of inquiry, being consistently at its forefront. (3) They develop new tools and methods that enable creative experimental approaches to biological questions, bringing to bear, when necessary, concepts or techniques from other disciplines. (4) They forge links between basic biology and medicine. (5) They demonstrate great promise of future original and innovative contributions.”

What are the criteria for an investigator review?

A shorthand way of defining the criteria: the “deletion test”

Scientific Review Process

Addresses the current five year appointment period

Investigators submit curriculum vitae, bibliography, progress report and

description of future plans, and five significant publications

At HHMI Headquarters, each investigator makes a 35-minute presentation

Advisors and investigator have a 20-minute question and discussion period

Advisors meet in executive session to develop a consensus recommendation

HHMI leadership uses recommendation to make final reappointment decision

Successful review: five-year renewable appointment

Unsuccessful review: two-year nonrenewable term

Investigator Review Outcomes: 2000 - 2011

Year # Reviews # Terminated % Terminated

2000 28 5 18

2001 36 7 19

2002 65 17 26

2003 67 16 24

2004 74 14 19

2005 58 6 10

2006 30 4 13

2007 60 7 12

2008 41 10 24

2009 48 10 21

2010 60 12 20

2011 59 10 17

Total 626 118 19 23

Early Career Scientists

Applicants must be within 2 – 6 years of initial academic appointment Single, non-renewable appointment term of 6 years Salary and benefits covered by HHMI Annual research budgets from $150,000 – $300,000 over 6 year term Eligible for justified equipment purchases

50 Early Career Scientists selected for funding from 2100 initial applications >30 institutions represented among the finalists

Janelia Farm: The First Five Years

Objective

Identify important biomedical problems for which future progress requires technological innovation and then foster the establishment of integrated teams of biologists and tool builders who seek to break through the existing barriers.

Recruitment

Neurobiologists

Molecular biologists

Chemists

Geneticists

Physicists

Instrument designers/engineers

Computer scientists/mathematicians

To accomplish these goals, JFRC recruits

Current Research at JFRC

Two synergistic objectives:

Identify general principles that govern how information is processed by groups of neurons

Develop enabling imaging technologies

JFRC Scientific Staff under initial 5 year plan:

24 Group leaders (20 as of today)

20 Fellows (19 as of today)

Senior Fellows (5 as of today)

Applied Physics and Instrumentation Group

Visitors and Project Teams (53 active projects)

Graduate student program (21)

Junior Fellow (independent postdoctorals; 4)

Shared Scientific Support (8 different) Scientific Computing (20)

Instrument Design and Fabrication (14)

Optical Microscopy with Resolution of Electron Microscopy

Figure 1A: A high-resolution optical microscope image of a fluorescently labeled Golgi in a cell, demonstrating the limits of optical resolution. 1B: The same area imaged and processed by the PALM approach, resulting in significantly higher resolution.

New Directions for JFRC: Structural Biology, with an emphasis on Cryo-Electron Microscopy Stephen Harrison, Richard Henderson, Roderick MacKinnon, Eva Nogales & Thomas Walz, advisors Development and Evolution of Nervous Systems Sydney Brenner, Sean Carroll & Larry Zipursky, advisors Cell Biology of Neurons

Karel Svoboda, Mary Kennedy & Michael Greenberg, advisors

Hughes Collaborative Innovation Award Program

HCIA Program supports innovative, collaborative projects led by HHMI investigators with collaborators including non-HHMI and international scientists

Current program supports 8 projects for four years each (2008-2012), with an annual budget of ~$1.2M ($10M/year)

Examples of funded projects:

- Peter Walter: Deciphering the role of the unfolded protein response in disease

- Xiaowei Zhuang: Wiring diagrams of mammalian brain

- Simon John: An implantable ultra-miniature sensor with remote interrogation system

Catherine Dulac, Ph.D. HHMI Investigator Harvard University How Does Gene Imprinting Shape Behavior and Brain Development?

Simon John, Ph.D. HHMI Investigator Jackson Laboratory Developing a Tiny, Wireless Sensor to Monitor Glaucoma Around the Clock

Danny Reinberg, Ph.D. HHMI Investigator New York University School of Medicine What Can Ants Teach Us About Aging and Behavior?

Collaborative Innovator Awards: Project Leaders

Susan Lindquist, Ph.D. HHMI Investigator Whitehead Institute for Biomedical Research Discovering New Strategies to Treat Neurodegenerative Diseases

Douglas C. Rees, Ph.D. HHMI Investigator California Institute of Technology Building a Better Foundation for Structural Studies of Membrane Proteins

Xiaowei Zhuang, Ph.D. HHMI Investigator Harvard University A Better Wiring Guide to the Mammalian Brain

Huda Y. Zoghbi, M.D. HHMI Investigator Baylor College of Medicine Speed Scanning the Genome for Neurodegenerative Disease Therapies

Peter Walter, Ph.D. Univ. of California-San Francisco The Unfolded Protein Response: A Good Target for Drug Design?

New Competition for Hughes CIA Projects

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Competition announced December 2, 2011

Project leader must be an HHMI investigator

Collaborators may be ECS, HHMI investigator, non-HHMI and international

4 year projects; typically ~$1.1M annual budget

71 proposals submitted by March 13, 2012

Selection of funded projects by July 1, 2012

Project funding to begin on or after Sept. 1, 2012