Computational and Mathematical Biology Applications to Genomics and Genetics Research: A Review of Trends and Activities in Academia

Computational and Mathematical Biology Applications to Genomics and Genetics Research:
A Review of Trends and Activities in Academia

Contents

• I. Executive Summary
• II. Background
• III. Methodology
• IV. What is Needed:

• Infrastructure
• Curriculum Development
• Career Paths in Academia
• Research Training and Career Development
• Research

• V. Role for Industry
• VI. What is Available

• Infrastructure
• Career Development
• Research Training

• VII. Recommendations
• Appendix
• Footnotes

 

I. Executive Summary

The Human Genome Program (HGP) will produce vast amounts of genomic DNA sequence information within the next five to ten years. This information will be of little value to biologists if the tools to manage and interpret the information are not available and are not user friendly. In order to develop a plan for how the National Human Genome Research Institute (NHGRI) will ensure that these resources are in place, discussions by telephone were held with approximately 15 scientists with backgrounds in mathematics, physics, informatics, statistics, computer science, and molecular biology who are also concerned about these issues. They were all asked to describe barriers/ opportunities that could be addressed by the NHGRI acting individually or in collaboration with other components of the National Institutes of Health (NIH) or the private section. Five areas were identified: infrastructure; career development; career paths in academia; research training; and research. In addition, it was recognized that industry also has a very important role in these areas. Thus, a dialogue with leaders in academia, industry and government was considered appropriate and timely. The following recommendations were offered for consideration:

Infrastructure

1. Provide opportunities for individuals in leadership positions in academia (Provosts, Chancellors, Deans, and Department/ Division Heads) to learn more about the broad range of opportunities that computational and mathematical biology present in biology and medicine.
   
   
2. Encourage private and philanthropic organizations to support endowed chairs in departments of mathematics and computer sciences and related disciplines for those working on biological problems.

Curriculum Development

1. Use the academic career award (K07) mechanism to support faculty to develop curricula in computational and mathematical sciences as they relate to genomics and genome analysis.

Career Development and Research Training

1. Develop an institutional K01 program award that would provide a critical mass of non-biologists working in the areas of computational and mathematical biology in institutions where there are foci of scientists working in interdisciplinary areas critical to genome research and genome analysis and interpretation.
   
   
2. Increase the number of individual K01 awards.
   
   
3. Increase the number of training grants in genomics that have a significant emphasis on computational or mathematical biology.
   
   
4. Encourage departments of mathematics and computer sciences to partner with genome scientists in applying for NHGRI interdisciplinary training grants.
   
   
5. Address the stipend levels for training. The current NRSA stipend levels are not competitive for students with degrees in the mathematical and computer sciences. Alternatives to consider are developing a non-NRSA training mechanism, establishing an institutional K01 mechanism, and encouraging industry to supplement stipends.
   
   
6. Address the tuition policy for NIH training programs. The newly instituted policy of paying only 60 percent of tuition costs above $2,000 will not encourage the development of new training programs, particularly in the physical sciences.
   
   
7. Encourage other components of the NIH to initiate or increase the number of training programs that interface with mathematics, statistics and computer sciences.

Research

1. Evaluate why research projects in computational and/or mathematical biology receive poor priority scores.
   
   
2. Consider funding research projects in computational and mathematical biology for more than three years.
   
   
3. Increase the dialogue with the research community so that they are aware of the research opportunities in computational and mathematical biology.

Outreach

1. Convene leaders in industry and academia to discuss common interests and needs in research and training.

II. Background

The Human Genome Program (HGP) will produce vast amounts of genomic DNA sequence information. The management and interpretation of this information will require 1) appropriate analytical methods, computer tools and information systems for the collection, storage, and distribution of the mapping and sequencing data and 2) a trained cadre of scientists with interdisciplinary skills--those who understand the biological problem at hand and can find solutions by applying skills from other disciplines.⁽³⁾ Scientific disciplines that are key to the management and interpretation of genome data include computational and mathematical biology and statistics. In the 1995-96 annual progress report, the need to establish bioinformatics as a profession was emphasized. The document identified the problems in establishing a new profession, such as "winning acceptance for a new interdisciplinary specialty in academic institutions (particularly in an era in which resources are not growing) and winning academic acceptance for an application-oriented (as opposed to theory-oriented) discipline." It was noted that some progress is being made in that a few institutions are beginning to establish graduate programs in bioinformatics and the success of the NHGRIs Special Emphasis Research Career Award in supporting the training of a few mathematical and computational biologists. However, these efforts are inadequate given that the large scale genome sequencing efforts in model organisms and humans are ramping up at a rate that will result in tens to hundreds of millions of base pair information in sequence databases. This information will be of little value if the tools to manage and interpret the information are not in place and are not user friendly. Thus, at least two types of experts are needed: 1) individuals with solid backgrounds in the mathematical, physical or computer sciences who also have sufficient knowledge about the biology to understand the challenges and can develop appropriate analytical methods and computer tools and 2) biologists who understand the questions that can be addressed with these data and have a thorough grounding in mathematics, statistics or computer science who can develop user-friendly tools for general use.

III. Methodology

I interviewed by telephone the individuals listed in Appendix A. Most are establishing or attempting to establish departments, programs or foci for computational or mathematical biology within their academic institutions. Each was asked to describe their current situation, address whether or not there is a need to strengthen computational or mathematical biology in academia, and if so what were the barriers, what model programs exist and what NIH mechanisms besides the institutional training grants (T32) and the mentored research scientist development award (K01) should be developed to increase the potential for establishing visible and viable computational and/or mathematical biology programs or departments in academia.

A draft of this report was shared with all the interviewees and many of them provided comments. Most of the suggestions were incorporated, however, the author of this report takes full responsibility for its contents. The author also acknowledges that this is a select and not a statistical sampling of views, therefore, some of the suggestions and opinions may represent the interviewees biases. In addition, the opinions of university (with one exception) and industry leaders are not represented in this report.

This report is an outgrowth of an internal informal discussion by staff in October 1996.

IV. What is Needed

The interviewees identified five areas that need to be developed or strengthened in order for mathematical and computational biology to thrive as interdisciplinary areas relevant to genomics/genetics research in academia. These are infrastructure, curriculum development, career development, research training and research. Below is a summary discussion about each of these areas.

Infrastructure

In order for a new discipline to thrive in academia, it must have an intellectual and fiscal infrastructure in the form of a department. This is the ideal situation. It is probably an accurate statement that at present, there are very few computational or mathematical biology departments in U.S. institutions. Several barriers to establishing departments or programs were identified: 1) Most academic institutions have not as yet recognized computational and mathematical biology as important emerging areas of science worthy of elevation to a department level. 2) The application of mathematical or computer science principles to biology is an expanding discipline that forges interactions between two disciplines (biology and the mathematical or computer sciences) that normally do not interact scientifically and tend to be separated physically and organizationally. 3) In making tenured appointments for individuals in interdisciplinary research, decisions must be made about which departments slot will be used; in times when growth is restricted, this can make such decisions difficult; and 4) The type of interdisciplinary research that is being pursued may not be considered valued in the primary department. For example, most computer science and mathematics departments focus on theoretical rather than applied research.

In spite of these barriers, there are several universities that have made some progress in developing a program or focus for mathematical and computational biology. There are a few institutions where the leadership has recognized the importance of this interdiscipline and supports this effort formally (i.e., top down approach). Some examples are the Center for Discrete Mathematics and Theoretical Computer Sciences (DIMACS) ⁽⁴⁾ at Rutgers University and the University of California, Santa Cruz where the leadership has made interdisciplinary research and bioinformatics a part of the universitys strategic plan. The Department of Biomathematics at the UCLA School of Medicine trains doctoral students in a variety of disciplines including mathematical genetics. The institute/center at Washington University in St. Louis and the University of Pennsylvania are examples of bioinformatics programs being established as a result of the computational biology needs of the current or formerly NHGRI-supported Genome Science and Technology Centers (GESTECS) being located at these institutions (i.e., bottom up approach). The need to have information management systems for laboratory management and data interpretation was the nucleus around which these programs were established. Another arrangement that has proved productive are the current arrangements at the Washington State University and the University of Southern California between highly motivated individual faculty members in the departments of mathematics and biology who work with graduate students interested in interdisciplinary projects(i.e. ad hoc approach). Whereas a scientific discipline is probably better housed in a department, it is clear from the examples above that universities are using other mechanisms to develop interconnections within disciplines outside of departments through the establishment of centers, bureaus, and institutes.

One interviewee cautioned about the difficulty of establishing new departments that are amalgamations of two or more disciplines. A counter argument is that if no efforts were made to establish new departments, no new interdisciplinary departments would ever be established in academia. An alternative and still useful model is for graduate students to meet the requirements of an established discipline/department and then use that foundation to pursue an interdisciplinary project in another department.

Whereas all the approaches discussed above have worked to train students at the interface of biology and mathematical and computer sciences, they are less than ideal and are tenuous depending on the chairpersons of the collaborating departments and each universitys vision of its future. In order for a new discipline to grow and be stable, there are other requirements that must complement the academic structure--a curriculum specific to that discipline, a recognized career path, quality graduate students and resources to support them, and a strong research program which generates new approaches and technology for the new discipline.

Curriculum Development

A curriculum is the intellectual base upon which a new discipline is established and new concepts from different disciplines are integrated. There is a tendency in multi- disciplinary fields to require that candidates learn everything from all related fields rather than synthesize a new curriculum tailored to the needs of the new discipline. The lack of a discipline specific curriculum usually means that an individual will take longer to complete the requirements for a degree. Accordingly, students will be less attracted to enroll in a degree program that requires double course requirements. Curriculum development requires time that most faculty do not have given their teaching, research, administrative/committee and training responsibilities. There are several examples where individuals have developed new interdisciplinary courses, but because of lack of time, the courses, in their opinion, are not as comprehensive as is needed to really convey new approaches and concepts. All interviewees were of the opinion that a mechanism to give faculty release time to develop appropriate curricula and interdisciplinary courses would be extremely useful for the field and for training.

Career Paths in Academia

Individuals trained in computational or mathematical biology have several options for employment. The primary two are industry and academia. Industry offers better opportunities both in terms of compensation and a career path. Since the goal in industry is producing a product, individuals are hired for their expertise to get a job done without the constraints of needing to conform to the requirements of a home department or a discipline. The career path in academia is more complicated, especially for new untenured faculty. Because they are tenured, senior faculty are able to engage in interdisciplinary research since they have demonstrated their capabilities in their primary scientific discipline. However, as more universities recognize the need to foster interdisciplinary research, this may become less of a problem for untenured faculty.

One of the concerns of graduate students and postdoctoral fellows who are interested in interdisciplinary research is which academic department will hire them. One of the interviewees presented the following two examples to illustrate the problems facing young scientists. The first concerns an individual whose undergraduate degree is in biology. He became involved with the use of computers in molecular biology, gained considerable experience in this area, and now wants to get a Ph.D. The question for him is how/where? After much discussion and soul-searching, he opted to pursue a degree in computer science. He has passed the departments course requirements and now must choose a thesis topic. He is struggling with should it be a traditional computer science project as understood by computer scientists or should it be relevant to biology? The dilemma is what can be very valuable research for biologists, and in a sense innovative, may not involve any new theoretical concepts in new computer science research. According to the interviewee, the individual is still working through these issues and the departmental structure makes it very difficult for him to make a decision. The second case is an individual with two Ph.D.s, one in mathematics and one in electrical engineering/computer science, who is now working on a genome related project and has been extremely productive. He would like to stay in academia, but not as a research associate. He is an excellent researcher and would be an asset to many programs. The problem is which department? Can he hope to get an appointment in a department of mathematics or computer science that will welcome him to work on algorithm development in computational biology? The experience of this interviewee is that it will not be easy, but he plans to do whatever is necessary to help this person secure an appropriate academic position in a first-rate university. These two cases would not be problematic if interdisciplinary research were recognized as a legitimate research area either in a biology or computer science department.

Research Training and Career Development

Training programs provide the academic structure by which graduate students and postdoctoral fellows learn the fundamental concepts of science and have the opportunity to test hypotheses to increase the intellectual basis of the field. The interviewees unanimously agreed that more individuals needed to be trained through organized and well supported research training programs. There were at least three barriers identified in securing interdisciplinary training grants. One was the requirement that the applicant have well documented and established relationships between faculty in collaborating departments. Many of the interviewees spoke of the difficulty of new training programs meeting this eligibility requirements primarily because of the amount of time it takes to interest faculty in other departments to make a real commitment to interdisciplinary research. However, once faculty members do become involved, usually because of the value added to their own research, the interactions are very productive for faculty, graduate students and postdoctoral fellows. The second was that the stipends paid to non-biologists tended to be significantly higher than stipends paid to biologists. The stipend level of postdoctoral fellows with degrees in computer science or mathematics with less than two years of experience ranges between $35,000 and $42,000. The National Research Service Award stipends for postdoctoral fellows range from $20,292 to $32,300. The latter rate is for postdoctoral fellows who have seven or more years of training beyond the doctorate degree. Graduate student stipends are $11,496. These stipends are geared more to the support of biologists, rather than non-biologists. Thus, trying to attract non-biologists to training programs at these stipend levels is very difficult, if not impossible. The third was that the new NIH policy of limiting tuition costs on training grants ⁽⁵⁾ will make it difficult for institutions to start new or maintain existing training programs.

Another area of discussion was what should be the undergraduate background of graduate students trained in computational or mathematical biology. Many interviewees were of the opinion that it would be more desirable to recruit into these areas graduate students with undergraduate degrees in mathematics, statistics or computer science, rather than biology. The reason for this position was that a strong foundation in mathematical concepts is difficult to acquire late in the educational process. Such students would be given sufficient training (didactic and practical) in biology, but not to the same intensity as that required for graduate students/postdoctoral fellows in biology. Again, the emphasis would be on developing a appropriate curriculum. Not everyone interviewed was in agreement about the type of undergraduate background necessary for computational or mathematical biology. It was noted that excellence can be achieved in many ways and that the perspective of those trained in biology, but who have been cross-trained in the mathematical and computer sciences is also important. In fact, many of the current leaders in the field of computational and mathematical biology today are individuals whose doctoral degree is in one of the specialties in biology.

One of the interviewees suggested that the role of mathematics in biology extends beyond the HGP and into other disciplines in biology and thus other components of NIH should also be considering the establishment of interdisciplinary training programs. Given the role that mathematics and computational biology will play in molecular medicine, i.e., the identification of all or most of the genes causing disease and one of the several factors in the common diseases, MD/Ph.D training program should also expand training opportunities in these areas.

The NHGRIs Special Emphasis Research Career Award (K01) was established in 1991 to recruit individuals with formal backgrounds in mathematics, computer science, chemistry, physics and engineering to pursue genomics research. Approximately 3-4 awards are made annually. All of the awardees have as mentors genome researchers. Most of the interviewees had not heard about this program, but were enthusiastic about this type of award as well as an institution-type award that would support a critical mass of individuals to work in the are of computational or mathematical biology projects in their institutions.

NHGRI staff expressed concern that because of the demand and high pay, many individuals who have been trained on government funds would opt for employment in industry rather than remaining in academia. Most interviewees did not view that as a problem. In many instances they cited colleagues who are periodically offered more lucrative positions in industry, but instead opted for academic freedom, the opportunity to train students, and the ability to pursue their own research interest.

Research

In order for a new scientific field to establish intellectual independence and to be strong in graduate training, an intense, stable research program is essential. Several problems were identified as barriers to getting research projects in computational and mathematical biology established. A major concern was the scientific peer review of interdisciplinary projects. In the opinion of many interviewees, study sections as presently constituted were not always capable of reviewing interdisciplinary research projects. Short project periods were also considered disruptive to research activities. Developing new concepts or applying concepts to new problems usually requires more than two years to demonstrate feasibility or progress. A three year grant in essence gives the principal investigator approximately two years to demonstrate success. A three-year grant also makes it difficult to recruit postdoctoral fellows to work on the project, because the tenuousness of support in future years. In several cases, interviewees were told that an NIH institute/center/division was not interested in supporting their research at that particular time. After briefly discussing their proposed research, NHGRI staff was of the opinion that the research appeared appropriate to one or several NIH components.

One interviewee suggested that funds be used to support individuals through research grants (R01s) rather than research career development (K) awards. The rationale is that individuals who receive salary support for career development may not be successful in obtaining peer-reviewed funds at the end of their award period, whereas if you fund research projects, the principal investigator has demonstrated her/his potential to generate new research findings in the field and the research project could serve as a means of training graduate students and postdoctoral fellows.

V. A Role for Industry

Most of the individuals interviewed stressed the importance of industry supporting, in a substantial way, the development and maintenance of strong foci of computational and mathematical biology in academia for several reasons. First, industry has been very successful in recruiting trained individuals at all levels to work in industry. As the large-scale DNA genomic sequencing effort ramps up, there will be an ever increasing need for individuals who can manage and interpret the data that will be the platform upon which research in industry is pursued for the purposes of prevention, treatment and cure of diseases. Second, academia is usually the place where innovative, risky technologies are developed which are then used by industry. To drain trained personnel from academia without efforts to replace and increase the number of individuals involved in intellectual pursuits will eventually result in loss of adequate human resources to feed the genetics revolution. Thus, for industry to partner with academia to ensure that there are sufficiently trained personnel to develop new knowledge is a must. There are some commercial enterprises that do contribute to this effort, but the level of commitment and the duration of the commitment is unknown. Also , it was stressed that industrial funds committed should be unrestricted to give the institutions the needed flexibility to use the funds to strengthen its research effort where and when appropriate.

VI. What is Available

Before developing new programs, it is important to document what is available and to determine whether there are model programs in computational and mathematical biology should be replicated. The following list of programs, while not representative of all that is available, probably represents the major efforts in this area. The contributions from industry are not presented because there was no easy way to document or ascertain this information. The identifiable programs could be divided into three categories: 1) infrastructure; 2) career development; and 3) research training. Support of these activities is primarily through foundations and the federal government.

Infrastructure

The Whitaker Foundation⁽⁶⁾ [whitaker.org]
The Foundation's Leadership Awards in Biomedical Engineering provide funds to institutions with excellent educational programs in engineering or medicine to establish academic structures (departments or physical structures) for biomedical engineering. The duration and amount of the award is flexible, but is contingent on an equal or greater commitment from the applicant institution. Leadership awards address opportunities whose goals or external funding needs are outside the scope of two existing programs.

The Foundation's Biomedical Engineering Development Awards are designed to create centers of excellence in biomedical engineering education by establishing or enhancing academic programs. Typical grants have three elements: a start-up award of up to $1 million (capital needs, such as renovations and laboratory enhancements), annual awards up to $500,000 for four years with an optional two-year extension (faculty salaries and graduate student support), and a continuation award of up to $1 million (strengthens the academic program). This award requires an affiliation between engineering programs and graduate or medical schools.

Career Development

The Charles E. Culpeper Foundation's Scholarships in Medical Science [goldmanpartnerships.org]
This program provides U.S. medical schools up to three years of support, on behalf of carefully selected physicians of high potential achievement who are committed to careers in academic medicine. Eligible disciplines are basic biomedical research with a special emphasis on molecular genetics, molecular pharmacology and bio-engineering. Provisions include $100,000 per year in direct cost to support salary (partial), research and travel expenses. Award is for three years.

National Human Genome Research Institute's Mentored Scientist Development Award [grants2.nih.gov]
The purpose of this K01 award (formerly known as the Special Emphasis Research Career Award) is to foster the career development of individuals with expertise in scientific disciplines (mathematics, chemistry, physics, engineering, and computer sciences) that would further technological developments critical to the success of the Human Genome Program. Provisions include: 1) annual salary up to $75,000; 2) up to $20,000 for research-related expenses; and 3) tuition. The duration of the award is three to five years. The number of awards made annually depends on the quality of the applications received.

Research Training

Burroughs Wellcome Fund's Interfaces between the Physical/Chemical/Computational Sciences and the Biological Sciences [bwfund.org]
The goals of this program are to break down the traditional barriers at academic institutions and to train investigators coming from quantitative and theoretical backgrounds so they can bring different approaches and new ideas into the biological arena. This is a program for degree-granting institutions to propose graduate or postdoctoral training programs, or a combination of both. Ancillary activities may include undergraduate student research programs, faculty seed grants, or invited lectures. Grants of $350,000 to $500,000 per year for five years are made to four to six U.S. and Canadian institutions.

Alexander Hollaender Distinguished Postdoctoral Fellowships [orau.gov]
This is a Department of Energy fellowship program to provide training in research areas of interest to the Office of Health and Environmental Research. Eligible disciplines are life, biomedical and environmental sciences and other supporting scientific disciplines. This is a one year fellowship renewable for a second year. The provisions are: beginning stipend of $37,500 and up to $2,500 to cover the cost of relocation.

Alfred P. Sloan Foundation and U. S. Department of Energy Postdoctoral Fellowships in Computational Molecular Biology [sloan.org]
The purpose of these fellowships is to catalyze career transitions into computational molecular biology from physics, mathematics, computer science, chemistry, and related fields. The program is designed to give computationally sophisticated young scientists an intensive postdoctoral opportunity in an appropriate molecular biology laboratory. This is a two year program with a total budget of $100,000 per awardee; annually $42,000 is allotted for a stipend and $1,500 is allotted for research expenses. Up to ten fellowships are awarded annually.

The Whitaker Foundation Graduate Fellowship Program [whitaker.org]
This program supports students with engineering backgrounds to develop the skills required for a successful career in biomedical engineering. Awards are made for three years with an option to extend for up to two additional years. Provisions include a stipend of $17,000, a cost-of-education allowance of up to $13,500 and $1,500 for research-related fees. About 30 predoctoral fellowships are awarded annually.

National Science Foundation [nsf.gov]
The NSF has several training initiatives. The goal of the Integrative Graduate Education and Research Training Program is to enable the development of innovative, research-based, graduate education and training activities that will produce a diverse group of new scientists and engineers well-prepared for a broad spectrum of career opportunities. The emphasis is on critical and emerging areas of science and engineering. This is an institutional training grant; provisions include 1) annual stipend of $15,000 per graduate student; postdoctoral stipends are determined by the host institution; 2) up to $200,000 for equipment and special purpose materials; and 3) limited funds to defray the costs of research by students. Awards are made in amounts up to $500,000 annually, not including the maximum of $200,000 for equipment. Up to twenty awards will be made during the first three years of the program.

Several Directorates at NSF, Mathematical and Physical Sciences and Computer and Information Sciences and Engineering, support interdisciplinary training in the biological sciences.

Howard Hughes Medical Institute Graduate Fellowship Program [hhmi.org]
The purpose of this program is to promote excellence in biomedical research by helping prospective researchers with exceptional promise obtain a high quality graduate education. Several areas of training have been identified, including mathematical and computational biology. These awards are made for three years. Provisions include a stipend of $15,000 for the student and a $15,000 cost-of-education allowance for the institution. At least $2,200 of the latter must be used for the student's health insurance, books and supplies, computer and computer-related expenses, and travel to scientific meetings. Approximately 80 awards are made each year.

National Library of Medicine's Fellowship in Applied Informatics [nlm.nih.gov]
The purpose of the NLM Fellowship in Applied Informatics (F38) award is to provide individuals with various educational backgrounds ( scientific, clinical and administrative) the opportunity to apply the knowledge and technology of health informatics to help solve biomedical information management problems. Because NLM wishes to encourage applications from mid-career professionals as well as more junior applicants, the amount of the stipend is based on the salary or remuneration that the individual would have been paid by the home institution on the date of the award, but shall not exceed $58,000 per year. A $4,000 per year institutional allowance will be paid to defray the costs of supplies, equipment, travel, tuition, fees, insurance, and other trainee-related costs. The fellowship is limited to two years. This is a non-NRSA fellowship.

National Human Genome Research Institutes Institutional Training Grant in Genomic Sciences [grants1.nih.gov]
This is an institutional training program (T32) in genomic sciences to train scientists with multidisciplinary skills that will allow them to engage in research that will accomplish the goals of the Human Genome Program (HGP) and to take full advantage of the resulting genomic data and resources to solve biomedical problems and increase our understanding of human biology. This training program is intended to expand the research capabilities of individuals with backgrounds in either molecular biology or a nonbiological scientific discipline relevant to genomic sciences (e.g., physical, chemical, mathematical, computer or engineering sciences). Provisions include: 1) annual stipends-$11,496 for graduate students and $20,292-$32,300 for postdoctoral fellows; 2) tuition; and 3) partial support of research-related expenses annually-up to $1,500 per year per graduate student and up to $2,500 per year per postdoctoral trainee. The number of grants awarded annually depends on the quality of the applications received. Duration of the institutional awards is up to five years; individuals are usually supported for two to three years under this mechanism. This is a National Research Service Award and as such, the provisions are determined by the NIH.

VII. Recommendations

The following recommendations are distilled from the discussions with the interviewees. Staff suggests that these recommendations serve as the starting point of a discussion with leaders in academia, industry and non-profits. There are clearly some areas where new mechanisms can be established, but the success of computational and mathematical biology depends upon developing a strategy in which all parties that have a collected vested interest in the area are brought together to discuss what needs to be done, who will/can do what, and how resources can be leveraged, once there has been an agreement that an opportunity exists to provide stable support to a new discipline.

Infrastructure

1. Provide opportunities for individuals in leadership positions in academia (Provosts, Chancellors, Deans, and Department/ Division Heads) to learn more about the broad range of opportunities that computational and mathematical biology present in biology and medicine. Presentations at annual meetings of professional societies (such as the Society for Industrial and Applied Mathematics, Pacific Symposium on Biocomputing, etc) and the American Association of Medical Colleges by members who are working at the interface of biology and mathematics or computer science would be one way to discuss the opportunities this interdiscipline provides to the future of biology and medicine.
   
   
2. Encourage private and philanthropic organizations to support endowed chairs in departments of mathematics and computer sciences and related disciplines for those working on biological problems. NIH career development awards could be leveraged to obtain additional funds from non-governmental organizations to support endowed chairs in academia.

Curriculum Development

1. Use the academic career award (K07) mechanism to support faculty to develop curricula in computational and mathematical sciences as they relate to genomics and genome analysis. Curricula should be developed for students at the undergraduate and graduate levels.

Career Development and Research Training

1. Develop an institutional K01 program award that would provide a critical mass of non-biologists working in the areas of computational and mathematical biology in institutions where there are foci of scientists working in interdisciplinary areas critical to genome research and genome analysis and interpretation.
   
   
2. Increase the number of individual K01 awards.
   
   
3. Increase the number of training grants in genomics that have a significant emphasis on computational or mathematical biology. The requirement that departments demonstrate long-term collaboration should be relaxed for new applicants, providing they can demonstrate commitment to interdisciplinary research in other ways.
   
   
4. Encourage departments of mathematics and computer sciences to partner with genome scientists in applying for NHGRI interdisciplinary training grants.
   
   
5. Address the stipend levels for training. The current NRSA stipend levels are not competitive for students with degrees in the mathematical and computer sciences. Alternatives to consider are developing a non-NRSA training mechanism, establishing an institutional K01 mechanism, and encouraging industry to supplement stipends.
   
   
6. Address the tuition policy for NIH training programs. The newly instituted policy of paying only 60 percent of tuition costs above $2,000 will not encourage the development of new training programs, particularly in the physical sciences.
   
   
7. Encourage other components of the NIH to initiate or increase the number of training programs that interface with mathematics, statistics and computer sciences.

Research

1. Evaluate why research projects in computational and/or mathematical biology receive poor priority scores.
   
   
2. Consider funding research projects in computational and mathematical biology for more than three years.
   
   
3. Increase the dialogue with the research community so that they are aware of the research opportunities in computational and mathematical biology.

Outreach

1. Convene leaders in industry and academia to discuss common interests and needs in research and training.

Immediate Action Items

1. Develop brochures about NHGRIs training and career development opportunities.
   
   
2. Develop concept papers for K07 (curriculum development) and institutional K01 (mentored research scientist development award) programs for discussion at February 1998 Council. Check other ICDs programs for models.
   
   
3. Discuss report at February 1998 Council.

Appendix Interviewees

Russ B. Altman, MD, Ph.D. (Medical Information Sciences)
Assistant Professor of Medicine and (Computer Science by courtesy)
Department of Medicine (Department of Computer Science by courtesy)
Stanford University School of Medicine
Stanford, CA

Michael Boehnke, Ph.D. (Biomathematics)
Professor
Department of Biostatistics
School of Public Health
University of Michigan
Ann Arbor, MI

Dan Davison, Ph.D. (Biological Sciences-Genetics)
Principal Scientist
Bioinformatics Department
Bristol-Myers Squibb Pharmaceutical Company
Wallingford, CT

Keith A. Dunker, Ph.D. (Biophysics)
Professor
Departments of Biochemistry and Biophysics, Chemistry
Washington State University
Pullman, WA

Philip Green, Ph.D (Mathematics)
Associate Professor
Molecular Biotechnology Department
University of Washington
Seattle, WA

David Haussler, Ph.D. (Computer Science)
Professor, Computer Information Science
Division of Natural Science
University of California
Santa Cruz, CA

Edward Holmes, MD
Senior Associate Dean for Research and
Vice President for Translational Medicine and Clinical Research
Stanford University School of Medicine
Stanford, CA

Webb Miller, Ph .D. (Mathematics)
Professor
Department of Computer Science
Pennsylvania State University
University Park, PA

Chris Overton, Ph.D. (Biophysics), MSE (Computer Science)
Director, Center for Bioinformatics
University of Pennsylvania
Philadelphia, PA

Neil Risch, Ph.D. (Biomathematics)
Professor
Department of Genetics
School of Medicine
Stanford University
Stanford, CA

Fred Roberts, Ph.D. (Mathematics)
Professor of Mathematics
Director, Center for Discrete Mathematics and Theoretical Computer Science
Rutgers University
Piscataway, NJ

Temple Smith, Ph.D. (Physics)
Director
BioMolecular Engineering Research Center
College of Engineering
Boston University
Boston, MA

Terence P. Speed, Ph.D. (Mathematics)
Professor
Department of Statistics
University of California, Berkeley
Berkeley, CA

David States, MD, Ph.D. (Biophysics)
Director
Institute for Biomedical Computing
School of Medicine
Washington University
St. Louis, MO

Gary Stormo, Ph.D. (Molecular Biology)
Associate Professor
Department of Molecular, Cellular and Developmental Biology
University of Colorado
Boulder, CO

Clark Tibbetts, Ph.D. (Biophysics/Chemistry)
Professor of Microbiology
Institute for Molecular Bioscience and Technology
George Mason University
Fairfax, VA

Michael Waterman, Ph.D. (Statistics)
Professor
Department of Mathematics (Joint Appointments in Biological Sciences and Computer Sciences

Footnotes

1. This review was initially focused on bioinformatics. During the course of my interviews, it was expanded to include the application of mathematics, statistics, and computer science to genomics and genetics research. Thus, the title, while not ideal, is meant to be inclusive, rather than exclusive, of these scientific disciplines.
   
   
2. Prepared by Bettie J. Graham, Ph.D., Division of Extramural Programs, National Human Genome Research Institute, National Institutes of Health. E-mail address: bettie_graham@nih.gov.
   
   
3. U.S. Department of Health and Human Services and Department of Energy, Understanding our Genetic Inheritance. The U.S. Human Genome Project: The First Five Years (April 1990).
   
   
4. An NSF Science and Technology Center in partnership with Princeton University, AT and T Research, Bellcore, and Bell Laboratories/Lucent Technologies.
   
   
5. The policy states that NIH will pay 100 percent of the cost of tuition up to $2,000 and 60 percent of the cost of tuition over $2,000.
   
   
6. It has been reported, but not confirmed, that the Whitaker Foundation has no interest in continuing the foundation activities and plans to spend down the principal within ten years.