NHLBI Special Emphasis Panel on Integrative Research

April 19, 1996

Minutes and Consensus

SUMMARY:

This document highlights the discussions of a meeting hosted by
National Heart, Lung, and Blood Institute (NHLBI) on April 19,
1996 in Bethesda, Maryland to explore promising areas of research
and training that might benefit from greater emphasis on the
integration of molecular biological processes with physiological
function. The meeting also provided a forum to assess the
potential for cooperation among the NHLBI, professional
organizations, and industry.   A list of invited attendees and
participants is attached.

Integrative research was defined as investigations into the role
of molecular biological processes on the physiologic function or
regulation of a cell, tissue, organ, or intact organism.

In addition to providing a summary of discussions about research
areas, opportunities for research and training support, this
report presents the major points on which there appeared a
consensus of opinion. A follow-up plan of action is also
presented.

STATEMENT OF NEED:

There is a growing concern among some in the biomedical research
community that integrative physiology is on the decline at a time
when advances in molecular and genetic research would warrant
studies of how the molecular/genetic changes influence the intact
organism.  It is generally believed that there is a divergence
between molecular and physiological types of research.  Many
investigators believe that the NIH peer review system favors
reductive research over integrative research.  Young scientists
are opting for training in molecular biology, with a reduced
emphasis on physiology.  The needs are: 1) to improve the
integration of molecular approaches into physiological processes
that address major health concerns, and 2) enhance the training
opportunities for scientists to be knowledgeable in both fields.

PROMISING AREAS OF RESEARCH:

It was agreed by all participants that an enhanced integrative
approach would benefit every area in heart, vascular, lung, and
blood research.  Rather than focusing on each area individually,
participants moved toward discussing more general concepts that
cover all these areas.

Expression of a molecular change in a small animal (e.g., mouse)
is relevant if it has some direct implication or expression in
humans.  While there are some knock-out models in larger animals
(e.g., rat, rabbit, pig) the mouse model remains the standard for
molecular/genetic research, even though it has species
limitations.  Development of a national resource for larger
animal models would require more basic research on smaller
animals.

Remodeling is an example where integrative research can be
applied to heart, vascular, and lung investigations.  A
perturbation causes an acute change in the organ system which
results, in turn, in a change in molecular/genetic expression. 
This expression leads to a more chronic change.  The issue
becomes a question of how to best use molecular tools to
determine the physiological mechanisms or to assess the efficacy
of therapy.  Tools include the appropriate animal model,
manipulation of gene expression, analysis of short term changes,
and appropriately trained individuals to use particular
resources.

OPPORTUNITIES TO PROMOTE INTEGRATIVE RESEARCH:

There was unanimous opinion that National Institutes of Health
(NIH) Study Sections need to have a better focus on, and
sensitivity toward, integrative research.  It was acknowledged
that reductive molecular studies are often perceived as more
tightly focused than integrative studies; thus, the integrative
applications do not fare as well as the molecular applications.

At present there is no DRG Study Section devoted to integrative
applications.  A single Study Section in this area may be
impractical because of the broad focus of integrative research.
Several integrative research groups might be needed, each
covering a specific area.  For instance, there might be one Study
Section that reviewed all integrative applications in heart,
lung, and blood research areas.

A paradigm shift in thinking about research is needed.  Industry
focuses on a specific issue with a project team made up of
members with particular expertise.  Academic researchers tend to
focus on projects of direct interest, and infrequently use their
skills in projects peripheral to their own interests.  Paradigm
shifts need to involve better collaboration among investigators,
and greater interactions between academia, professional
organizations, and industry.

The idea of a coupled grant was discussed at some length.  In
essence, a coupled grant would be like an R01 grant that had two
(or more) co-principal investigators.  One investigator would
have expertise in physiology, the other in molecular biology. 
Both would have an equal share of responsibility.  This type of
grant would bring together the two disciplines to address a
specific integrative research objective.  The synergy between the
investigators would be like that of a Program Project Grant
(i.e., the whole is greater than the sum of the individual
efforts).

Review of coupled grant applications would likely require a
special Study Section that realized the unique nature of this
type of integrative approach.  Part of the review would evaluate
evidence of active collaboration between the co-principal
investigators.  The cost of a coupled grant would probably be
greater than the average R01 grant, but would likely be less than
double the average R01 grant. Training slots could be included in
the requirements for a coupled grant? possibly supported, in
part, by cooperative partnerships.

The need for preliminary data might be a major stumbling block to
the development of coupled grants.  Pilot or feasibility studies
might need to be conducted before submission of a coupled grant
application.  A model for such an approach exists with the NHLBI
and Cystic Fibrosis Foundation cooperative effort.  In this
model, the CF Foundation supports pilot studies at $50,000/year
for two years.  The pilot studies are competitively reviewed
apart from the subsequent submission of the main application (a
Program Project Grant application, in this example).  For the
coupled grants, it might be possible for outside organizations to
provide support for the pilot studies.  This approach was
appealing to some industry representatives.

Partnerships for joint support of clinical studies were also
discussed.  Using asthma research as an example, it was suggested
that the clinical research might be supported by NHLBI, industry
could provide crucial drugs or reagents, and a professional
organization might support a coordinating center.

OPPORTUNITIES FOR TRAINING IN INTEGRATIVE RESEARCH:

Academic training fellowships were considered an important means
to cross train individuals, but most discussants felt that
applicants were mainly from the area of molecular biology because
it is perceived as a more glamorous area.  Industry has a need is
to find scientists with a solid physiological background and an
understanding of molecular biology.  Academic fellowships in
integrative research represent an area of opportunity for
industry to jointly provide support for trainees.

Most of the academic trainees are supported through Institutional
National Research Service Award Training Grant mechanisms, rather
than individual fellowships.  It was estimated that less than 10%
of NHLBI Institutional Training Grants support integrative
research.  Those that do serve as a model for integrative
research whereby the trainee works primarily in one field, but
must become conversant and knowledgeable in the second field. 
Examples were cited of how this is done at some institutions
through seminars, journal clubs, hands-on tutorials, and use of
secondary mentors.

Another simple, yet effective, way to promote training would be
to provide training supplements to existing integrative research
grants.  The usual NHLBI mechanism for application and review
could be followed.  Possibilities for cooperative partnerships
with professional organizations and industry to offer training
supplements were mentioned.

A post-graduate integrative research training course was
discussed.  It would be about a two week course designed to
provide both a physiologist with a working knowledge of molecular
biology and a molecular biologist with a hands-on appreciation of
physiological processes.  The NHLBI-supported Genetic Approaches
to Complex Heart, Lung, and Blood Diseases course is a model for
such a course.  Development of an integrative course is another
area where cooperation among agencies, organizations, and
industry would permit outstanding faculty to be recruited,
tuition costs offset, and increase the likelihood of the course
becoming self-sustaining.

CONSENSUS OPINIONS:

The following points represent a consensus of opinion expressed
at the meeting.  They do not represent official policy statements
of the NHLBI nor any of the professional organizations or
companies represented at the meeting.  They are presented here as
a summary of the discussions and recommendations of the Special
Emphasis Panel on Integrative Research.

a.   Study Sections reviewing research applications need to have
a greater awareness of integrative research, and to view the
uniqueness of integrative applications separately from the
uniqueness of reductive applications.

b.   New paradigms are needed for research and training that
involve collaborative partnerships among the NHLBI, professional
organizations, and industry.

c.   Integrative research can be promoted by the development of
coupled grants involving two or more co-principal investigators,
one with expertise in molecular biology and one with expertise in
physiology. Pilot or feasibility studies that would enhance the
competitiveness of the coupled grant might be supported by
professional organizations or industry.

d.   Individual training fellowships in integrative research
should be promoted. Endorsement and potential co-sponsorship by
professional societies and industry should be considered.

e.   Institutional training grants should be encouraged in the
area of integrative research.


f.   Innovative partnerships could develop a training course in
integrative research that provides cross-training to
physiologists and molecular biologists.

PLAN OF ACTION:

a.   These minutes will be sent to all invited attendees,
including those who were unable to attend.

b.   Individuals are encouraged to provide suggestions for
further development of integrative research opportunities for: 1)
the coupled grants concept, 2) supplements to existing grants, 3)
increasing the use of training grants, and 4) developing an
integrative research course.

c.   Organizations and industry will be asked to indicate their
willingness to support any of the specific opportunities listed
above.

d.   NHLBI staff will review the issues and suggestions.
Follow-up conference calls may be made to solidify ideas and
issues. Organization of Special Emphasis Panels or Workshops, or
the development of research/training announcements are possible
outcomes of this effort.
NHLBI Special Emphasis Panel on Integrative Research

April 19, 1996

ATTENDEES


Donald Heistad, M.D., Chair
Cardiovascular Division 
Department of Internal Medicine
University of Iowa College of Medicine 
Iowa City, IA

Roberto Bolli, M.D.
Division of Cardiology
Department of Medicine
University of Louisville
550 South Jackson Street
Louisville, KY

Barbara Campaigne, Ph.D.
American College of Sports Medicine
401 W. Michigan Avenue
Indianapolis, IN

Brian Duling, Ph.D. 
Department of Physiology
University of Virginia 
School of Medicine
Charlottesville, VA 

Martin Frank, Ph.D.
Executive Director
American Physiological Society
9650 Rockville Pike
Bethesda, MD 

Francine Gingras
Biomedical Research Grants Program
Bristol-Myers Squibb
10154 Park Avenue
New York, NY

Marilyn Hansen 
Executive Director
American Thoracic Society
1740 Broadway 
New York, NY 

Thomas Hintze, Ph.D. 
Department of Physiology
New York Medical College 
Valhalla, NY

Michelle Hogan, Ph.D. 
Executive Director
American Association of  Immunology
9650 Rockville Pike
Bethesda, MD

Leonard Hudson, M.D. 
Department of Medicine
Harborview Medical Center
University of Washington
Seattle, WA

William Kramer, Ph.D. 
Department of Clinical Research, 
Boehringer Mannheim
Gaithersburg, MD

Michael Rosen, M.D. 
Department of Pharmacology
Columbia University  
College of Physicians & Surgeons
630 West 168th Street
New York, NY 

Walter Spinelli, Ph.D.
Cardiovascular and Diabetes Division
Wyeth-Ayerst Research
Princeton, NJ

Marc Thames, M.D.
Division of Cardiology 
Case Western Reserve University
2074 Abington Road 
Cleveland, OH

Richard Walsh, M.D.
Division of Cardiology 
University of Cincinnati 
231 Bethesda Avenue
Cincinnati, OH 

Edward Zambraski, Ph.D.
Professor
Biological Science
Nelson Labs
Rutgers University 
Piscataway, NJ

Thomas Doubt, Ph.D.
Division of Heart & Vascular Diseases
National Heart, Lung, and Blood Institute
Bethesda, MD
.