QUANTITATIVE APPROACHES TO THE ANALYSIS OF COMPLEX BIOLOGICAL SYSTEMS

Release Date:  June 4 1998

PA NUMBER:  PA-98-077

P.T.

National Institute of General Medical Sciences
National Institute of Mental Health

PURPOSE

The purpose of this program announcement is to advertise National Institute of
General Medical Sciences (NIGMS) and National Institute of Mental Health (NIMH)
interest in supporting research projects that develop quantitative approaches to
describe, analyze, and predict the behavior of complex biological systems,
especially those requiring the integration of potentially large amounts of
molecular, biochemical, cell biological, and physiological data.  Such studies,
adapted to the analysis of complex systems in humans, will ultimately have an
impact on the treatment of human disorders and disease.  These projects are
expected to require the participation of individuals with diverse expertise and
therefore to be of a collaborative and cross-disciplinary nature.  Applicants are
strongly encouraged to consider research areas in which systems approaches are
likely to make significant contributions. These include NIGMS supported research
on basic studies in genetics, biochemistry, neuroscience, cell biology, and
developmental biology that typically utilize non-human model systems; basic
studies in pharmacology, physiology, metabolic engineering, anesthesiology, and
inflammation, burn, and trauma. The NIMH expresses particular interest in studies
using mathematical, computational, or theoretical approaches to understanding the
fundamental biological mechanisms underlying behavior.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by foreign and domestic, for-profit and non-profit
organizations, both public and private, such as universities, colleges,
hospitals, and laboratories, units of state and local governments, and eligible
agencies of the Federal government.  Foreign institutions are not eligible for
program project (P01) grants.  Racial/ethnic minority individuals, women, and
persons with disabilities are encouraged to apply as principal investigators.

MECHANISM OF SUPPORT

Applications may be submitted for the investigator-initiated research project
grant (R01) or program project (P01).  In addition, applications requesting
direct costs of $500,000 in any one year must obtain written agreement from the
assigned institute that the application will be accepted for consideration of
award, in accordance with NIH policy, which is available at
http://www.nih.gov/grants/guide/notice-files/not98-030.html.  Consultation with
NIGMS or NIMH program staff listed under INQUIRIES, is recommended.

Related Initiatives

Current NIGMS grantees wishing to expand the scope of their projects to
incorporate the objectives of this program announcement may apply for
supplementary support as described in program announcement PA-98-024,
"Supplements for the Study of Complex Biological Systems."  Information on this
program can be found in the NIH Guide dated January 16, 1998, or on the website,
http://www.nih.gov/nigms/funding/pa/comsupp.html

For short term feasibility studies related to the research areas of this program
announcement that qualify as "high risk, high impact," applicants should consult
program announcement PA-97-049, "Exploratory Studies for High Risk/High Impact
Research," found in the NIH Guide, Vol. 26, No. 10, March 28, 1997, and on the
NIGMS website, http://www.nih.gov/nigms/funding/pa/r21.html

RESEARCH OBJECTIVES

Background

Dramatic progress has been made during the last few decades in our understanding
of biological phenomena.  Technical developments in genetics, molecular biology,
structural biology, cell biology, and physiology have accelerated the production
of high-quality data and the discovery of increasingly complicated, interrelated
pathways and sophisticated mechanisms.  In some cases, sufficient data exist to
begin analyses of the large-scale functioning of biological processes
encompassing many interacting elements; for the purpose of this announcement
these will be referred to as complex systems.  Such analyses are likely to
require new strategies.  Examples of the challenges include: the analysis of
massive datasets of gene expression data that currently are being generated as
a result of the availability of complete genome sequences; analysis of extended
interaction networks such as proinflammatory and antiinflammatory signaling
systems; the modeling of networks generated by combinatorial control of gene
transcription; studies of the organization and dynamics of structures such as the
mitotic spindle and secretory apparatus; and analysis of synchronous, multiple
channel physiologic data to characterize dynamic interactions among vital organs
in health and disease. In the case of the nervous system, the challenge is to
decipher the mechanisms that underlie specific neuronal and behavioral systems.

Most of our knowledge of these and related biomedical phenomena results from
approaches in which individual components of complicated pathways or structures
have been identified, by genetic and/or biochemical means, and their individual
properties determined, often by in vitro methods.  As components of an observed
complex system are found, explicit tests and hypotheses are formulated to
determine how the components functionally interact, and what other elements may
be involved. Iterations of this approach gradually develop an overall description
of a complex process.

There are other, more mathematical approaches to understanding complex systems.
So-called "top down" approaches engage large datasets of related genetic,
biochemical or physiological information, especially as these data change in
response to perturbation. Using analytical methods that study the network
structure of these large-scale changes, hypotheses can be crafted that attempt
to define the rules by which the system behaves as well as the scope, strength,
and bias of the system's interacting components even though the underlying
individual mechanisms responsible for the data may not be known in detail.  Where
a great deal of detail on a system is available, e.g., the identity,
concentration, localization and properties of individual components, approaches
relying on engineering and other mathematical analyses become feasible.  The goal
of the various computational, or mathematical, analyses is similar, to discover
the principles of organization of the system as a whole, and to acquire the means
to model its dynamics.

In the particular case of the nervous system, information processing is based on
a massively parallel structure employing, as the basic processing units, neurons,
whose activity appears to exhibit significant stochastic as well as deterministic
components.  To understand how these neurons control behavior, neuroscientists
have developed a broad set of techniques that are producing ever-increasing
amounts of data from the nervous system, in the context of ongoing behavior. The
research goal now is to combine mathematical and computational tools with
neurophysiological, neuroanatomical, or neurochemical techniques in order to
analyze and model such complex data.

Scientific Objectives

Systemic analyses of diverse biomedical processes, at different levels of
organization and with different tools available for the collection of data, will
likely require different quantitative treatments.  Commonly, however, projects
responsive to this announcement will share the characteristics that they 1) treat
a biological problem as a system of interacting components; 2) employ
quantitative approaches appropriate to the level of organization of the process
under study; and 3) seek to determine organizing principles of the larger
assemblage and/or the system dynamics. It is not the purpose of this announcement
to specify approaches, but to emphasize the importance of quantitative treatments
that focus on the behavior of the integrated system.  Responsive proposals are
likely to combine the expertise of individuals thoroughly familiar with the
biological problems and experts in the quantitative disciplines, e.g., physics,
engineering, chemistry, computer sciences, or applied mathematics.

Examples of projects that might be supported by the NIGMS include, but are not
limited to, the following: computationally-based modeling of phenomena such as
the cell cycle, pattern formation during embryogenesis, the flux of substrates
and intermediates in metabolism, and the application of network analysis to
understanding the integrated systemic host responses to trauma, burn, or other
injury. Some projects may require, in conjunction with the testing of hypotheses,
the development of methods, e.g., acquiring simultaneous measurements of key
cellular parameters such as the concentrations of intermediates or
phosphorylation states of key proteins.  Other projects may require the
elaboration of theory that can guide the formulation of hypotheses that are
specific to a problem under study. Similarly, an ancillary need for databases
and/or software for their analysis may be an intrinsic requirement of some
projects.  The development of methods, theory, and informatics tools must be
proposed in the experimental context of a specific biological problem to be
solved.

Applications that facilitate independent verification and validation of
computations and interpretations are encouraged.  The application must state
whether detailed methods, including computer source code (for noncommercial
scholarly use and reserving proprietary rights) will be made available to other
scholars.

The following are examples of research topics (not all inclusive) that would be
of particular interest to the NIMH: self organizing neural systems in perception
and behavior:  nonlinear dynamics; neural encoding of natural scenes: information
theory analysis;  nonlinear systems analysis of the functional properties of the
hippocampus;  mathematical approaches to modeling nonstationary processes; 
periodic orbits as applied to neuronal control systems;  models of oscillatory
behavior in neuronal cell cultures and simple nervous systems;  nonequilibrium
behavior of brain enzyme and receptor systems;  analyses of information
processing revealed by voltage sensitive dyes;  development of columnar
organization in cerebral cortex - computational models and comparison to
neurophysiology;  choice: principles of behavior selection in model systems; 
principal component analysis of neuronal temporal patterns during discriminatory
behavior;  analysis of cyclic behavior in affective disorders and schizophrenia; 
calculating the information content of temporally modulated spike trains -
relating neuronal activity to the environment;  stochastic processes in neural
structures that represent spatial location.

The projects must support the NIGMS or NIMH mission.  NIGMS specific information
is detailed in the publication "Divisions and Grant Award Mechanisms," available
from the NIGMS Public Information Office (301/496-7301); additional information
can be found on the NIGMS World Wide Web home page at http://www.nih.gov/nigms/.
In brief, the NIGMS supports research in (a) cell biology and molecular
biophysics, including basic studies of the structure and function of cells,
cellular components, and the biological macromolecules that make up these
components; (b) fundamental mechanisms of inheritance and development that
typically utilize non-human model systems; (c) basic studies in pharmacology, 
physiology, biochemistry, biorelated chemistry; (d) basic studies in
anesthesiology; (e) basic studies in biotechnology, including biocatalysis and
metabolic engineering; (f) bioengineering, including instrumentation development
and refinement and development of bioanalytical methods and biomaterials; and (g)
trauma and burn injury. The NIMH requests applications to develop and/or apply
quantitative analytic and simulation techniques to physiological and
neurochemical data to elucidate the basic mechanisms of information processing
in the nervous system.  The proposed research can study any neural system,
including in vitro, invertebrate, non-human vertebrate, and human, and may apply
any appropriately adapted quantitative approach including, but not limited to,
nonlinear analysis, models based on massively parallel organizations, statistics,
and information theory.  Work should be based on experimental data and be aimed
at uncovering fundamental knowledge about neural mechanisms, with the ultimate
aim of understanding human information processing.  Purely theoretical approaches
or analyses will be considered if relevance to neurobiology is clear.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and their
subpopulations must be included in all NIH supported biomedical and behavioral
research projects involving human subjects, unless a clear and compelling
rationale and justification is provided that inclusion is inappropriate with
respect to the health of the subjects or the purpose of the research.  This
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public
Law 103 43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23,
Number 11, March 18, 1994.

NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN
RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them.  This
policy applies to all initial (Type 1) applications submitted for receipt dates
after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for Grants
and Contracts, March 6, 1998, and is available at the following URL address:
http://www.nih.gov/grants/guide/notice-files/not98-024.html

Investigators also may obtain copies of the policy from the program staff listed
under INQUIRIES.  Program staff may also provide additional relevant information
concerning the policy.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
5/95) and will be accepted at the standard application deadlines as indicated in
the application kit.  Application kits are available at most institutional
offices of sponsored research and may be obtained from the Division of Extramural
Outreach and Information Resources, National Institutes of Health, 6701 Rockledge
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email:
GrantsInfo@nih.gov.

The title and number of this program announcement must be typed in Section 2 on
the face page of the application.

The completed original application and five legible copies must be sent or
delivered to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established Public Health Service
referral guidelines.  Applications will be reviewed for scientific and technical
merit by an appropriate initial review group. As part of the initial merit
review, a process will be used by the initial review group in which applications
will be determined to be competitive or non-competitive based on their scientific
merit relative to other applications received in response to the program
announcement.  Applications judged to be competitive will be discussed and
assigned a priority score.  Applications determined to be non-competitive will
be withdrawn from further consideration and the Principal Investigator and the
official signing for the applicant organization will be notified.  Following the
initial scientific-technical review, the applications will receive a second-level
review by the relevant Council or Advisory Board.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In the
written review, comments on the following aspects of the application will be made
in order to judge the likelihood that the proposed research will have a
substantial impact on the pursuit of these goals.  Each of these criteria will
be addressed and considered in the assignment of the overall score.

1.  Significance:  Does the proposed research address an important problem?  If
the aims of the application are achieved, how will scientific knowledge be
advanced?  What will be the effect of these studies on the concepts or methods
that drive this field?

2.  Approach:  Are the conceptual framework, design, methods, and analyses
adequately developed, well integrated, and appropriate to the aims of the
project?  Are there strong interdisciplinary components?  Does the applicant
acknowledge potential problem areas and consider alternative tactics?

3.  Innovation:  Does the project employ novel concepts, approaches or methods?
Are the aims original and innovative?  Does the project challenge existing
paradigms or develop new methodologies or technologies, especially
interdisciplinary ones?

4.  Investigator:  Are the investigator and any collaborators appropriately
trained and well suited to carry out this work?  Is the work proposed appropriate
to the experience level of the principal investigator and other researchers (if
any)?

5.  Environment:  Does the scientific environment in which the work will be done
contribute to the probability of success?  Do the proposed experiments take
advantage of unique features of the scientific environment or employ useful
collaborative arrangements?  Is there evidence of institutional support?"

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications.  The following will be considered in making funding decisions:

o  quality of the proposed project as determined by peer review;
o  availability of funds;
o  extent to which the proposed research project will introduce powerful,
quantitative approaches to the study of complex biomedical problems.

INQUIRIES

Inquiries are encouraged.  The opportunity to clarify any issues or questions
from potential applicants is welcome.

Direct inquiries regarding programmatic issues to either the program director
listed on your award statement, or:

Dr. James C. Cassatt
Division of Cell Biology and Biophysics
National Institute of General Medical Sciences
45 Center Drive, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-0828
FAX:  (301) 480-2004
Email:  czj@cu.nih.gov

Dr. Judith H. Greenberg
Division of Genetics and Developmental Biology
National Institute of General Medical Sciences
45 Center Drive, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-0943
FAX:  (301) 480-2228
Email:  greenbej@nigms.nih.gov

Dr. Michael E. Rogers
Division of Pharmacology, Physiology and Biological Chemistry
National Institute of General Medical Sciences
45 Center Drive, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-3827
FAX:  (301) 480-2802
Email:  rogersm@nigms.nih.gov

Dr. Dennis L. Glanzman
Theoretical and Computational Neuroscience Program
Division of Basic and Clinical Neuroscience Research
National Institute of Mental Health
5600 Fishers Lane, Room 11C-16
Rockville, MD  20857
Telephone:  (301) 443-1576
FAX:  (301) 443-4822
E-mail:  glanzman@helix.nih.gov

Direct inquiries regarding fiscal matters to either the grants management
specialist listed on your award statement, or:

Ms. Carol Tippery
Grants Management Office
National Institute of General Medical Sciences
45 Center Drive, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-5135
FAX:  (301) 480-1969
Email:  tipperyc@nigms.nih.gov

Ms. Diana S. Trunnell
Office of Resource Management
Grants Management Branch
National Institute of Mental Health
5600 Fishers Lane, Room 7C-08
Rockville, MD  20857
Telephone:  (301) 443-2805
FAX:  (301) 443-6885
E-mail:  dtrunnel@ngmsmtp.nimh.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Numbers
93.242, 93.821, 93.859, and 93.862.  Awards are made under authorization of the
Public Health Service Act, as amended and administered under PHS grants policies
and Federal Regulations 42 CFR 52 and 45 CFR Part 74.  This program is not
subject to the intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.

The PHS strongly encourages all grant and contract recipients to provide a smoke-
free workplace and promote the non-use of all tobacco products.  In addition,
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain
facilities (or in some cases, and portion of a facility) in which regular or
routine education, library, day care, health care or early childhood development
services are provided to children.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American people.

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