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Report of program activities : National Institutes of Health. Division of Research Resources (Volume 1971) online

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Fiscal Year I97I


(July 1, 1970 - June 30, 1971)


i/,^ National Institutes of Health, Dil^^'S/d"^^ '^' '^^"^^'^*''^'^ '

Bethesda, Md. 20014




Report of the Director 1

Biotechnology Resources Branch 5

Chemical/Biological Information Handling Program. 16

General Clinical Research Centers Branch 21

Animal Resources Branch 43

General Research Support Branch 59

Program Analysis Branch , 71

Office of Information. . 74

Dr. Thomas G. Bowery

Report of the Divisioa Director

In both the Fiscal Years 1969 and 1970 Annual Reports, I raised a pessimistic
outlook concerning the future viability of the Division, not because of lack
of "....confidence in the Division's program concepts and the capability of
its staff....", but rather, with the severe budgetary restraints facing the
Division I questioned whether we would be able to effectively respond to the
needs of the research community.

Two significant factors which occurred during the Fiscal Year 1971 have however
induced me to temper somewhat my previous attitude and approach the new fiscal
year with renewed enthusiasm. The first of these events was that on October 6,
1970, the Division, as part of the reorganization of the Bureau of Health
Professions Eduation and Manpower Training, became an independent Division
within the research components of the National Institutes of Health. This
organizational change has given greater visibility both within and without the
NIH to the role of the DRR in the execution of the Institutional research
support program policies of the NIH.

The second event of consequence was that the Fiscal Year 1971 budget provided
increases for the General Clinical Research Centers Program, the Animal
Resources Program, and for the Primate Centers Program. The increase in the
budget for the latter program was especially significant since it precluded
the closure of at least one of the seven Primate Centers.

Of continual concern to us, however, is the fact that despite the documented
evidence of the worth of the General Research Support Program, the budget for
this program was once again reduced and still further reductions appear in
the President's Budget Request for Fiscal Year 1972.

Within the Division, several organizational changes were made. On November 3,
1970, the name of the Special Research Resources Branch was changed to the
Biotechnology Resources Branch to give greater identity to the nature of the
programs supported. On March 23, 1971, the Program Analysis Branch was estab-
lished, replacing the old Office of Program Analysis. This latter organization-
al change reflected the increased emphasis being placed on program analysis
activities in the Division. Authority for the National Advisory Research
Resources Council to review the General Research Support Grant Program was
obtained on March 14, 1971. This authority had previously been vested with
the National Advisory Health Council. All of the Division's programs are now
reviewed by the National Advisory Research Resources Council.

Several notable staffing changes occurred during the year in the Office of
the Director. Dr. James F. O'Donnell was appointed Assistant Director;
Mr. David L. Chicchirichi , Executive Officer; and Mr. Richard L. Shafer,
Administrative Officer. Dr. Charles W. McPherson was appointed Chief, Animal
Resources Branch. Dr. Carl R, Brewer, formerly Chief, General Research Support
(GRS) Branch, was named Special Assistant for Institutional Relations. Dr.
Robert J. Gibbs succeeded Dr. Brewer as Chief, GRS Branch.

A significant program development this year was the initiation of the resource-
related research grant as a funding mechanism within the Biotechnology Resources

Branch. Through this mechanism, the Branch can support sophisticated biomedical
research at a resource which is being currently supported by other than NIH
funds. The first of these awards was made this year.

Thus 5 during the past year DRR has regained much of the momentum lost during
reorganization with the Bureau of Health Professions and Manpower Training;
made key staffing changes; weathered several fiscal crises; and is moving
forward again confident, albeit cautious.


Fiscal Year 1971

Biotechnology Resources Branch
Division of Research Resources




Cardiovascular Research

Cancer Research

Human Reproductive Mechanisms Research

Transplantation Immunology and Human Genetics Research °

Attainment of Atomic Resolution with Computer-Assisted


Electron Microscopy

Structural Analysis of Large Biomolecules by Mass

On-Line Acquisition and Analysis of High Data Rate
Signals -' - '■



Digital Computation I: Pennsylvania State University
Medical School ^^

Digital Computation II: Rutgers University -^^

Mass Spectrometry : Stanford University

Nuclear Magnetic Resonance: University of Utah

Electron Microscopy: University of Colorado...


Provision of Mass Spectrometry Services on a Regional
Basis 13

Evaluation of a Display-Oriented Computer Terminal 13

Preliminary Experience With a High Voltage Microscopy
Resource 1^

A Prototype Resource for Biochemical Reaction
Kinetics 1^





During Fiscal Year 1971 the Biotechnology Resources Branch (BRB) continued
to make available to grantees and contractors of the various NIH categorical
programs the kinds of tools without which their research efforts would be
seriously hampered, if not precluded entirely. Emphasizing digital
computation, mass spectrometry, nuclear magnetic resonance spectroscopy, and
electron microscopy, the BRB and its clientele have been increasingly
successful in establishing a mutually enriching interplay between biology
and medicine on the one hand and the physical sciences, mathematics, and
engineering on the other. This past year demonstrated more than ever before
that regional centers of scientific and technical excellence such as the
Biotechnology Resources can be a powerful administrative form for encouraging
multidisciplinary inquiry and for bringing the results of technological
innovation smoothly and quickly to the service of the biomedical community.
This report highlights a few of the many BRB- sponsored activities whose
accomplishments during the past year are eloquent testimony to the viability
and importance of the research resource concept.


During FY 1971 the BRB provided support to 51 resources, 1 resource- related
research project, and 2 contracts at an aggregate funding level of
$9,757,000. As in previous years the bulk of the branch's expenditures
($8,312,523) supported computer resources, underscoring the fact that this
technology takes more forms and has greater breadth of applicability to
health research problems than any other. Nevertheless, this strong
commitment to the support of digital computation has not prevented the BRB
from continuing its emphasis on mass spectrometry and nuclear magnetic
spectroscopy, or from increasing its impact in the area of high voltage
electron microscopy. Overall, the staff and its advisors have achieved an
effective balance between the exploration of new technologies, and the
continued support of established research tools vital to NIH categorical
programs .


One of the primary measures of accomplishment that can be applied to the
Biotechnology Resources Program is the extent to which its sponsored
activities markedly assist the various NIH categorical programs. With
their cadres of highly skilled staff scientists, and their specialized
and often unique facilities. Biotechnology Resources are frequently the
scene of productive encounters between experts in a given technology and
experts in a given medical discipline. These examples are but a few of
the many such encounters during the past year:

Cardiovascular Research

At Washington University in St. Louis, Missouri, the digital
computer is finding yet another new application as a tool for
human clinical investigation. The Biotechnology Resource at
this institution has for many years been one of the leading
centers in the Nation developing techniques for the automatic
monitoring of heart rhythms. The resource personnel have
designed and put into routine operation in a coronary
intensive care unit a network of small computers which
continuously record and analyze the cardiac rhythm patterns
of every patient in the unit. This computer network not only
alerts the attending medical personnel to the occurrence of
unusual heart rhythms (which often presage impending cardiac
crisis), but also records the measurements in computer-based
files to allow subsequent retrieval and detailed analysis.
This computer system will soon be produced by a commercial
organization and, thus, will be available to other centers
throughout the Nation.

Even more exciting than its routine patient care applications
is the computer system's uses in clinical research. Because
it can make measurements reliably and precisely for long
epochs, the computer system can provide scientists with
sufficient data to put many of their estimates about the
status of the heart's functioning on a statistical basis.
This opportunity to perform more vigorous experimentation
should be especially valuable in cases such as the clinical
trials of drugs which affect heart rhythm. It seems
inevitable that the ability to routinely obtain statistically
valid measurements on human subjects will lead to better
understanding of the consequences of these agents and, hence,
both to improved efficacy and to increased experimentation to
unravel the actual mechanisms by which the drugs act.

Cancer Research

Computer methods have also had an important impact on cancer
research as is illustrated by the work at the Biotechnology
Resource at the University of Pennsylvania, In this case the
investigators have developed a computer program which
automatically determines the growth rate characteristics of
tumor cell populations, given data on the extent of the uptake
of radioactively labelled material by the cells' DNA molecules
during cell division. Once these growth rate characteristics
are known, it is possible to predict how the tumor will behave
under various conditions and/or to select drugs and dosage
schedules to combat the tumor via chemotherapy. The analysis
is based on a complete model of how cell populations divide
and grow, and it represents a level of computation which can
only be carried out by electronic means.

Human Reproductive Mechanisms Research

The Biotechnology Resource at the University of Pittsburgh
has applied the techniques of gas chromatography and mass
spectrometry to research projects involving the mechanisms
of spontaneous abortum and the cause of male infertility.
In both instances the research focuses upon the role of
prostaglandins, small-molecule hormones which are of
widespread occurrence in the human body and which are
thought to have a crucial function in many reproductive
processes. There are many known prostaglandins, and the
ability to associate the presence or absence of specific
ones with various physiological states could contribute much
to understanding the normal and abnormal biochemistry of
human reproduction.

The importance of gas chromatography and mass spectrometry
to this research results from the investigators' need to
identify the presence or absence of specific prostaglandins
in small quantities of human tissue fluids (e.g., amniotic
or semen). The resource at the University of Pittsburgh can
perform these analyses routinely and thereby bring to bear
on these problems a set of tools that is at the leading
edge of the state-of-the-art. Not only will this line of
research become increasingly more significant but, as
interest throughout the Nation in the subject of synthetic
prostaglandins and their possible role in contraception grows,
gas chromatography and mass spectrometry will almost
inevitably be relied upon to identify and characterize the
structures of the substances under investigation.

Transplantation Immunology and Human Genetics Research

In many cases the expertise possessed by the staff of a
Biotechnology Resource is far more important than even the
specialized facilities that it makes available, and nowhere
is this better illustrated than in the transplantation
immunology research being performed at UCLA. This project
represents a long-term collaboration between a major user of
the resource and a senior resource staff member. The goals
of the project are the elucidation of the full set of human
tissue types and the development of means to identify them
quickly and economically. If well understood, the ability to
"type" human tissues similar to the way blood is "typed"
would certainly allow for closer matches between donors and
recipients in transplant interactions and markedly reduce the
likelihood that the recipient's immunological system would
eventually reject the foreign organ.

In addition to providing excellent computer services, the UCLA
resource has made major substantive contributions which have
proved indispensible to progress on this project. Most notable
is the discovery and refinement of a new statistical method
(Boolean factor analysis) which is specially tailored to deal
with the type of analyses required in the search for tissue types
via serological procedures - i.e. , explaining the patterns of
"reaction/no reaction" results from large series of cross
matches between suspensions of white blood cells and various
sera. With over two dozen tissue types already known and many
others anticipated, it would be almost impossible to carry out
these studies in the absence of these powerful statistical
methods and the supporting computer installations. Moreover,
as the genetic basis of these tissue types become better
understood, the computer will take on additional functions in
both the storage of information on many individuals and the
testing of genetic models designed to explain the data.


The major reason that Biotechnology Resources have been able to build a
record of high quality service to and research collaboration with the
grantees and contractors of almost every NIH categorical program is not
difficult to identify: it can be given in a single phrase - core research.
Since technologies such as digital computation, mass spectrometry, and the
like are evolving as rapidly (and in some cases as unpredictably) as
biomedical science, a resource would soon begin to fail its clientele badly
if its staff were not able to have the center's capabilities at any point
in time reasonably approximate the state-of-the-art. And, indeed, since
the resource staff frequently select their own areas of investigation as a
result of the demands which biomedical problems are placing upon their
technology, the research resource can do much to insure that the tools are
fitted to the need and not vice versa . In the following paragraphs a
sampling of such core research efforts is presented.

Attainment of Atomic Resolution With Computer- Assisted Electron

One of the most spectacular technological achievements produced
anywhere in the Nation was recently accomplished by the
Biotechnology Resource at the Jet Propulsion Laboratory of the
California Institute of Technology. As part of its overall
program in biomedical image processing, this resource has
concentrated upon methods for enhancing the resolution of
electron microscopes. In brief, the staff at the JPL resource
combined a complex set of computer programs for image
enhancement and "noise" elimination to improve the quality of
the ordinary microscope image and then applied to the diffraction
patterns a set of mathematical procedures essentially identical

to those used by X-ray crystallographers. The result was an
image with resolution in the range of 1 Angstrom - sufficient
detail in at least some preliminary areas to discern
individual atoms .

The JPL group is now actively working to make this computer-
assisted microscopy technique available on a relatively routine
basis so they and their collaborators can apply it to many
molecules over and above the few organic crystalline materials
(e.g., the dye indanthrene olive) which have been employed to
date. These additional studies involve experiments with a
high vacuum microscope and extensions of the computer's role
to actual control of the instrument itself. The latter is
especially important where large biomolecules are involved,
because the increased speed of focusing and final- imaging the
molecule under observation will lessen the likelihood that
there will be structural alteration (or complete destruction)
of the material by the electron beam before a micrograph can be

Structural Analysis of Large Biomolecules by Mass Spectrometry

At the Yale University Biotechnology Resource the elucidation
of complex molecular structures is also the goal, but the
methodological approach differs from that .of the JPL resource.
The Yale group has been experimenting with techniques for
introducing large molecules (such as proteins) into mass
spectrometers in a reproducible and efficient manner. The
scarcity of methods for doing this has severely limited the
utility of mass spectrometry in this area of biomedical science -
the low volatility of these substances being the primary

The Yale group has begun to overcome this obstacle by finding
ways to produce sprays of droplets of various solvent systems,
each droplet ideally containing a single large molecule. This
spray is then introduced into the mass spectrometer, and the
analysis carried out. While this technique is only in its
preliminary stages, and many technical problems need be resolved
before routine application is feasible, it seems clear that this
will be a fruitful approach. This project demonstrates how the
expertise and insight of a resource's staff with regard to a
major problem besetting the biomedical community can find
tangible expression in the form of a technique which can
eventually be placed into direct application within the setting
of its origin.


On-Line Acquisition and Analysis of High Data Rate Signals

One of the major problem areas in biomedical computation is the
processing of high data rate signals from experimental animals
and human subjects in real time. This problem is especially
acute in the field of neurophysiology where many thousands of
data-points must be handled each second in order to achieve the
required degree of temporal resolution (e.g., to discern the
initial, fast rising portion of a nerve cell's action potential).
A given investigator's options for experimental inquiry in this
field are severely limited by the measurement techniques he has
available to him. A major step forward in the handling of high
data rate signals via digital computer has recently been
completed by the personnel of the Biotechnology Resource at the
University of Alabama. This group has designed and built a
computer network which can not only serve several high data
users simultaneously but can also guarantee that once a user
enters the system there will be no degradation in the service
to his respective station. No other system offers this feature.
The users of this resource now have available to them a unique
facility for on-line computation, and their experiences over
the next few years will not only shape the future development of
the Alabama system but also influence the extent to which the
system (or at least the concepts upon which it is based) finds
application in other research settings.


During FY 1971 the BRB was able to add five new efforts to its list of
sponsored activities - 2 in digital computation, 1 in mass spectrometry,
1 in nuclear magnetic resonance, and 1 in electron microscopy. While
these activities have in common extremely high scientific merit ratings,
they differ markedly both in their objectives and in the nature of the
opportunities they will offer to biomedical scientists in their geographic

Digital Computation I: Pennsylvania State University Medical

This resource actually has two commitments: (a) a remote job
entry station communicating via telephone lines to the large
control computer on the University's main campus over fifty
miles away and (b) an on-site small computer especially well
suited for use in acquiring data from and controlling the
operation of laboratory instruments. The combination of these
two types of computer systems gives this new medical school
ample capability without committing it prematurely to any given
large-scale facility. In a rapidly developing scientific
environment such as this, the flexibility offered by the current
computer resource planning will almost certainly be an important
factor in bringing this young institution quickly and smoothly
up to its full potential,


Digital Computation II: Rutgers University

Unlike the first new resource, the emphasis at this resource
is upon concepts rather than instrumentation. That is, this
resource's principal focus is the aggregate expertise of its
staff in the area of model building and artificial
intelligence. The resource's goal is to make these skills
available to biomedical scientists in the eastern United
States and, in so doing, to identify research topics for
further elaboration of those aspects of these computer
methods which seem to have biomedical import. While this
resource is somewhat analogous to others where major foci
are image processing or biomathematics, it nevertheless does
represent the first of its kind ever established and will be
the subject of considerable attention by DRR staff and the
members of the biomedical computing community as a possible
model for comparable endeavors elsewhere.

Mass Spectrometry: Stanford University

The BRB's newest initiative in this area also has the
distinction of being the first instance of its new class of
award- -the resource-related research project grant . In this
case the mass spectrometry facility at Stanford University
(not itself a BRB-sponsored center) will be the setting for
a project involving the application of artificial intelligence
methods to the interpretation of the mass spectra of steroids.
This represents the first attempt to place a sophisticated
analytical instrument under the control of a complex problem-
solving computer system and, if successful, will do much to
enhance the capabilities of the mass spectrometric facilities
not only at Stanford, but throughout the Nation,

Nuclear Magnetic Resonance: University of Utah

This resource will be concerned specifically
of the stable isotope of carbon (C ) in natt

with the detection
:ope of carbon (C''"'^) in natural abundance.
Once this can be done routinely, biomedical investigators in
the intermountain region will have almost unprecedented
opportunities to directly study conformational changes of
molecules in solution - such as those which are known to occur
during enzyme/substrate interations - without having to undertake
the often arduous task of preparing isotopically enriched
versions of these molecules.

Electron Microscopy: University of Colorado

This resource will provide the Nation's second one-million volt
instrument dedicated to biomedical research (the first being
the BRB-sponsored installation now under construction at the
University of Wisconsin), The Colorado resource will provide
scientists in the western United States with a unique facility


for examining thick-sectioned biological material, and it
should be especially valuable for studies of chromosomes ,
tubular systems within cells, and basic skeletal muscle
structure. This resource, along with the Wisconsin center,
will soon provide ultrastructural scientists in the United
States with the research opportunities their counterparts
in England, France, and Japan have been enjoying for several
years o


Over the past several years the research contract has become a powerful

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