wm. ge £ i oO rom approvea
SECTION ! Bucowt Bursau No, 6A
DEPARTMENT OF LEAVE BLANKA
HEALTH, EDUCATION, AND WELFARE TYPE PAOGRAM NUMSER
PUBLIC HEALTH SERVICE 2 POl G420832-05
REVIEW GROUP rFOAMEALY

GRANT APPLICATION

 

COUNCIL (Month, Yoor) DATE RECEIVED

 

 

 

TO BE COMPLETED BY PRINCIPAL INVESTIGATOR (Items 7 through
,t. TITLE OF PROPOSAL {Do not exceed 53 typewriter spaces)

7 ond 1EA)}

 

Genetics Research Project
2. PRINCIPAL INVESTIGATOA T3. DATES OF ENTIAE PROPOSED PAQJECT PERIOD (This aoplication}
2A. NAME (Last, First, Initial) [FROM THROUGH
05-01-79 04-30-84

Cavalli-Sforza, Luigi L.

 

28. TITLE OF POSITION

Professor of Genetics

§ DIRECT COSTS REQUESTED
QUESTED FOR PERIOD IN FOR FIRST 12-MONTH PERIOD

ITEMS 5 594,947 481,681

4. TOTAL DIRECT COSTS Re-

 

 

 

2C. MAILING ADDRESS (Street, City, Stare, <ip Codes.

Department of Genetics
Stanford School of Medicine
94305

Stanford, California

  
     

M.D.

2F.TELE-
PHONE

 

r E(s) (Saw Instructions)
Department of Genetics
Stanford School of Medicine
Stanford, California 94305

 

OATA
3G. DEPARTMENT, SERVICE, LASORATORY OR EQUIVALENT
(Sea Instructions)
Department of Genetics
3H. MAJON SUDOIVISION (see Instructions)

School of Medicine
%. Weseerch Involving Human Subjects (020 InstrueGons}

AI NO 8.0.) YES Approved:
C. [ZK YES — Pending Reviow

 

Oate

OL Inventions (Aenewsl Applicants Only - Sea lnstruetions}

A[ad NO B.[_] YES — Not previously reported
CCIVES — Praviously reported .

TO BE COMPLETED SY RESPONSIBLE ADMINISTRATIVE AUTHORITY fieems & through 73 ard 153)

9, APPLICANT ORGANIZATION(S) (560 fnsteuctions}
Stanford University

Stanford, California 94305

TRS No. 94-1156365
Congressional District No. 12

TL NAME, TITLE, AND TELEPHONE NUMBER OF OFFiciALis) = |

SIGNING FOR APPLICANT ORGANIZATIONIS)
D'Ann B . Downey

Sponsored Projects Officer
Sponsored Projects Office

ii, TYPE OF ORGANIZATION [Check applicable item}
COreperaL Cistare CJ LocAt XAJOTHER (Specify)
Non-Profit University _

12 NAME, TITLE, ADDRESS, ANO TELEPHONE NUMBER OF
OFFICIAL IN BUSINESS OFFICE WHO SHOULD ALSO BE
NOTIFIED IF AN AWARD IS MADE

K.D. Creighton

Associate Vice President - Controller
Stanford University

Stanford, California 94305

Telephone Number 415) 497-225]

EN ‘ a CéiVe CREDI
FOR INSTITUTIONAL GRANT PURPOSES [Soe instructions)

School of Medicine - 01

14, ENTITY NUMBER (Formerly PHS Account Number)

 

Telephone Number (3) (415) 497 2883

16 CERTIFICATION AND ACCEPTANCE. Via, tha undersigned, certify that the stoternents horsl
ton to comply with Public Health Service terms and conditions in effect at the timaof the

knowledge ond accept, os to any orsnt owarded, the obligat
wrird,

IRS No. 94-1156365

fA ere true snd complete to tha best of our

 

SIGNATURES TST ATOnSOR PERSON NAMED

(Signstures required on

UN TEMA AN

Pe 8

 

 

 

original copy only.
Use ink, °Par”’ signatures
not scceprobis)

 

8. SIGNATUAEIS) OF PERSON(S) NAMED IN ITE?A 10

v

DATE\ —

 

 

1H 999 (FORUERLY PAS 393
Aav. 1/73
2 PO] GM20832-05 - Summary

GENETICS RESEARCH PROJECT

PROGRAM SUMMARY AND MANAGEMENT 5

The program project outlined here is a request for the extension
and renewal of an ongoing effort that was initiated 15 May 1974. The
principal investigator up to the present date was Professor Joshua
Lederberg. Dr. Lederberg has been called to the presidency of
Rockefeller University, in New York City, effective July 1, 1978 --
an event that was not clearly settled and announced until a few days
before the present writing. In anticipation of that possibility, the
present material has been aggregated in close collaboration with
Professor L. L. Cavalli-Sforza, who will also assume the responsibilities
of the role of Principal Investigator, effective July 1, both for the
continuation of the present term of the grant, and for the renewal, as
noted by the inscription of his name on the front sheet. The appropriate
forms for requesting this succession will be furnished for the continuation
applications. Dr. Cavalli-Sforza is well known for his work on _human
genetic variation, which constitutes the central theme of this project.
‘Dr. Lederberg will continue his longstanding interest in the substantive
research which he has helped to coordinate here, but will do this in an
informal way without appearing on any of the budgets.

The renewal program includes several new projects, and a substantial
evolution of the ones currently under way, as indicated in the following
table:
OLD PROJECTS

1. Screening for Inborn Errors of
Hetabolism
Dr. Joshua Lederberg
Department of Genetics

2. Fetal Cells in Maternal Circulation
Dr. Leonard A. Herzenberg
Department of Genetics

3. Polymorphic Genetic Markers
Dr. Howard M. Cann
Departments of Pediatrics and

Genetics

4. Polymorphisms of Specific Binding
Proteins
Dr. Luigi L. Cavalli-Sforza
Department of Genetics

5. Impact of Genetic Counseling
Practices
Dr. Clifford Barnett
Department of Pediatrics

NEW

05 - Summ

2 PO? GN20832- ary

PROJECTS
Terminated

The Maternal Bloodstream - Another
Source of Fetal Tissue for Prenatal
Diagnosis of Genetic Disorders ,

binka ge Pe latronships of Gene Loci

In Man®
a:

Genetic Polymorphisms and Disease
Etiology

Will seek other avenue of funding

Hereditary Resistance to Oral
Anticoagulant Drugs

Dr. Terrence F. Blaschke

Department*of Medicine, Division of
Clinical Pharmacology

Isolation and Characterization of Male-
Specific Chromosomal DNA by Motecular
Cloning Methods

Dr. Stanley N. Cohen

Department of Medicine, Division of
Clinical Pharmacology aad Department
of Genetics

Chromosome Mediated Transformation in
Human Cells

Dr. A. T. Ganesan

Department of Genetics

Interchange of fetal and maternal
erythrocytes bearing gemetically
determined polymorphic markers

Dr. Leonard A. Herzenberg, Department
of Genetics

Dr. Paul A. Hensleigh, Department of
Gynecology and Obstetrics

Genetic Heterogeneity of Hyperuricema
Dr. Elizabeth M. Short
Department of Medicine

Human Mitochondrial Diseases
Dr. Douglas C. Wallace
Department of Genetics
2 POT GM20832-05 - Summary

Although this program is centered within the Genetics Department at
Stanford University Medical School, it has been developed so as to maximize
its ramifications for other, especially clinical disciplines. We have spent
substantial effort during the past six months in seeking out such opportunities,
and in developing the scientific rationale for the proposed efforts. That
very process has opened up many opportunities that were not previously evident
to us, already a highly rewarding justification for the program-project style
of funding. At Stanford, the Genetics Department does not have clinical
responsibilities; a program of this kind is then especially important in
providing the means and the resources to override departmental boundaries in
the prosecution of research of the greatest human impertance. The development
of the utility of monoclonal antibody reagents for seYeral projects, resulting
from the work in Dr. Herzenberg's laboratory, illustrates the cross-fertili-
zation of technical thinking at a more basic level.

The present roster of projects is manifestly more closely integrated
than was its predecessor - again testimony to the intellectual interchange
and experimental cooperation fostered by this kind of program support.

The underlying theme that unifies the range of specific studies outlined
below is genetic variation in man. The physician views this as the source
of genetic disease; the basic scientist as an expression of gene mutation and
evolutionary pressures. These are roles shared within as well as among
individual investigators. To these challenges are brought a combination of
Clinical insights, experience with several aspects of basic genetics, and
new analytical technologies -- the application of instruments and reagents
like the computer, the cell sorter, monoclonal antibodies, radiolabelled
ligands.

Although several departments are represented in this project, we have
found that an informal organization, based primarily on intellectual kinship,
is quite effective. All of the participants, whatever their department,
recognize Genetics as the common focus, and respect the leadership of
Dr. Cavalli-Sforza as a well-known leader of research in both the demographic
and physiological aspects of polymorphisms.

As Principal Investigator, Dr. Cavalli-Sforza will have executive
responsibility for the program, including the formulation and budget alloca-
tions of extended and new projects, with the advice of the group of participants.
He will confer periodically with the project leaders and staff, which is no
more than his intellectual responsibility for the relevant themes, and seek
out other avenues of cooperation and coordination within the institution.

He will be responsible for the critical drafting, internal discussion, and
submission of periodic progress reports to NIGMS. However, these functions
are so deeply embedded in the natural professorial relationships, that we
have not felt it essential to segregate a separate budget category for these
responsibilities. This is in keeping with the existing decentralization of
academic and administrative authority at a mature research organization.
2 PO] GH203832-05 - Summary

Dr. Howard Cann, who shares a joint appointment between the Genetics
and Pediatrics departments will have particular responsibility for the
integrity of clinical liaisons, and for the exercise of legal anc ethical
responsibilities where human subjects are involved.

At this time, a committee of the medical school is engaged in the
designation of a successor to Dr. Lederberg as chairman of the deparment
of Genetics. Its recommendations will almost surely be available before
the review of this proposal is completed. In the current climate of the
school, the appointment will almost certainly be made_from amongst the
present faculty and his positive involvement in this project is therefore
essentially assured. :

CLINICAL FACILITIES

The faculty of the School are organized into seven basic science and
ten clinical departments. They are based mainly at the Stanford University
Medical Center, a complex of ten interconnecting buildings that include the
Stanford University Hospital, the University Clinics, the Lane Medical
Library, the Fleischman Laboratories and Learning Center, and the teaching
and research facilities of the School. The most recent additions, completed
in 1976, are the expansion of the Hospital and the Sherman Fairchild Center,
which provides space for several basic science departments and an auditorium.

Stanford University Hospital: Located within the Stanford University
Medical Center complex, the 643-bed Stanford University ‘Hospital is the major
clinical facility of the School of Medicine. The Hospital includes two large
pavilions for patients joined by a central core containing service facilities,
diagnostic and therapeutic radiology, pediatrics, emergency medicine, operating
and delivery suites, and clinical laboratories. Beds for dermatology, gynecology
and obstetrics, internal medicine, neurology, pediatrics, psychiatry, and
surgery are located in the patient pavilions.

Stanford University Clinics: Immediately adjoining the central core of
the Stanford University Hospital is a building containing Stanford University
Clinics, outpatient areas for internal medicine and its divisions, surgery
and tne surgical specialties, pediatrics, and gynecology and obstetrics.
Psychiatry (including child psychiatry) is located adjacent to the Clinics
building. Since Stanford serves as a center of consultation, patients are
drawn not only from northern California but also from several neighboring
States. The Clinics have a capacity of more than 135,000 patient visits
yearly.

Children’s Hospital at Stanford: Located on Stanford lands near the
School of Medicine, the Children's Hospital has 65 beds for infants, children,
and adolescents. An independent, charitable institution affiliated with the
School of Medicine and Medical Center, the Children's Hospital specializes
in acute and chronic care for children with major and sometimes catastrophic
illness, offering both inpatient and outpatient services. The Hospital has
been completely rebuilt in the last few years and now provides the finest
in pediatric facilities. The program emphasizes child and family centered
care, utilizing the full complement of professional disciplines for

10
2 PO] GN20832-05 - Summary

comprehensive planning. Under an affiliation agreement, all physicians on
the staff of the Children's Hospital are members of the voluntary or full-
time School of Medicine faculty. Residents from the Department of Pediatrics
and Surgery (Orthopedics) rotate through the Children's Hospital and partici-
pate in the care of patients. Laboratories for investigations related to
selected disease states are situated at the Children’s Hospital.

Santa Clara Valley Medical Center: Operated by the County of Santa
Clara and located approximately 22 miles southeast of the campus, the
Santa Clara Valley Medical Center has 378 beds, including 60 acute
rehabilitation beds. The outpatient department has 120,000 visits annually.
Certain affiliated residency training programs are undertaken at the Santa
Clara Valley Medical Center.

Palo Alto Veterans Administration Hospital: Located on Stanford lands,
approximately four miles souteast of the School of Medicine, the Veterans
Administration Hospital has 803 beds, including 296 for general medical and
surgical patients and 507 for psychiatry including geriatrics. A Dean's
Committee of the Medical School supervises the educational and research
activities of the Veterans Administration Hospital. Residency training,
student teaching, and research are integrated with similar programs at the
Stanford University Medical Center.

RESEARCH FACILITIES:

Department of Genetics: The department is located in the Clinical
Research Building of the Stanford Medical Center, with modern, well-equiped
laboratories and instrumentation provided for research in molecular,
microbial, cell and human genetics, as well as in population studies.
Included are advanced instrumentation for chemical and biophysical analysis
with sophisticated computer support, in :connection with advanced computer
research and an interdisciplinary research program in human genetic poly-
morphisms.

Additional detail is discussed within each projects description.

The undersigned agrees to accept responsibility for the
scientific and technical conduct of the project and for
the provision of required progress reports if a grant is
awarded as the result of this application.

Jan 24,1978 Chin: bar Cort fg

Date Program Director
Luigi L. Cavalli-Sforza

 

 

1