The Endocrine
Society
1107
revealed a previously unsuspected
relatedness
between hormone receptors of this class and the light
receptor rhodopsin.
This observation
paved the way
for using recombinant
DNA techniques
for the characterization of an ever-increasing
number of these G
protein-coupled
receptors and the determination
of
their mechanism of activation.
Along another line of investigation,
Bob Lefkowitz
has made seminal contributions
to our understanding
of the molecular mechanisms
by which target tissue
responsiveness
desensitizes
in response to a signal.
The discovery that G protein-coupled
receptors are
regulated via phosphorylation
by signal transductionactivated kinases as well as specific receptor kinases
has provided a handle for the elucidation of two families of signal transduction
components
involved in the
desensitization
process, the G protein-coupled
receptor kinases and the arrestin proteins. The elucidation
of the specificity principles governing the interactions
of the receptors and kinases has revealed previously
unsuspected
roles of G proteins and protein farnesylation. Recent experiments
by the Lefkowitz group
using transgenic
animal technology
have further revealed that desensitization
of G protein-coupled
receptor responses is a phenomenon
not only important
in the clinical use of pharmacological
agents but in the
instantaneous
regulation of physiological
responses.
Robert J. Lefkowitz, currently serving as investigator
with the Howard Hughes Medical Institute and James
B. Duke professor of Medicine and professor of Biochemistry at Duke University Medical Center, has
been recognized nationally and internationally.
Bob is
a member of the National Academy of Science and is
a past president of the American Society for Clinical
Investigation. He has authored and coauthored
more
than 500 publications.
His contributions
have been
recognized
with numerous
awards,
including
The
Ernst Oppenheimer
Memorial Award of The Endocrine
Society (1982), the Lita Annenberg
Hazen Award for
Excellence in Clinical Research (1983), the Goodman
and Gilman Award of the American Society for Pharmacology and Experimental
Therapeutics
(1986), the
Gairdner Foundation
International Award (1988), and
the Bristol-Myers
Squibb Award for Distinguished
Achievement in Cardiovascular
Research (1992).
Those who have known Bob Lefkowitz can count
him as a mentor, a colleague, and a friend. It is a
particular privilege to present Bob with this award,
which honors another friend and a great scientist,
Gerald D. Aurbach.
Citation for the 1995 Robert H. Williams
Distinguished
Leadership
Award of The
Endocrine
Society to David N. Orth
The Endocrine
Society
Orth with the 1995 Robert
Leadership
Award, given
a member who has served
is proud to honor David N.
H. Williams Distinguished
annually by the Society to
the field of endocrinology
and has nurtured
generations
of endocrinological
scholars.
David Otth was born in New Jersey on March 3,
1933, the auspicious day President Roosevelt closed
the banks because of the financial crash. David grew
up in East Orange,
New Jersey, Syracuse,
New
York, and Grand Rapids, Michigan
as one of four
children. He was highly successful at school despite
having moved many times and was deeply influenced by his English teacher, who instilled in him a
great and lasting love of and respect for the English
language. He was also a highly gifted artist. He went
to Brown University
on a Naval Reserve Officer
Training
Corps scholarship,
majored in chemistry,
and then spent 3 yr as an officer in the Navy. Perhaps his interest in endocrinology
appeared
earlier
than he realized when he became the first person to
control full-sized aircraft drones out of sight using a
radar to track them and a black box (an early version
of a Nintendo control). His time in the Navy allowed
him to immerse himself in English and American
literature and to make some lasting friendships.
David entered Vanderbilt University medical school
and graduated second in his class. Having decided to
pursue a surgical career, a number of events drew
David to internal medicine and endocrinology.
The
strongest influence was a medicine rotation in his second year in the Clinical Research Center under Dr.
Grant Liddle. Other important mentors were David E.
Rogers and Victor A Najjar. He did his Internal Medicine residency at Johns Hopkins before returning to
Vanderbilt to pursue fellowship training under Grant
Liddle.
David is the quintessential
endocrinologist-physician, teacher, clinical investigator,
physiologist,
cell
biologist, and, most recently, molecular biologist. He
has made major research contributions,
which are too
numerous to chronicle. The major theme of his work
MOL
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. 1995
has been the elucidation of the function of the hypothalamic-pituitary-adrenal
axis in health and disease.
The hallmark of his research contributions
is that they
were made both at the bedside and in the laboratory.
He has always been compulsively careful, but he has
never been wrong, and it is for this reason that his
work stands out.
His contributions
include pioneering studies on the
circadian
rhythm of pituitary adrenal function.
He
showed that alterations in day length rather than its
timing altered the rhythm in plasma cortisol; specifically, the shift from dark to light synchronized
the
rhythm, and that blind people have a 24.5-h free running rhythm. These studies placed man with all other
plants and animals and stressed the importance
of
circadian timing. He developed one of the first clinically useful ACTH RlAs and assays for the lipotropins.
One of his ACTH antibodies is the most sensitive antibody ever developed for ACTH and has been widely
used, producing data for more than 200 papers. He
helped Dr. K. Abe develop the first assay for human
PMSH, which he and others later showed to be p-lipotropin and ylipotropin.
He demonstrated
that immunoreactive
ACTH and bioactive ACTH concentrations did not correlate.
David always stressed the
great importance of characterizing
the binding sites of
antibodies
with synthetic peptides. This served the
field well and cleared up a great deal of the confusion
that existed in the early days.
David performed some of the early work in the field
of ectopic ACTH and POMC production by tumors. He
found that immunoreactive
PMSH was in fact smaller
than the synthetic 22-residue
peptide. He identified
the C-terminal ACTH peptide CLIP in tumors, which
was later shown to occur normally in species with an
intermediate lobe. David proposed from his characterization of POMC peptides that they were derived from
a common glycopeptide
precursor,
a concept that
was elegantly proven by the studies of Eipper and
Mains in AtT20 cells. David established
an ACTHsecreting melanoma
cell line that lacked a cytosol
glucocorticoid
receptor, which may account for the
autonomy of the ACTH secretion by this cell line in
contrast to the regulation of ACTH secretion by AtT20
cells, which have a cytosolic glucocorticoid
receptor.
He partially sequenced
the POMC complementary
DNA (cDNA) from an ectopic ACTH-producing
tumor,
the first POMC messenger
RNA (mRNA) or ectopic
mRNA, and the first ectopic hormone peptide to be
sequenced. These studies demonstrated
that ectopic
hormone production
is not simply inappropriate
production of a normal tissue product.
Central to David’s contributions
have been studies
on the characterization,
diagnosis, and treatment of
Cushing’s syndrome.
David demonstrated
in a now
classic paper that childhood
Cushing’s disease was
effectively treated by external pituitary radiation. His
numerous
presentations
at national
and international meetings
are always controversial
and well
argued. His 1992 debate at 74th Annual Meeting of
Vol 9 No. 8
The Endocrine Society in San Antonio on the role of
petrosal
sampling
in the differential
diagnosis
of
Cushing’s
syndrome
was vintage David Orth. His
message was that it has a role, but it is limited and
specific. True to character,
David saw beyond the
immediate
problem
at hand and explored
animal
models of Cushing’s
syndrome, including the horse
and the dog.
David provided his ACTH assay to Wylie Vale. The
assay was central to the purification, isolation, characterization, and ultimate synthesis of ACTH-releasing
hormone (CRH). Wylie and Jean Rivier provided David
with both ovine and human CRH. David performed
some of the early and most careful human studies with
CRH and characterized
the dose response, the interaction and synergy with vasopressin,
and the clinical
effects. He also demonstrated
that patients with Cushing’s disease respond, although variably, to CRH, and
that it could not serve as the only test for the differential diagnosis of Cushing’s syndrome. He demonstrated that CRH could be administered
with the other
hypothalamic
hormones to make up the combined
anterior pituitary test to test anterior pituitary reserve in
the outpatient setting. He and his group were the first
to describe the CRH-binding
protein, which was subsequently purified and cloned by Phil Lowry and Wylie
Vale and colleagues.
David and his colleagues characterized the intracellular signal transduction
systems
regulating
ACTH
secretion,
demonstrating
that
vasopressin
and CRH acted through separate but
complementary
pathways.
Working together with Peter Loosen, he has been
examining
the relationship
between endocrine
and
psychiatric function. One of the more interesting findings of their studies is that the psychiatric histories of
patients with Cushing’s disease are indistinguishable
from those of patients with major depressive disorder
and that there is a high frequency of alcoholism, usually in males, and depression, usually in female family
members. They have proposed that Cushing’s disease
may be a two-hit phenomenon;
an individual with a
family predisposition
to respond inappropriately
to life
stress and a second abnormality,
perhaps a point
mutation in a pituitary cotticotrope,
making it susceptible to growth with chronic hypothalamic
stimulation.
David has either jointly or single-handedly
directed
the training program in endocrinology
at Vanderbilt for
more than 24 yr. The Vanderbilt
Endocrine Society,
composed of past and present faculty and postdoctoral fellows, consists of more than 150 physicians,
and David acts as its de facto president. Of the many
fellows that were trained, 34 worked under David’s
supervision, and 20 are in academic positions ranging
from vice chancellor and division chief to instructor.
Others have chosen the clinical practice of endocrinology, and each is an outstanding
endocrinologist.
The Endocrine
Society has always been David’s
professional
home. David gave his first IO-min presentation at the 48th Annual Meeting in Chicago in
1966 on the topic of altering circadian rhythms. He has
The Endocrine Society
held multiple offices in the Society, including serving
as its representative
on the Central Committee of the
International Society for Endocrinology
and as Finance
Committee chair from 1984-1988.
When David was
asked to run for secretary-treasurer,
he was told that it
would take no longer than being chair of the Finance
Committee.
However, the way David does a job, it
takes considerable
time, and he threw himself into the
job. The Society as it stands today is a tribute to
David’s leadership.
Under his guard, the Society expanded greatly to encompass all groups of the endocrine community,
including
clinicians,
academics,
veterinarians, comparative endocrinologists,
and gastroenterologists.
The Society set out to serve all of
them and has been doing an excellent job. The highlights of the reorganization
of the Society under
David’s leadership are many. We now have continuity
and a corporate memory The achievements include: a
new journal, Molecular Endocrinology;
addressing the
challenge of the American Association
of Clinical Endocrinology and the needs of our clinical colleagues in
practice and in academic medical centers; self-publishing of our journals; and the transition from a small
intimate Society to a national and international
organization. This required the development
of an efficient
and well run central office under the direction of Scott
Hunt (who was appointed
by a committee consisting
of David, Gerald Aurbach, and Nick Christy). David
also played a role in the establishment
of an Executive
Committee of the Council, which has the authority to
make far-reaching
decisions between council meetings, and the establishment
of a long-range
plan for
the Society, with the appropriate
changes in the committee structure of the Society to meet these challenges. David would immediately point to many people
who made huge contributions
to these changes, specifically our president, Susan Smith, and Peter Kohler,
who supervised and headed the long-range
planning
committee, but it was David who had the vision, perseverance, and drive to see that this all happened. He
served under 10 presidents, and the healthy and vibrant Society that we have today is in no small measure due to David’s heroic efforts during the past 11
years. David has been supported
in every way by his
wife Linda, who has given selflessly to the Society for
many years.
It is particularly fitting that the award should be given
to David. The award is named after Robert Williams,
who was on the house staff at Vanderbilt. The first
recipient of the Robert H. Williams Distinguished
Leadership Award was Grant Liddle, David’s mentor.
(Incidentally,
David wrote the citation for Dr Liddle’s
award.) David has contributed
to our Society in all
ways. Perhaps his greatest legacy is that he has been
responsible for the transportation
of our Society from
a small and intimate operation to the large, professional, and well run Endocrine Society that stands in
high esteem today and is ready to face any challenge.
1109
Citation for the 1995 Ernst Oppenheimer
Memorial
Award of The Endocrine
Society
Deborah L. Segaloff
to
In recognition
of her seminal research on the gonadotropin receptors, The Endocrine Society is pleased
to bestow the Ernst Oppenheimer
Memorial Award on
Deborah L. Segaloff. Deborah received her undergraduate biochemistry
training at the Pennsylvania State
University in State College, PA, graduating with a B.S.
degree in 1976. From Penn State she entered the
graduate program in biochemistry
at Vanderbilt University, Nashville, TN, where she performed her doctoral research in the laboratory of Dr. David Puett. It
was there that she first began her work on gonadotropins. Deborah was awarded
the Ph.D. degree in
1980 and then performed postdoctoral
research in the
laboratories
of Dr. Mario Ascoli (Department of Medicine, Vanderbilt
University), Dr. Jose M. Saez (INSERM, Lyon, France), and Dr. Lee E. Limbird (Department of Pharmacology,
Vanderbilt
University). The
early part of the 1980s proved to be a formative period
of research for Deborah because it was during this
time that she first began her studies on the LH/CG
receptor.
On completion of her postdoctoral
training in 1985,
Deborah accepted a position at the Population Council in New York, where she continued research on the
gonadotropins
LH and human CG and on the purification and characterization
of their common receptor.
It was at the Population
Council that her years of
painstaking
work on receptor purification
bore fruit.
Oligonucleotides
based on peptides sequenced from
the rat ovarian receptor were used as primers with the
rat luteal cDNA as a template. Using this polymerase
chain reaction product to screen a rat luteal cDNA
library, she and collaborators
from Genentech,
Inc.