The Not-So-Odd CoupleThe Clinician and the Experimentalist
Gerard Karsenty
Department of Molecular and Human Genetics
Baylor College of Medicine
Houston, Texas 77030
Address correspondence and requests for reprints to: Gerard Karsenty, M.D., Ph.D., Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030.
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Do clinicians and experimentalists need each other?
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No one should forget that clinical medicine is an
exceptionally hard job. It is not only hard but it can also be
extremely frustrating because the goal is, by definition, repetitive:
to cure the same disease day in and day out. Most often this must be
accomplished promptly, to the expense of the true intellectual pleasure
to elucidate how the disease observed develops. The impression of
performing a routine job may dampen enthusiasm of physicians over time
and also the prestige of the profession for outsiders. Indeed, the
necessity to achieve primarily a cure, or at least a satisfactory
treatment of any disease, may be perceived for the wrong reason by
uninformed experimentalists as a lack of intellectual curiosity. This
is forgetting that for every profession there is a first line of duty.
For clinicians it is to cure first and to understand second. For
experimentalists it is to understand first and only second to cure, or
"rescue" as one says in the world of animal experimentation. And
this is not easy either. These totally symmetrical goals and the
enormous amount of work they both require daily explain, for the most
part, the apparent difficulties sometimes observed in the necessary
communication between clinicians and experimentalists. This dialogue is
necessary because their two goals are complementary if not identical.
Nothing comes easy in either profession, and, to a large extent,
clinicians and experimentalists should be both viewed as
scientiststhey both practice biology, only under a different form.
It is in this spirit that the dialogue between clinicians and
experimentalists can develop. Beyond the cat and dog superficial aspect
that the obligatory relationship between clinician and experimentalist
sometimes adopts lies the real nature of their relation and why it is a
lasting one: there is no biology without clinical validation at one
point or another. Likewise, there is no progress in clinical medicine
without animal experimentation.
Animal experimentation has a more profound influence than ever before
on the way clinicians think, for at least two reasons. First, unlike
what was the case until 10 yr ago, animals are not used anymore for
pharmacologic experiments but to understand the biology as one can now
dissect a genetic cascade, one mutant mouse after another. Moreover,
genetic manipulations allow one to perform physiologic experiments at
the molecular level in the entire animal, a feat that could not have
been achieved before. The second reason explaining why the mouse has
become such an important model for biology and medicine is the overall
reproducibility of the observation made in mice when it comes to
pathology. This is why clinicians cannot afford to ignore the findings
of the mouse genetic field. Importantly, this does not apply only to
developmental syndrome(s) but also to the elucidation of the molecular
basis of acquired, late onset, degenerative disease(s). Conversely,
mouse geneticists cannot afford to ignore the challenge facing the
clinicians as they are often in a privileged, if not the best,
situation to solve them. This is because the constant and sometimes
unnoticed dialogue between clinicians and experimentalists is never
interrupted that biology is making progress and will continue to do so.
These statements do not reflect the viewpoint of an experimentalist but
rather the one of a former clinician who, as an experimentalist,
measures the wealth of information that resides at both ends of this
dialogue provided that both sides listen to, or at least hear, each
other. In short, assuming or believing that biologists and clinicians
are not asking the same question is not an illusion, it is a
delusion.
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Control and common control of bone formation and body
weight
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Two observations that could only come from clinical medicine are
at the origin of a new line of research in bone biology and
osteoporosis research. Conversely, this line of research could only be
conducted in animals. The clinical observations are that gonadal
function favors bone loss and that obesity protects from bone loss
(1, 2, 3, 4, 5). Those two observations are true in every
population studied. In molecular terms this was viewed as suggesting
that body weight, reproduction, and bone remodeling share one or
several common endocrine regulators. Given the neuroendocrine nature of
the control of body weight and of reproduction a corollary of this
hypothesis is that the control of bone remodeling could also be of
neuroendocrine nature. As is the case for every hypothesis, whether it
was wrong or right did not matter as much as the fact that it was
testable in the entire animal. The test of this hypothesis led after
many vicissitudes to the identification of leptin, a hormone that
precisely controls body weight and reproduction, as the most potent
inhibitor of bone formation identified to date. This also led to the
demonstration that there was a neuroendocrine control of bone mass as
infusion of leptin in the third ventricle of ob/ob or wild-type mice
led to a decrease of bone mass (6). The central control of
bone remodeling was shortly thereafter shown not to be restricted to
leptin because it was shown that obese patients with an inactivating
mutation in the melanocortin receptor 4 gene (MCR-4) have a higher bone
mass than obese control individuals (7). Obviously,
additional experiments are needed to understand, and possibly to
use therapeutically, all the subtleties of this emerging concept
of a central control of bone remodeling.
The two studies mentioned above were analyzing animals or patients that
were obese. In this issue of JCEM, the study by Pasco
et al. (8) goes one step further, in the same
direction. Indeed, it shows that the level of serum leptin correlates,
to a certain extent, with the bone mass of nonobese women when using a
noninvasive method to measure bone mass. This is, in fact, in agreement
with the observation that leptin-deficient mice have a high bone mass
phenotype before they become obese. The study is, in fact, an eloquent
example of how clinical medicine feeds animal experimentation, and vice
versa. The differences observed between the group of women analyzed are
small, yet this is still an important finding because it strengthens
and broadens the role of leptin in the control bone mass to nonobese
people. It also postulates that serum leptin is a predictor of bone
mass. This, as well as several other points raised in the discussion of
this interesting study, will need to be established more firmly in the
future. It is likely that other studies, clinical and experimental,
will continue to explore the role and mechanism of action of leptin on
bone remodeling. More precisely, the underlying questions, beyond this
clinical work and the previous one in rodents, are to know which
structure in the hypothalamus responds to leptin input to control bone
formation, what type of signals are sent by this putative bone
remodeling center and which route does this downstream mediator(s)
use(s) to affect bone formation so powerfully throughout the skeleton.
The first answers to these questions will most likely not come from
clinical investigations but rather from other animal studies. Yet, they
will eventually receive their ultimate validation from clinical
studies.
The long-term goal for this line of research, clinical and
experimental, is eventually to shed a more molecular and mechanistic
light to osteoporosis. This may lead to a novel bone-forming
therapeutic for the disease. This, in my opinion, matters because we
are still looking for such therapies. If this is the case, this line of
research will illustrate in the most productive way how biology relies
on the synergy between clinical and molecular investigations to thrive.
Beyond biology itself there is the reasonable hope that this dialogue
may change our therapeutic approach to osteoporosis. The study by Pasco
et al. (8), by acknowledging the importance of
leptin in the control of bone mass, pays tribute to the usefulness of
the dialogue between clinical medicine and animal experimentation. It
is the task of each of us to foster an even more productive
dialogue.
Received March 12, 2001.
Accepted March 12, 2001.
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References
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Riggs BL, Melton LJI. 1986 Medical progress:
involutional osteoporosis. N Engl J Med. 314:16761686.[Medline]
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Riggs B, Khosla S III MJ. 1998 A
unitary model for involutional osteoporosis: estrogen deficiency causes
both type I and type II osteoporosis in postmenopausal women and
contributes to bone loss in aging men. J Bone Miner Res. 13:763773.[Medline]
-
Felson DT, Zhang Y, Hannan MT, Anderson JJ. 1993 Effects of weight and body mass index on bone mineral density in men
and women: the Framingham study. J Bone Miner Res. 8:567573.[Medline]
-
Tremollieres FA, Pouilles JM, Ribot C. 1993 Vertebral post-menopausal bone loss is reduced in overweight women: a
longitudinal study in 155 early postmenopausal women. J Clin
Endocrinol Metab. 77:683686.[Abstract]
-
Ravn P, Cizza G, Bjarnason NH, et al. 1999 Low
body mass index is an important risk factor for low bone mass and
increased bone loss in early postmenopausal women. J Bone Miner
Res. 14:16221627.[Medline]
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Ducy P, Amling M, Takeda S, et al. 2000 Leptin
inhibits bone formation through a hypothalamic relay: a central control
of bone mass. Cell. 100:197207.[Medline]
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Farooqi IS, Yeo GS, Keogh JM, et al. 2000 Dominant
and recessive inheritance of morbid obesity associated with
melanocortin 4 receptor deficiency. J Clin Invest. 2:271279.
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Pasco JA, Henry MJ, Kotowicz MA, et al. 2001 Serum
leptin levels are associated with bone mass in non-obese women. J
Clin Endocrinol Metab. 86:18841887.[Abstract/Free Full Text]