Beth Levine & Guido
Kroemer talk with ScienceWatch.com and answer a
few questions about this month's New Hot Paper in the field
of Molecular Biology & Genetics.
Article Title: Autophagy in the pathogenesis of
disease
Authors: Levine,
B;Kroemer, G
Journal: CELL, Volume: 132
Issue: 1
Page: 27-42
Year: JAN 11 2008
* Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas,
TX 75390 USA.
* Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas,
TX 75390 USA.
* Univ Texas SW Med Ctr Dallas, Dept Microbiol, Dallas, TX
75390 USA.
* Univ Paris 11, Paris, France.
* INSERM, U848, F-94805 Villejuif, France.
Why do you think your paper is highly
cited?
Autophagy is an important emerging topic in biomedical research. Autophagy
(literally "self-eating") consists in the sequestration of portions of a
cell's cytoplasm within a specific organelle, termed the autophagosome,
which subsequently delivers its contents to the lysosome for degradation.
Recently, basic cell biologists and disease-oriented researchers have
teamed up to discover the immense importance of autophagy in normal
physiological processes and aging as well as in the pathogenesis of
multiple diseases, including cancer, neurodegenerative disorders,
infectious diseases, and inflammatory bowel disorders such as Crohn's
disease. This rapidly growing appreciation of the implications of autophagy
(and the deregulation of autophagy) in human diseases is a major reason why
our paper is highly cited.
Does it describe a new discovery,
methodology, or synthesis of knowledge?
Coauthor
Guido Kroemer
Our review article provides a state-of-the-art synthesis of knowledge on
the role of autophagy deregulation in human disease. When a cell is
stressed or damaged, it often responds by activating the autophagic
machinery. Autophagy allows the cell to mobilize its energy resources and
to survive in conditions of reduced nutrient or oxygen supply. Autophagy is
also involved in the removal of superfluous or damaged proteins or
organelles—for instance, uncoupled or permeabilized
mitochondria—and hence, has an important role in the maintenance of
cellular homeostasis.
Autophagy is also essential for the maintenance of genomic stability. As a
result, disabled autophagy can lead to malignant transformation and
participate in tumor progression. Reduced autophagy can also accelerate
degenerative processes in the heart, liver, muscle, and brain, and the
stimulation of autophagy can retard organismal aging and postpone the
manifestations of neurodegenerative diseases.
Defective autophagy can also compromise the ability of the host to fight
infections and control inflammatory responses, which may explain the
recently described genetic association between a polymorphism in an
autophagy protein and susceptibility to Crohn's disease. So, in this
article, we emphasize the likely contribution of deregulated autophagy to a
variety of major diseases.
Would you summarize the significance of your
paper in layman's terms?
Autophagy has been regarded by many investigators as a mode of cellular
self-destruction. In our paper, we emphasize the contribution of autophagy
to the maintenance of cellular and organismal health. If insufficient
autophagy is indeed involved in the development of major human diseases,
including age-associated degenerative processes, its pharmacological
induction may have a therapeutic effect. There are also specific
circumstances in which inhibition of autophagy may constitute a therapeutic
goal, and this is also discussed in our paper.
How did you become involved in this research,
and were there any problems along the way?
In the '90s, Beth Levine discovered a protein, named Beclin 1, that
physically interacts with Bcl-2, one of the major regulators of apoptosis.
This protein turned out to be a tumor suppressor protein and to be required
for autophagy, thus providing the first example how defective autophagy may
be pathogenic. Dr. Levine also first defined a role for autophagy genes in
fighting viral infections and in preventing aging. Since then, she has
explored the mechanisms by which Beclin 1 contributes to autophagy
regulation and she is studying the pathophysiological implications of
deregulated autophagy in a variety of important medical diseases.
"Our review article provides a
state-of-the-art synthesis of knowledge on
the role of autophagy deregulation in human
disease."
Guido Kroemer challenged the idea that autophagy would constitute a
modality of programmed cell death starting in 2005, when he published that
inhibition of autophagy can accelerate the apoptotic demise of stressed
cells in vitro. Since then, he has been interested in the
crosstalk between apoptosis and autophagy in molecular terms. This has
turned out to be a fascinating and complex area of research, with wide
implications for various diseases.
Where do you see your research leading in the
future? Do you foresee any social or political implications for your
research?
Perhaps, along with cell division, cell differentiation, and cell death,
autophagy is one of the most fundamental phenomena in cell biology.
However, the molecular comprehension of autophagy is still in its infancy.
We anticipate that a more detailed comprehension of the autophagic process
and its complex regulation will facilitate its therapeutic manipulation.
Given the broad impact of autophagy on major, socioeconomically relevant
diseases, including cancer, neurodegeneration, and global infectious
diseases, we believe that therapeutic measures designed to correct disease-
or age-related autophagic defects might have a major impact on public
health.
At present, the only known strategy to induce autophagy without major side
effects is fasting, and caloric restriction indeed prolongs the longevity
of animals through the induction of autophagy. Therefore, it will be
interesting to invent strategies to induce autophagy in such a way that the
discomfort of caloric restriction is avoided, while stimulating autophagy
in a manner that will conserve its beneficial actions on human health.
Beth Levine, M.D. Howard Hughes Medical Institute Professor of Internal Medicine and Microbiology Jay P. Sanford Professor in Infectious Diseases Chief, Division of Infectious Diseases University of Texas Southwestern Medical Center Dallas, Texas, USA
Guido Kroemer, M.D., Ph.D. Research Director INSERM Institut Gustave Roussy Villejuif, France