Masayasu Kojima & Kenji
Featured Paper Interview
Essential Science IndicatorsSMfrom
Reuters, the 1999 Nature paper by Dr.
Masayasu Kojima and colleagues, "Ghrelin is a
growth-hormone-releasing acylated peptide from
stomach," (Kojima M, et al., Nature 402(6762):
656-60, 9 December 1999), is ranked at #4 among Highly
Cited Papers in Biology & Biochemistry. It has
accrued 2,586 citations from its publication to August
Dr. Kojima's work ranks in the top 1% of the database in the fields of
Biology & Biochemistry, Clinical Medicine, and Molecular Biology &
Genetics. He is Professor of Molecular Genetics at the Institute of Life
Science at Kurume University. His coauthor, Dr. Kenji Kangawa, is in the
top 1% in the fields of Biology & Biochemistry and Clinical Medicine.
Dr. Kangawa is the Director General of the National Cardiovascular Center
Research Institute and Professor at the Kyoto University Graduate School of
talks with Dr. Kojima about this paper and its impact on
the research community.
What factors promoted you and your coauthors to
undertake this study?
Our research style is "in the beginning was a novel peptide." We have been
searching for novel unknown peptides for almost 30 years. We discovered
opioid peptides (a-neoendorphin, etc.), neuromedins, and the
natriuretic peptide family (ANP, BNP, and CNP). It is a very exciting
experiment to find a novel peptide and explore unknown physiological
functions. It is just like a treasure hunt or climbing a virgin peak.
Academy Prize: Dr.
received the Japan
Academy Prize in 2008
for his discoveries of
many peptide hormones.
He is standing
Dr. Kojima (right) and
Dr. Matsuo (left),
their teacher and
mentor. Dr. Matsuo had
worked under Dr. Andrew
Schally and helped
determine the structure
of LHRH, for which Dr.
Schally received the
We used several orphan GPCRs as target receptors. Orphan GPCR means that
the endogenous ligands have not been identified, and luckily we found the
GHS-R ligand, ghrelin. In fact, the GHS-R ligand was the most desired one
to be discovered. One reason is that the GHS-R ligand stimulates GH release
and seems to be very useful for clinical purposes, such as low GH
concentration and anti-aging.
How was it conducted, and what were your
We and all other groups had tried to find the undiscovered GHS-R ligand
from the brain, because GHS-R is expressed in hypothalamus and pituitary.
However, we discovered the ligand from the stomach. Only our group changed
the target tissue and no other groups tried stomach samples. This was very
lucky for us, because content of ghrelin in the stomach was so high that
every group should have succeeded in finding the ligand, if only they tried
to find it in the stomach.
Please read my essay on the discovery of ghrelin*, in which I
describe the story from the beginning of our research to the publication in
How was the paper received by the community?
We had five reviews for accepting our paper to Nature. Usually
three reviews are enough for Nature reviewing. I think that the
production tissue (stomach) and the structure (octanoyl modification) of
ghrelin were without precedent and the editor of Nature wanted
assurance that our results were correct.
The endocrinology community was very positive and very excited about our
results. However, to my disappointment, my grant for ghrelin research was
rejected even after the paper was accepted by Nature.
Where have you taken your ghrelin research since this
After the publication of the ghrelin paper, we examined the physiological
functions of ghrelin and found that it is a potent orexigenic hormone. This
was very exciting too, since ghrelin is a circulating hormone and these
results indicated that peripheral injection of ghrelin can be used for
treatment of eating disorders, such as anorexia nervosa.
We also created a ghrelin knockout mouse and have been examining what
happens if there is no ghrelin. This study is very difficult; however,
recently we found interesting phenotypes in these mice. I hope that the
results will be published in a high-ranking journal in the near future.
Another interesting subject on ghrelin was the identification of the
enzyme, ghrelin O-acyltransferase, which modifies and activates ghrelin. We
had searched for the enzyme since the discovery of ghrelin. However, last
year two groups reported on the enzyme and we lost. But the results were
very surprising and exciting for me, because the enzyme was exclusively
specific for acyl-modification of ghrelin.
What makes ghrelin so important?
Since the discovery of leptin in 1994, the importance of humoral factors
for regulating appetite has been recognized. Ghrelin is a counter-hormone
to leptin not only for its physiological activity but also for its
pharmacological functions. It is 10 years since the discovery of ghrelin
and even now ghrelin is the only circulating orexigenic hormone. Thus,
ghrelin seems to be a good target for developing drugs to regulate appetite
or to treat obesity by antagonizing or suppressing its effects.
Finally, please let me talk about my personal pleasure. I am very, very
happy and honored to find that "ghrelin" is described in
Lehninger’s Biochemistry and Stryer’s
Biochemistry, which I studied as textbooks in biochemical courses in
my college student days. I could not have imagined when I was a young
student that my discovery would be included in these textbooks 30 years
*M Kojima, "The discovery of ghrelin—A personal memory,"
Regulatory Peptides 145(1-3): 2-6, 2008.
Masayasu Kojima, M.D., Ph.D.
Institute of Life Science
Kenji Kangawa, Ph.D.
National Cardiovascular Center Research Institute
Kyoto University Graduate School of Medicine