 n
this essay, Professor Anthony Barnett talks about his highly
cited work in diabetes investigation. Professor Barnett is
among the top 20 scientists cited in our Special Topics
analysis of diabetes over the past decade, with 74 papers
cited a total of 2,034 times. He is a co-author of the paper
ranked at #3, "A genome-wide search for human type-1
diabetes susceptibility genes," (Nature 371[6493]:
130-6, 8 September 1994). This paper, which had been cited 757
times at the time of the analysis, now shows 774 cites in ISI
Essential
Science Indicators
Web product. *Read
more about Professor Barnett at the bottom of the essay.
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Diabetes mellitus is a major worldwide public health problem
presently affecting close to 200 million people with numbers expected
to reach 300 million by 2025. It is associated with greatly increased
risks of cardiovascular disease (particularly heart disease), kidney
failure, blindness, and lower limb amputation.
As a young doctor I found this condition fascinating, providing an
opportunity for close patient contact whilst helping to manage a
chronic multi-system disease. In addition, it became clear to me that  diabetes
was extremely interesting from a scientific point of view and that
better understanding of the pathophysiology of the disease and its
complications would provide the potential for improved treatment and
even the possibility of disease prevention.
I started my research career in the late 1970s with Dr. David Pyke
and Dr. Peter Watkins at King’s College Hospital, London, where they
not only further stimulated my interest in clinical diabetes, but also
helped me formulate research ideas and how to take these forward in a
constructive way. In 1979 I was fortunate to be appointed as a Medical
Research Council Senior Research Fellow in David Pyke’s Unit where I
was able to work with a large group of identical twins, where one or
both had diabetes, whom he had identified from all over the UK. We
were able to use this large patient resource to study the relative
contribution of genetic and environmental factors in disease
development1. At the same time I also became interested in
risk factors for the long-term complications of diabetes. Both of
these areas laid the foundation for much of my later work.
When I moved to the University of Birmingham, UK, to a senior post
in 1983 I set up my own research group in which we studied the
molecular genetics of "complex" diseases, i.e. those
diseases caused by an interaction between one or more susceptibility
genes and environmental factors. These diseases include many of the
big killers in the world today, e.g. heart disease, stroke, cancer,
multiple sclerosis, and a range of other endocrine diseases, including
diabetes.
 
Read a Special Topics interview with Professor John
Todd. One of the most-cited scientists in diabetes
research in the past decade, Dr. John Todd, relates the progress that
has been made in elucidating the causes and prevention of type 1
diabetes in recent years. In our Special Topics analysis of diabetes
research, Dr. Todd ranks at #2, with 76 papers meeting the search
criteria cited a total of 4,002 times. Two of his papers also made the
top 25 papers list in this analysis.
[read]  |
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My initial interest was in type 1 diabetes which is responsible for
around 10-15% of all cases of diabetes—it occurs as a result of
destruction of the insulin producing b
-cells of the pancreas by the body’s own immune system. In
collaboration with Professor John Todd, who was then working in
Oxford, we were the first group to report an association between a
particular immune response gene (HLA-DQ) on the short arm of
chromosome 6 and type 1 diabetes2. We did this by utilising
the techniques of recombinant DNA technology in different racial
groups. We later went on to set up a collection of families under the
auspices of the British Diabetic Association (now called Diabetes UK)
where at least two siblings in the family had type 1 diabetes and both
parents were alive and available for study. This enabled us to collect
a bank of DNA from family members allowing study of the inheritance of
various genetic markers in relation to disease. We used the then
relatively new "micro-satellite" technology (molecular
"signposts") to identify areas of the genome associated with
disease susceptibility. This enabled us to identify the location
within the human genome of other susceptibility genes for this disease3.
This was the first report using this technology in the study of
"complex" disease and has since been extended to studies of
other important diseases.
Since then we have continued to collaborate with Professor Todd’s
group (now in Cambridge) to try and more precisely define diabetes
susceptibility genes4-17. We have also extended our work
into other areas, including multiple sclerosis and thyroid disease.
My group has since gone on to try and more precisely define the
functional relationship between the immune response (HLA-DQ) genes
located on chromosome 6 and disease development. We have reported that
particular variants (alleles) of these HLA genes are associated with
increased risk of type 1 diabetes and that other variants of the same
gene are associated with protection against the disease18-46.
These findings are consistent across all racial groups studied so far.
These variants code for proteins (HLA-molecules) which are present on
the surface of specialised cells in the immune system, where they
regulate activation of the immune response. These variants differ from
each other by only a few amino acids but these differences appear to
have a major effect on either increasing or reducing susceptibility to
disease. It is likely that disease susceptibility/protection relates
to the ability of these different variants to regulate the immune
response against the pancreatic b
-cells. One of these variant molecules (HLA-DQ6) confers strong
natural protection against the disease and we are presently trying to
determine how it does this. The ultimate aim of this work is to
develop new therapies which will prevent immune destruction of the
insulin-producing cells of the pancreas, thereby preventing type 1
diabetes. This type of work has obvious long-term practical
implications for other diseases of disordered immunity such as
multiple sclerosis and some types of thyroid disease.
Other areas of interest include work to try and better understand
the relationship between diabetes and its long-term vascular
complications. My group has long been studying the relationship
between diabetes and various risk factors for vascular disease,
including hypertension, lipid problems, clotting abnormalities, and
free radical activity. We are also presently studying possible
hormonal links between diabetes and obesity and have suggested that a
newly described hormone secreted by fat cells might provide such a
link in humans47.
We have also been involved in helping develop a whole range of new
therapies for diabetes and its complications. These include new types
of insulins (insulin analogues48), new formulations of
insulin (e.g. inhaled insulin), new insulin devices (insulin pumps and
insulin pens), new oral agents for diabetes (e.g. thiazolidinediones
and rapid acting insulin secretagogues), and new treatments for
vascular complications (ACE inhibitors, angiotensin II receptor
blockers, aldose reductase inhibitors, thromboxane synthetase
inhibitors, etc.).
Diabetes is such an important and fascinating disease that it is
difficult to concentrate interest in one area. Genetics of diabetes
has been my major interest, but in many respects my greatest pleasure
has been to be involved in development of new drugs and subsequently
to see them benefiting my patients. This is the great thing about
being a clinical scientist—you can not only help in understanding
the disease but can (hopefully) see the results in your own patients.
The genetic side may be even more important in providing a better
understanding of disease development and prevention but unfortunately
this is a much longer-term issue and there is still a long way to go!
Professor Anthony Barnett
Birmingham Heartlands Hospital
Birmingham, United Kingdom
* About
Professor Barnett
Professor Barnett gained his
medical degree from the University of London, King’s College, in
1975, having previously obtained a first class honours degree in
pharmacology from the same university in 1972. He subsequently
trained in a range of hospitals and universities, including spending
two years as a Medical Research Council Senior Fellow in the
Diabetes Unit at King’s College Hospital between 1979 and 1981. He
was promoted to Senior Lecturer, Reader, and subsequently Professor
of Medicine at the University of Birmingham, UK, and has been
Consultant Physician and Clinical Director of Diabetes and
Endocrinology at Birmingham Heartlands Hospital since 1983.
He runs one of the biggest Diabetes
Units in the UK. He has major research interests in genetics of
diabetes and other "complex" diseases; causes of diabetes
complications; and the development of new therapies to treat
diabetes and its long-term vascular complications. He has published
over 300 original papers and has written many books, reviews, and
editorials, and has contributed chapters in many of the major
diabetes textbooks.
References
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Nature 1989;338:587-589.
Nature 1994;371:130-136.
Nature Genetics 1992;2:212-215.
Nature Genetics 1995;9:80-85.
Human Molecular Genetics 1995;4:197-202.
Nature Genetics 1995;9:284-292.
Human Molecular Genetics 1996;5:1071-1074.2
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Human Molecular Genetics 1997;6:1017-1020.
Human Molecular Genetics 1997;6:1003-1010.
Human Molecular Genetics 1997;6:1011-1016.
Nature Genetics 1998;19:297-300.
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Diabetologia 1991;34:576-578.
Human Immunology 1992;33:53-57.
American Journal of Human Genetics 1992;50:1018-1021.
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Diabetologia 1993;36:252-257.
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Human Immunology 1993;38:179-183.
Autoimmunity 1994;17:123-125.
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Human Immunology 1994;40:135-137.
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Human Molecular Genetics 1995;4:1609-1612.
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Lancet 2002;359:46-47.
Lancet 1997;349:47-51.
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ESI Special Topics,
July 2002
Citing URL - http://www.esi-topics.com/diabetes/interviews/ProfAnthonyBarnett.html
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