Gut Instincts: The Endocrinologists Behind the 2020 Warren Alpert Foundation Prize

Endocrine Society members Daniel J. Drucker, MD, and Joel F. Habener, MA, MD,  talk to Endocrine News about their 2020 Warren Alpert Foundation Prize-winning research of key intestinal hormones, as well as their distinguished careers and what this award means to them.

On October 1, the Warren Alpert Foundation Prize will be presented in a virtual symposium to a trio of researchers for their for their discoveries about the function of key intestinal hormones, their effects on metabolism, and the subsequent design of treatments for type 2 diabetes, obesity, and short bowel syndrome — the first time in many years in this prestigious award has gone to investigators in the field of endocrinology.

Two longstanding Endocrine Society members will be recognized: Daniel J. Drucker, MD, professor of medicine, University of Toronto, Toronto, Canada; editor-in-chief, Endocrine Reviews, and Joel F. Habener, MA, MD, chief of Laboratory of Molecular Endocrinology, Massachusetts General Hospital; professor of medicine, Harvard Medical School in Boston, Massachusetts along with Jens Juul Holst, MD, DMSc, professor, Department of Biomedical Sciences; Group Leader, Translational Metabolic Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Denmark. The understanding of the complex hormonal symphony underlying the regulation of metabolism and gastrointestinal function flows from the work of many scientists. However, it is the seminal discoveries of Holst, Habener, and Drucker that propelled the field forward and enabled the design of several new classes of disease-altering treatments.

The three award-winners identified a family of glucagon-like peptides in the 1970s and 1980s and since then have led the field of metabolism research with studies that went from basic science observations to the clinic and ultimately enabled the development of several new classes of medications for the treatment of metabolic disorders.

Endocrine News caught up with Drucker and Habener to discuss what this prize means for the field of endocrinology, the work that led to this recognition, and where we go from here.

What does this mean to you and your lab to have your work recognized like this?

Joel F. Habener: The Alpert Foundation prize is a very prestigious award given to workers whose discoveries have made an impact in the treatment of disease. I am honored to receive this award, shared with my colleagues Drs. Drucker and Holst, on behalf of all of my co-workers over the years. My lab members, current and past, are proud to have this award bestowed on me as a spokesman for our accomplishments. Favorable peer recognition is one of the highest awards one can receive as a scientist.

It is important to recognize that the work was done by the lab staff including fellows, post-docs, students, visiting scientists, technicians, under my guidance, as well as with numerous collaborators.

Daniel J. Drucker: The Warren Alpert Foundation Prize recognizes the importance of this series of discoveries for people with diabetes, obesity, cardiovascular disease and short bowel syndrome. Importantly, it is also terrific recognition for all the trainees and colleagues who have made so many important contributions to this field along the way.

I should note that hundreds of talented scientists and clinician investigators have done important work over the past few decades to slowly build the body of knowledge enabling the successful translation of this basic science to the clinic. It really does take a village to help make a safe and effective medicine.

What was your reaction when you heard that you would be receiving the 2020 Warren Alpert Prize?

JFH: It was quite a surprise when I received the email from Harvard Medical School and the phone call from Dean George Daley informing me of the award. I was aware of the existence of the Alpert award as the highest award given by Harvard Medical School in recognition of outstanding scientific achievement. However, I did not consider that I would ever be an awardee.

DJD: It is very gratifying to see that basic science work in the area of gut endocrinology can ultimately find an application in human health and provide advances in care not previously attainable with conventional established therapies.

This is the first time in a long time that the prize has been awarded for endocrinology. What does this mean for you to have the field recognized like this?

JFH: It seems perfectly reasonable to include the field of endocrinology and metabolism in the running for the prize as we see the increasing prevalence of obesity and diabetes with associated metabolic and cardiovascular disorders (now including COVID-19). These are diseases with a high morbidity and mortality and are attracting greater research efforts to understand the pathophysiology and to develop effective therapies to combat them. Obesity and its ensuing constellation of ensuing disorders known as the metabolic syndrome include diabetes, steatohepatitis, hypertension, and even dementia and certain types of cancer.

Can you give us a little background and tell us a little about your involvement in this work? What made you want to look at gut hormones as potential therapeutic targets?

JFH: My interests and work in this field evolved stepwise with several discoveries over several decades starting in the middle 1970s. Earlier I had spent two years (1967-1969) at the National Institutes of Health conducting research in molecular biology. That was a time when recombinant DNA technology was being developed and my experience at the NIH convinced me to pursue a career in basic discovery research and to exploit the power of recombinant DNA technology. After completing my clinical training in internal medicine at the MGH in 1972, and further basic laboratory research on the biosynthesis of parathyroid hormone under the tutorship of John Potts at the MGH and Alexander Rich at MIT, it was my great fortune to become an investigator with the Howard Hughes Medical Institute (who provided support for 31 years).  At the same time the MGH appointed me as the chief of a newly established Laboratory of Molecular Endocrinology.

To begin my independent research career at the MGH I chose to explore the biosynthetic pathways of glucagon and somatostatin, two of the three major hormones produced by the endocrine pancreas (islets of Langerhans). Insulin, the third hormone made in the islets, had recently been found by the Donald Steiner laboratory to be synthesized in the form of a large prohormone (proinsulin) serving as a precursor protein from which insulin was formed by the joining of two peptide fragments cleaved from proinsulin by an endopeptidase (prohormone convertase) in the beta cells. We chose to go about pursuing the goal of determining the structures (amino acid sequences) of the initial translation products of glucagon and somatostatin using a recombinant DNA technology approach. As a source of tissue, we used the Brockmann body of the Atlantic anglerfish, in which the endocrine cells of the pancreas are contained apart from the exocrine pancreas, providing a rich source of the mRNAs encoding the hormones.

The recombinant DNA approach succeeded resulting in the discoveries of the prohormone for somatostatin and two distinct non-allelic prohormones for glucagon in the late 1970s. Each of the individual anglerfish proglucagons encoded the fish versions of glucagon and a second peptide resembling but distinct from glucagon. We named these distinct second peptides GRPs, glucagon-related peptides. Comparisons of the amino acid sequences of the GRPs, suggested sequence similarities with mammalian GIP, termed gastric inhibitory peptide, later re-named glucose-dependent insulinotropic polypeptide. GIP had been previously identified and defined by Hans Creutzfelt as an “incretin,” a factor produced in the intestines in response to meals or an oral glucose load, that augmented glucose-dependent insulin secretion. The seemingly sequence similarities of the anglerfish GRPs to GIP thusly raised the possibility that the anglerfish GRPs might be related to mammalian incretin factors. Thusly, the determination of the structures of the mammalian proglucagon became an important initial goal. This undertaking was achieved in the ensuing two to three years, establishing the amino acid sequences of the rat proglucagon mRNA, and the rat proglucagon gene in my lab (1984), and the guinea pig and human counter parts by Graeme Bell in William Rutter’s lab at UCSF (1983), and Donald Steiner’s lab (1986).

The remarkable findings in the studies of mammalian proglucagons was that they contained the sequence of glucagon, and not one but two additional GRPs, re- named GLP-1 and GLP-2. One of the GLPs (GLP-1) appears to be the homolog of anglerfish GRP. In addition, at the level of the gene structure and organization, each of the three peptides, glucagon, GLP-1, and GLP-2 are encoded in separate exons.

DJD: One of my projects was to try and uncover a role for GLP-1. I examined many cell lines for GLP-1 responsivity, reasoning that like glucagon, GLP-1 might stimulate cyclic AMP-I finally found a robust cyclic AMP response to GLP-1, together with stimulation of glucose-dependent insulin secretion, using islet beta cell lines.

Daniel J. Drucker, MD

“It is amazing, today, to see that a GLP-1R agonist has also been approved for and is the number one selling prescription medicine for obesity. Moreover, GLP-1R agonists reduce the rates of heart attacks, stroke, and death in people with diabetes at risk for cardiovascular disease, which we could not have predicted back in the early 1980s.”- Daniel J. Drucker, MD, professor of medicine, University of Toronto, Toronto, Canada; editor-in-chief, Endocrine Reviews

A decade later, I stumbled upon the first actions of GLP-2, which had also eluded detection till the mid-1990s. We found that GLP-2 was a potent stimulator of bowel growth, recapitulating a subset of actions that had been described in case reports of a few rare patients with glucagon-producing tumors. Having learned a bit about intellectual property in the Habener lab, I also filed a series of patents describing GLP-2 action for the treatment of intestinal disorders, but could not have predicted that teduglutide, a GLP-2 analogue originally developed in our lab, would be approved decades later for the treatment of short bowel syndrome. Most gratifyingly, teduglutide enables 10% – 20% of people with SBS to discontinue intravenous feeding, and a much greater proportion of teduglutide-treated subjects reduce the number of nights per week of IV nutrition required to sustain their fluid and energy requirements. Collectively, these results have made a big difference in the quality of life for some people with short bowel syndrome.

Dr. Habener, tell us a little about bringing Dr. Drucker on as a fellow.

JFH: The word had gotten out that our lab had discovered some novel glucagon-related peptides that might be important. As a consequence, Dr. Drucker was encouraged to apply for a position in my lab by his Toronto mentor Gerald Burrow to work on GLP-1 and to obtain some basic training in laboratory research. It was obvious from his outstanding references that Daniel was a superb applicant, so I readily accepted him. Soon after his arrival I became struck by his intense dedication to learning the technology but also applying the technology to address questions concerning how GLP-1 functions in pancreatic beta cells. During the three years that he spent in my lab before returning to Toronto, he first-authored, or co-authored, 12 publications describing his work, a clearly impressive accomplishment for someone who had little prior background in basic research. This high level of research productivity focused on the GLP-1s continued in Toronto. Notable early accomplishments were the creation and characterization of the GLP-1 receptor knock-out mouse and the demonstration that GLP-2 promoted the growth of the intestinal epithelium.

Dr. Drucker, what was it like going to work in Dr. Habener’s lab?

DJD: I was very fortunate as a MD with no lab research experience, to be offered an opportunity for postdoctoral research studies in the lab of Dr. Joel Habener in 1983. Joel, himself a MD graduate, was known for providing training opportunities in the new science of molecular biology early in the 1980s. The laboratory, at the Massachusetts General Hospital, was populated by many talented colleagues, and was a terrific environment in which to learn science.

Frankly, I was originally supposed to work on thyroid hormone and TSH action in the Habener lab, however this thyroid work was transitioning to the Brigham and Women’s Hospital under the direction of Dr. Bill Chin, so I was reassigned to work on the glucagon gene. I just wanted to learn molecular biology, and the project did not make a big difference at the time. In hindsight, I was so fortunate to be at the right place and time to benefit from the opportunity to work on the glucagon gene.

The lab was well-funded and they had just cloned the glucagon gene, which encoded glucagon-like peptides with no known biological function.

This was many years of hard work. Can you share some highlights? Any eureka moments or disappointing moments?

JFH: There were several pleasant surprises along the way and remarkably few disappointments, attesting to the validity of the concept that GLP-1 is truly an active metabolic peptide hormone with many diverse actions. I recall our satisfaction when we identified the active GLP-1 peptide was the 9-36a/37 and not the anticipated amino-terminally extended 1-36a/37 peptide (Mojsov et al 1987).

Joel F. Habener, MA, MD

“It seems perfectly reasonable to include the field of endocrinology and metabolism in the running for the prize as we see the increasing prevalence of obesity and diabetes with associated metabolic and cardiovascular disorders (now including COVID-19). These are diseases with a high morbidity and mortality and are attracting greater research efforts to understand the pathophysiology and to develop effective therapies to combat them.” – Joel Habener, MA, MD, chief of Laboratory of Molecular Endocrinology, Massachusetts General Hospital; professor of medicine, Harvard Medical School in Boston, Massachusetts

Another finding of great satisfaction (and relief) was that in human subjects with and without diabetes, GLP-1 administration lowered blood glucose levels and did so without causing hypoglycemia. This was an important difference compared to insulin, which has the serious side effect of hypoglycemic shock. The therapeutic index for insulin therapy is narrow, whereas with GLP-1 therapy there is complete safety regarding hypoglycemia. There appeared to be a “glucostat” built into the actions of GLP-1 that required a plasma level of glucose of 60 mg/dl or higher for GLP-1 to effectively stimulate insulin secretion. We referred to this property of GLP-1 as the “glucose competence concept” (Holz et al 1993).

Later studies clearly demonstrated that GLP-1 stimulated both the growth and survival of the pancreatic beta cells that produce insulin. Surprisingly, we discovered that injuries to beta cells produce chemokines, such as SDF-1 that stimulate the glucagon-producing pancreatic alpha cells that lie adjacent to the beta cells in the islets, to produce GLP-1. The GLP-1 so produced repairs beta cell injury and stimulates their growth. The mechanism for this induction of GLP-1 production in alpha cells involves the induction of the expression of the prohormone convertase PC1/3 that cleaves GLP-1 from proglucagon.

In this regard we realized that the alpha cells in the islets appear to serve as guardians of the beta cells. The alpha cells are so to speak on standby next to the beta cells and when the beta cells are injured, such as by glucotoxicity, they secrete factors that switch on the production of GLP-1 in alpha cells that then rescues the injured beta cells and nurtures them back to health. Remarkably, shortly after we made this discovery, it was shown that severe experimentally induced injuries of beta cells induce alpha cells to transdifferentiate into beta cells (Pedro Herrera lab). This is a final sacrifice of the guardian alpha cells to the health of beta cells and is a testimony to how important insulin made by beta cells is to survival of the organism.

A quite rewarding finding was that the GLP-1-derived nonapeptide, GLP-1(28-36)amide was bioactive in mice and cultured hepatocytes and beta cells. To explain the increasing evidence pointing to receptor independent actions of GLP-1 in a number of tissues I had postulated that the C-terminal region of GLP-1 formed a cationic amphipathic helical structure and would be cleaved from GLP-1 by the endopeptidase, neprilysin (NEP 24.11) based on a report by Hupe-Sodemann et al 1995. When the studies were carried out, they completely supported the prediction that the nonapeptide mimicked the receptor-independent actions of GLP-1. A recent study reported by the Mansoor Husain lab in Toronto showed that the GLP-1 nonapeptide attenuates post-ischemia reperfusion injury in the hearts of mice and does so by inhibiting fatty acid oxidation (Siraj, 2020).

Remarkably, the nonapeptide does not bind to the GLP-1 receptor but rather appears to enter cells via a cell-penetrating mechanism and then targets to mitochondria where it modulates energy metabolism. The peptide increases basal energy expenditure in diet-induced obese mice resulting in an inhibition of weight gain, reduces oxidative stress in pancreatic beta cells, and reduces hepatic glucose production.

DJD: Although exciting at the time, I don’t think any of us could have fully predicted the translational story that unfolded gradually over several decades. However, based on these early findings in 1980/1982, Joel Habener filed the first patent on the actions of GLP-1 to treat diabetes, so he clearly understood the potential of these very early experimental results.

It is amazing, today, to see that a GLP-1R agonist has also been approved for and is the number one selling prescription medicine for obesity. Moreover, GLP-1R agonists reduce the rates of heart attacks, stroke, and death in people with diabetes at risk for cardiovascular disease, which we could not have predicted back in the early 1980s.

What’s next for your lab? How will this award help you with your upcoming work?

DJD: I am optimistic that GLP-1-based drugs may find new applications in the clinic, perhaps in the treatment of non-alcoholic steatosis, or in the therapy of one or more neurodegenerative disorders. So, there is still a great deal of work to do to explore the mechanisms and therapeutic potential of gut hormone action, and I feel very privileged to be able to contribute to this area of science.

JFH: Our current work and future plans are to explore the mechanisms involved in the actions of the two small peptides, a nonapeptide and a pentapeptide, derived from GLP-1 on energy metabolism in mitochondria. Our preliminary studies point to a direct interaction of the peptides with both the fatty acid oxidation and the apoptosis pathways in mitochondria. The recognition obtained from the award should enhance interest in our studies and the award money itself will be helpful in providing support for the work.

Bagley is the senior editor of Endocrine News. He wrote the September cover story on how artificial intelligence could possibly change the way that osteoporosis is treated.

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