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Q&A: Dr. Alberto Hayek, Interim Co-Director, PDRC

Alberto Hayek, M.D.

PDRC Interim Co-Director Alberto Hayek, M.D. has played an important role in the science and development of islet cell therapy. Below, Dr. Hayek describes key advances in the history of diabetes research and the impact of contemporary discoveries.

How did you get involved in diabetes research?

When I began my training in pediatric endocrinology , diabetes research was not at the forefront of endocrine research and much less in pediatrics. Who was to know that diabetes would one day make up more than 50% of the activities of pediatric endocrinologists and pediatric endocrine clinics. Clinical care in the 1970's was rather primitive, as compared to today, when for instance pediatric diabetes patients were seen every six months, received one insulin shot a day and urine was tested for glucose as the only monitoring tool then available.

Then, around the mid-1980's, there was a huge change in the way that pediatric endocrinologists began to look at pediatric diabetes. This change came about mostly through the introduction of two important tools: the ability to measure glucose through finger pricking, and recognition of the importance of the glycosylated hemoglobins. Clinics began to develop independence from the general endocrine clinic and saw strictly children with diabetes.

Next came developments such as the new formulations of insulin and the early introduction of pumps, in the late 1980's. For pediatric endocrinologists most of the research was clinically oriented; there were very few of us doing any sort of basic research. In my particular case the main reason to move into basic research was the realization that clinical experience was not going to provide a more viable platform for investigations into a different treatment than that provided by insulin injections.

Starting in the early 1980's several reports appeared about the regulation of pancreas development in rats and mice and, and career changing articles such as the demonstration that islets could be isolated from the pancreas of small animals. However, very little on human pancreatic development was known. Fundamental questions were unanswered, such as where do islets come from, how do beta cells regenerate or replicate, how are they destroyed during the course of type 1 diabetes. Answers to those questions were and continue to be fertile grounds for investigation.

What have been the most exciting moments of discovery in your career?

The first one was when we decided to move our research from animal cells to human cells, and we realized that it was possible to replicate human islets. When we began that work, the conventional wisdom was that like neurons, brain cells, islets did not replicate. It was really, really exciting to find that wasn't true.

The second exciting moment was when we realized that stem cells could be manipulated for differentiation into insulin cells. Although we were not the first ones in inducing insulin production from embryonic stem cells, contributions that we made in the past were essential to set up the experiments where this was feasible.

What are you trying to learn with your research right now?

Sometimes you discover something and you think that it has been a significant step in trying to eliminate diabetes, but then another discovery tells you that things are not as easy as they were supposed to be. For instance in the case of replicating human islets we found out that as cells replicate they lose their main function, which is to manufacture proteins. In the case of beta cells, they replicate but they don't make insulin. This has been a real problem for everybody that is working in the field. Up to today nobody has been able to bring back insulin after the cells have replicated in tissue culture dishes.

Therefore, it was very interesting to do the opposite; to take cells that have never expressed insulin, such as stem cells, and put them through protocols that have been refined by several laboratories in the United States. We are very much involved in trying not only to improve the protocols for stem cells for the production of insulin, but also using a more recent discovery: the reprogramming of somatic cells such as skin cells into insulin-producing cells.

To give one an idea of how fast these events are occurring, mouse stem cells were available for the first time in 1988, human stem cells in 1998, and then about five years ago came the incredibly good development of reprogramming of somatic cells into stem cells

We have been quite successful mixing several of the protocols that have been published to make islet cells, but we, like everybody else, still have problems, like those encountered with embryonic stem cells. For instance, the reprogrammed cells do not release insulin in response to glucose in the lab, so we need to transplant them to animals.

Once they are transplanted we face another big problem; the formation of benign tumors, called teratomas. It's hard to know the real incidence of teratomas nowadays because most people don't like to publish negative results, but in our hands it's quite high. We are putting a lot of our research efforts into the elimination of these tumors. Human therapy will be impossible until this problem is solved.

How will that help those living with the disease?

Obviously if we were to develop a cell that is derived from either embryonic stem cells or from reprogrammed somatic cells, then we could replace the damaged islets in a patient with diabetes by cell transplantation. Differentiated embryonic stem cells at this point would still require anti-rejection therapy, but this sort of cell transplantation would nonetheless be a significant advance in therapy.

The other possibility, reprogramming somatic cells, carries no risk of rejection, because the persons with diabetes would receive their own cells. However three issues remain. In addition to the teratomas, which appear to be more common than with embryonic stem cells, are those related to recurrence of diabetes in the newly formed insulin cells. Finally are the problems related to so-called genetic memory, in which the cells don't forget where they came from. All these topics require much more research.

What do you feel is unique about the PDRC?

The PDRC is a unique concept for San Diego, but not for the rest of the country because there are other pediatric diabetes centers in The U.S. What is unique about ours is that eventually under one roof we will have a group of outstanding researchers and clinicians all prominent in their own fields of research and surrounded by some of the best scientific minds in the United States.

What important changes do you anticipate for the PDRC in coming years?

There is little question that the upcoming inauguration of La Jolla's Sanford Consortium Stem Cell Center is going to bring more scientists, innovation, and resources, that will facilitate the work of stem cells in diabetes. Second, we need to devote significant attention to the immune aspects of diabetes. The PDRC will spend a considerable amount of time and resources in recruiting a group of immunologists to complement the group of basic biologists that we have now.

How can we help those who want to find out more about diabetes research?

Once under one roof, the PDRC will undoubtedly facilitate the transfer of information from patients to basic research. It will be wonderful when people ask about current research to be able to take them to our labs and explain what we are doing. In addition to our routine activities, such as giving talks to the public, the direct person-to-person interaction between families and researchers will be a key activity in our enterprise.​