The Juvenile Diabetes Foundation International (JDFI) and the National Aeronautics and Space Administration (NASA) organized a 2-day conference in Washington, DC on December 2-3, 1997 to which I had the good fortune to be invited by JDFI. The focus of the conference was beta cell replacement technologies as a treatment for type 1 diabetes.
I would first like to extend my thanks to those who organized this conference, and who pulled together some of the top diabetes researchers in the world on extremely short notice. I may get into trouble for omitting some key people, but those present at the conference whose tireless contribution was evident included Patricia Rivera (National Manager of Meetings and Travel for JDFI), Emily Spitzer (Chair of Research for JDFI), and Philippe Halban (Chair, JDFI Science Advisory Board and Medical Science Review Committee). Their extraordinary efforts resulted in a conference that succeeded in presenting the state-of-the-art in diabetes cure research.
I would also like to thank the many researchers who came from all over the world to be part of this event. I am sure that everybody learned something new , and as a result, each individual effort will be more effective. In addition, several potentially important collaborations were initiated at the conference.
The atmosphere of the conference created an open exchange of ideas, results, opportunities, challenges, and risks in the pursuit of a cure for diabetes. Although organized primarily by JDFI, the ideas and debates were allowed to flow freely with no attempt on the part of the foundation to impose any agenda of their own. I am convinced that the JDFI people at the conference, most of whom have diabetes in their families, were absolutely genuine and unequivocal in their desire to focus the organization on a single goal - finding a cure for juvenile diabetes as soon as possible. On more than one occasion the participants were asked by Emily Spitzer, "What should the role of JDFI be in reaching the goal that we all are seeking?" Ironically, when confronted with the question in such a forum, and in light of the superb conference that was underway, many of us (me!) who have been rather vocal about JDFI failed to deliver the kind of specifics that Emily was seeking. I am sure that over the coming days and weeks, many ideas will gel and we can all work together to return the direction of JDFI to those people whose only goal is the eradication of diabetes.
The conference was a two-day onslaught of information from some of the world's most promising diabetes researchers. The information flow felt, at times, like drinking from a fire hose. Each section leader at the conference will be preparing a summary of the information presented, so I will focus more on overall impressions than on specifics. That also reduces the chance of my making some really embarrassing errors and omissions.
Still, this report may contain errors, omissions, and misinterpretations.
I would welcome comments from anybody, whether you attended the conference
or not, to help make this report as complete as possible. Please
do not hesitate to send your comments
to me. I have included a list of the attendees
at the end.
Among the researchers, there was a wide spectrum of talent and contribution
- the same bell curve that imposes itself on any group of human beings.
Some extraordinary work was presented, work that seemed tantalizingly close
to clinical trials in people. Some of the work offered little or
no near-term potential, but may form the bedrock of even better and cheaper
methods of reversing diabetes in the decades to come. There were
many cases of researchers working on similar narrowly-defined challenges,
but with the subtle variations that spell the difference between success
and failure. Others were conspicuous in the sheer novelty of their
approaches, and their willingness to stand outside the widely accepted
circle of conventional wisdom. And of course, others left me wondering,
The two days were divided into the following four panels:
Panel 1 - Human and Animal Islet Transplantation - This section focused on the most immediate sources of islet cells for transplantation into people with diabetes, specifically human cadavers and pigs. Other sources of islets such as proliferated human islets, insulinoma islets, genetically engineered islets, fish islets, and internally regenerated islets were discussed in subsequent sections of the conference.
Human islets were seen as an opportunity to treat several thousand diabetics per year, and to learn more about harvesting, encapsulation, and transplant sites. Everybody recognized the fact that human donors could satisfy only a tiny fraction of the need and do not represent a long-term solution. However, Bernhard Hering from the University of Minnesota pointed out that 2,000 pancreases go to waste every year in the United States, and should be used for islet transplants. We learned about the many successes of human islet transplantation at the University of Giessen, and the resultant Giessen Protocols are a road map for transplant clinicians around the world. Human islets are an immediate opportunity to learn and to heal.
Pig islets were favored by the researchers who seem closest to human trials, but the process of harvesting and isolation still presents some engineering challenges in order to meet a large scale demand for consistent product. A successful seventy-five-year history of using injected pig insulin provides comfort as to the efficacy and safety of this hormone for regulating human blood glucose. The theoretical risk of transfection by Pig Endogenous Retrovirus (PERV) was discussed, and as Jeffrey Platt of Duke University elegantly summarized the situation, AIDS was not caused by xenografts of pig tissue. He pointed out that pathways for PERV infection have existed for hundreds of years, and there has never been a public health issue. We also learned that a surprisingly large number of people have already received living pig tissue, including neurons, without infection. Pig islets are a near-term opportunity.
Insulinoma cells may offer some contribution as a source of islets. These cells derive from a human malignant tumor whose dominant characteristic is that it secretes insulin and ultimately kills the patient through hypoglycemia. There are major challenges in this initiative, including assuring that the secretion of insulin is responsive to blood glucose, and that a reliable off-switch can be found to disable the malignant cell multiplication once the required islet mass has been established. This cell source would appear to be long term and highly speculative.
Proliferated human islets and internally regenerated islets also represent longer-term prospects for sourcing islets, and were discussed in detail in subsequent sections.
In this section, the role of endocrine secretions that a normal islet produces in addition to insulin were also discussed, especially the potentially beneficial role of C-peptide in preventing complications. As was pointed out at the conference, and earlier on our own forum, people with type 2 diabetes often have very high insulin and C-peptide levels, and yet suffer the same complications. The common denominator is elevated blood sugar, and the cure is normoglycemia.
The value of partial cures - treatments which do not allow complete insulin independence - was discussed. Some researchers felt that without complete freedom from insulin injections, a technology could not be deemed a success. Those living with diabetes were generally supportive of a partial cure, in which the patient would be responsible for a couple of shots per day of long-acting insulin to provide background coverage, but the transplanted islets would provide closed-loop insulin control in response to variations in food intake and activity. Such a treatment would almost certainly mean near-normal glycated hemoglobins and avoidance of dangerous hypoglycemic episodes. For some reason, people who do not have diabetes seem to imagine that taking shots is the main problem. Speaking personally, I find injections to be a complete non-issue. The real problem with this disease is the fact that all the shots and testing still result in lousy blood glucose control. The restoration of even a small measure of closed-loop insulin control would be an immense improvement.
Panel 2 - Physical Barriers to Immune Rejection of Implanted Islets - This section dealt with immunobarriers, physical screens that block access to the foreign islets by the recipient's immune system. These barriers need to offer a delicate balance of characteristics, including physical strength, immunocompatibility, capacity to induce vascularization, and selective permeability that will block large immune components while allowing smaller molecules such as oxygen, glucose, water, and insulin to pass easily. While protecting the islets, the barrier material must not itself attract an inflammatory or fibrotic response from the person's immune system. This is not an easy challenge, but many are closing in on a materials that now appear ready, or have already been used, for human testing.
It is expected that some form of immunobarrier will be required, whether the source of islets is human, pigs, proliferated, insulinoma, or engineered. Our immune system is aggressive when it comes to foreign tissue, and immunobarriers seem to represent the best hope for protecting the transplanted tissue, while not compromising our entire immune system.
One of the issues that came up with almost all the researchers was the role played by small toxic molecules that can kill islets. A semi-permeable screen can keep out the large components of the immune system, but what about very small molecules that are also toxic to the islets, in particular cytokines and free radicals? These molecules are actually smaller than glucose, insulin, and oxygen molecules, and so can in theory reach the islets and damage them. Some researchers felt that the barriers would not allow the normal chain of events in an immune attack to get started, and so these tiny killers would not be present in the region of the capsules. Others proposed more complex cell engineering solutions that would circumvent this problem. It is unclear if the successes of encapsulated islets to date have actually been compromised by these very small agents, or if the rate of damage would simply mean that a periodic booster would be needed to retain normoglycemia.
We heard presentations from several researchers who are using a range of natural materials (alginate being a dominant choice), a stealth polymer that is both semi-permeable and presents no binding sites for adhesion of proteins, synthetic polymers (such as Polyethylene Glycol, or PEG), and a semi-permeable fabric from the makers of GoreTex. There is a very high degree of agreement on the characteristics that need to be achieved, and on the use of immunobarrier technology as a safe and potentially effective way to protect transplanted islets.
There was a great deal of discussion on the different kinds of attacks that a transplanted islet would face. As with any foreign tissue, there would be the normal allograft or xenograft immune response, but people with type 1 diabetes also may be able to again mount an autoimmune response, just as they did against their original islets. Since both immune attacks utilize a similar chain of events, it is likely that immunobarriers will be effective in hiding the islets from both attackers. There was considerable discussion as to whether xenotissue or engineered cells would attract the same autoimmune reaction as our original beta cells. Even if the autoimmune response is still present, and even if immunobarriers are less effective in blocking it, diabetic autoimmunity seems to be a very slow process occurring over many years. Perhaps autoimmunity would just be another of those slow killers of transplanted islets that would force us to consider periodic boosters to assure continuing normoglycemia.
As well as physical barriers to an immune attack, other agents which can hopefully create tolerance of the transplanted tissue were discussed. Most were in agreement that the use of existing immunosuppressants, such as cyclosporin, was not ethical as a means of reversing diabetes, as the side effects in some people may be worse than the disease. Newer agents, such as Anti-CD40 Ligand, appear much less toxic, but the early hope that a single administration would confer a lifetime of transplant tolerance seems to be under question. Animal tests indicated that a repeat dose of the agent was required every few months to maintain tolerance of the transplanted tissue. Another technique for inducing tolerance to human islets, which involves a transplant of the donor's bone marrow along with the islets, has had some encouraging outcomes in whole organ transplants with minimal adverse effects, but some researchers at the conference expressed concern about triggering graft-versus-host disease in which the transplanted marrow creates antibodies that attack the new host. In contrast, the apparently benign nature, and the low probability of unexpected consequences, of a physical barrier held a lot of appeal for both researchers and potential recipients.
Panel 3 - Beta Cell Growth and Differentiation - Several researchers presented their work in the area of islet cell replication and regeneration, falling into two distinct categories:
Exogenous Islet Replication - Some researchers are developing growth factors as a means to force the reproduction of an ideal islet cell line external to the recipient. These islets are then immunoprotected and transplanted into the recipient. The appeal of this approach seems to be the ability to make consistent generations of islets, when compared to the variability found in naturally occurring pig and human islets. There were dramatic claims of human islet replication, and we eagerly await the supporting data.
Endogenous Islet Replication - Some researchers were looking for the precursor cells that, in the embryonic state, differentiate into islet cells as the pancreas forms. Most agreed that duct cells within the forming pancreas are stimulated by some growth factor to become islets. Therefore, there may be an opportunity to stimulate the duct cells within the pancreas of a person with diabetes to differentiate into functioning islets. Such islets would reside in the pancreas, their normal home, and would not require immunoprotection. This work is very early and speculative, as an effective growth factor has not been identified, and some researchers questioned the ability of any growth factor to stimulate only the growth of islets and no other cell type. As for the possibility of a continuing autoimmune attack on the new islets, very little is known; however, the slowness of autoimmunity provides hope that the replication rate could outstrip autoimmune destruction, and normoglycemia could be maintained over time. Of all the approaches to islet replacement, endogenous islet replication could theoretically come nearest to restoring normal pre-diabetic conditions.
Panel 4 - Engineering of Surrogate Beta Cells - This section focused on the hope of engineering the perfect islet, having all the characteristics that we want. Genetic engineering technologies were presented which had the potential to allow the insertion of gene fragments into the DNA of cells and cause those cells to assume new and more useful characteristics.
Genetically engineered islets may represent an opportunity to create just the islet that we all want. In an ideal world, these islets would secrete human insulin, be responsive to glucose, express other proteins such as C-peptide, have just the right glucose setpoint, present no adverse effects, be available in large quantities, last a lifetime, and be immunocompatible without the use of immunobarriers. In other words, they would be just like the islets we used to have before diabetes. With increasingly precise tools for inserting genetic material into cells (including gene guns and adenoviruses), we may converge on these ideal characteristics in the longer term. Some caution was expressed about the possible creation of infectious viral material in the process of radically engineering the genome of these cells, as well as the potential of viral-based gene insertion to make the islets more irritating to the immune system.
Most researchers expected that no engineered islet could provide all
the characteristics that we would consider ideal, and that some form of
immunobarrier would be required to protect these cells.
Short Term versus Long Term...
And so we were presented with a research landscape that included immediate
prospects for testing encapsulated human islets, near-term opportunities
for testing pig islets in immunobarriers, and longer-term opportunities
to create the perfect replacement islet technology. Taylor Wang
of Vanderbilt University summarized the situation succinctly when he suggested
that we need to immediately fund the near-term prospects, while in parallel
supporting the science that may represent subsequent generations of cure.
In a field like this, it is unlikely that the cure we first test will be
the same one used in 20 years, and therefore the work to develop even better
and cheaper solutions must continue. (As an aside, we must remember
that the treatment for diabetes invented 75 years ago persists to this
day. Good job we didn't wait for something more ideal! )
Some Personal Conclusions...
The following are my own conclusions based on what I heard during these two days. I must emphasize that these are the personal conclusions of a lay person, and I would welcome an email with suggestions or corrections from anybody. Over time, these conclusions can hopefully be refined to be an increasingly accurate reflection of the current state-of-the-art in diabetes cure research, and a mechanism for prioritizing future research funding.
Having had an opportunity to reflect on the information presented at
this conference, and to consider Emily Spitzer's request for some real
ideas as to how JDFI could better direct its research dollars to the goal
we all share, I would like to offer some suggestions:
This workshop definitely left me with a feeling of hope. Despite
the sense of pride and commitment that each researcher has in his or her
own approach, there is a high level of concurrence as to the most promising
near-term technologies. I feel we are at a point in history not unlike
when the Wright brothers demonstrated that heavier-than-air flight is possible,
albeit only for a few seconds. This early demonstration caused many in
the aeronautic world to concentrate on the emerging technologies of fixed-wing
and propellors, and to set aside some of the less successful approaches.
As always, others ridiculed the short, awkward, bumpy Kittyhawk adventure,
warning the world of the terrible risks, and failing to see the beginning
of a new era. Within a decade, commercial air travel was a reality.
In a similar way, islet transplantation has had its own early Kittyhawk
flights, and with a little vision we too can enter a new era free of diabetes.
Attendees from Juvenile Diabetes Foundation International (JDFI)...
Deb Butterfield, Member of Government Relations Steering Committee,
Philippe Halban, Chair, Medical Science Advisory Board and Medical Science Review Committee, JDFI
Margaret Himmelfarb, Director and Lay Review Board Member, JDFI
Sandra Puczynski, Director and Lay Review Board Member, JDFI
Patricia Rivera, National Manager of Meetings and Travel, JDFI
Sandra Silvestri, Director and Lay Review Board Member, JDFI
Emily Spitzer, Director and Chair of Research, JDFI
Attendees from The National Institutes of Health (NIH)...
Richard Eastman, Division of Diabetes,
Endocrinology and Metabolic Diseases, NIDDK
Judith Fradkin, Division of Diabetes, Endocrinology and Metabolic Diseases, NIDDK
Joan Harmon, Division of Diabetes, Endocrinology and Metabolic Diseases, NIDDK
Elaine Young, National Center for Research Resources, NIH
Attendees from National Aeronautic and Space Administration (NASA)...
Neal R. Pellis, Biotechnology Cell Science Program, Johnson Space Center, Houston, TX
Attendees from the Research Community...
Patrick Aebischer, Gene Therapy Center, Lausanne, Switzerland
Rodolfo Alejandro, Diabetes Research Institute Miami, FL
Arne Andersson, Uppsala University, Sweden
Shirin Asina, The Rogosin Institute, Xenia, OH
Hugh Auchincloss, Massachusetts General Hospital, Boston, MA
Clyde F. Barker, University of Pennsylvania Hospital, Philadelphia, PA
Stephen Bartlett, University of Maryland School of Medicine, Baltimore, MD
Reinhard G. Bretzel, University of Giessen Medical School, Giessen , Germany
Michael Brownlee, Albert Einstein College of Medicine, Bronx, NY
Linda C. Burkly, Biogen, Inc., Cambridge, MA
Debra Butterfield, Insulin-Free World Foundation, Minneapolis, MN
Clark K Colton, Massachusetts Institute of Technology, Cambridge, MA
Greg Dane, Neocrin Company, Irvine, CA
Kevin Docherty, University of Aberdeen, Aberdeen, Scotland
William Drake, Islet Technology,Inc., North Oaks, MN
Helena Edlund, University of Umea, Umea, Sweden
John F. Elliott, University of Alberta, Edmonton, Canada
Robert Elliott, Auckland School of Medicine, Auckland, New Zealand
Steven Ertel, Biogen, Inc., Cambridge, MA
Elan Ezickson, Biogen, Inc., Cambridge, MA
Terry Fetterhoff, Boehringer Mannheim, Indianapolis, IN
Norman Fleischer, Albert Einstein College of Medicine, Bronx, NY
Ronald G. Gill, Barbara Davis Center, Denver, CO
Alastair T. Gordon, The Islet Foundation, Toronto, Canada
George K. Gittes, New York University Medical Center, New York, NY
Dale L. Greiner, University of Massachusetts Medical Center, Worcester, MA
Mark W Grinstaff, Duke University, Durham, NC
Peter Gruss, Max-Planck-Institute of Biophysical Chemistry, Gottingen, Germany
Philippe Halban, Centre Medical Universitaire, Geneva, Switzerland
Alberto Hayek, Whittier Institute, La Jolla, CA
Bernard J. Hering, University of Minnesota, Minneapolis, MN
Rosemarie Hunziker, National Institute of Standards & Technology, Washington, DC
Kanti Jain, The Rogosin Institute, Xenia, OH
Robert C. Johnson, Baxter Healthcare Corporation, Round Lake, IL
Judy Kapp, The Emory Eye Center, Atlanta, GA
Shaun Kirkpatrick, Sertoli Technologies, Inc., Tucson, AZ
Richard Klann, Encelle, Inc., Greenville, NC
Robert Lanza, Biohybrid Technologies Inc., Shrewsbury, MA
Tom Loudovaris, Baxter Healthcare Corporation, Round Lake, IL
Ole D. Madsen, Hagedorn Research Institute, Gentofte, Denmark
Douglas Melton, Harvard University, Cambridge, MA
Larry Gene Moss, Tufts New England Medical Center, Boston, MA
Ali Naji, University of Pennsylvania, Philadelphia, PA
Christopher Newgard, University of Texas, Dallas, TX
Mark Noble, University of Utah, Salt Lake City, UT
Jeffrey Platt, Duke University Medical Center, Durham, NC
Ray V. Rajotte, University of Alberta, Edmonton, Canada
Dr. Lola Reid, University of North Carolina, Chapel Hill, NC
Christopher J Rhodes, University of Texas, Dallas TX
Nora Sarvetnick, The Scripps Research Institute, LaJolla, CA
Rafael Scharfmann, INSERM, Paris France
David Scharp, Neocrin Company, Irvine, CA
George S. Simon, VivoRx, Inc. Santa Monica, CA
Patrick Soon-Shiong, VivoRx, Inc., Santa Monica, CA
Timothy Stewart, Genetech, Inc., South San Francisco, CA
Luc St-Onge, Max Planck Institute for Biophysical Chemistry, Gottingiem, Germany
Angus Thomson, University of Pittsburgh, Pittsburgh, PA
Anton-Lewis Usala, Encelle, Inc. Greenville, NC
Ivan Vacek, University of Toronto, Toronto, Canada
Taylor Wang, Vanderbilt University, Nashville, TN
Colin J. Weber, Emory University School of Medicine, Atlanta, GA
Gordon C. Weir, Joslin Diabetes Center, Boston, MA
Lisa-Anne Whittemore, Genetics Institute, Cambridge, MA
James Woodward, Encelle, Inc., Greenville, NC
Christopher V.E. Wright, Vanderbilt University School of Medicine, Nashville, TN
Tobias Zekorn, University of Geissen Medical School, Geissen, Germany