Senate Commerce Subcommittee on Science, Technology, and Space – Testimony by Robert A. Goldstein, MD, PhD

Date: 07/14/2004

July 14, 2004

Dr. Robert A. Goldstein, MD, PhD

Chief Scientific Officer, Juvenile Diabetes Research Foundation International

*** With Annotated Rebuttal by the Autoimmune Disease Research Foundation ***

Chairman Brownback and members of this Subcommittee, thank you for the opportunity to appear before you today to participate in this important hearing on adult stem cell research. I am Robert Goldstein, Chief Scientific Officer of the Juvenile Diabetes Research Foundation (JDRF). I am joined today by the Langbein family who represent the millions of families who struggle with the daily challenges and fears of caring for a loved one with juvenile diabetes. Jamie was diagnosed at the age of one, and she has been on an insulin pump since the age of four. Jamie’s diabetes affects her life every day, all day. Her parents must test her blood sugar eight times a day, and every time she eats, exercises, or goes to a birthday party, Jamie must account for what she eats or how much exercise she does and adjust her dose of insulin accordingly so she doesn’t end up in the hospital or in a coma. Her mom gave up her career as an attorney so that she could always be nearby if Jamie had problems with her pump or blood sugar while at school, and her parents get up frequently during the night to check her blood sugar level. Jamie worries about being different from her friends in school, and her parents worry about the long-term complications of diabetes and their daughter’s future and whether their other children will be diagnosed with the disease. This is just one child of the nearly two million people who battle juvenile diabetes each and every day.

JDRF is the leading charitable funder of juvenile diabetes research worldwide. Established more than 30 years ago by parents of children with juvenile diabetes, our mission is to find a cure for juvenile diabetes and its complications. Over the years, JDRF has provided some $800 million in grants for diabetes research at most of the world’s leading universities, laboratories, and hospitals. To fund that science, JDRF volunteers do their part every day to raise money in our communities across the country—through walks, galas, and other events—and we are proud of the strong partnership for funding research that we have developed with the federal government.

JDRF, as the world’s leading charitable funder of diabetes research, aggressively pursues all avenues of promising research and makes its funding decisions based upon vigorous scientific review based, in many ways, upon the NIH model.

[This “vigorous” review process missed the opportunity 8 times over 4 years to fund the underlying basic research that led to the first permanent cure of type I diabetes in the NOD mouse as well as the funding for the first FDA approved clinical trial to convert the science to a human cure.]

In the area of stem cell science, JDRF funds scientists exploring the opportunities created by both adult and embryonic stem cell research. In Fiscal year 2004, JDRF commitments in the area of stem cell research total $8.2 million. Of this amount, $6.3 million is spent in the area of embryonic stem cell research and less than $2 million is spent on other areas of stem cell research, including adult stem cells. We focus on both areas—as well as dozens of other avenues of scientific investigation—because no one can predict what area of research will produce new therapies or a cure for juvenile diabetes.

Adult stem cell research has been pursued for more than 35 years, and as you know, embryonic stem cells were just discovered in 1998. JDRF will continue to support both adult and embryonic stem cell research so that we can pursue a cure as strongly as possible. However, the research community believes that embryonic stem cells offer more promise in the area of diabetes. Let me explain why, using pancreatic islet cell transplantation as an example. Islet transplantation has been a spectacular breakthrough in diabetes research.

[There are many in the scientific community who do not agree with this statement, because until you stop the autoimmune process, these cells are also eventually destroyed. This is why several islet transplant centers around the US have had difficulty replicating the successes of the Edmonton Protocol and this has resulted in the closure of several islet transplant programs including the bulk of the Harvard Islet Center and the NIH Islet program. It is becoming increasingly evident that transplanted islets are still vulnerable to autoimmune destruction, in spite of powerful immune suppressing cocktails.

James Thompson, anatomy professor at the University of Wisconsin and a pioneer in embryonic stem cell research who created some of the federally “approved” embryonic stem cell lines, recently said: “There are significant safety issues with transplanting tissue from the lab into humans. We don’t understand how they might grow into cancer, for example, which is a theoretical worry” Instead, he said that basic science has to be conducted to understand (for example) why pancreatic tissue is killed by a diabetic’s immune system in the first place. Wisconson Technology Network 9-13-04 ]

In islet transplantation, the beta—or insulin-producing—cells are isolated from a cadaver pancreas and then infused into a person with juvenile diabetes through a catheter inserted into the portal vein of their liver. Once transplanted, these new islets recognize blood sugar levels and begin to produce and release insulin into the patient’s body. Islet transplantation had been attempted since the 1970s with limited success. However, in the year 2000, researchers made a breakthrough in the procedure, and since that time nearly 300 people have received islet transplants and the majority of them lead significantly better and healthier lives. In most of these individuals, therapeutic control of their diabetes has improved remarkably, and in many instances they do not even have to take insulin injections.

[The data indicates another story—May 20, 2004 (Boston) Medscape— Half of the 36 patients with type 1 diabetes who have received islet cell transplants under the Edmonton Protocol are insulin-free, researchers reported here Tuesday. (Reviewed by Gary D. Vogin, MD)

At the University of Miami, 14 of the 15 patients in a slightly different protocol were initially insulin-free, said Rodolfo Alejandro, MD. Thirteen patients received two infusions, and one patient received just one. But nine of the 14 patients had a deterioration of glucose control that required them to go back on insulin, Dr. Alejandro said. Two of those patients subsequently dropped out.

Enrollment in this phase I/II study ended in January 2003 and has now reached its goal of 36 patients, Dr. Shapiro told attendees. Nineteen of the 36 patients who have received transplants are insulin-free. Five of those 19 received one infusion, seven received two infusions, and seven received three infusions. Seven of the 36 are insulin-dependent; six patients had primary islet nonfunction, and four patients withdrew from the study. For those still taking insulin, there has been a decrease from 36 units at baseline to an average 21 units per day now, he said. For patients who are insulin-free, glucose control has been excellent, with fasting glucose and hemoglobin A1c levels within the normal range, said Dr. Shapiro.]

Furthermore, many of the patients have reported a reversal in some of their complications, especially hypoglycemia unawareness but also improvement in vision and less pain from neuropathy. These results are very exciting, but there are significant hurdles in moving this from an experimental procedure to a standard therapy that could benefit the millions of people with diabetes—many of them children. One such hurdle is the severe shortage of donated pancreases. In 2001, approximately 400 pancreata were available for islet transplantation and research, compared to the almost two million Americans with juvenile diabetes.

Here, then, is one reason why we are so excited about recent advances in embryonic stem cell research. Recent studies have demonstrated the ability to coax embryonic stem cells into insulin-producing cells in the lab. [Dr. Melton , although heavily funded by JDRF, disagrees with this characterization and believes that Goldstein and researchers advocating this are wrong. (WSJ 8-12-04]

We have good reason to believe that embryonic stem cells will one day be able to grow large amounts of insulin-producing beta cells for transplant, but more work needs to be done. [Despite all efforts to produce insulin-making cells in the lab Dr. Melton says he has failed. He is convinced it can be done, he says, he just doesn’t know how (WSJ 8-12-04]

Unfortunately, adult stem cells have not shown the same promise when it comes to diabetes.

[After the creation a embryonic stem cells over 20 years ago there is a paucity of scientific reports that mouse ES cells, as well as ES cells of other species, have a well established role in disease reversal in mice, let alone animals model of disease. Although this technology is “old” by scientific standards the paucity of data demonstrating merit of this technology is not a mark of strength, but rather of weakness in the approach. Furthermore, the scientific literature demonstrates the problem of tumor formation with ES cell lines.

A highly regarded and widely reported research team at Massachuseets General Hospital stopped the autoimmune process in the NOD mouse, the mouse’ pancreas was able to regenerate its islet cells, thus permanently curing diabetes. This regeneration used adult stem cells that appear to be ever-present in the pancreas. It took 40 days for the mice to regenerate their islet cells. In a study in a similar animal model recently conducted in Canada, it took only 14 days for the islets to regenerate. (Nature Biotechnology Volume 21;Number 7 July:2003) This would imply that the pancreas is constantly producing new beta cells that are then destroyed by the bad cells. In addition you can expect to see a flurry of new research confirming the existence and flexibility of adult stem cells].

Last month, Harvard University researcher Douglas Melton published a paper in Nature pointing out that in mice, new beta cells in the pancreas are formed through the replication of existing beta cells rather than through the differentiation of adult stem cells. This finding indicates that adult stem cells in the pancreas do not contribute to beta cell formation, and that embryonic stem cells may prove to be the only stem cells that will be useful to generate beta cells for the treatment of Type 1 diabetes. Other studies indicate that mouse embryonic stem cells can be differentiated into insulin-producing cells, and several studies suggest that this can be done using human embryonic stem cells.

[This paper by Dr. Melton confirms the opposite of Dr. Goldstein’s conclusion. Dr. Melton confirms that embryonic stem cells are not needed to replace islets. Dr. Melton’s paper shows that even in normal adult mice, without any diabetes and without any introduced fetal or adult precursor cells, pancreatic islets once again re-grow. This new work shows that even in non-diabetic animals the islets turnover and self-renewal occurs. Declaring having proved the negative—that these are not adult stem cells at work—is audacious given the preponderance of published data to the contrary.

Published research has shown that this re-growth occurred rapidly once the underlying autoimmunity was removed. In 2003 researchers went on to show that the once diabetic mice had at least two ways of re-growing the islets in the pancreas—spontaneous re-growth or re-growth promoted by a newly identified adult stem cell harvested from normal animals.]

JDRF funds research to develop beta cells from adult stem cells, or to regenerate beta cells from existing precursor cells. Researchers have reported that human adult duct tissue might have the potential to develop into beta cells. Other groups have results that indicate that transplanted bone marrow cells may be able to show insulin production. Some have used these findings to argue that adult stem cells may be the answer for curing juvenile diabetes. [As stated previously the cure of the NOD mouse demonstrates the opposite and the FDA approved clinical trial about to get underway at Massachusetts General Hospital will hopefully translate these results to a human cure.]

JDRF takes the position that research using both embryonic and adult stem cells, perhaps even in side-by-side comparisons, will get us to our goal fastest. [Why then not fund them proportionately?]

Mr. Chairman, adult stem cells may one day prove to be the answer to alleviating the pain and suffering caused by certain diseases—I certainly hope that is the case. We have heard some remarkable stories from some of the witnesses today. But we have no idea of knowing which diseases those may be, and unfortunately we are not certain of the widespread application of these treatments.

We do know that to date, adult stem cells have not been shown to hold as much promise for juvenile diabetes as embryonic stem cells.

[In a study recently conducted in Canada, it took only 14 days for the islets to regenerate after destruction of the islets.(Nature Biotechnology Volume 21;Number 7 July:2003) This result has also been seen in the autoimmune mouse model (Science Vol 302 14 November 2003) after the autoimmune process was reversed.

This would imply that the pancreas is constantly producing new beta cells that are then destroyed by the bad cells. Dr. Melton’s data also showed the pancreas “self-healed” with a 120 day time line.

To prevent the bad cells from being reproduced by the immune system, the procedure introduced normal immune cells, which then reeducated the immune system to stop making the bad cell. This resulted in 92% of more than 250 mice being permanently cured of type I diabetes. Their lifespan grew to 5—8 times longer than that of untreated mice. This reeducation process also works in humans who are critically ill with autoimmune disease and who have had their immune system destroyed with radiation. Normal (genetically) matched immune cells are injected, resulting in a healthy, immune system free of all bad cells (Arthritis Rheum 1999 Nov;42(11):2281-5). Hundreds more cites can be noted demonstrating the use of adult stem cells in human therapies]

Given this reality, how can we turn our backs on other exciting research opportunities, such as embryonic stem cell research, thereby potentially delaying life-saving therapies and cures for millions of people? And how can we adequately compare the effectiveness of adult and embryonic stem cell research unless both avenues are pursued simultaneously and with equal rigor?

We are in an extraordinary time of opportunity in the area of medical research, and this country is leading the way. Scientists around the world agree that stem cell research holds tremendous promise for hundreds of millions of people. I applaud you for continuing to monitor advances in the area of adult stem cell research, and I encourage you to do the same for embryonic stem cell research. For certain diseases such as juvenile diabetes, embryonic stem cells hold the most promise, and we can’t afford to lose any more time.

While we have made great strides towards our goal of a cure, more needs to be done, and we don’t have time to wait. Insulin is not a cure for juvenile diabetes, nor does it prevent the onset of complications such as kidney failure, blindness, heart disease and amputations. Diabetic retinopathy is the leading cause of adult blindness in the United States; ninety percent of patients have evidence of retinopathy after fifteen years of diabetes with approximately 25,000 new cases of blindness per year. Diabetes is also the leading cause of renal failure in the United States, accounting for forty percent of new cases per year. Greater than half of all patients with diabetes develop neuropathy, making diabetic neuropathy the most common cause of non-traumatic amputations and autonomic failure. In his or her lifetime, a diabetic patient with neuropathy has a fifteen percent chance to undergo one or more amputations. Mr. Chairman, in the battle against diabetes, we are in a race against time.

Not a day goes by that JDRF doesn’t receive calls or letters or email messages from mothers or fathers of children with type 1 diabetes asking “When will my child be cured?” On the one hand, it is extremely difficult to explain the pace of science, particularly to a mother whose five-year-old has to prick his finger six or seven times a day to test his blood sugar, who needs three or four injections of insulin every day, who is afraid to go to sleepovers or summer camp for fear of falling into a coma, and who is at constant risk of developing a host of complications that could cut short his life. But on the other hand, it is downright tragic to have to explain how the pace of science could be slowed even further by focusing on one area of research and excluding another.

To put the urgency of finding a cure into perspective, I’d like to share some words from Mary Tyler Moore, JDRF’s International Chairman, that she shared with Members of the House. Mary states that “in the nearly six years since human embryonic stem cells were first successfully cultured in a lab,…diabetes has contributed to the deaths of as many as 3 million people and cost our nation over $750 billion. It has caused nearly 500,000 amputations, rendered over 100,000 people blind, and forced a quarter million people to require kidney transplants or dialysis. And 120,000 moms have been told that their child has Type 1 diabetes—a disease which during that time period would require each of these children to have 8,700 injections of insulin and 17,500 pricks of their fingers to check blood sugar levels—just for that child to survive.”

Thank you again for the opportunity to appear before you today. I am happy to answer any questions you may have.

This testimony with the included rebuttals appeared first at