By: Scott R. King
Mr. Metabolism has received numerous questions concerning the first human clinical trial of encapsulated islets announced on the CBS Evening News Thursday, May 13.
He answers them below.
Q: How long has the patient at St. Vincent’s been off insulin?
A: The patient at St. Vincent’s has had a reduction in the insulin required of 4/5, but is not off insulin.
Q: When will the patient be off insulin?
A: News reports mentioned that the goal is to wean him off over a period of weeks. This is normal in islet transplants; studies have suggested that islets do better if they are helped along by injected insulin as they engraft-that is, as they learn to function in the new host.
Q: When can we be sure that these islets are really functioning well?
A: Most workers in this field would consider six months off insulin a good milestone. At that time, you would want to see the results of a glucose tolerance test to see how well the patient’s implanted islets handle a glucose load (that is, after all, how diabetes is diagnosed). The glucose tolerance test would not only tell you whether the islets are functioning, but whether they secrete insulin at the right rate-that is, what researchers call normal kinetics of response.
Q: One thing that seems to be new is that the islets were “encapsulated.” What is this?
A: The idea is that islets, like all foreign tissues, are rapidly rejected if implanted with no protection. It is necessary to provide a barrier to prevent rejection. But this barrier must be permeable so nutrients and glucose can get to the islets and secreted insulin can get out, but must prevent white blood cells and antibodies from passing through.
Many immune barriers have been developed. The material used in this experiment was first used over fifteen years ago. Recently chemists have succeeded in modifying the material so as to reduce fibrosis, the process of “walling off” a foreign object (like a splinter). In fact, Italian researchers have previously transplanted islets in a similar capsule without success (R. Calafiore, ASAIO Journal 38, 34-37, 1992). They did so in a vascular graft rather than in the peritoneal cavity.
Q: What exactly was implanted?
A: Pea-sized spheres of alginate (a polymer derived from seaweed) and other materials. The capsules appear in the photograph to be on the order of 5 millimeters in diameter. An islet is usually about 150 micrometers (15/100 millimeters) in diameter, thus each capsule could hold about 37,000 islets. The entire volume of islets implanted (680,000 islets) could have fit in 20 capsules. In the photograph there appear to be over 100 milliliters of pea sized capsules. They were placed in the peritoneal cavity, the space surrounding the abdominal viscera (the intestines, etc.).
Q: How can the islets function in such a huge sphere?
A: It is hard to see how they could. Islets normally have blood vessels flowing through them; encapsulated islets do not. They depend on diffusion to supply their nutritional needs, a much slower process. Studies have shown that oxygen can effectively diffuse only 200 micrometers (0.2 millimeters) or so into capsules. Based on these studies, one would expect that the outer shell of the spheres would contain functioning islets, and that as you moved into the interior of the sphere the islets would be more distressed; the ones at the center of the sphere would probably die of starvation.
Q: How is rejection of whole, transplanted organs prevented?
A: With drugs that suppress the immune system.
Q: But didn’t this patient already have a kidney graft from five years ago?
A: Yes. Therefore he is immune suppressed or he would reject the kidney. These drugs are used in high doses at the time of the organ transplant, then cut back. But they are used at low levels for the rest of their lives.
Q: Wouldn’t the immune suppression that allows the kidney to function also prevent rejection of the islets?
A: That is correct. In fact, in all of the successful islet transplants done at St. Louis, Pittsburgh, and Edmonton, the main center of islet transplant research, the patients also had other transplants and were immune suppressed.
Q: Are these immune suppression drugs safe?
A: These drugs are quite toxic, and
even when given at maintenance doses long after the transplant, they must be carefully monitored. Most doctors believe that the effects of these drugs are worse than the consequences of normal insulin therapy, so they do not believe that islet transplants can be recommended for people with diabetes who have not received kidney transplants.
Q: So this procedure could not be used on the vast majority of people with diabetes who have not had kidney transplants?
Q: But wasn’t the procedure proven in animals?
A: Partially, but the animals were immune suppressed. The press release mentioned five dogs that had been transplanted. According to the previously published reports (P. Soon-Shiong, et. al., Cell Transplantation 1, 173, 1992), these dogs had “spontaneous” diabetes. This is unusual; other researchers in this field do a total pancreatectomy (removal of the pancreas and its islets) to assure that the animal is completely diabetic-such dogs never recover from their diabetes. In addition, these dogs were treated with immune suppression drugs. Four of the five dogs required repeated implants of the capsules to maintain normal blood sugar. One has lasted over two years with a single transplant.
Q: Even so, isn’t the use of a capsule to control diabetes a breakthrough?
A: Actually, other researchers have achieved reasonably good control in dogs using similar spheres made with a different chemistry (R. Lanza, et. al., Diabetes 41, 155A, 1992). And these dogs were not immune suppressed.
Q: Why did they use human islets in the human patient?
A: Human islets are less likely to be rejected by a human than animal islets.
Q: Is it difficult to get to get human islets?
A: The availability of human pancreases is so limited that only a few thousand people with diabetes could conceivably be treated with them per year.
Q: Would this encapsulation procedure work in fully immune-competent humans receiving animal islets?
A: Since the relevant experiment in dogs has not been done, there is no way to be sure.
Q: So is this really a breakthrough?
A: In the opinion of Mr. Metabolism, there is no significant aspect of this experiment that has not been done previously by other researchers either in humans or in pancreatectomized dogs.
Q: So why did this transplant make the national news when this other work did not?
A: Other researchers in this field publish in the scientific medical literature to allow other scientists to review and duplicate their work. These results were announced by press release before scientific publication.
Mr. Metabolism (aka S. Robert King) has a masters degree from Harvard in biochemistry and is a former biotechnology analyst with Montgomery Securities. Besides having type I diabetes, Mr. Metabolism is currently vice president in charge of technology for Metabolex, a biotechnology research firm in Hayward, California.