The Latest Tech in the Struggle to Cure Diabetes: An Interview with Dr. Eli Lewis
The Latest Tech in the Struggle to Cure Diabetes: An Interview with Dr. Eli Lewis
April 16, 2010
Introduction To This Interview:
I wish to thank Dr. Lewis for taking the time from his breakthrough research work in diabetes I, and islet transplantation therapy to speak with me today. Dr. Lewis is the Director of the Clinical Islet Laboratory and senior lecturer in the Department of Clinical Biochemistry at Ben-Gurion University of the Negev in Beer Sheva, Israel. Dr Lewis received a PhD, summa cum laude from Ben-Gurion University and accepted a post doctoral fellowship from the University of Colorado Health and Science Center.
He has published in peer- reviewed journals on diabetes the disease and his own studies using alpha-1-antitrypsin (AAT) monotheraphy. He has proven that eliminating inflammation is the key to pancreatic islet Beta cell survival and the restoration of normal glucose levels.
Dr. Lewis also serves as the coordinator for the BGU School of Medical Lab Science and is the recipient of many awards, citations and fellowships. He has been invited to lecture at Oxford, Harvard, Haddassah Medical Center, The Weizman Institute of Science and medical centers in Baltimore and Washington, D.C. He is an advisor for biopharmaceutical companies and is an active competitor for research grants.
Dr. Lewis has received a five-year award of $750,000 from the Juvenile Diabetes Research Foundation. JDRF is the worldwide leader in funding research to cure type I diabetes. In March of this year JDRF and AABGU co-sponsored a lecture entitled “Breakthrough for a Cure” with Dr. Eli Lewis. The event was held at the Hilton in Arlington, VA. This informative lecture provided an opportunity for me to meet Dr. Lewis and request this interview.
Dr. Lewis your study treating diabetic mice with alpha-1- antitrypsin (AAT) following an islet transplantation has aroused the interest of the medical community worldwide. Diabetes is a disease that occurs when the immune cells destroy pancreatic insulin production. Your research is demonstrating that islet survival and islet restoration in diabetic pancreas can return the pancreas to normal function. What is an islet and how can its malfunction cause insulin resistance?
When one uses the word ‘diabetes’ he/she should realize that the term will merely describe excess glucose in the blood. But we encounter two diseases that result in this injurious phenomenon. Juvenile diabetes, or type 1, is the one where there appears to be an immune attack on our cells that produce insulin. These reside in the pancreas in specialized areas called the islets of Langerhans. The disease indeed strikes at a young age, anywhere from half a year to teenage, yet we also find cases that surface as sudden as ever in adults.
Then there is the other type of diabetes, type 2. In this case, the disease is much more prevalent, in fact we’re talking about 10 time more frequent. The pancreas is apparently uninvolved in the cause of disease, or at least that’s what was thought until recently. Because in this disease, insulin circulates the blood but fails to work. You must understand that for insulin to function, a whole set of molecules must be at its command throughout the body, and when these refuse to respond to insuliln, as in type 2 diabetes, we encounter insulin resistance.
Now the latest thing that came to our awareness is that islets might actually be involved in the progression of type 2 diabetes. One theory has it that they actually begin by generated distorted insulin secretion patterns, and thus promote a reflex of resistance in the periphery. We still don’t know, but we do know that many genes that were associated with type 2 diabetes have to do with islet function. Now you can appreciate that in both type 1 and type 2 we are helpless in the face of rising glucose levels in our blood. Islet transplantation, in the case of type 1 diabetes, is the closest way to replace normalcy in glucose control, as insulin injections are still far from completely correcting patients’ blood glucose levels.
Insulin injection and islet transplantation have been the standard treatment approach to date. However, five-year follow-up studies on islet transplantations have recorded many failures. The Science Daily quoted you saying ”We have found that by targeting multiple inflammatory molecules using a safe non-toxic and non-steroidal drug, we can block inflammation so effectively that we literally modify the immune response, facilitating transplant acceptance to treat diabetes and those at risk”. Please explain why you suspected inflammation to be the problem and what is meant by modifying the immune response?
That’s an excellent question. Especially in these days when the molecule related to Aspirin, salsalate, showed promising outcomes in diabetes based on being merely an anti-inflammatory drug. This, by the way, after Aspirin itself was shown to be beneficial for diabetes patients in a paper published in 1876. To best answer the question, I must bring you to pace with the meaning of the term inflammation.
Our cells interpret their environment using molecular tools that have been sculpted over many years to enable us to survive. As such, we can sense danger, damage, injury, infection, stress, extreme conditions and so on, and readily respond. Why the term inflammation? Becasue many times, when a signal for danger is picked up by our cells, they respond by amplifying the message, so as better and more efficiently recruit the immune system. The message sent is, appropriately, perceived as danger. So, the outcome resembles the spread of flames: from a center of damage outward, the environment trasnmits signals like flames through dry weeds.
This is supposed to be a flawless design of nature and allow the correction of erroneous conditions. For example, a bacteria will be readily rid of in this way. But when things this primitive are mishandled, we get into trouble. Chronic stress was never the case in the evolving multicellular organisms, as were some toxins, habits and environments. Thus, our systems detect danger, and respond to it, at times, even though uncalled for.
When research teams grafted freshly isolated islets into diabetic recipients, 60% of the islets were lost withing less than 48 hours. This time frame is too short for the immune system to determine that the graft is foreign. Rather, it is identified as injured, and rightfully so; the cells are beaten-up pretty roughly in preperation for engraftment. Even if they were not, consider they came from a brain-dead donor, at a point of organ harvest which is low in the list of priorities, way after heart and lungs are harvested. This is by all means stressful for the cells. Stress, that spreads as inflammation upon impact with the recipient.
Since standard immunosuppression appeared to fail in the follow-up that ensued after islet transplantaion, and since this cocktail of drugs was lacking an anti-inflammatory aspect to it, we hypothesized that targeting inflammation was logical. This, while avoiding steroids, which would provide a great answer to inflammation but would also carry the risk for diabetes. Now, after our work bravely placed this concept on the table, so to speak, more and more groups are finding that inflammation stands at the point of decision for the immune system to attack, or to accept.
Several weeks ago I asked you to itemize the most important elements in securing a cure and in the delivery of the best diabetic treatment. You mentioned regenerating of existing islet cells, identifying behavioral predisposition of islet to destruction and targeting molecules aside from T cells that orchestrate damage. Please elaborate on these and other elements you see as important.
There are too many elements left unturned in this fascinating area of medicine. The reason, to my opinion, is not one but several. An important aspect is the underappreciation of the connections that occur between branches of our immune system. For example, people who work on T cells would, understandably, invest a great deal of research into this cell type, analyze all that can be analyzed and try to produce the best understanding of what it does and how we can control it. Yet, a separate group would study inflammation, develop their own systems to figure out what goes on during an inflammatory response and elaborate discussions around their world of findings to facilitate a better grasp of things.
What do you think happens when group 2 suggests that one of their molecules affects the entire system that is the domain of group 1? Some conflict is stirred, by simple laws of human nature. To bridge these gaps it took some courage and persistance. In our work, we prove that our molecular approach is completely absent of any direct effect on T cells. We can block inflammation, and in the presence of the same molecule T cells still proliferate, respond, secrete and kill. But we do absolutely affect the inflammatory system, and the outcome is protection from graft rejection, a pure textbook T cell process. Therefore, we pretty much prove that one system relies on the other. Two categories unite.
During the same years, many other molecules have surfaced to our awareness as being mediators of inflammation, in which they would link an infection to a response, and also link tissue damage of our own source, not foreign, with a similar aggressive response. Suddenly diseases such as autoimmune diabetes and other immune disorders expose a volnerable target site for clinical intervention. An islet will shut down during injury, and soon after start the process of death; this appears to precede the entry of a T cell to the site and is therefore worth addressing, more than blunting all T cells from proper function. Why do the islets undergo such damage in the begining of the disease to begin with is still to be discovered.
The Harvard Medical School in Boston, MA tested your hypothesis that inflammatory mechanisms trigger the destruction of insulin producing Beta cells. They supported your findings and sited that AAT actually increased the functioning mass of Beta cells and remarkably restored immune tolerance after AAT was removed. They were astonished to find this was possible. Do you believe that the ATT- curative treatment response will be permanent or is there still research that needs to be done?
Oh there is a lot of research to be done. First, we must recognize that all research is rather limited, to some degree, in the sense that we can only describe what we measure. For example, take a mouse and cure it. This still doesn’t mean you can take an 8-year old kid and cure him. So the group in Harvard took another path to test our findings and they used a different mouse model. This is great, as the findings that remain consistent across two models are stronger than one. But our model and their model are both deficient, they both are not really an exact replica of the human disease. They get close to it, but are not perfect.
For example, someone counted almost 500 positive outcomes in the Harvard model, and only a handful resulted in positive outcomes in humans. The problem with a good animal model is, quite unexpectedly, not the research group, but rather the lack of current knowledge pertaining the disease itself. If we knew what caused diabetes, and what the processes that take place from day 1 of disease, not day 1 of presentation of symptoms, which by the way might be years apart, then we can have a good starting point for generating a proper animal model. So we do with what we have.
For this, I feel safe that our choice began with human material given to humans. Naturally occurring, safe for use for more than two decades at high doses, with no side effects. Is it lacking in the diabetic patient? Yes. How does it work? We don’t know. Several arms of study are being undertaken, as we try to understand what our approach has achieved on a more specific mechanistic level.
For example, what is its effect of this molecule on various cells of the immune system? What parts of the molecule are required for function? What is it doing to islets and what is it doing to insulin activity? We do have hints for Beta cell expansion. We definitely have more idea of the immune system’s behavior in its presence. But all these are still being studied and the road is long before we know exactly how this naturally occurring molecule allows the islets to survive and function in a hostile host. By figuring this all out, we increase the chances of fine-tuning the approach until we can provide a permanent cure.
The Harvard study highlighted that ATT restores insulin signaling and that T-cells were converted to protective Treg cells. What does this transformation mean? How are Treg cells proactive in the cure for diabetes I?
You actually mention a pivotal player in the game. Both Harvard and us soon identified the involvement of protective T regulatory cells. A while ago, these were known as T suppressor cells. Turns out our T cell repertoire contains not only aggressive T cells, the ones you count-on to combat invaders, but also so to speak good T cells, that hold the same capacity for identifying molecules, but spread anti-inflammation rather than damage.
As these cells were recognized, researchers realized that they in fact exist throughout life as protectors of our own self tissues from our own self T cells. In fact, in some autoimmune diseases, a drop in their levels was associated with disease severity. Thus, diabetes patients also benefit form Treg expansion. How does this fit with our treatment? Well the body doesn’t just generate these cells for no reason. I wish I knew exactly what determines their elaboration, but some parts are well established. For example, an inflammatory state counters their differentiation. So, it was very easy to explain how they started to rise as we introduced our anti-inflammatory therapy course.
This is an ability that’s good for diabetes in many regards. For one, islets are being attacked during diabetes and we need to help Tregs do their job. Two, an islet graft is being attacked by host T cells and again, we need to block these from reaching their goal. Three, and perhaps the most important of all, Tregs are the only approach known today that enables antigen specific immune tolerance. This is a term that holds great meaning for the transplant community; blocking T cells from working is easy. We can irradiate, give chemo, this is not the challenge here.
In fact, a European clinical study showed improved outcome for diabetes using cyclosporin A, an immunosuppressant. But the side-effects were too harsh and the study was terminated. Tregs, on the other hand, are capable of being specific protectors. So with proper use, you can have a fully funcitoning immune system, plus a protective population of Tregs, and you’re free to go home and not carry a high risk for infections.
Indeed, in our studies, Tregs increased in numbers, accumulated at graft sites, and were also responsible for long-term protection after therapy withdrawal. No other immunesuppressive regimen can do this so elegantly at this point in time, or at least be as feasible and available as the one we found to work so well.
The Islet transplant procedure that you developed is remarkably safe. It requires no-organ related transplant risk such as those from surgical procedures, excessive immuno-suppression nor CMV transmission. It appears amazingly simple. Please describe the actual step-by-step medical procedure. How many days will the patient be in the hospital?
Well first of all we didn’t develop the procedure, it was a long process that began before the year 2000 by very fine teams with great foresight. Then a group in Canada perfected the method to the degree that they were actually approved to do a trial, and they rapidly published the initial findings, which were seven out of seven patients being insulin-free after transplantation. By now there are many centers around the globe that carry out the procedure. When a donor is found, the pancreas is transfered to a unit where it undergoes the process of islet isolation.
Basically, the organ is first digested by an enzyme to break away the non-endocrine parts, and then the islets are collected and inspected for yield and purity. This takes several hours. The FDA provided clear guidelines for the degree of islet purification that can enter a patient. If an islet isolation team reached anything inferior to this, the islets go to research. Now comes the diabetic recipient, a candidate in a list of standby patients. A rather non-invasive approach is performed by which the islets are released into the patient’s liver by injection. Being local, the patient is not under full anesthesia, but rather under local anesthesia.
Once the islets are fully embolized into the small spaces that exist in the liver, the patient is free to go. In the background, he or she are given immunosuppression, and a follow-up is initiated to test for islet function and for drug toxicities. The cost of this procedure, surprisingly, is not so much the act of administering the islets, but more the accompanying therapy, which is at times twenty pills a day, a follow-up and multiple lab tests. So yes, it is amazingly simple, but still imprefect as far as the therapy is concerned.
The choice to deliver the cells in this particular way is actually part of the breakthrough. Why is that? See, a diabetic patient will always have the option of injecting insulin. Why would a mother allow her kid to undergo surgery and receive immunosuppression, when he can go through life with insulin. So the first seven patients were chosen for being extremely poorly controlled, and thus the procedure was relatively and comparatively safe.
I must add though that the choice of the liver is not ideal, as it is a violent environment for islets to get lodged in, but at least it allowed this increadible breakthrough to occur and push this field to great advances. In some conferences people bluntly admit that it probably won’t be the site of transplantation in the future.
A key element in any medical procedure is cost. It can severely affect the income and savings of people suffering with diabetes. Bankruptcy due to illness is too common in these times. Efficient, competent and cost effective treatment for diabetes is essential. Dr. Lewis your islet transplant procedure does just that.
The drug cost in a traditional transplant runs approximately $50,000 dollars per patient. The new islet transplant brings this cost down to $5,000 dollars. That is remarkable. Can you explain how this is achieved? Do you feel that there can be more cost reductions possible?
Well the numbers are very roughly rounded, I must say, but the jump in cost is definitely there. I mentioned before that the procedure itself, up to the point of islet introduction into the patient, is only a small part of the cost, which is significantly inflated due to drugs and related follow-up tests. We still haven’t determined how many weekly injections are required, we’ll know more as the studies advance.
But the fact that the drug is not as expensive as the others, and is not administered as frequently as the others but rather once a week, and considering that there will not be the need for many other accompanying drugs that are added secondary to to immunosuppression, such as antibiotics and anti-fungals, and considering that the follow-up may be reduced in expanse so as not to require liver scans and kidney function tests, the cost falls to a much more manageable range. This translates into a greater numbers of patients per trial and thus a greater chance to reach conclusions fast and optimize therapy.
Your work is primarily with diabetes I, yet it has been noted that “50% of patients with Type II diabetes can also benefit from your approach”. The focus of diabetes II rests on the function of the insulin in the peripheral cells not the spherical cells of the pancreas as in diabetes I. The Human Genome Project identified 27 genes associated with diabetes II and of these 27 it was determined that 18 were islet function related. Do you think your research can benefit patients with DII? How?
Many studies spurred after we published this association between the benefit of the naturally occuring molecule and diabetes. One such study was held in Sweden, where they established that 50% of type 2 diabetes patients have below-normal levels of circulating alpha-1-antitrypsin. Also, the Harvard group had one finding that supports this to be true in mice. It appears that in many cases of type 2 diabetes, inflammation is a prominent factor, enough to alter disease course when removed. To test this directly we will need the type 2 study to begin, but it’s still in the planning.
Because AAT is already an approved drug FDA has moved rapidly in support of human clinical trail for your procedure. Trials are scheduled to begin this year. However, FDA has decided to add a group to the study. What does this mean and how will this effect results? Do you feel it is necessary?
I have great respect for the work of FDA, it is a vital aspect of everything that we translate from research into the clinic. You can’t imagine the optimism and motivation I have and my students have as we unfold more of these findings, if it were up to us, each phone call from each family that finds us would grant the patients an immediate positive reply. That’s what the FDA is for. Here, we designed the trial with an initial dose that was slightly higher than that reported until today, arguing that we feel the impact would be greater on disease. Noticing this novelty in dosing, we were advised to add an arm which verifies that this is OK and in paralel add specific follow-ups to answer to concerns of dose-related effects. This is understandable and luckily not a great hold-back.
In scientific terms, we must remember that this molecule circulates our blood system at a concentration range of 1 to 6 mg per milliliter depending on the state of the individual; the therapy still does not reach these levels, so we are confident that we’re good to go. The molecule falls into a rare category that seems more and more attractive as research advances, that is, a group of protective moelcules that the body makes, but not enough, and not long enough. Add them, and you gain the benefits with a remarkable safety range.
Thank you Dr. Lewis for speaking with me today.