Dr Eli Lewis, professor of clinical biochemistry and pharmacology at Ben Gurion University of the Negev, a public research university in Beersheba, Israel, may have stumbled across one of modern medicine’s most enduring holy grails: a safe, effective way to reverse type 1 diabetes. Lewis’s research focuses on the tissue damage that plays a role in type 1 diabetes, and which he says is often overlooked and under-studied. Back in 2003, Lewis began researching the role of inflammation in injured islets – tiny clusters of insulin-producing cells in the pancreas – and the effects of transfusions of an anti-inflammatory drug based on a protein the body produces naturally all the time, known as Alpha 1 Antitrypsin (AAT, or alpha1). AAT has so far been used mostly only to treat emphysema, but Lewis’s breakthrough research shows the protein’s promise via transfusion in reducing insulin dependence in type 1 diabetics, and in some cases actually reversing the condition completely, if caught early enough. He believes it may help type 2 diabetes, again if the disease is caught early enough, and supported with lifestyle change, including keeping carbohydrates low, which he says is essential for diabetics.
Lewis describes AAT as a form of ‘immuno-modulation’, and says its application goes beyond diabetes: US researchers are currently studying inflammatory bowel disease in patients; bone-marrow transplant prognosis is ‘phenomenal’ with AAT according to a Seattle trial; researchers are testing it in ischemic heart disease for diminished cardiac scar size; and it shows promise in multiple sclerosis (MS). Other diseases in the pipeline for testing include lupus and rheumatoid arthritis, transplants of all kinds and even pig-to-human grafting experiments that are starving for a safe therapeutic to accommodate the grafts. Since his group is focused on the immune assault on cells, Lewis says they are limited in funding and scope, and are reaching out to collaborate with any group, ‘as long as it is as enthusiastic as we are’. Here Lewis explains how the therapy works for type 1 diabetes. – Marika Sboros
My guest today is Dr Eli Lewis, professor of clinical biochemistry and pharmacology at Ben Gurion University of the Negev in Israel. He is in the university’s clinical islet lab that is part of the university’s department of health sciences. Dr Lewis is a medical scientist who could be bringing the world closer to a cure for type 1 diabetes.
Dr Lewis, first of all tell me what’s a clinical islet?
A clinical islet is what you end up with when you have to name your lab in any way that’s relevant to your work,. I try to combine everything to we do into one title. So Islets are these little tiny spheres that you have in your pancreas making insulin.
I remember in biology at school learning about islets of Langerhans?
Those are the ones. Every person has in his or her pancreas one million of these spheres, one million islets. In them, most of the cells are beta cells that make insulin. It’s the only hormone that is able to lower glucose in the blood, the only cells that make it, and it’s the only location where they are placed.
So it’s a very dangerous entity when you consider that if you lose the beta cells for any reason, glucose will rise in the blood. It will just rise in the blood, that’s how it goes, no way to pull it down, there’s no other hormone.
Are we talking now about type 1 diabetes?
The state of art today is changing: Type 1 diabetes has been renamed type 1 auto immune diabetes to be more precise. It is an auto immune condition, you literally see int he blood circulating antibodies against the islets, against insulin. So it’s an auto immune condition. It used to be called juvenile diabetes, but we actually see it today also in adults and later on, patients engaging in with 1 auto immune any time in life, so it’s no longer juvenile.
So you mean type 1 diabetes can be diagnosed at any age?
Different ages, in some cases, after 30 years. The trigger can be one of many. We still don’t know what no longer what instigates the actual condition, but it’s no longer reserved only for kids.
In type 1 diabetes, the pancreas does not make any insulin at all?
That is what we call the end point of the disease, the point where the disease is called end stage, as if there is no next step for it. You basically lose a mass of viable cells.
For treatment, what patients have today, what caregivers have to offer is insulin. It’s basically that component that’s missing in the blood circulating. The therapy is roughly 100 years old. Unfortunately, since its discovery insulin in different forms, although there are different ways of introduction in actually fascinating technology advancements, it is still basically insulin. It is very difficult for us to manually know how much insulin you need at every moment, but it is helping the condition, it is treating the patients.
But what about the cells that have expired – that’s something that is not addressed today. What my works is trying to do over the past 10 years is to do deal not with with levels of insulin which can always be introduced, but with the actual disease, the death of the islets or their absence or function. Those are things I’m trying to alter.
You are trying to do that with this new drug – Alpha-1 antitrypsin (A1AT, aka AAT or alpha 1) – is it a drug? In your research you say it’s natural compound that occurs in the body?
Precisely. It’s a molecule, a protein. Everyone of us makes this protein, you and I …
And people with Type 1 diabetes?
Actually yes, they also make it, but there’s a point I’ll get back to in a second. We all make AAT in the bloodstream all the time. When we are sick, we make more of it. What do I mean “sick”? If you have flu, an infection, you feel horrible, inflamed, and the body makes more AAT in the blood. That has been known for decades; people have been measuring it; doctors have used that level of higher AAT as if it is a marker of whether or not there was an actual infection or disease.
But if you study it deeply enough as I have done for past 10 years, it turns out it actually has a function, and the body doesn’t just release it and increase the levels when we are sick. It does so on purpose appropriately so.
It’s one of a series of molecules we use to protect our tissues. Why do we need to protect our tissue when we are sick? Because the involvement of the immune system in correcting an infection, in clearing or decontaminating it, is very drastic. Our cells are very sensitive. The immune system has to use that platform of innocent, sensitive tissue to destroy bacteria, viruses, fungi, parasites, cancer cells, dead tissue
It’s a very drastic event, and while it happens, you want it to execute its full ability to decontaminate the area, but meanwhile the tissue suffers, actually endures a lot of inflammation, injury. It’s not the best way to go through illness.
At the point when AAT rises in the blood, it circulates in the body systemically, it reaches everywhere; some tissues – like the lungs and gut – make the molecule for their own sake. it helps to facilitate closing these micro wounds. It speeds up the wound healing process. It is anti inflammatory, so it downplays inflammation.
It allows inflammation to exist, but at a very low level. And when you are sick, your body enjoys this extra protection around the areas that are experiencing the immune event.
So what does this have to do with type 1 diabetes?
AAT has a very close relationship with diabetes. It turns out that circulating glucose levels, when they are high, actually stick to proteins. Some of your listeners may know about the measurement HbA1C – Hb for haemoglobin, A for adult, and 1C means it is coated with glucose. It’s actually stuck to glucose.
Everything in the blood gets coated with glucose in diabetes, both type 1 and type 2 diseases. When it is coated with glucose, even albumen gets coated with glucose, everything you put in a glassful of glucose over time will be coated. You don’t need enzymes to do that.
For AAT, this means it becomes inactivated. It has been shown for the past almost 20 years, that what levels of AAt the body makes becomes inactivated in diabetics; it’s not functioning.
In clinical trials we have been running, trying to see if AAT infusion may alter the disease, the first thing we found (with patients) was when they came in, they had an inactive form of AAT.
The form of AAT you are giving type 1 diabetics via transfusion – is it natural or synthetic? It would have to be what you call exogenous?
Exogenous, but luckily it is purified from plasma. So we are basically introducing the native molecule that is in the plasma.
Apparently the companies that work with blood products share – I learnt this recently – 50 000 litres of plasma globally. They extract human albumen, human anti bodies for medical purposes, and AAT enjoys this extraction. It is purified and bottled up, and the reason they do that has nothing to do with diabetes.
We came very late with the concept we have (on AAT for type 1 diabetes), before we knew about the advance (for its use) in another disease.
Which disease is that?
It’s called A1AT deficiency. It has been with us for quite a while. Medical textbooks will have half a page on it, showing that if you have less than normal AAT genetically, it turns out that it is slightly mutated; instead of being produced and released into the blood, it is just produced and stuck in the cells.
For those individuals, that doesn’t change much until they develop lung emphysema – the breakdown of the lung walls; also they endure more inflammatory bouts, vasculitis (inflammation of blood vessels), things like that , from having lower levels of AAT.
So AAT can be used to treat emphysema?
At present, that’s almost the only indication. But we feel lucky because for the past 30 years it has been bottled up on the shelf exactly for this rare condition – around one in 10 000 individuals roughly will be diagnosed with A1AT deficiency. They are eligible for AAT infusions
For us, it’s wonderful, when you consider that we have a drug or regimen to give to people, including children, maybe for life, men to give to kids, and who knows maybe, for life, you are not sure. Ten years ago we decided to adhere completely to testing on safety and feasibility on a drug that is identified already as usable and clinically safe.
How long would it take to reverse type 1 diabetes using this drug?
We have a lot more experience now than we had before. At the time we started testing AAT infusions in patients, it took a very long while to identify the window of opportunity. We had no idea how long we would need to administer the infusion. In pre-clinical studies, in the early years of intensive experiments in animal studies, we discovered that it takes a few weeks at least for the immune system to alter for the better. It can’t be done overnight, or a week or two. It needs four weeks at least in mice and rat models.
But if it’s animal studies, particularly in rodents, you can’t generalise to humans?
Will you be doing human trials soon?
Oh yes, the next trial is running already – one at Ben Gurion University, two others currently recruiting in the States; we have several teams in multi centre working on it.
This is really revolutionary! Is your hypothesis that this will be a long-term cure, or you don’t know that at this stage?
We don’t know exactly. The longest we have followed a patient that has been treated for a while with AAT, is eight years. That is in a child who was for eight weeks, and still has no need for insulin. He is still making his own after eight weeks of infusions.
But that said, we still have to find the best window opportunity for each patient. We are not sure. We are thinking that it is very close to that close to time of diagnosis, so that really doesn’t help those who are years down the line with the disease.
All clinical trial will usually always recruit individuals who are soon after diagnosis, as that it the dynamic point of the disease. One clinical study of 59 patients showed that all started to make their own insulin after receiving 37 weeks of A1AT, so it could be that the longer the better. But we never knew at the time, so we could afford to try it for a few weeks and then stop.
But also, every type 1 diabetic is slightly different. It depends on at what age the patient gets it, the age of onset, the patient’s background, level of antibodies that goes up and down, other diseases that may be present. So we don’t think this will be a uniform, mass treatment. Type 1 diabetes is a disease that deserves to be individualised.
Yes, personalised medicine is proving to be the way to go, and also I presume, supported by lifestyle change?
That is always in the background – one of things that I strongly support. I turn to parents all the time, and say they have actually have a lot more information that all the medical groups put together. When parents have a child who is type 1 diabetic and the years go by, they individually calibrate what ’s good for the kid, what’s not good for the kid, what aggravates the condition what fits well. They know best.
There are no two kids who get the same diet, but the longer the parents follow what works, the better they fit the diet to their kids, when the kids grow up they follow this on their own. They are very responsible individuals, very aware of themselves.
Do you have any thoughts on the role of carbohydrate in the diet for diabetics?
Oh yes, completely! In diabetes, the pancreas in this disease is suffering an attack, an assault; the pancreas is injured. These spherical entities, the islets are actually destroyed by high levels of glucose; they are sensitive in ways that mean they can actually expire if someone has a lot of glucose.
Carbohydrates – consider them macromolecules of a lot of sugar – actually load a burden on anyone, but especially someone with type 1 diabetes. Carbohydrates force the pancreas to work harder. I will never say something like reduce (carbohydrates) to zero percent anything. We have never been designed to survive on earth with diets that contain zero percent anything, just moderation and common sense.
It make intuitive sense to keep carbohydrates down.
Can AAT treatment help type 2 diabetics as well?
Great point! First of all, you have to consider that what we sit upon here, this molecule, and shedding light on a particular juncture in immunology, is not necessarily completely restricted to type 1 diabetes. That’s because there is an interface where inflammation, immune cells and suffering cells meet. AAT disengages some of those vicious cycles that tend to aggravate themselves.
First of all we have to consider other immune conditions. There is some evidence that AAT infusion can help to deviate the course of multiple sclerosis (MS). That’s an exciting (avenue of research), as my mother suffered from MS. It was from a pre-clinical study done between our group at Ben Gurion University and (US scientists) in Portland. Can I take half a minute here to tell you what it means to be a researcher?
We shipped over shipped over those special animals that make human antitrypsin to Portland for them to study MS, because that’s their specialty. I work on diabetes, they work on MS.
The first phone we got was two days after the beginning of the experiment and they said: “It’s such a shame, we had so much invested in shipping the mice and coordinating (the trial), but you should know they all got MS, they all entered the disease just the same way as the others.” That was disappointing, but you live through it.
After two days they called again to say: “Prof Lewis, they all recovered and the other mice continued to get paralysis and died.” I still get chills thinking about it because of what the other mice did in this treatment – the disease did have one step forward to act, but having so much AAT, it regressed,
That’s what we actually think the body is doing when it normally makes more AAT: it’s part of speeding up wound healing when there is an event.
It’s really hard for me to give seminars to clinicians on this subject, especially, there are no side effects to this molecule at the range we are considering, and at the duration, definitely.
People until now have taken (AAT) for life and at higher doses. (For diabetes), we mimic those doses and limit treatment for several weeks. Safety is no issue, absolutely. In fact, even the FDA (Food and Drug Administration, the US regulatory body) immediately approved phase 2 trials of AAT in patients. There was no need for toxicology trials, because everyone knows if a healthy person gets it, nothing bad happens.
That’s impressive, but clinicians find it hard to accept. It is hard to accept, I agree. You would want to know what happens long-term, after many years. Well, these patients have been followed for 13 years, 25 years on A1AT infusions. That’s vey long-term for weekly infusions.
And we do know that if anything, patients have lower infection rates, and lower cancer rates than normal populations. Because they are being treated all the time with A1AT, their bodies are basically submerged in this mode where their immune system is functioning but their tissues are protected. That mode is very precious
So this is one of the holy grails of modern medicine – a cure for diabetes, but not only for type 1 diabetes, as it has many other applications?
You mention type 2 diabetes. When it is diagnosed, it is in many ways worse than type 1, because the patient has probably had type 2 diabetes for more than 10 years.
Type 2 diabetes is heavily underdiagnosed, and goes undetected for a very long time. Usually if you ask type 2 diabetics what happened that they were diagnosed, it could have been a routine check up at work, and suddenly their glucose levels were very high. All that time A1AT is neutralised, inactivated, hard to control, in people whose lifestyle is pretty much fixed.