I first became aware of the work of internationally acclaimed neuroimmunologist Professor Dimitrios Karussis and his colleagues some years ago, when discussing research into possible treatments for multiple sclerosis with a friend who had been diagnosed with the disease. More recent reports of astonishing results of a clinical trial using stem cells in patients suffering from amyotrophic lateral sclerosis (also known as Motor Neuron disease and Lou Gehrig’s disease) and multiple sclerosis (MS), prompted me to seek out the Greek-born scientist. I wanted to find out just how close he really is to proving a revolutionary treatment that not only may stop the progression of these until-now incurable neurological diseases, but even reverse some of the damage and debilitation already caused.
From a modest set of offices and laboratories at Hadassah, Karussis and his small team – which includes fellow Greek-born neurologist Dr. Panayiota Petrou, and Dr. Ibrahim Kassis, an expert in tissue regeneration and mesenchymal stem cells – working in collaboration with the Israeli biotechnology company BrainStorm Cell Therapeutics, are causing many in the medical world to take notice.
A clinical trial in which the patient’s stem cells are removed from their own bone marrow, cultivated under laboratory conditions, then returned to the patient by intrathecal injection, has shown significant indications with a number of patients, including some whose previously disabled limbs have recovered to a point that was scientifically unimaginable even a couple of years ago.
One of the subjects of this latest clinical trial, who suffers from primary progressive multiple sclerosis and in recent years had become increasingly challenged by his growing disability, spoke exclusively to The Jerusalem Report on condition of anonymity, citing medical privacy.
Now in his late 40s, the dual Israeli-British passport holder and a former marathon runner had sought help from many sources to fight MS, but had been told in Britain that “they had nothing at all to offer” other than a little help from speech and physical therapists or cholesterol tablets. There was nothing that could be done to help stem the progression of the disease that made walking increasingly challenging, and caused the once capable athlete, who despite his deterioration continued to push himself to run, (albeit much slower and with obvious disability), to fall on a regular basis. He can be referred to as “D.”
D was accepted for Karussis’s current clinical trial, and within 24 hours of having the first set of his own adult stem cells injected back into his body experienced something extraordinary.
“The day after [the treatment], a junior doctor asked me to lift my leg up in the air. Normally, she would put her little finger on my leg and it would fall back onto the couch, but I could actually keep the leg up on my own. I remember her leaving my room and I just cried. I never cry, but it was the realization that this treatment appeared to be working. I was able to achieve resistance because my muscles were working again. Seventy-two hours after receiving the treatment, I went for a run.
“Prior to the treatment I had run around three kilometers, but was quite slow and disabled,” D continued. “Now, I was able to run five kilometers, quite happily, with minimal disability. But, more than that, after my five-kilometer run I went for a seven-kilometer walk! I could not believe it. It was just unbelievable how fast the change had been brought about. I can say now, many months after the first of the two treatments I have received, that not only has the progression of my MS been stopped, it has been reversed and taken me back to where I was around seven years ago.”
ADJACENT TO Karussis’s desk at Hadassah is a plaque bearing a quotation from Hippocrates, the 5th century BCE Greek physician whose teachings are encapsulated in the Hippocratic oath by which medical practitioners for centuries have pledged to do all they can to heal the sick.
Hippocrates’s ancient teachings are clearly central to Karussis’s modern-day thinking. It came as no surprise that very early in our discussion, when asked what it was about neurological medicine that had initially inspired him to dedicate his life to this field, the softly-spoken professor answered with a wry smile: “Even from the 5th century BCE, Hippocrates said: 'The center of all our existence, of all our thoughts, all of our emotions, is the brain.'”
The Thessaloniki-born Karussis first came to Israel as a medical exchange student in 1986, and he fell in love with the country and the Israeli people. Two weeks after marrying in 1988, he and his wife (also a scientist) left Greece and came to work at Hadassah. They have remained in Israel ever since, are now Israeli citizens, and their son will soon begin three years of service in the Israeli military.
“Some things you feel are like home,” Karussis smiles. “You feel the familiarity. It’s something unexplainable. Despite the fact that I was not Jewish, I felt that this place was home from the very beginning. The head of the department at the time, Professor Abramsky, was like a father to me. We developed relationships with many friends here, and had developments in science and research, [and I stayed to] develop this field of multiple sclerosis and neuroimmunology.
“My philosophical view on this is that the Jewish and the Greek way of thinking ‒ on one hand, the unconditional and “crazy” faith, and on the other hand, the analytical and philosophical way of thinking ‒ represent the two essential and basic cornerstones of Western civilization. These are seemingly opposite but also complementary elements, and their ‘marriage’ can lead to great achievements. So, for me, this marriage and interaction represents also a great challenge both in science and in life, in general.
“Now, more than half our lives have been here, and it seems like it is more than a second home ‒ probably the first.”
There’s an almost mesmerizing lilt to the professor’s gentle Greek-intonated English. He verbally walks me through a variety of areas of his expertise with both patience and a recognition ‒ I admitted to as much when we began our discussion ‒ that he is speaking to a scientific novice. The burning passion for his work and his quest for a cure to neurological incapacity is highly infectious. This was a meeting that will live very long in my memory.
I want to know where his research is now, and about the road trodden thus far.
“The conception for many centuries was that if you have a disease like progressive multiple sclerosis, ALS and others that causes destruction of the nerves, there is no way back. There is no way to rebuild the myelin, the sheath around the nerves which isolates them and gives the ability to conduct electrical stimuli very fast. I think that in the last few years we have started to questions this axiom. Is it indeed impossible?
“Many things in medicine come not like new inventions, but as discoveries of something that already exists. I believe that most of the secrets of many diseases are hidden in our bodies. We can learn from this. Let’s observe what is happening in the body. There are patients with multiple sclerosis and stroke and other diseases who recover [to varying degrees]. How do they recover if there is damage in the brain? There is some possibility in our body for recovery and repair, but it is limited. So we said, ‘What is doing this?’ It is common knowledge that what induces this repair is stem cells.
“The whole body is built by a few cells which are multi-potent, that’s why they are called stem cells, because they can produce anything... even the brain.”
Karussis’s path to closing in on a possible cure for MS and other neurological diseases began more than 25 years ago during his PhD studies. In 1991, he was invited to the United States to present initial elements of his stem cell theory and admits he received a cool reception.
“I presented this first concept of using stem cells to replace the immune system at the American Academy of Immunology. This was a very novel approach which was not accepted. People were laughing at the idea of using stem cells for multiple sclerosis. Today, things are completely different." What was once cause for laughter is now increasingly being accepted in medical circles as a likely route to a landmark scientific breakthrough.
“This was the first approach to replace the immune system by stem cells in order to stop this reactivity against self proteins, in the case of multiple sclerosis,” he continues. “We, indeed, progressed with this by applying models in patients after some years, in the beginning in collaboration with the [now retired] head of bone marrow transplantation at Hadassah, Professor Shimon Slavin. We did this with transplantation of stem cells in patients with multiple sclerosis. Many thought at this point that it was a very extreme approach, but today it is much more accepted and done in many centers across the world.
“During the following years I found another way, because with MS you have not only to stop the immune inflammatory activity, you have to find a way to rebuild the myelin that has been destroyed. In MS, as you may know, the autoimmune reaction destroys the myelin. So, if the myelin is destroyed by this autoimmune inflammation the conduction becomes slower, or is even blocked.
“Depending on the area of the brain that has been affected, what we call a plaque of de-myelinization is expressed by various clinical symptoms like weakness of the muscles, problems with sensations, instability of gait, loss of vision, and many other things,” Karussis says.
There was a time, not very long ago, that talk of using stem cells was the subject of huge and passionate ethical debate. Stem cell research was being carried out using cells from human embryos, and the furor was something that might have stopped research into stem cell technology in its tracks.
Karussis’s answer, and a seemingly much better alternative, was to use the adult patient’s own stem cells sourced from the tiniest fraction of stromal stem cells found in the bone marrow. This technique overcomes the ethical implications of embryo stem cell implantation, the problem of finding a donor, and also drastically reduces the likelihood of rejection by the patient who receives his own cells back into his body.
“These stromal stem cells are more flexible, and that’s why, although they represent less than 0.1% of those cells in the bone marrow, we take them, we expand and purify them, we produce tens of millions of those, and then we try to inject them. First we tried in the mice models of multiple sclerosis and it was fantastic.”
Karussis is reliving this “eureka” moment some 10 years ago right before my eyes. He’s still calm and soft-spoken, but there is no hiding the thrill in his voice.
“We saw that paralyzed mice regained their walking and jumping abilities, so this means that these cells induce recovery and prevent damage to the nerves.”
I wonder if, as he saw the recovered mice, he immediately felt such a reaction would be replicated in human beings?
“I was very, very optimistic, because I know there is a good correlation with the same basic biology in these types of animals. The treatment in animal models with stem cells might give hope for the application in humans.”
RECEIVING A license to go to trials on humans took time, and there was reluctance to allow testing on multiple sclerosis patients, seemingly because their life span may still be long, even though their condition might make life very difficult.
“ 'You know,' ” Karussis recalls the committee telling him, “ 'we have to try with an incurable disease, so try ALS where there is no other chance and people die. It will be more ethically approvable because we don’t know too much about the stem cells.' This is the reason that I started to deal with ALS, because my field is more multiple sclerosis and neuroimmunology, and that’s why we started a combined trial. This was the agreement: more patients with ALS (19), and 15 with multiple sclerosis. Thirty-four in total. That was in 2007. Its findings were published in 2010 in the Neurology journal.
“Of course, when you do such a study, your main target is to see the safety of the treatment, especially since we had the approach to inject those cells into the spinal fluid, which means that we needed the patients to undergo lumber puncture so the cells would go and circulate in the cerebral spinal fluid that circulates all the way around the brain and the spinal cord.
“This was a very unique approach, and the first time it had been applied in neurological diseases. This is recognized as the first study in this area. The safety was excellent. There was absolutely no serious adverse event, and we saw that, as a secondary observation ‒ because there was no placebo with which to compare it ‒ patients with ALS stopped progressing for at least six months, the length of the study. And patients with multiple sclerosis sometimes had a significant improvement in their disability.”
I ask him to describe the level of physical improvement shown in the subjects of that first trial.
“There is a grading of disability on a scale called EDSS, so when a patient has an EDSS of 7, it means that he is in a wheelchair. Six and a half he needs a walker. So, from a mean of 6.7 ‒ which is between a wheelchair and a walker ‒ the [subjects] improved by one degree, which means they are able to walk without assistance or with one stick. This is a very significant change, especially in patients with progressive multiple sclerosis... but, of course, it cannot be interpreted as proof of efficacy because we didn’t have a placebo group to control, but is a very strong indication.”
It took three more years for permission for another trial to be granted. That trial started a year-and-a-half ago, and was described in Hadassah’s own press statement as follows:
“THE TRIAL, under the direction of Prof. Dimitrios Karussis, head of Hadassah’s Multiple Sclerosis Center, is a large randomized double-blind, placebo-controlled study that will eventually have 48 MS patients. While the patients in the control group will not know if they are initially getting the actual treatment or a placebo, the trial contains a crossover design so that eventually everyone will get the stem cell treatment, although some patients will receive the actual treatment six months later.”
This is the trial in which D participated, which in his case appears to have brought about a stunning recovery of movement, as well as a marked general improvement in his all-around health.
Responding to my query about notable side-effects, Karrussis says the Health Ministry believes the treatment is “harmless, and they are not afraid of it.” He adds that it could be “the door to a new era in medicine, which is regenerative medicine.”
The team at Hadassah is by no means the only group of scientists racing to try find a way to treat diseases such as MS and ALS. Karussis is one of between 30 and 40 experts sitting on international consortiums that act as a steering committee for stem cell research. And there is great debate as to whether the intrathecal (via spinal cord) method promoted by Karussis and his colleagues in Jerusalem is preferable to the intravenous administering of stem cells to patients.
A number of international centers have observed the Hadassah trials, and three US medical centers – Massachusetts General Hospital in Boston, MA; University of Massachusetts Memorial Hospital in Worcester, MA; and Mayo Clinic in Rochester, MN – are now running a Phase 2 double-blind placebo controlled study using an identical protocol to the trial at Hadassah, also based on BrainStorm’s mesenchymal stem cell-based platform for treating neurodegenerative diseases.
The independent ALS Therapy Development Institute highlights worldwide clinical trials looking at differing aspects of ALS and MS taking place from Japan to Germany, Iran to Italy, many with different objectives but all seeking to find answers to the diseases. The Institute’s own slogan, “ALS is not an incurable disease. It is an underfunded one,” clearly reflects its belief that there is indeed hope for sufferers.
But why is it that only an Israeli hospital dared to break such new ground, I wonder. Could it be that Israelis have been more willing to offer their bodies as subjects for a trial in which others might have been less willing to participate?
“I definitely think that this thirst for doing new things and having no limits [is an Israeli characteristic],” Karussis suggests. “The Europeans and Americans have for many years had a kind of taboo in working with stem cells because they thought it may be dangerous. They are a little conservative. Fortunately, this conservatism about stem cells didn’t exist here in Israel, and there is a better spirit for research and an unlimited ability to investigate.
“The patients in Israel trust the researchers and physicians, are very open to new approaches, and are not conservative. This has helped us proceed, this mentality that people in Israel believe in the future, they believe in novelties. I think this is something that makes the country so progressive in the field of research.”
It is an incredibly frustrating irony then, that while countries such as the US are relatively awash with funds for medical research but local legislation there makes permission for groundbreaking stem cell tests incredibly hard to receive, in Israel, where the research is warmly encouraged, the final stage of a potentially historic clinical trial is being delayed due to financial difficulties. The clinical trial still requires the last third of the 48 subjects to undergo the stem cell treatment.
In the grand scheme of things, the $1.5 million required to finish this stage of the research and publish the findings does not appear to be a large amount of money, especially when one considers the millions of people whose lives might be so transformed if this procedure is clinically proven beyond doubt. But it’s a sum that cash-strapped Hadassah is struggling to find, although Karussis is cautiously optimistic that the money will soon be forthcoming.
The professor considers his response to my final two questions for a few moments before giving carefully worded answers ‒ there could doubtless be many people hanging on every syllable he utters. First, if your research is able to proceed to a successful conclusion, how possible is it that conditions such as ALS and MS may no longer be considered terminal illnesses, and second, what time frame are we looking at?
“We can say that if things continue to go like this and continue in the same direction, this will definitely change the face of neurology and the management of these diseases, which have been very impotent, you could say, all these years,” he says.
“You know, about 10 years ago, in lectures to every forum, my colleagues and I would discuss treatments for multiple sclerosis and other diseases. We posed the question: when would the use of stem cells be a possible future option? It was theoretically in our target, but it was like science fiction ‒ it would happen sometime. But after having this data, safety data, after having the whole setting ready, after having some proof of concept of what is happening, I think it will not take too much more time.
“It is a matter of definitely less than 10 years, maybe less than five, that we can have this treatment available, and not only for this indication, because if it works in one type of regeneration of the brain in MS, it may work equally or even better in those such as Alzheimer’s, Parkinson’s, stroke, and spinal trauma.”