Interview with Professor Michel Revel - Inventor of Rebif (interferon-beta), Chief Scientist at Kadimastem

Professor Revel began his career in a laboratory associated with the Pasteur Institute in Paris, where he discovered the initiation factors of protein synthesis. This discovery opened up a field of research on the mechanisms controlling the translation of genetic information.

Prof Revel’s scientific path continued at the Weizmann Institute, where he conducted extensive research on the mechanisms of action and the isolation of the human Interferon-beta gene. These studies have led to the biotechnological development of recombinant Interferon-beta (Rebif) at Interpharm.  Rebif is today the lead product of Merck Serono, a $2.4 billion-a-year commercial drug, widely used to treat multiple sclerosis (MS), a disease that destroys the myelin coating of nerves in the brain.

Revel also discovered the human gene for the cytokine Interleukin-6, and elucidated its activity in protecting nerve functions and the nerve myelin coating in neuropathies. In recent years, Revel's laboratory focused on human embryonic stem cells (hESC) and succeeded to produce from them mature nerve myelinating cells that reconstitute the myelin coating after transplantation into myelin-deficient animals. Large scale culture technology for hESC can also be used to produce differentiated human cells such as insulin-producing pancreatic beta cells. This in recent years has lead Prof Revel to become involved in a novel commercial project—Kadimastem, a biotechnology company focused on the industrial development and commercialization of hESC-based products. One of their products, already in use by Merck-Serono, applies the hESC-derived myelinating cells in a drug-screening platform for new MS drugs.

A WORD WITH PROFESSOR REVEL:

Bioassociate: What do you feel has been the most rewarding accomplishment in your scientific career?

Prof Revel: The opportunity to pursue my basic science interests and to translate results into medical applications. I studied Interferons (IFN) as a translation control system which selectively inhibits viral protein synthesis. These studies required us to produce a lot of IFN and we therefore cloned the human gene for IFN-beta and developed the first efficient expression of this glycoprotein in mammalian cells. This attracted the attention of Serono, making it possible to develop IFN-beta production in their Israeli plant Interpharm, where I worked as Chief Scientist. Our studies on IFN-induced genes, in particular the HLA genes, shed new light on immuno-regulatory effects of IFN-beta which could be applied in autoimmune diseases. Serono’s clinical trials led to the registration of Rebif as an MS drug in 1998. To see one's research become a medication that helps hundreds of thousands of patients is indeed most rewarding.

Bioassociate: Tell us a little about your current project – KadimaStem

Prof Revel: This is really a continuation of our efforts to find new treatments for MS and other neurological diseases, by using pluripotent stem cells to produce cells that are damaged in such diseases.  We developed at the Weizmann Institute a procedure to derive human oligodendrocytes, and these myelinating cells can be applied to screen chemical libraries for molecules that stimulate nerve myelination. Present drugs for MS slow down the destruction of myelin by the immune system, but agents which stimulate the repair of myelin could be of great interest. The first product of Kadimastem, a three-year old biotechnology start-up at the Weizmann Science Park of which I am today the Chief Scientist, is such a drug screening platform already in use under contract with Merck Serono in their search for new oral drugs for treatment of MS.  A main project of Kadimastem is the production of pancreatic islet cells which could be applied in the future for cell replacement therapy in Diabetes. A third project is production of human astrocytes which hold promises for treatment of ALS, since ALS patients have abnormal astrocytes that do not anymore exert their neurotrophic functions. Kadimastem has a scientific staff of 25 (with 6 PhD researchers), and works with human embryonic stem cells and iPS cells licensed from Hadassah (from Prof. B. Reubinoff) and from Shaarei Zedek Medical centers.

Bioassociate: What do you think about the President’s recent initiative to make Israel a leading neurotech hub in 

the world?

Prof Revel: All initiatives to support and promote scientific research in Israel are welcome. A country is not measured by its size and Israel can be a big country by its contributions to Science and Technology. President Shimon Peres always understood this and his Israel Brain Hub initiative should therefore be taken seriously. Hopefully, the government, granting agencies and investment funds will listen to his appeal and make it happen. Financing academic and biotech research is one of the best investments for the State of Israel.

Bioassociate: Many people have said that Israel has been exceptionally successful at attaining scientific progress and commercializing scientific developments. Why do you think this is?

Prof Revel: The vision and support from generous donators in the Jewish Diaspora have given Israel the means to make important discoveries. Commercializing research is relatively easy in Israel, and technology transfer offices do help many scientists become involved in industry. Israel is excellent in the medical device sector, and it is no accident that analysts say that it is uniquely positioned to develop leadership in Brain-Machine interface and therapeutic neuro-stimulation devices. The pharmaceutical market is slower to grow mainly because it takes so much time to reach the market. But successes in developing new drugs can bring much larger returns, in the many billions of dollars, which should appeal to long-term investors. The two medications for multiple sclerosis coming out of Israel, Teva's Copaxone and Merck Serono/Interpharm’s Rebif, are examples that make the point. The Biotech drug, gene and cell therapy sector ought to be supported much more actively, with larger R&D budgets, and treated as national priority projects. Personally, I am proud that contributions to development of Israeli Biotechnology were mentioned in my Israel Prize and Emet prize awards.

Bioassociate: What do you think is today’s most important/pressing therapeutic area which neuroscience could address?

Prof Revel: Understanding the human brain is the new frontier following the genome project. For therapeutics, the main challenges are neuro-degenerative diseases like strokes, Alzheimer's disease, Parkinson's disease, ALS, neuropathies, spinal cord injuries and progressive forms of MS. There are many advances in these and other neurological diseases, with new drugs (e.g. Azilect of Teva, developed by Prof. Moussa Youdim), gene products (e.g. antisense RNA for myasthenia gravis of Prof. Hermona Soreq) and stem cell derived products (e.g. Hadassah stem cell pioneering trials in ALS patients of Prof. Karousis, BenHur and Slavin, and stem cell-derived astrocyte-like cells for ALS treatment being developed by Dr Daniel Offen at Brainstorm).

Bioassociate: Which obstacles do you perceive in Israel’s path to becoming a world leader in neurotechnology?

Prof Revel: The main obstacle is that the scientific potential of Israel is still not estimated at its real potential by government and Industry. Compared to other sectors in which receive millions of dollars in funding, many bio- laboratories and startups could thrive with five to ten millions, but lack the funds. Opportunities are lost due to lack of understanding of the needs of scientist. To become a world leader in neurotech, dedicated funds must be earmarked and long-term investments be encouraged by the Israeli government. The Industry and Trade Ministry's Chief Scientist Office is doing a marvelous job but it is not enough. The private business sector and large companies (e.g. Teva) ought to join hands with the government to create the real opportunities that will better exploit the human resources with which Israel is blessed. 

Interview with Prof Marta Weinstock-Rosin, Israel's leading Neuroscientist, Inventor of Alzheimer's treatment Exelon (rivastigmine) and ladogstigil

PROFESSOR MARTA WEINSTOCK-ROSIN 

Professor Emeritus, School of Pharmacy-Institute for Drug Research, Hebrew University of Jerusalem

Professor Weinstock-Rosin received her B. Pharm. Hons, M.Sc. and Ph.D. degrees at London University, UK. At Hebrew University, she was Chairman of the Department of Pharmacology from 1983-1986, and President of the Israel Society for Neuroscience from 2003-2005.

Rosin was the developer of rivastigmine in 1985 (commercially available as Exelon), for the treatment of mild to moderate dementia and dementia due to Parkinson's disease. Rivastigmine was sold to Novartis through Hebrew University’s Yissum TTO and in 2009 the sales of Exelon neared US$ 1 billion worldwide.

Recently, together with Prof Moussa Youdim, Rosin developed ladostigil – a novel neuroprotective agent which combines the mechanisms of action of older drugs like rivastigmine and rasagiline into a single molecule. Ladostigil is currently in Phase II clinical trials carried out by Avraham Pharmaceuticals Ltd for the treatment of Alzheimer’s disease, Lewy Body disease and Parkinson’s. Avraham Pharmaceuticals recently completed a $9 million financing round from investors Yissum TTO, Prof Weinstock-Rosin, Eli Hurvitz’s Pontifax Fund and Clal Biotechnology.

In addition to drug development Professor Weinstock-Rosin’s major research for the past 27 years has centered on the neurochemical and hormonal mechanisms underlying the behavioral alterations induced by prenatal stress. In addition to Exelon and ladostigil, Professor Weinstock-Rosin is currently developing a new series of neuroprotective drugs with novel mechanisms of anti-inflammatory activity.

A WORD WITH PROFESSOR WEINSTOCK-ROSIN

Professor Rosin has dedicated her scientific career to understanding of the processes which take place in the ageing brain, and what causes accelerated neurodegeneration. She admits that at the time of rivastigmine discovery in 1985, the only known fact about Alzheimer’s disease was the correlation between memory loss and diminished amounts of acetylcholine – one of the most ubiquitous neurotransmitters in the brain. Rivastigmine’s mode of action is thought to be the blocking of acetylcholinesterase, an enzyme which breaks down acetylcholine, although the drug’s exact mode of action remains unknown. By the time rivastigmine was reaching the market, a substantial amount of new evidence emerged suggesting that the drug might be treating the symptom, rather than the cause, as a wide array of new underlying processes were attributed to impaired cognitive ability in rat models.

On the discovery of ladostigil:

Prof Rosin’s research has led to the isolation of a distinct change in the ageing brain, in Alzheimer’s disease and in Mild Cognitive Impairment (MCI)—a significant drop in the function of mitochondria, the cell’s power station. Because oxygen isn’t sufficiently utilized by the ageing cells, a decline in energy production results in oxidative stress and in the activation of microglial cells – cells in the brain and spinal cord which act as the first and main form of defense. It is the chronic over-activity of microglia which has been strongly implicated in neuronal damage and neurodegeneration. 

In numerous experiments in ageing rats, Prof Weinstock-Rosin discovered that administration of rivastigmine in much lower doses than those marketed under the Exelon name significantly lowered microglial inflammation, so much so that microglia of 16-months-old rats (a rat’s life span is on average two years) resembled those of young rats. Furthermore, aged rats exhibited substantially improved cognitive ability after lower-dosage rivastigmine administration.

Joining forces with Israel’s other Alzheimer’s drug, Azilect (rasagiline), Prof Weinstock worked with Prof Moussa Youdim on creating an amalgamated form of rasagiline and rivastigmine, creating ladostigil. If Prof Rosin’s laboratory studies are to be taken as an indication of ladostigil’s efficacy, we may expect excellent results in the drug’s clinical trials. Although, says Prof Rosin, ladostigil’s success may be a long way away—clinical trials of neurodegenerative diseases are notoriously difficult and lengthy to run, as patient selection is a tricky art in MCI and Alzheimer’s cases.

Speaking of the Israel Brain Technologies Initiative, Prof Rosin is perhaps more down-to-earth than her Israeli colleagues. With the right priorities, direction and financing, Israel has a great chance of becoming a world neurotech leader. But perseverance and motivation are a must, particularly because she anticipates this to be a rather costly project. 

Israel's Reign in the Golden Age of Neuroscience: Introduction

Bioassociate has been working hard on interviewing Israel's most prominent neuroscientists and leaders of exciting young neurotech companies. Our latest report, titled "Israel's Reign in the Golden Age of Neuroscience" was written in conjunction with President Shimon Peres's Israel Brain Technologies initiative, which aims to make Israel a leading global neurotech hub. 

Below is an introduction to Bioassociate's latest white paper, which will be ready shortly. If you would like to receive a free copy of the report, make sure to subscribe to our mailing list on the Bioassociate homepage - www.Bioassociate.com

The blind can see, the deaf can hear, and the paralyzed can walk—without a doubt, the Golden Age of Neuroscience is upon us. And if that weren’t enough, mind control, telepathy and in fact elaborate real-life Avatar scenarios are so nigh that scores of the neurotech-savvy have begun to pre-order their titanium thought defense helmets. So awesome have the leaps of neurotechnology been in recent years that the media has struggled to deliver this industry a deserved timely coverage, and public awareness has just barely caught up with humanity’s neuro-prowess of late. 

It is no surprise that we pondered so much of our vast universe before tapping into the microcosmic mystery of the mind: the human brain is riddled with millions of neuronal connections, all intertwined in a jungle so dense that the intricacy of galaxies and nebulas could pale in comparison. Having understood the basic principles which guide brain formation, scientists’ success in elucidating grey matter’s modus operandi has witnessed exponential growth in recent years, and one could safely say that our ability to harness this knowledge is at its most fruitful level yet. Neuroscientists have proudly treated depression, Parkinson’s disease, a range of psychological disorders, blindness, paralysis, and have even been able to communicate with long-comatose patients. Hardly any achievement of the last century could contest to be as jaw-dropping as giving a man thought to be in a decade-long vegetative state the ability to tell his parents he can hear them. 

Israel, a country which boasts the highest R&D per capita spend in the world, is one of only a handful of players actively pursuing a neurotech vision today. Most impressively, the countries or continents with which it shares this vision are at least ten times larger than it, both in size and budget. Thus, in celebration of the unraveling Neuro-Renaissance, and particularly as tribute to Israel’s increased involvement in the ever-expanding neuro-cosm, we present the current global neurotech situation, leading worldwide initiatives to raise awareness and to aid this ever-growing industry, followed by a summary of Israel’s very own academic and commercial neuro-arena. Place your titanium helmet orders!

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