A team of researchers led by Prof. Irun Cohen of the Weizmann Institute of Science has developed a vaccine that halts the progression of Type I (juvenile or insulin-dependent) diabetes. The vaccine functions by blocking the destruction of insulin-secreting pancreatic cells.

Diabetes is a chronic disease associated with elevated blood sugar levels, in which the body does not produce or improperly uses insulin - a hormone needed to convert sugar, starches and other foods into energy. Recent data show that between 120 and 140 million people suffer from diabetes worldwide. Type I diabetes usually results from an autoimmune disorder in which the immune system mistakenly attacks the body's own insulin-producing pancreatic cells, reducing and ultimately eliminating all insulin production. All Type I diabetes patients eventually must receive insulin injections to compensate for their loss of natural insulin production.

For the past several years researchers at the Weizmann Institute's Department of Immunology led by Cohen have been studying the mechanism by which the immune system destroys the insulin-producing pancreatic cells. Working with mice, the scientists discovered that a particular protein called HSP60 was closely linked to this destructive process.

The protein acts like an antigen, prompting the immune cells to attack. Further investigation by Cohen, Dr. Dana Elias (first a graduate student and then a postdoctoral fellow at the Institute), and other students and colleagues revealed that injecting sick mice with p277, a small peptide fragment of the HSP60 protein, shut down the immune response, preventing the progression of Type I diabetes. This led Peptor Ltd., a biopharmaceutical company based in Rehovot, Israel, to develop the experimental drug DiaPep277, designed to prevent or treat Type I diabetes.

A combined clinical study performed recently by researchers at Hadassah-Hebrew University Medical School, Peptor Ltd., and Cohen proved that DiaPep277 is successful in arresting the progression of Type I diabetes in newly diagnosed patients. The research findings were published in the Lancet.

The study involved 35 patients newly diagnosed with Type I diabetes. Eighteen patients received injections of DiaPep277 - at the beginning of the study, after one month, and after six months; 17 patients received three injections of an inert substance (a placebo). Patients in the treatment group (those receiving DiaPep277) showed a delay or even a cessation in the attack by the immune system upon their pancreatic insulin-producing cells. These results were evident in the level of the body's own insulin production and a decreased need for insulin injections. The researchers were able to trace the mechanism of this improvement to changes in the patients' immune lymphocytes called T-cells. In contrast, patients receiving the placebo showed a significant decline in their natural insulin production and a persistent rise in the need for insulin injections. No significant side effects as a result of injecting DiaPep277 were found.

'The idea of using p277 stemmed from the discovery that the immune system has different options to choose from in responding to an antigen,' says Cohen. 'It can act to destroy the antigen or alternatively protect it from being destroyed. In the latter case it protects the antigen, thereby indirectly preventing damage to the pancreatic cells. The peptide essentially acts to 'reeducate' the immune cells, switching off their destructive activity.'

The scientists participating in this study are: Prof. Itamar Raz and Dr. Muriel Metzger of Hadassah-Hebrew University Medical School; Dr. Dana Elias (now VP R&D at Peptor Ltd.); and Drs. Ann Avron and Merana Tamir, also of Peptor Ltd.

Prevention rather than replacement

 

Back in 1920 Dr. Federick Banting and Charles Best of the University of Toronto made a discovery that would change the course of medical history. They had succeeded in obtaining a pancreatic extract which proved to have potent anti-diabetic characteristics when tested on dogs. Within two years their team would isolate and purify the extract's key ingredient, a hormone known as insulin, and the first human trial would begin, extending the life of Leonard Thomson, a fourteen year-old-boy who lay dying in hospital, for an additional 13 years.
 

Today extensive research efforts have yielded dramatically improved high-quality insulin as well as better delivery methods. Nevertheless insulin is not a cure, it merely helps to maintain blood sugar levels in check. A cure would be to stop the autoimmune destruction, sparing the insulin-producing beta cells. In contrast to the replacement therapy offered by insulin, the vaccine currently in development by Prof. Cohen's team has been shown to prevent the destruction of pancreatic cells.

Prof. Cohen holds the Helen and Morris Mauerberger Professorial Chair in Immunology. His research is supported by the Robert Koch Minerva Center for Research in Autoimmune Disease, the Yeshaya Horowitz Association, and Mr. and Mrs. Samuel T. Cohen, Illinois.

One needs a good reason to go to the South Pole. The night there lasts six months, and the annual temperature averages -50°C. The Pole has long been a prized goal of Arctic explorers, but why would a scientist interested in outer space, like Prof. Eli Waxman of the Weizmann Institute, want to travel to this forbidding frosty desert? Surprisingly enough, Waxman and a handful of astrophysicists in other countries believe the South Pole may become the next frontier in space exploration. They consider turning the 3,000-meter-thick plateau of ice hugging the Pole into a giant trap for elusive cosmic particles called neutrinos that may help reveal the secrets of the universe.

From time immemorial people have sought to understand the universe by gazing at the sky - first with the naked eye, then through optic telescopes. Next came more advanced telescopes, which examined celestial bodies by capturing the electromagnetic radiation they emit - from radio and infrared waves to ultraviolet radiation, X-rays, and gamma radiation. More information about celestial objects, such as black holes and galactic nuclei, can be gleaned from cosmic radiation - the rays of elementary particles, including protons, neutrons, electrons, alpha particles, and neutrinos - emitted by celestial bodies. However, because most of these particles have an electric charge, their path toward the

Earth is affected by various magnetic and electric fields whose magnitude and location in the universe is unknown. This makes it very difficult to trace these particles back to their sources, which in turn significantly reduces the amount of information they can provide about the universe.

Neutrinos may offer a solution. Lacking an electrical charge and with only a tiny mass, neutrinos behave in an 'unsociable' manner: they hardly interact with other particles of matter and travel to Earth in a straight line. Therefore, by observing the universe as it emerges from the rays of neutrinos one can perhaps gain valuable insights into the location and physical properties of the celestial bodies emitting the neutrinos. Physicists believe that these sources, such as active nuclei of galaxies affected by a black hole, could become enormous 'physics laboratories.' But realizing this fantastic prospect won't come easy.

Tracking down a loner

Physicist Wolfgang Pauli was the first to propose the existence of a particle later to be called the neutrino, back in the 1930s. Pauli was examining the law of energy conservation, which seemed to be violated by certain radioactive processes. However, many years passed before neutrinos were discovered - once again, mainly because these particles interact so sparsely with their surroundings. In fact, they interact with matter only via the weak force, which governs various radioactive processes such as the splitting of the neutron. But so weak is this force that the neutrinos hardly leave any tracks. For example, a neutrino can travel through the Earth in a split second without slowing down. During this journey very few neutrinos will forge any traceable 'connections' with other particles.

To spot neutrinos and learn about the celestial bodies that emitted them, physicists build giant detectors, each containing thousands of tons of matter, with which one out of the trillions of neutrinos is likely to collide, leaving a tiny flash of detectable light.

In this way scientists, including the Weizmann Institute's Prof. Israel Dostrovsky, have succeeded in detecting neutrinos spewed out by the sun - an observation that confirmed the theory about the way in which stars produce the energy they release. Other experiments led to the observation of additional neutrinos originating in the relatively close supernova of the Magellanic Cloud - a satellite galaxy of our own galaxy, the Milky Way. With these successes in hand, the appetite for neutrino sightings grew. Astrophysicists started observing the universe via detectors that can spot high-energy neutrinos emitted by the most distant and energetic sources. Equipment based on the absorption of electromagnetic radiation is unsuitable for studying these sources, since it does not allow the passage of photons - which is why physicists believe that the neutrino telescope may offer the best opportunity for exploring the universe.

Yet how realistic is it to build such a system? To answer this question, it's necessary to know how many neutrinos reach the Earth from different sources during a given period of time. This is where Prof. Eli Waxman of the Weizmann Institute's Physics Faculty enters the picture. Together with Prof. John Bahcall of Princeton University, he performed calculations showing that there is an upper boundary to the neutrino flux. Existence of the so-called Waxman-Bahcall bound means that detecting high-energy neutrinos would require a transparent detector containing at least a trillion tons of liquid.

This transparent detector would have to be surrounded by an array of light detectors, which would register the tiny flashes of light produced by the collisions of cosmic neutrinos with particles on Earth.

Waxman is a member of an international committee of scientists examining the possibility of building such a giant detector in Antarctica, inside the entirely transparent ice cap covering the South Pole. Another possibility is to set up a detector for high-energy neutrinos on the floor of the Mediterranean Sea, whose waters at great depth are also transparent. In any event, the project's cost is estimated at some $100 million - a sum that, astronomical as it may sound, is far lower than the cost of building the advanced particle accelerators needed to study elementary particles.

What can be learned with the help of giant neutrino detectors? 'When a proton of cosmic radiation hits a photon, a neutrino particle is emitted,' explains Waxman. 'If we could detect these neutrinos, we would be able to chart the sites of these collisions and use them to trace cosmic radiation back to its source - today one of the greatest mysteries of astrophysics.

'Another mystery that may be solved with the help of high-energy neutrino astronomy is the source of gamma-ray bursts occasionally occurring in the universe. Waxman and Bahcall, together with Prof. Peter Meszaros of the University of Pennsylvania have shown in theoretical studies that these gamma-ray bursts may originate in streams of matter bursting out when a black hole sucks in the remains of matter from a star that initially gave rise to it during the collapse of its core. High-energy neutrinos are emitted during this process, and the ability to detect them may lead scientists to the sources of gamma-ray bursts.

Neutrino relativity

Giant neutrino detectors may also make it possible to examine several underlying principles of the general relativity theory, by comparing the speed of the energetic neutrinos with the speed of photons coming from the same source. In this manner it will be possible to identify, among other things, the slowing of particles passing through gravitational fields. A neutrino detector that allows scientists to study this phenomenon was built recently near the South Pole. Sunk deep in the Antarctic ice, the installation is about twice the height of the Eiffel Tower. But according to Waxman's calculations, astrophysical studies of high-energy neutrinos would require an installation a hundred times larger. Hopefully, says Waxman, the international committee studying the feasibility of such a detector will reach a decision to open this new window of opportunity for astrophysics.

Prof. Waxman's research is supported by the Minerva Stiftung Gesellschaft fuer die Forschung m.b.H.

Wise people learn from the experience of others, but such wisdom is rare. Most of us learn only from our own successes... and failures (which of course is why the irksome 'I told you so' will most likely never gather dust).

But how does such learning take place? How does the brain store new knowledge or readjust the old to reflect the current reality? Prof. Yadin Dudai and graduate student Diego Berman of the Weizmann Institute's Neurobiology Department have zeroed in on one of the underlying mechanisms. Their findings were recently published in Science.

Let's assume you try a certain delicious-looking dish and discover that it doesn't agree with you. Chances are you'll refuse it next time around. Your brain stores information that associates this dish with something unpleasant. A future encounter will trigger the 'retrieval' of this associative information, essentially a warning that your best recourse is a polite decline. This, of course, is what happens if you're wise enough to learn from experience.

But it's also wise not to hold on to the same opinions forever without reevaluation. In the case of the dish, the following turn of events is possible: somebody you like or trust persuades you to try it again, and much to your surprise you discover that it tastes great and doesn't disagree with you. This being the case, you're less likely to turn it down in the future. And if things go well again, your opinion about this dish, based on your more recent experiences, will change entirely. The old, negative association will no longer spring to mind. In fact, the opposite will occur - every time you see this dish, you'll remember how wonderful it tastes, forgetting that in the distant past it rubbed you the wrong way. In technical language this updating process is called 'extinction' - the brain has erased the old information and 'filed' new data reflecting your latest experiences.

How does this extinction process occur? Dudai and Berman discovered that the same brain regions gear into action whether we're learning new facts of life or updating old information. But in information-update - in other words, in relearning something - the brain does not make use of the entire learning machinery, only a few 'core' mechanisms are involved.

Learning is a complex, multistep, and multiplayer process, orchestrated with great precision. When we learn something for the first time, all components pitch in: a type of signaling enzyme, called MAPK, and receptors for glutamate, acetylcholine, and norepinephrine - all key neurotransmitters. Protein synthesis inside neuronal cells must also be efficient.

These efforts, however, are trimmed down when it comes to reevaluating and updating existing knowledge. The scientists found that only two elements - beta-adrenergic norepinephrine receptors and protein synthesis in brain nerve cells - are involved. Operating independently of all the others, these 'core' learning components are crucial for both first-time learning and memory extinction.

'These findings emphasize the brain's evolutionary efficiency,' says Dudai. 'The same mechanism is capable of working in different ways, at different levels.' Future applications of these and other research findings may make it possible to chemically control the way we update information according to experience. Of course, we'll probably still be hard put to explain why, if information updating is so efficient, so many people are entirely mulish when it comes to changing their mind.

Prof. Dudai holds the Sara and Michael Sela Professorial Chair of Neurobiology. His research is supported by the Abe and Kathryn Selsky Foundation, North Bethesda, MD; the Nella and Leon Benoziyo Center for Neurosciences; the Lester Crown Brain Research Fun; the Abramson Family Brain Research Program; and the Carl and Michaela Einhorn-Dominic Brain Research Institute.