When learning a new language, it’s hard enough trying to follow a conversation between two native speakers, but when one is in a room full of natives all speaking at once, it can be nearly impossible. Dr. Nir Friedman of the Weizmann Institute of Science’s Immunology Department knows only too well how difficult this can be: The molecular “language” of the immune cells he studies is “spoken” only in extremely noisy crowds.

When faced with a challenge such as an infection or cancer, the body’s corps of immune cells cooperate with one another in launching a coordinated counterattack. “Instructions” are passed down from one immune cell “rank” to another, and each type of immune cell carries out its specific “orders.” These instructions, however, are passed through molecules like cytokines – small proteins that carry information. But there is so much background “chatter,” it is difficult for scientists to understand exactly what is going on – which cell is “talking” to which, and how the molecular instructions they exchange get translated into cellular responses. To grasp the process, scientists just learning the language would prefer to narrow their observations down to single cells – in essence, to “listen” to just one cell at a time.

Although he is a physicist by training, Friedman was attracted to the life sciences; he wanted to apply experimental and theoretical tools from physics to the study of biological systems. During his postdoctoral studies at Harvard University, he and his colleagues developed a new method for detecting protein production that is so sensitive it can pick out single molecules in the single cells of the bacterium Escherichia coli. While many of today’s researchers work with green fluorescent reporter genes that, when inserted into DNA, glow brightly upon activation, Friedman and his colleagues employed an enzyme called beta-galactosidase as a reporter. The fluorescence does not come from the reporter molecule itself; it is produced when the enzyme cleaves a second substrate. The enzyme can cleave many substrate molecules per second, thus amplifying weak signals from even tiny amounts of protein. Unfortunately, in the first trials, as soon as the fluorescent signals were produced, they were pumped out of the cell – too quickly to be detected. To circumvent the problem, the scientists employed sophisticated miniature devices etched with closed chambers to trap individual cells, thus keeping the signals in one place long enough to be detected.  

Now, at the Weizmann Institute, Friedman and his team intend to elaborate on the design of these artificial microenvironments so that they will finally be able to “listen in”  on individual cytokine “conversations.” His initial research will concentrate on T helper cells – a type of white blood cell that secretes the instruction-bearing cytokines. The questions he is asking: Why do some of these T cells possess receptors for their own cytokines, giving them the ability to respond to their own signals? What benefit does this provide to the system, and how does it influence the response? Could this mean the response is all-or-nothing?

Combining these newly developed techniques with mathematical modeling and quantitative analyses may allow the scientists to predict how the cells will respond under varying conditions. These mathematical generalizations could then help shed light on processes concerning cell types other than T cells. Once the scientists are able to grasp basic “words” of the cytokine “language” from listening to individual cells, they hope to be more adventurous and open some of the chambers in the miniature devices, allowing more cells to “talk” to each other, even eavesdropping on the “chatter” of the crowd to hear what it can tell them.
 

Crossroads

Born in Tel Aviv, Dr. Nir Friedman received a B.Sc. in physics and mathematics from the Hebrew University of Jerusalem in 1989, via the prestigious “Talpiot” army study program. During his IDF service, he conducted M.Sc. studies in physics at Tel Aviv University, earning his degree in 1996. Friedman completed his Ph.D. studies under the guidance of Prof. Nir Davidson of the Weizmann Institute’s Physics of Complex Systems Department in 2001; he then stayed on as a postdoctoral fellow for two years in the lab of Prof. Joel Stavans of the same Department. He went on to spend four years as a postdoctoral fellow at Harvard University with Prof. Sunney Xie. In September 2007, Friedman joined the Weizmann Institute’s Immunology Department as a senior scientist. He is the recipient of a number of prestigious fellowships and awards, including the 2007 Career Development Award from the Human Frontier Science Program and the Weizmann Institute’s 2007 Sir Charles Clore Prize.

Friedman is married and is the father of three children. His hobbies include photography, listening to jazz and playing the drums in a jazz band.

Dr. Nir Friedman’s research is supported by the Sir Charles Clore Research Prize; the Crown Endowment Fund for Immunological Research; and the Abisch-Frenkel Foundation for the Promotion of Life Sciences.

Sensations like pain or heat travel in a fraction of a second along the extensions – the axons – of nerve cells, an impressive feat considering that axons such as those that run from the base of the spine all the way down the leg can reach over a meter in length – 40,000 times longer than their width. But when a nerve cell is injured somewhere along its length, a different kind of signal must be sent – one that more closely resembles a mechanical railway car than an electrical impulse. Thus getting the call for help back to the remote cell nucleus is something like sending a message by boxcar to headquarters halfway across the state.

Prof. Michael Fainzilber of the Weizmann Institute’s Biological Chemistry Department has been investigating emergency transportation systems in nerve cells. His previous research had shown that this information is packaged in a molecular “railcar” complex: A motor protein called dynein works together with importins to move the complex along microtubule “tracks.” The importins are nuclear import proteins that ferry various molecules in and out of the nucleus, thus delivering the message straight to the command center of the cell.

Fainzilber and research students Dmitry Yudin and Shlomit Hanz, working in collaboration with the group of Dr. Jeffrey Twiss (Nemours Institute, Wilmington, DE) wanted to know what controls the triggering of this system right after injury, as it gears up for the long journey. Using rat sciatic nerves as their model, the scientists looked for changes in the molecular makeup up of the nerve cell material around the injury site. Their findings recently appeared in Neuron.

To their surprise, they found molecules that until now were believed to exist only around the cell nucleus. These molecules, known collectively as the Ran system, are found in two main configurations, one inside the nucleus and one outside, and they help to control the importins’ molecule-ferrying activities through gates in the walls surrounding the nucleus. The research team found that the nuclear form of Ran sits on the axonal complex, preventing importins from coupling with the rest of the transport machinery. When damage occurs, Ran is switched to the second configuration, which causes it to disengage. The waiting importin can then plug into the machinery, and the expedition gets under way.

The researchers believe the Ran system works like a safety catch – preventing unwanted activation of the alarm machinery until an actual emergency occurs, and then switching quickly to allow efficient triggering of the system. Understanding this mechanism may help devise ways by which nerve cells can be induced to repair damage and may aid in developing treatments for nerve injury in the future.

Prof. Michael Fainzilber’s research is supported by the M.D. Moross Institute for Cancer Research; the Nella and Leon Benoziyo Center for Neurological Diseases; the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; the PW-Bes Foundation; the European Union FP6 NEST Axon Support project; the J&R Center for Scientific Research; the Minerva Foundation; and the USA-Israel Binational Science Foundation. Prof. Fainzilber is the incumbent of the Chaya Professorial Chair for Molecular Neuroscience.

Alternative energy promises a bright future thanks, in part, to dark paint. Our buildings, cars, ships and airplanes could one day be powered by a thin coat of special paint that will convert solar energy to electricity or fuel. Preference will be given to dark hues, which are better at absorbing sunlight. Thus a new Ferrari might, alas, come in black instead of red.

Making such futuristic energy concepts a reality will take radically new scientific approaches. “We haven’t made much progress in our use of energy,” says Dr. Boris Rybtchinski of the Weizmann Institute’s Organic Chemistry Department. “Our resources of oil and coal are limited, yet we continue to burn these fossil fuels and pollute the environment. In the meantime, the world’s demand for energy is soaring and the threat of global warming looms. There’s a huge gap between the enormity of the problem and the progress in finding alternative energy sources. We badly need fresh, creative ideas.”

Rybtchinski’s team is working on one such idea. He draws his inspiration from photosynthesis, the process by which plants and certain bacteria convert sunlight into chemical energy by employing an organic “paint” – chlorophyll. Certain artificial pigments are already more effective than chlorophyll, but combining them into functional systems is no simple matter. Rybtchinski seeks to create “well-connected” molecular systems that will harvest sunlight in clever ways intended to generate solar electricity and fuels.

Solar cells, which convert sunlight into electricity, are already available commercially; but their use is limited, in part, by their high cost and the difficulty of storing the energy, as these cells work only when the sun shines. The storage problem could be overcome by converting sunlight into chemical energy. In other words, fuels might be created using sunlight – just what photosynthesis achieves in nature.

Rybtchinski seeks to build artificial photosynthetic systems from cheap and readily available organic materials. Such systems might be able to produce various fuels from freely available ingredients – for example, hydrogen from water, or methanol from water and carbon dioxide. Solar paint would be a type of artificial photosynthetic system.

Rybtchinski believes that a better understanding of natural photosynthesis, combined with advances in organic chemistry and nanotechnology, can lead to innovative solutions in this field of research. In his lab, one doesn’t see the familiar panels or mirrors of solar installations. In fact, without an electron microscope one doesn’t see much of anything at all, as his solar energy nano-systems measure only several millionths of a millimeter.

To manufacture these systems, he takes a cue from yet another natural process – self-assembly – which governs the emergence of biological systems, from proteins to living organisms. Water plays a key structural role in self-assembly: Various biological molecules are either repelled or attracted to water molecules, and this property determines their position in living cells and tissues. With the help of an array of advanced technologies, Rybtchinski uses sophisticated molecular methods to exploit the hydrophobic – that is, “water-hating” – properties of certain organic molecules, manipulating them to self-assemble into efficient solar-energy-converting units.

In one of their projects, Rybtchinski’s group builds molecular “wires” that must perform three types of function, in rising order of complexity: moving photons while absorbing the energy of sunlight (a step occurring at the beginning of photosynthesis); moving electrons to convey an electric current in solar cells; and, finally, moving both electrons and protons to generate solar fuels.

In parallel, Rybtchinski collaborates with a number of other Institute scientists on creating hybrid solar conversion systems composed of organic molecules, catalysts and nano-particles. “In this work, we are solving basic science questions that are key to finding practical alternative energy solutions,” he says. “The need to find such solutions is what ultimately motivates us all.”

The long-term goal is not just to achieve plants’ efficiency at using sunlight – already a formidable challenge – but to overtake them. “Plants don’t run around the way we do, so our energy needs are vastly higher,” Rybtchinski explains. “Therefore, we need to generate much more energy and with greater efficiency.”   

 On a Personal Note

Born in Kiev, Ukraine, Dr. Boris Rybtchinski received a B.Sc. in chemistry from Kiev State University in 1992. He then immigrated to Israel and, in 1993, embarked on graduate studies at the Weizmann Institute under the guidance of Prof. David Milstein. After serving in the medical corps of the Israel Defense Forces, he earned his Ph.D. with distinction in 2002. He conducted postgraduate research at Northwestern University for three years and joined the Weizmann faculty in the fall of 2005. He has received a number of prestigious awards, including the Sir Charles Clore Prize. He lives in Tel Aviv with his wife, Revital, whom he met when both were students at Weizmann, and their son, Gal, several months old. He enjoys sports and reading history books.
 

Dr. Boris Rybtchinski’s research is supported by the Helen and Martin Kimmel Center for Molecular Design; the Alternative Energy Research Initiative; Mr. and Mrs. Yossie Hollander, Israel; the Robert Rees Applied Research Fund; Sir Harry Djanogly, CBE, UK; and Mr. and Mrs. Larry Taylor, Los Angeles, CA. Dr. Rybtchinski is the incumbent of the Abraham and Jennie Fialkow Career Development Chair.