Dr. Elad Schneidman of the Weizmann Institute’s Neurobiology Department likens studying how neurons in the brain communicate to learning a new language just by listening to a native speaker. At first the task seems insurmountable, but little by little we begin to pick up on basic words and phrases that repeat themselves. By the time we understand a thousand or so words, we also have a primitive grasp of the grammar and can incorporate new words as we learn them.

 

To reveal some of the ground rules for neuron activity, the scientists used a mathematical model similar to one commonly used in physics, where it was developed to study the behavior of large numbers of magnets in magnetic fields. An equivalent model is also used in statistics and in machine learning. In all these domains, complex behavior arises from pair-wise interactions between elements – attraction and repulsion in magnets, on and off states in binary variables, firing and silence in neurons. When the scientists first applied the model to small networks, it fit perfectly. Even for large networks, the experimental data seemed to fit fairly well, except for a few points that fell off the scale. Upon closer inspection, however, they realized that the data points that didn’t conform to the model belonged to the most frequently occurring activity patterns, and these reflected more complex grammar. In particular, they reflected dependencies between cells that could not be explained by pair relations alone. As a result, their model was good at predicting the rare “phrases” but less accurate when it came to the common ones. But just as we must learn to say: “I am hungry,” before we progress to ordering a full meal with wine, side dishes and dessert in a restaurant, Schneidman and his team realized that they couldn’t ignore the everyday expressions used in brain communication if they wanted to get a feel for its language. Their challenge was to find a way to deal with the common patterns and the rare ones at the same time.

Surprisingly, making a small change in the mathematical formula led to a very simple and accurate way to infer the grammar of this complex system. The original physics equation encodes the interactions between magnets with the numbers 1 and -1. Instead of representing a silent neuron with a -1 – as though it were a negative magnetic pole – they used a 0. While this may seem to be a mere “accounting” issue, it has a profound effect on the formula’s terms in one special case: that in which the elements in the network are only rarely active. This is exactly the situation in the brain: Most neurons are silent most of the time. Suddenly the common phrases could be interpreted, revealing fundamental interactions between neurons. Differences among the various phrases also enabled the researchers to infer different rules from each of the common patterns.

In fact, from an incredibly complex network of possible interactions, the researchers obtained a picture of basic neural communication that is decidedly sparse, yet extremely accurate. “We could assemble a basic grammar of millions of activity patterns from about 500 common phrases that rely on two-, three- and four-way connections – provided we knew which examples to choose,” says Schneidman. “The grammar of neuron networks is eminently learnable.” He thinks it may be learnable precisely because it seems to work like language. The common, constantly repeated phrases may be the way that neurons gain their communications skills and continue to understand one another.

With this new insight into the nature of neural communication, the researchers were able to decode the visual information carried by large groups of retinal cells. Schneidman believes that this new approach could enable us to obtain a detailed picture of the workings of large groups of neurons in different parts of the brain. This might, eventually, lead the way to reading the information encoded in such networks and point to new approaches to treating neurological disorders.

 

Dr. Elad Schneidman's research is supported by the Jeanne and Joseph Nissim Foundation for Life Sciences Research; the Peter and Patricia Gruber Award; and the J&R Foundation.
 
 
 

“If you want something done, ask a busy person to do it.” On second thought this advice (originally from Lucille Ball), makes quite a bit of sense. So it is no wonder that the protein p53, which works in our cells day and night to keep cancer at bay, has also been handed an important task in embryonic development. This finding emerged from research conducted by Dr. Eldad Tzahor of the Biological Regulation Department, whose expertise includes embryonic development, and Prof. Varda Rotter of the Molecular Cell Biology Department, a pioneer of p53 research.

Sometimes called the “guardian of the genome,” p53 puts the brakes on processes that could lead to cancer when the cell’s genetic material is injured. But scientists who in the past looked for a role for p53 in embryonic development had concluded that its “day job” was keeping it busy enough: “Erasing” the gene in mouse embryos did not affect their development (though, unsurprisingly, they did develop cancer early on). Nonetheless, recent findings hinted at p53 involvement in the process of embryonic cell differentiation, suggesting that the previous conclusion needed reexamining.

“It is illogical to think that a crucial protein like p53 would play no role at all in embryonic development,” says Tzahor. “What actually happens in the mice missing the gene is that the genetic system is completely “rewired” to compensate for the protein’s loss. Other proteins cover for it, and while this enables development to proceed, it also frustrates the efforts of scientists to get at the mechanisms underlying that development.” To overcome this difficulty, the scientists targeted the p53 protein or its activity at only a limited number of sites, and only at certain times, so that the cell didn’t have a chance to cover for the lost protein.

The researchers focused on a group of cells called neural crest cells, which are tied to the development of the face, brain and peripheral nervous system. These early cells differentiate into a number of types, including nerve cells, facial cartilage, pigment-producing cells and more. Before their rapid differentiation, these cells undergo another process, called epithelial mesenchymal transition (EMT), which enables them to begin migrating from their original site in the neural tube – the embryonic template of the central nervous system – to the facial area.

This key process is similar in many respects to processes that cancer cells undergo when they become malignant. And this suggested to the researchers that p53, which is found to malfunction in a high percentage of cancers, might play a role in regulating EMT. To investigate, Tzahor’s group, which included research students Ariel Rinon and Elisha Nathan, and Dr. Rachel Sarig, first asked whether p53 does, after all, play any sort of role in embryonic development. They found that mouse embryos lacking p53 did indeed have mild defects in their facial structure. Next, the team used chicken embryos to pinpoint both the timing and location of p53 activation. Although the protein was present in the neural crest cells, they discovered that it was silenced for the duration of the EMT process.

The researchers concluded that the reduction in p53 was a necessary condition for EMT. To investigate further, they artificially stabilized levels of the protein; and this was the result: EMT was indeed reduced with fewer neural crest cells migrating out of the neural tube, there was a drop in the expression of EMT-related genes and there were structural defects in the face and brain. Conversely, when the researchers delayed p53 activity, they found an excess of neural crest cells along with increased proliferation. Additional experiments with mouse embryonic cells by research student Alina Molchadsky in Rotter’s lab confirmed these findings: Without p53, there is an increase in the expression of genes tied to EMT as well as those involved in cell division. These findings recently appeared in the journal Development.

Neural crest cell migration in a chicken embryo

Tzahor: “p53 puts the brakes on cell division, and this is what prevents cancer. Its levels need to drop for neural crest cells to divide and migrate, but a drop beyond that which takes place naturally during EMT is harmful as well.”

The study’s findings hint that p53 links two parallel developmental processes – cell division/proliferation and EMT. But they may also have relevance for cancer studies: “We have known for a long time that cancer processes are similar to those of embryonic development, only deregulated and uncontrolled,” says Tzahor. “But much less is known about the connections between p53, cell migration and tumor growth. Our study has not only identified yet another job assigned to p53, it also points to promising new directions in cancer research.”
 

Prof. Varda Rotter's research is supported by the Yad Abraham Research Center for Cancer Diagnostics and Therapy, which she heads; the Women's Health Research Center, which she heads; the Jeanne and Joseph Nissim Family Foundation for Life Sciences; the Leir Charitable Foundations; the Centre Leon Berard Lyon; Donald Schwarz, Sherman Oaks, CA; and the estate of John M. Lang. Prof. Rotter is the incumbent of the Norman and Helen Asher Professorial Chair of Cancer Research.

Dr. Eldad Tzahor's research is supported by the Kahn Family Research Center for Systems Biology of the Human Cell; the Helen and Martin Kimmel Institute for Stem Cell Research; the Kirk Center for Childhood Cancer and Immunological Disorders; the Jeanne and Joseph Nissim Foundation for Life Sciences Research; the Yeda-Sela Center for Basic Research; the estate of Jack Gitlitz; the Women's Health Research Center funded by the Bennett-Pritzker Endowment Fund, the Marvelle Koffler Program for Breast Cancer Research, the Harry and Jeanette Weinberg Women's Health Research Endowment and the Oprah Winfrey Biomedical Research Fund; and the estate of Fannie Sherr. Dr. Tzahor is the incumbent of the Gertrude and Philip Nollman Career Development Chair.