^{Guenter ALBRECHT-BUEHLER. Ph.D. Robert Laughlin Rea Professor Emeritus, Feinberg School of Medicine Northwestern University.}

For me as a freshly baked PhD physicist, who was increasingly fascinated by biophysics, the biology of animal cells seemed particularly attractive. For more than half a century, biology had been dominated by genetics and biochemistry. As a result, the leading biologists of the time focused on molecules, bacteria, and flies, convinced that the answers gleaned from these research targets would uncover all fundamental secrets of life. I was told that Francois Jacob (1920–2013) had famously formulated this belief with the words: «What is true for E. coli, is true for the elephant.»

Being especially fascinated by the strange movements of human and animal cells, I had my doubts. Obviously, the cells in the human body moved in the most complex ways and for the most mysterious reasons. However, they neither used flagella like E. coli, nor did they have little muscles to flex like Drosophila flies. I had learned this from the pioneering work of Michael Abercrombie (1912–1979). He had found that animal cells, while migrating on a flat glass surface, extended and retracted three universal surface extensions.

One class of cellular surface extensions were the so-called «blebs». They were hemispherical «bubbles» that the cells blew up and deflated again. A second kind of extensions, the so-called «filopodia» were long, thin needles that the cells waved around, reminiscent of probing tentacles. Finally, and perhaps most bewilderingly, the cells pushed thin sheets of cytoplasm, called «lamel-lipodia», predominantly in the direction of migration and parallel to the plane substratum on which they migrated. Periodically, however, they folded the lamellipodia back onto their main body, where they fused with it. That was called «ruffling», and it was particularly intriguing, because a cells lamellipodia never fused with the body of another cell that it happened to touch. It was as if the cells had a sense of «self».

Whatever the role of these cytoplasmic projections in the mechanism of locomotion of non-muscle cells, it was clear, that one would not understand them better by studying muscle cells and the molecular interactions between the muscle proteins actin and myosin of the Drosophila fly. After all, when migrating, the non-muscle cells extended their cytoplasm. In contrast, the muscle cells could only contract their bodies. They could not expand them…

This was one of those moments in science, when the method of stretching the established common theories cannot fit the novel data. A breakthrough was needed, which required ignoring the accepted wisdom and starting afresh.

Yuri Vasiliev and his friend and famous mathematician Israel Gelfand did just that. They ignored the widely researched question: «How does the molecular motor of muscle cells deliver the energy required for locomotion?» Instead, they asked the profound and entirely novel question: «What determines inside the amorphous body of a migrating non-muscle cell, where its next front is?» Thus, they replaced the familiar question about the energy spent on locomotion with the novel question about the spatial information guiding it.

It was not an academic question. Yuri Vasiliev answered it in very practical terms. The beautiful flower of Col-chicum autumnale had protected itself for millions of years from grazing animals by spiking its leaves and fruits with a poisonous alkaloid, called colchicine. Since the drug inhibits cell division, it had become an important component of cancer chemotherapy. Yuri Vasiliev, since 1963 a Professor of Biology at the Cancer Institute at the State University of Moscow, had seen its use in medicine many times. However, he wanted to understand its function better. In 1970 he found that animal cells exposed to colchicine not only stopped dividing, they also stopped directed locomotion, even though all parts of their bodies continued to move quite well in the presence of the drug.

Until that point, nobody had proposed a link between cell division and locomotion. To solve the riddle, scientific minds were needed, who ignored the conventional wisdom, which tried to explain animal cell movement with muscle proteins, and cell division with chromosome behavior. Together with Israel Gelfand, Yuri Vasiliev found the common denominator. Colchicine disassembled the microtubules, one of the three major components of the «cytoskeleton».

The discovery explained the inhibition of cell division, because the mitotic spindle consisted predominantly of microtubules. What was entirely new was the finding that microtubules also played a central role during the long time in a cells life between one division and the next. During this so-called «interphase» microtubules were indispensible for designating a part of a non-muscle cells body as its front. More generally speaking, the «polarity» of non-muscle cells depended on their intact microtubules. Correspondingly, the disassembly of their microtubules prevented fibroblast from expressing directed locomotion, and epithelial cells from differentiating between their apical and basal faces.

In 1970, Yuri Vasiliev and Israel Gelfand published their finding that microtubules linked the deployment of biochemical energy by animal cells to their ability to handle spatial information. It was one of those rare discoveries that points future research into entirely novel directions. At the same time it needed not fear that the more sophisticated concepts and advanced experimental methods of that very future would ever overturn it. Arguably, Yuri Vasiliev s finding shares this exceptional quality with Ivan Pavlovs (1849–1936) discovery of classical conditioning.

What may be equally impressive as the discovery itself, may be the atrocious conditions under which Yuri Vasiliev and his students had to work. I saw them first hand in October 1986, when Israel Gelfand invited me to speak at a Workshop organized by the Academy of Science, USSR. At that time I also gave a lecture to the joint group of Yuri Vasiliev and Israel Gelfand at Moscow State University. They showed me their totally antiquated labs. They showed me the single ancient microscope that all of them had to share, and the small film camera that they used for their timelapse observations of cell movements.

On the other hand, only once in my life did I have the privilege of lecturing to a group of such power and life of intellect. That, too, reminded me of Pavlov. All the equipment he had available to make one of the most momentous discoveries of neurobiology were a few dogs, a few feeding bowls, and a handheld bell.

Come to think of it, Galileos telescope had pathetic lenses. Mendel had only a small flower bed of pea plants. Henrietta Leavitt showed the way to measure the true size of the universe with a magnifying glass and a stack of old photographs of the sky. Barbara McClintock had an old microscope, a knife, and a small plot of land for her maize plants to prove the genomes life and creativity. Rosalind Franklin had only a self-build X-ray tube with no radiation protection. Watson and Crick had no equipment at all. I wonder whether it is always like that.