For centuries, biologists have been hard at work - each studying a tiny piece in the great puzzle of nature. The underlying belief has been that the examination of smaller and smaller parts of nature would, when all the findings were assembled, explain the whole. But so many bits and pieces have accumulated by now that scientists are beginning to wonder how the puzzle will ever be put together. Ph.D. student Na'aman Kam of the Weizmann Institute's Computer Science and Applied Mathematics Department as well as its Immunology Department is trying to tackle just this aspect of biology. In the process, he has highlighted the importance of aiming for the whole picture: without it, some pieces may get lost on the way.
As a student, Kam came across a method for visually representing the behavior of such complex systems as aircraft, cellular phones, and automobiles. This method, called Statecharts, was developed by Prof. David Harel of the Computer Science and Applied Mathematics Department at the urgent request of the Israel Aircraft Industries, who were having trouble organizing information on a fighter jet project. Harel came up with the idea of putting all the information into computerized charts that would pack in all the possibilities of action. 'For instance,' explains Kam, 'we know that when we press one button at the side of our watch we will see the date and if we press two buttons we will hear a sound. But have engineers determined what will happen if we press three or all four buttons, or has this been left to chance? Similarly, we may know how a cell in our body reacts to a certain stimulant, but we don't always take into consideration the range of possible combinations and interactions. This is something that is difficult for us as humans and easier for computers.'
Kam, who at the time was studying for an M.Sc. in biology and mathematics under the joint supervision of Prof. Irun Cohen of the Immunology Department and Harel, quickly recognized the potential of applying Statecharts to biological systems. As a test model, he took the immune system - more specifically, its patrol units called T-cells, which among other functions, identify and attack pathogens invading the body. Although there was an explosion of experimental data on how these cells become activated, no mechanism existed to make possible an all-inclusive, comprehensible picture.
Using the language of Statecharts, Kam set to work building a model that maps how each component participating in the process of T-cell activation changes its internal state according to signals received from other system components or those arriving from the external environment. He tested this model using a software tool called Rhapsody, also based on Harel's ideas, (developed by I-Logix, Inc., which Harel co-founded).
It worked fine, except for one quirk. In our body and in lab experiments, after a T-cell has been activated, it can return to an inactive, stable, 'memory' state; yet in Kam's model, the memory state was unstable, and the T-cell jumped back to an activated state. 'If the model doesn't work, it means something is missing,' says Kam. 'Either the model has uncovered the need to answer a biological question or a piece of information has been overlooked.' In this case, after extensively reviewing the relevant scientific literature, Kam found a piece of information that had commonly been overlooked: when moving from an activated to a memory state, the T-cell loses a receptor that plays a crucial role in its activation. After including this piece of information, the model worked properly. The study won the Best Paper Award of the IEEE Symposium on Visual Languages and Formal Methods, Italy, 2001.
Kam is now working on one of biology's ultimate dreams: to describe the development of an organism in its entirety, with all influencing factors and the interactions between them taken into consideration. His idea for this ambitious project took root last year and quickly captured the interest of an interdisciplinary team of scientists from the Institute and abroad. Jointly supervised by Prof. Amir Pnueli and Harel, both of the Computer Science and Applied Mathematics Department, and Institute immunologist Prof. Cohen, Kam has also forged a unique collaboration with Prof. Michael Stern of Yale University School of Medicine and Prof. Jane Hubbard of New York University.
The right worm for the job
The object garnering the collective attention of this varied team is none other than a tiny worm called C. elegans, whose most recent claim to fame was being the first multicellular organism to have its genome fully sequenced.
It wasn't chosen at random. The trick in searching for an appropriate experimental model is to find a system that is relatively simple and yet complex enough to provide relevant insights into broader fields of biology, including how our bodies work. C. elegans offers important experimental advantages in this respect: it has a small number of cells, 959 to be exact, which are generated from the fertilized egg by an invariant pattern of cell divisions and movements; it is transparent, allowing all of its cellular processes to be followed in living animals; and finally, it has a short life span, reaching adulthood in a mere three days. Equally important, numerous studies have shown that biologically we humans have much in common with this worm.
Research in the past decade has increasingly demonstrated a striking thread of unity at the molecular level of life, where many of the molecules have similar structure and function in all multicellular animals. Since worms and other 'simple' organisms are relatively easy to study, they offer an ideal research setting for understanding the molecular workings of the human body.
All this explains why C. elegans has been studied in a wide variety of fields, from cancer-related research to aging. In tackling the challenge of bringing these data together, Kam has started out by focusing on one aspect of this well-studied worm, using the computerized tools mentioned above to put together a clear picture of the developmental processes underlying its reproductive machinery. He still has a long way to go, however, and is currently working closely with the two U.S. labs headed by Stern and Hubbard. Offering their experimental expertise, these scientists are presently assisting in the construction and analysis of the model, and will later test its validity, using experimental trials to examine predictions emerging from the model.
Once this task is completed, many others will follow - perhaps eventually leading to an accurate blueprint of biology's most famous worm. And as for the even bigger picture? Who knows, say the scientists. Hopefully, we may one day even be able to chart the intricate networks giving rise to that incurably inquisitive organism - Homo sapiens.
Prof. Harel holds the William Sussman Professorial Chair. His research is supported by the Arthur and Rochelle Belfer Institute of Mathematics and Computer Science.
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 of Lincolnwood, Illinois.