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Home | Seminars and Symposia | Past seminars/symposia: Tuesday, April 11, 2006

DTC Science and Technology Innovators Lecture Series

Systems Biology: Past Genomics Medicine With Implications for Cancer

by

Stuart Kauffman
Institute for Biocomplexity and Informatics
University of Calgary

Tuesday, April 11, 2006
4:30 p.m. Reception
5:00 p.m. Seminar

402 Walter Library

Kauffman

WE HAVE ENTERED THE POST-GENOMIC ERA. The 30,000 human genes lie spread before us. We now confront the central task of Systems Biology: How do these genes and their products interact within and between cells to control normal development of the fertilized egg to the adult, and disease processes such as cancer? Worldwide, a gathering effort in Systems Biology is growing in momentum. The task promises to require several decades at least, for science has never sought to understand systems with perhaps a hundred thousdand molecular species interacting in complex ways dynamically and morphologically. Stuart Kauffman will present an overview of Systems Biology. Thereafter, he will discuss in qualitative terms mathematical models of large genetic regulatory networks. What we know is the following: the fertilized egg divides and the cells "differentiate" to form about 260 distinct cell types in the human adult. Genes make RNA make proteins. Different cell types differ because different genes are active in them, thus the cells express different sets of proteins. It has been known for 45 years that the protein made by one gene can bind to the DNA next to another gene and turn it on or off. Thus the genetic system is some vast regulatory network of genes and their products controlling one another's activity. Work on large model genetic networks for over the past 40 years has demonstrated that such networks behave in three regimes: ordered, critical, and chaotic. As Kauffman will describe, the ordered regime is astonishing — our intuitions for what is required for orderly dynamical behavior have been deeply wrong, so wrong that the self organization of the ordered regime suggests that evolution has two sources of order, natural selection and self organization. Two hypotheses have emerged from this work. Cells, as Kauffman argues, are likely to be in the ordered regime but nearly critical. Recent evidence is beginning to support this hypothesis. If true, it is the first "law" of cell dynamical behavior that we have discovered. Second, such networks settle down to recurrent patterns of gene expression, rather like streams all flowing to the same mountain lake. These "lakes" are called "attractors". A network typically has multiple attractors. A central hypothesis is that the 260 cell types of a human correspond to 260 distinct attractors, each with a unique pattern of gene expression. Perturbations to gene activities and mutations to the network, can cause the system to jump between attractors or create new attractors. This bears on cancer, where it is a reasonable hypothesis that the mutations in cancer cells create new attractor cell types, but leave most "old" or normal cell types intact. This suggests the critical possibility that chemical perturbations might cause cancer cells to differentiate into normal cells, which is called differentiation therapy. Two new facts about cancer are of central interest. First, it is now known that many cancers, if not all, have cancer stem cells. Killing most of the cells of a cancer will not cure the cancer unless the stem cells are also removed. Second, differentiation therapy already works. Treatment of acute mylogenous leukemia with vitimin A causes the cancer cells to differentiate into normal blood cells. Kauffman will describe a program to screen tens to hundreds of thousands of molecules to seek those that cause different cancer stem cells to differentiate into normal cells or to die. Differentiation therapy, along with stem cell regenerative medicine, may be the two most immediate health benefits of Systems Biology.

 

Stuart A. Kauffman has two bachelor of arts degrees in philospophy and psychology and physiology from Dartmouth (1960) and Oxford (1963) and received his M.D. at the University of California, San Francisco in 1968. He is currently the director of the Institute for Biocomplexity and Informatics at the University of Calgary. Previously he was a professor at the University of Pennsylvania and later a Senior Professor at the Sant Fe Institute. He is a MacArthur Fellow and a holder of founding patent in Combinatorial Chemistry Dr. Kauffman has published over 100 papers and has written four books. His main areas of research are: developmental genetics, theortetical biology, evolution and the origin of life.