THE NEW MEDICINE AND BIOLOGY Will they be Information Sciences? Dimitris Anastassiou “Engineering in Medicine” (BMEN 1001) Lecture October 2, 2006

WHAT HAPPENS INSIDE THE LIVING CELL “If you want to understand life… think about information technology” Richard Dawkins “The Blind Watchmaker” 1986

PARADIGM SHIFT A Biologist’s View of the 21st Century “The beginning of the 21st Century finds us poised at a grand inflection point in biological sciences and medicine. The way we think about and practice biology and medicine and the social consequences of work in these fields are changing in an unprecedented manner. These changes have been catalyzed, in large part, by the realization that biology is an informational science” Leroy Hood, M.D., Ph.D.

POST-GENOMIC ERA “The completion of the human genome project itself is a marvelous milestone, and it's the starting gate for … the postgenomic era … It has to do with how we understand the integrated behavior of all genes, turning one another on and off in cells and between cells, plus the cell signaling networks within and between cells” Stuart Kauffman, M.D. (Scientific American interview, 2000)

CROSS-DISCIPLINARY FIELDS Bioinformatics (using computers to store, organize, and analyze biological data Computational Biology (using computers to interpret data and infer biological mechanisms) Systems Biology (viewing biological mechanisms as components of integrated systems of multiple factors)

WHAT DOES MPEG-2 HAVE TO DO WITH GENOMICS?  Just like a DVD sequence of …001101100111… obeying the “MPEG-2 syntax” is played on a DVD player resulting in a movie So is a DNA sequence of …ATTCGGTCAG… obeying a particular syntax played in a yet little-known “player” inside the cell, resulting in a living organism.

DNA

WE ARE ALL SIMILAR

GENOMES Blueprint of life: The totality of DNA, including all genes Several organisms sequenced, e.g. E. coli K 12 For humans, basis for New drugs and treatments New diagnostic tests

GENES MAKE PROTEINS

THE GENETIC CODE

PROTEINS Strings of letters derived from a 20-character alphabet, forming a one-dimensional backbone. Fold into three-dimensional molecular machines, catalyzing the chemistry of life and giving shape and form to the body.

SELECTIVE BINDING OF PROTEINS

EXAMPLE: HEMOGLOBIN Each protein molecule contains two copies of α globin and two copies of β globin

Beginning of protein-coding region of β-globin gene

MUTATION RESPONSIBLE FOR SICKLE-CELL ANEMIA

RESULT OF MUTATION IN RED BLOOD CELLS

GENE REGULATION Genes are activated by the sequence-specific binding of regulatory proteins (transcription factors) at particular target sites on DNA, according to complex logic Transcription factors are themselves products of other genes, regulated according to their own rules.

INTERPLAY BETWEEN DNA & PROTEINS

SYSTEMS BIOLOGY L. Hood: Biologists have studied genes and proteins — one at a time — for the last 40 years… A third type of information arises from biological pathways and networks — groups of genes or proteins that work together to execute particular biological functions.

THE CELL AS A COMPLEX INFORMATION SYSTEM …For example, your brain is a network that gives rise to emergent properties such as memory, consciousness and the ability to learn. “Systems biology” requires that all of the gene or protein elements in a particular informational pathway be studied simultaneously to follow the informational flows — if we are ever to understand the systems properties. It is achieving an understanding of biological systems that constitutes the major challenge for biology and medicine in the 21st Century.

EXAMPLE OF USEFUL TOOL: MICROARRAYS Simultaneously monitor activity of many genes. Observation of activated genes under various conditions (tissues/times/diseases, etc.) Compatible with systems biology aims.

Example: Effect of a set of genes on cancer 4 6 1 18 5 2 9 22 15 17 Consider three particular genes with binary expression states G1, G2, G3 and a phenotype C, such as a particular cancer For each expression state, count the number N0 of healthy (C = 0) tissues and the number N1 of cancerous (C = 1) tissues. Cancer may be associated with particular joint expression states of multiple genes!

INDIVIDUALIZED MEDICINE Individual Genome Scan Identification of specific mutations Individualized treatment

GENE EXPRESSION PROFILING Example: Identification of distinct types of cancer Alizadeh et al: “Our study shows that the two subgroups differentially expressed entire transcriptional modules composed of hundreds of genes, many of which could be expected to contribute to the malignant behavior of the tumor”

GENE REGULATORY NETWORKS Web of Mutually Regulating Genes Integrated with intracellular signaling pathways Output: Timed set of gene activation/deactivation events “Script” that coordinates the execution of vital intracellular processes

SIGNALING PATHWAYS

CELL DIFFERENTIATION Multicellular organisms develop by self-assembly of cells “differentiated” into many cell types Decision to differentiate into particular type uses communication systems involving receptors and signaling proteins

MUSCLE CELLS HAVE THE SAME DNA AS …

… BRAIN CELLS

DEVELOPMENT Discovery of differentiation mechanisms facilitated by tracking which genes are “on” or “off” in each cell type at each stage of development “Regenerative Medicine” vision: Direct “Stem Cells” to divide and grow into specific tissues.

THE “HARDWIRING” OF DEVELOPMENT Davidson et al: The gene regulatory apparatus that directs development is encoded in the DNA, in the form of organized arrays of transcription factor target sites. Genes are regulated by interactions with multiple transcription factors .... These systems are remarkably complex. Their hardwired internal organization enables them to behave as genomic information processing systems.

EXAMPLE: Sea Urchin “Endomesoderm Gene Network” (Davidson Lab, Caltech)

VISION OF NEW MEDICINE Kauffman: “My dream is the following: 10 or 20 years from now, if you have prostatic cancer, we will [know its regulatory circuit and] be able to give drugs that will induce the cancer cells to differentiate in such a way that they will no longer behave in a malignant fashion, or they'll commit suicide”

BIOMOLECULAR CIRCUITS www.biocarta.com

Science and Technology Electrical Engineering / Computer Science / Biomedical Engineering E3060 Introduction to Genomic Information Science and Technology