THE NEW MEDICINE AND BIOLOGY

Will they be Information Sciences?

Dimitris Anastassiou

“Engineering in Medicine” (BMEN 1001) Lecture

September 16, 2002

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)

NEED FOR NEW GENERATION OF CROSS-DISCIPLINARY RESEARCHERS

Barrier: Two isolated and mutually intimidating research areas:

– Biological/Health Sciences– Engineering/Mathematics/Computer

Science

• NIH: Biomedical Information Science & Technology Initiative

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 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

• 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 MUTATIONIN RED BLOOD CELLS

A GENE FOR SPEECH?

• From The New York Times front page, 10/4/01

…The newfound gene's product is a protein that binds to different sites along the DNA, signaling the cell to activate the nearby genes. Identifying the set of genes that is switched on by the protein could yield a deep insight into how a distinctive faculty of the human brain is constructed…

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.

MAGICAL INTERPLAY BETWEEN DNA & PROTEINS

LIMITED USE OF “ONE-GENE-ONE-DISEASE”

• Complex system of molecular interactions

• Emergent properties of complex system at higher level of abstraction

• Reductionism versus holism

TYPES OF BIOLOGICAL INFORMATION

• 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.

GENE CHIPS

• Simultaneously monitor activity of many genes.

• Observation of activated genes under various conditions (tissues/times/diseases, etc.)

• Compatible with systems-based “post-genomic” paradigm.

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

INTRACELLULAR “BRAIN”?

ECB: Information received from different sources can converge on [integrating] proteins, which convert it to an onward signal… In this way, the intracellular signaling system may act like a network of nerve cells in the brain … interpreting complex information and generating complex responses.

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: “Stem Cells” can be directed 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.

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

“HACKING” THE CELL’S CIRCUITRY

• Barrier: Enormous complexity• Similarity with integrated electronic circuits

Arkin: “Good engineers in the 1960s could probably understand all the circuitry that people had built. But when integrated circuits were developed, that became impossible. There were just too many pieces to put together”

GENOMIC INFORMATION SYSTEMS LABORATORY

Vision: Discovery of high-level principles and patterns in biomolecular circuits allowing external control mechanisms.

Approaches to biomolecular network analysis:– Supercomputers (at Health Sciences Campus)– VLSI circuit simulation– Telecommunication Network Based Analysis