Transcript bmen1001

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 MUTATION
IN 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 sequencespecific 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 “postgenomic” 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 selfassembly 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