Visualizing Network Models for the Systems Biology of Aging

1
Visualizing Network Models for the Systems
Biology of Aging

• John D. Furber
• Legendary Pharmaceuticals
• johnfurber_at_legendarypharma.com
• Symposium on the Systems Biology of Aging
• Arizona State University
• 6 December 2008

2
Visual Network Models of Human Aging

• What is Aging?
• Designing Interventions
• Systems Biology and Network Models
• Pathways and Targets
• Visualizing the networks

3
What is Aging? Senescence?
4
What is Senescence?

• State Every organism is in a state or condition
  which changes with time.
• Process Life development proceed by metabolic
  reactions.
• Accumulation Some by-products of metabolism may
  accumulate and change the state of the organism.
• New State Senescent individuals are usually
  slower, weaker than young adults.
• Living creates aging.
• Aging is a process. Senescence is a condition.
• Accumulated metabolic by-products cause the
  condition to be senescent. Computationally and
  biologically, developmental programs of
  differentiation are equivalent to accumulations
  of "damage." They are changes of state.
• Surprisingly, it might prove easier to repair or
  reverse the senescent condition than it would be
  to "slow-down" the aging process.
• i.e. Rejuvenation might be easier than Slowing
  Aging.

5
Systems Biology Viewpoint

• Seeing the Whole Picture
• Creating a Network Model
• (NOT necessarily a Simulation Model )
• Assemble research results of many scientists
• Network of Processes acting on Entities
• Interactions across scales
• Molecular
• Cellular
• Tissue
• Organ
• Whole person and diseases

6
Halting Growth is Challenging

• Unicellular ancestors could grow divide, when
  resources were available, diluting damaged
  molecules.
• Young people are programmed to grow into adults.
• Young adults must transition to a developmental
  program of static-size
• Gene expression patterns must change
• Not sure if side-effects cause aging problems
• Gene exp control is achieved through physical
  chemical interactions of chemical substances.

7
Parts of a Typical Animal Cell

• Molecular Cell Biology. (4th ed) Lodish, et.al.

8
(No Transcript)
9
Parallel Pathways Produce Senescence

• Glycation, oxidation, and crosslinking of
  extracellular proteins
• gt Stiffer blood vessels promote stroke and heart
  disease
• Intracellular Aggregates clog proteasomes and
  lysosomes
• gt Damaging ROS produced by aggregates.
• gt Impaired repair and turnover of macromolecules
  and organelles
• Increased redox potential
• gt alters signaling and enzyme activities, and
  erodes telomeres
• Chromatin alterations change gene expression
• Stem cells stop dividing or die
• gt tissue wasting, neurodegeneration, and organ
  malfunction.
• Inflammatory cascades promoted by damaged
  molecules and sick cells.
• Neuroendocrine and immune systems degrade.

10
Network Pathways may show Opportunities for
Intervention

• Major opportunities
• ECM Glycation/crosslink breakers.
• Enhance ECM turnover fibroblast-like cells
• Enhance intracellular turnover lysosomes
  autophagy.
• Dissolve/remove aggregates outside of cells.
• Rejuvenate stem cells niches
• Delete anergic T-cell clones.
• Blood factors to enhance cell health.

11
Network Pathways show Opportunities for
Intervention

• Minor opportunities
• Exercise, relax, get enough sleep
• Fasting, calorie restriction
• Good nutrition
• Anti-oxidant foods drugs
• Anti-inflammatory foods drugs

12
However none of this came from a computer
program or simulation

• Hand - drawn chart base upon reading literature
  and talking to scientists
• Visual "notes" and teaching tool
• Not a simulation
• Not a picture of a cell

13
(No Transcript)
14
Diagram -gt Knowledge

• Events and pathways can be searched with keywords
  on PubMed.
• Eventually the Aging Network diagram will contain
  favorite references to representative papers in
  scientific literature.
• PubMed Related Articles button
• Could a program proofread the network for
  logical consistency?

15
Improving a Work in Progress

• Systems of community collaboration
• Tools for easier editing
• Client-side or server-side?
• Human must be able to override automated layout
• Swapping versions (copy modify)
• A visual counterpart to scientific discussions
• Seeking consensus
• Posting overlays with authorship
• Finding areas of multiple plausible explanations
• Wiki web sites?
• Wikis are story-based, not alternative images
• Open-source licenses

16
Summary Opportunities for Rejuvenation
Developments

• Glycation/crosslink breakers (ND, ED)
• Anti-Lipofuscin drug (ND)
• Mitochondria treatment (GT)
• Lamp2a Increase availability (ND)
• Enhance Lysosomal enzymes (ND)
• Dissolve/remove aggregates outside of cells (ED)
• Rejuvenate stem cells (ND or ECGT)
• Blood treatments enhance immune cell health
  (CP)
• Differentiation agents to regulate chromatin (ND,
  ED)
• Buy time with diet, exercise, hibernation. (CP,
  ND)
• New, Existing Drug Gene Ther Clin Proc
  ExCellGeneTher

17
Summary

• Aging research has been slow to produce
  therapeutic human results.
• Parallel pathways cause senescent changes or
  damage.
• Systems Biology provides an overview.
• Identify Targets
• Opportunities to develop effective interventions

18
SEEING THE WHOLE PICTURE

• Perhaps the most difficult changes we face in the
  transition to systems biology are the social
  ones. Today, most biological research is
  unapologetically reductionist. Efforts by the
  National Institutes of Health to encourage more
  ambitious, multidisciplinary research have met
  with resistance from study-section members who
  are less than enthusiastic when evaluating these
  proposals. We are victims, I fear, of our own
  success.
• H.S. Wiley. "Systems Biology" The Scientist.
  20(6) p 52.

19

• The most successful scientists are those who
  asked the "right (i.e., focused) questions" and
  proposed a scope of work that grant-review panels
  felt could reasonably be accomplished in three to
  five years. With the tools available over the
  last 20 years, this forced most of biology to
  become highly specialized. The more we
  investigated a subject area, the more complex it
  became, forcing us to work on increasingly narrow
  areas of research.
• H.S. Wiley. "Systems Biology" The Scientist.
  20(6) p 52.

20

• Posing a big, ambitious question was probably the
  fastest way to have a grant application end up on
  the reject pile. Perhaps reductionism was needed
  when you had to keep all pertinent facts in your
  head or a lab notebook, but technology has now
  provided us with a way to ask bigger, more
  important questions. We must not allow ourselves
  to be ruled by yesterday's scientific approaches.
• H.S. Wiley. "Systems Biology" The Scientist.
  20(6) p 52.

21

• Who is going to drive systems biology to the next
  level? We have become comfortable with our
  specialized niches, and the availability of new,
  high-throughput technologies is unlikely to tempt
  most biologists to venture into a new area of
  research. As is usually the case with scientific
  revolutions, the cause will most likely be passed
  to the new generation.
• H.S. Wiley. "Systems Biology" The Scientist.
  20(6) p 52.