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Stochasticity Open Seminar April 25, 2017, 14:00

Open Seminars of the Research Group on

 

Stochasticity and Control in the Dynamics and Diversity of Immune Repertories: an Example of Multi-Cellular Co-Operation

 

Tuesday, April 25, 2017, 14:00

at the Israel Institute for Advanced Studies, Room 128

 

 

Using technology to negotiate genotype-phenotype interface in health and disease

 

Izhak Haviv (BIU)

 

This talk aims to compare hypothesis driven research with high throughput sample profiling. I make an argument that the principal paradigm, responsible for the significant life span increase, offered by medical research, is the Koch postulates. Unfortunately, for some diseases such as cancer, this paradigm failed to provide the same level of cure. Simply knowing that cancer cells grow more, die less, and migrate is just not enough to develop molecules with sufficient therapeutic window to exhibit efficacy. We do know that cancer is a disease of DNA sequence, and had extensively catalogued the cancer genome, and yet, cancer mortality relents. While the abstract principle that cancer cells have altered DNA prevails, the actual sequence changes that occur in each case are so variable, that there is really no two cancer cases that formally are of identical etiology. Therefore, novel and commonly effective drugs only benefit a small fraction of the patients, thus the term “personalized medicine”. Furthermore, while novel cures appear very promising in pre-clinical models, for most cancer therapies, acquired resistance is the common case, and cure simply means delaying the end. This exceptional resilience to cure is shared between cancer and some viral infections, and the common mechanism is evolution. One simple conclusion is that cancer would be easier to prevent than cure. However, two methods have overcome this evolutionary plasticity challenge in the case of viral infectious diseases, and are starting to also impact cancer care. The first is combination therapy, and the second is evoking an immune reaction against the diseased cells. The field of genetics was founded on the attempt to understand outlier phenotypes. However, evidence in different fields of genetics point to the joint effect of both nature as well as nurture, i.e. the character traits of an organism are collectively contributed to by both innate qualities, such as DNA sequence, as well as the individual's personal experiences ("nurture" in the sense of environmental factors of lifestyle or lifetime exposure). We found multiple modes, by which cancer exploits both nature (sequence mutations) as well as nurture (cancer stromal neighboring cells and epigenetics) to derive novel variants that would evade therapy via simple evolutionary principles. The argument is therefore, that widely effective cancer cure would require integration of multiple parallel approaches, as well as significant widening of the way we interpret the cancer genomic information.

 

 

Related Research Questions

 

  1. Why do we conduct and support science; for education and professional training, for insight and accumulation of knowledge, or to benefit mankind?
  2. If the third answer to the previous question is partially true, how can we make research more effective in delivering benefit?
  3. What is the limiting step to more effective cancer cures; funding, knowledge, or paradigm change?

 

 

Suggested Reading

 

Patch AM et al. 
Nature. 2015 Nov 19;527(7578):398.
 
Helleday T, Eshtad S, Nik-Zainal S.
Nat Rev Genet. 2014 Sep;15(9):585-98. doi: 10.1038/nrg3729. Epub 2014 Jul 1. Review.
 
Tran E, Ahmadzadeh M, Lu YC, Gros A, Turcotte S, Robbins PF, Gartner JJ, Zheng Z, Li YF, Ray S, Wunderlich JR, Somerville RP, Rosenberg SA.
Science. 2015 Dec 11;350(6266):1387-90. doi: 10.1126/science.aad1253. Epub 2015 Oct 29.
 
Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, Ibrahim F, Bruggeman C, Gasmi B, Zappasodi R, Maeda Y, Sander C, Garon EB, Merghoub T, Wolchok JD, Schumacher TN, Chan TA.
Science. 2015 Apr 3;348(6230):124-8. doi: 10.1126/science.aaa1348. Epub 2015 Mar 12.
 
Goudey B, Abraham G, Kikianty E, Wang Q, Rawlinson D, Shi F, Haviv I, Stern L, Kowalczyk A, Inouye M.
PLoS One. 2017 Mar 10;12(3):e0172826. doi: 10.1371/journal.pone.0172826. eCollection 2017.
 
Farmer PE.
N Engl J Med. 2013 Dec 19;369(25):2424-36. doi: 10.1056/NEJMsa1310472. No abstract available.
 

 

 

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