Monthly Archives: October 2011

Cancer, Stress, Genomic Treatments & Steve Jobs

Of the billions of letters making up our life-code a few simple mistakes can cause a cell to stop following the rules, multiply endlessly and destroy it’s host eco-system, you. What can introduce such mistakes in our DNA? The riskiest time being when DNA is copied, a completely molecular-mechanical processes, something that happens billions of times each day in our bodies. It then comes as no surprise that given enough time the likelihood of cancer only increases. However, life is so incredible that it’s managed to develop ingenious ways to spell-check and prevent these mistakes. One of the more rockstar mechanisms are Telomeres, buffer regions at the ends of our chromosomes.

Telomere Caps

Because replication of our chromosomes begins near the center and works itself towards the ends, the two strands of DNA tend not to match up just right at the edges. This is where telomeres reside with their repetitive regions. The idea is it wouldn’t matter if we loose some of them, which is what happens, telomeres shorten over time. Recent research however, has shown strong correlation between the degree of shortening and disease risk, specifically diseases with genomics causes, i.e., cancer. In 2009 the Nobel Prize for Physiology or Medicine was awarded to Elizabeth Blackburn of UCSF for her work in telomeres, including demonstration of the relationship between telomere length, mental stress and cancer.

Genomic Instability and an Increased Incidence of Spontaneous Cancer in Aging mTR−/− Mice

As far as clinical applications of genomics for cancers, two conclusions can be drawn. For prevention, the importance of mental stress in the mechanism of DNA replication. For diagnostics and treatments, the adoption of DNA sequencing both in risk-assessment, i.e., measuring telomere lengths and the use of pharmacogenomics in picking a drug regimen for subjects. Availability of such sequencing technologies is for the moment confined to localities of active genomics industries like San Francisco and the greater Cambridge, Massachusetts region, though often unknown to those in need.
This made me all the more flustered with the failure of clinicians to win Steve Jobs’ battle against cancer. As a case study, he clearly had the resources and lived in an area that is the birthplace of the genomics industry. Jobs was a meticulous individual who was very involved with his work, which leaves us to question his ability to deal with stress and the role that played in his remission & recurrence rates. Another lingering question remains, are the “best” oncologists money can buy, necessarily those who would employ sequencing techniques? Perhaps as time goes on we will learn more about his treatment regiment but for me it shines a bright light in the gap between what researchers see as possible and what clinicians feel comfortable utilizing.

Impartial comparative analysis of measurement of leukocyte telomere length/DNA content by Southern blots and qPCR. Nucleic Acids Res. 2011 Aug 8. Aviv A, Hunt Sc, Lin J, Cao X, Kimura M, Blackburn E.

Longevity, Stress Response, and Cancer in Aging Telomerase-Deficient MiceKarl Lenhard Rudolph1, Sandy Chang, Han-Woong Lee, Maria Blasco, Geoffrey J Gottlieb, Carol Greider, Ronald A DePinho

Leukocyte Telomere Length in Major Depression: Correlations with Chronicity, Inflammation and Oxidative Stress – Preliminary Findings. Wolkowitz OM, Mellon SH, Epel ES, Lin J, Dhabhar FS, et al. 2011 PLoS ONE 6(3): e17837.

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Zero-mode Waveguide & Single Molecule Real Time Sequencing

Zero-mode Waveguide - a hole, tens of nanometers in diameter, smaller than the wavelength of light used. Providing a window for watching DNA polymerase write.

Last week saw something of a historic announcement that may well be seen in grander light by our offspring than us. 23 & Me announced the $999 Exome, all the protein coding regions of our genome. This for the first time makes it feasible to extract significant amounts of genomic information from patients, consumers & trial subjects. At the same time the founders of Complete Genomics wrote an article on the lowering costs of sequencing, showing some great numbers on technologies that use less reagents, cheaper machines and faster results. Advancements are so frequent in this field it seems, though what gets me really excited is the concept of SMRT (Single Molecule Real Time) sequencing; the idea of reading a strand of DNA one letter at a time as it’s written. Most of our progress, like the $999 exome or the success of Complete Genomics has been possible as a result of High-Throughput sequencing, which evolved from the original Sanger sequencing methods. Whereas, Sanger sequencing would spit out few hundred letters of  DNA at a time, HT sequencing would spit out much less but at a faster rate. SMRT offers to give us long-reads, thousands of letters, at a fast rate. Several “in-progress” technologies that are promising long-reads range from pulling a DNA strand through nano-pores or using a large single atom that would run across a strand. ZMW (zero-mode waveguide) takes a unique approach in that it uses DNA Polymerase, the default DNA writing nano-machine in our cells to give readings as the strand is being written with fluorescent letters.

PacBio's SMRT Prototype

Although this is exciting stuff, I wonder how much it will help in the adoption of genomics in medicine. The old paradigm of pills and vaccines &  seeking magic-bullets it seems is embedded deep in our economic and psychological fabric. Now that the cost of sequencing is comparable to most other medical tests will it become as common-place as ordering an MRI or getting a new hip? Doesn’t seem like a $1000 price-tag would stop anyone. No, what has happened is we’ve handed kindergardeners college textbooks, it’s too much information and they haven’t a clue what to use it for. More than faster and cheaper, we need user-friendly, digestible data interpretation. ZMW and SMRT is sci-fi cool but if there’s anything to be learned from the world’s largest technology company it’s that adoption is more a game of collective-psyches than raw science & engineering.


PacBio Technology Backgrounder 

How Low Can We Go? Molecules, Photons, and Bits by Clifford Reid

To the man who showed my whole generation the correlation between engineering, usability & adoption 

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