The Courage to Confront Unknown Unknowns

The Courage to Confront Unknown Unknowns

by Guest Blogger,
Tyler Kokjohn, Ph.D.

Liar mouse Mice will lie to you.  While there are some indisputable commonalities, scientists relying on them as disease models have observed that you can’t always be sure results obtained in mice will necessarily apply to humans (1, 2, 3).  Quite a number of cures for Alzheimer’s disease (AD) and cancer have succeeded spectacularly in laboratory mice and been complete duds in the clinic.

One problem is that animal models only approximate human diseases.  The other is that biotic systems are dynamic, more than a little mysterious and unpredictable.  Nature has surprises and we often discover how complex living systems really work by observing them in action.  Assumptions and predictions do not always survive when theory confronts data.

Complexity is the hallmark of the ecosystem we call the human body.  It may seem strange to think of our bodies in this way, but we are home to a diverse mix of viruses, bacteria, fungi and more.  For many microbial invaders our bodies are well-defended, hostile territory, while others seem adept at establishing permanent residence in and on us.  In fact, some occupants play important roles in the maintenance of normal health.  Human immunodeficiency virus (HIV) is able to invade its victims and escape the intense immune responses designed to eradicate it.  Early attempts to cure HIV infections using chemotherapy were frustrated by the ability of the virus to mutate rapidly to resistant forms.  HIV mutants appear so quickly that it is necessary to use treatments which provide multiple drugs simultaneously.  There is no cure for an established HIV infection, but the use of CRISPR gene editing to inactivate the HIV viral genomes lurking inside infected cells looked promising in the lab.  Instead, mutations, perhaps some created by the CRISPR editing process itself led to the emergence of resistant viruses (4).

There are other strategies to use gene editing methods to eradicate HIV infections and we can only hope they work (5).  From the rise of antibiotic resistant bacteria to the HIV pandemic pathogens have evaded attempts to drive them to extinction.  They persist because they are good at changing the rules of the evolution game.

Using animals like mice as stand-ins for human beings will take us only so far in our quest to defeat disease.  Our predictive abilities are limited and tests involving human subjects will be an essential component of developing new genetic editing therapies.  Approval to proceed with safety assessments of CRISPR-modified cancer-fighting cells in human subjects has been received (6).  A Nature editorial (7) discussing another gene therapy research proposal urged continued caution while calling for volunteers to take the leap of faith.  However, based on additional information reported in the editorial, such confidence might be a tough thing to sell.  A group of scientists proposing a gene therapy study reacted negatively when their advisory council colleagues attached additional conditions for approval (7).  The new proposal under review is similar to research that caused the death of Jesse Gelsinger (8), an event no one wants repeated.  Perhaps the protests reflect frustrations vented in the heat of the moment.  Research with human subjects requires informed consent and the goodwill of the participants.  The reaction projects a troubling and profoundly negative image of the company.  It is hard to imagine complaints that amount to ‘the standards are too high’ will help with recruitment and retention of volunteers.

In addition to trust, future gene therapy study participants will also have to possess a good measure of raw courage.

 

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(1)   J. J. Pippin.  2014.  The Failing Animal Research Paradigm for Human Disease.  Independent Science News, 20 May 2014.  https://www.independentsciencenews.org/health/the-failing-animal-research-paradigm-for-human-disease/
(2)   Gina Kolata.  2013.  Mice Fall Short as Test Subjects for Some of Humans’ Deadly Ills.  The New York Times, 11 February 2013. http://www.nytimes.com/2013/02/12/science/testing-of-some-deadly-diseases-on-mice-mislead-report-says.html
(3)   J. Seok et al. 2013. Genomic Responses in Mouse Models Poorly Mimic Human Inflammatory Diseases. Proc. Natl. Acad. Sci. U.S.A. [110(9):3507-3512].  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587220/
(4)   E. Callaway.  2016.  HIV Overcomes CRISPR Gene-editing Attack.  Nature, 7 April 2016.    http://www.nature.com/news/hiv-overcomes-crispr-gene-editing-attack-1.19712
(5)   S. Reardon.  2014.  Gene-editing Method Tackles HIV in First Clinical Test.  Nature, 5 March 2014. http://www.nature.com/news/gene-editing-method-tackles-hiv-in-first-clinical-test-1.14813
(6)   S. Reardon.  2016.  First CRISPR Clinical Trial Gets Green Light From U.S. Panel.  Nature, 22 June 2016.  http://www.nature.com/news/first-crispr-clinical-trial-gets-green-light-from-us-panel-1.20137
(7)   The Editorial Board.  2016. Gene-therapy Trials Must Proceed With Caution.  Nature, 28 June 2016 (534:590). http://www.nature.com/news/gene-therapy-trials-must-proceed-with-caution-1.20186
(8)   S. G. Stolberg.  1999.  The Biotech Death of Jesse Gelsinger.  The New York Times, 28 November 1999. http://www.nytimes.com/1999/11/28/magazine/the-biotech-death-of-jesse-gelsinger.html


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Immortality, Struldbrugs and the ad infinitum

Immortality, Struldbrugs and the ad infinitum

by Guest Blogger,
Tyler Kokjohn, Ph.D.

FleasHumankind may have forever dreamed of immortality.  Jonathan Swift ridiculed that undying wish in his masterwork Gulliver’s Travels by bringing struldbrugs to literary life.  Immortal, but still subject to the aging process, these unfortunates were condemned to suffer eternally all the negative physical, mental and emotional ravages afflicting the elderly.

Since Swift’s time, while still far from immortal, scientific and medical advances have improved the average person’s prospects greatly.  The typical baby born in 1900 had a mean life expectancy of 50 years and over the past century this has been extended to well over 80 years in some parts of the world today (1).  Improved living standards, effective control of infectious diseases and better diets have yielded a momentous demographic change; populations are older than ever.  Correlated with this change, chronic and degenerative diseases are increasing in significance.  Although poor health is not a certainty, chronic conditions afflict the elderly disproportionately (2).

The most common form of dementia is Alzheimer’s disease (3), an incurable, progressive brain disorder that impairs memory, thinking and behavior offers a good example of the aging dilemma.  Sometimes incorrectly termed senile dementia, the most significant risk for its appearance is advanced age (3).  Some persons may escape dementia, but most will exhibit some degree of cognitive impairment if they simply live long enough.  In a real sense life expectancy extension has been a double-edged sword; many of us can now anticipate living long enough to develop cognitive impairment or full-blown AD dementia.

Developing therapies to prevent or mitigate AD dementia has been a priority for biomedical scientists for decades (4).  Although the molecular mechanisms creating the toxic deposits associated with AD have been partially explained, therapies based on these findings have been disappointing to date.  Unraveling and eliminating AD may turn out to be a long and tedious process.  Perhaps once we vanquish AD formerly rare brain-destroying maladies like Creutzfeldt-Jakob disease will emerge to kill us.  Maybe we will ultimately become impatient with bodies so ill-suited to serve our demands for immortality and go cyborg.

Nearly 300 years after Gulliver’s Travels we remain entranced by immortality and scientists avidly pursue the dream with nightmarish ramifications.  The grand goal still eludes us, but in a sense we have drawn closer to one part of the Very Reverend Swift’s satirical prophecy.  Life expectancy increases have expanded the numbers of persons facing the chronic diseases and infirmities of old age like AD.  As we lurch step-by-frustrating-step along toward the longstanding ambition we may not really want to attain, another of his writings may be instructive:

So nat’ralists observe, a flea
Has smaller fleas that on him prey;
And these have smaller fleas to bite ’em.
And so proceeds Ad infinitum

                                               –Jonathan Swift

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(1)   Global Health and Aging. National Institutes of Health, National Institute on Aging, U. S. Department of Health and Human Services and World Health Organization.  https://www.nia.nih.gov/research/publication/global-health-and-aging/humanitys-aging
(2)   Centers for Disease Control and Prevention.  2009.  http://www.cdc.gov/nccdphp/publications/aag/pdf/healthy_aging.pdf
(3)   Alzheimer’s Association. http://www.alz.org/alzheimers_disease_causes_risk_factors.asp.
(4)   D. J. Selkoe and J. Hardy.  2016.  The Amyloid Hypothesis of Alzheimer’s Disease at 25 Years. EMBO Molecular Medicine, 3 March 2016. http://embomolmed.embopress.org/content/8/6/595.long

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Tighten Up or the Zombie Genes Will Get You

Tighten Up or the Zombie Genes Will Get You

by Guest Blogger,
Tyler Kokjohn, Ph.D. 

Tighten brainWhat happens when we die?  This immensely interesting question has been answered in several different ways.  The scientific study of death is challenging and results acquired from near death experience (NDE) subjects have produced controversy, not consensus.  However, scientists have managed to figure out quite a few things about how our cells die and sometimes, refuse to die (1).

Our understanding of the death process is rudimentary and a recent study of dead animals yielded some unexpected results (2, 3).  These scientists were working under a general assumption that the transcription of genes into RNA (gene expression) would cease quickly after death as physiologic failures mounted.  Examining animals that were indisputably and irreversibly dead, their experiments revealed a wide range of brain and liver genes actually became more active during the post mortem period.  Some genes just kept chugging along after death.

Absolutely fascinating, but what good is this knowledge?  The investigators offered some speculations (3).  If an afterlife for certain genes is found to be a general and reproducible phenomenon it might provide another means for forensic investigators to determine times of death.  Death is a complex process in which organs and body parts perish at markedly different rates.  This situation makes it possible to remove still-viable body parts from the dead and transplant them into others where they may continue to function for years.  More work may reveal that gene expression profiles provide a better means to assess the state of preservation and health of donated organs before they are transplanted.  Cadaveric transplants clearly provide tremendous benefits, but defining procedures for how and when potential donors may be declared dead poses significant medical and ethical challenges (4).  The criteria employed influence what materials will be possible to transplant and the outcomes can sometimes be confusing; hearts harvested from donors declared deceased using cardiac death criteria have been transplanted successfully (4).

The mechanism causing some genes to become activated after death must still be determined, but the investigators have suggested a plausible model to investigate.  They hypothesize that DNA chromosomes unwind in dead cells, allowing genes to become more accessible to the enzymes that transcribe them into RNA.  At this stage it is unclear if and when the post mortem chromosome unraveling process begins or how genes activated after death might influence cell preservation.  Perhaps donor organ preparation processes in the future will include measures to prevent activation of certain genes or inhibit their effects.  However, this area is so new that transplant scientists could easily discover allowing some genes to be activated after death is beneficial.

Researchers investigating brain cancer made sense of some puzzling observations when they realized disruptions in chromosome structure ultimately activated genes promoting malignancy (5).  Additional experiments using CRISPR gene editing methods support their idea specific changes in DNA folding patterns trigger cancer-promoting gene activity and suggest how to mitigate these pathologic alterations (6).  Whether the same mechanisms underlie other cancers is under active investigation.  It will be fascinating to see if death-induced genes are related to any diseases or the ageing process and how closely their activities correlate with DNA unwinding in living cells.

Perhaps it will become as routine for physicians of the future to assess the physical condition of your chromosomes as it is to take a peek at your tonsils today.

“That last gene expression profile suggests your chromosomes are starting to unwind.  I am going to prescribe a topoisomerase activator to tighten them up. Otherwise a zombie gene might wake up and give you cancer.”                    

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(1)   L. Hayflick.  1994.  How and Why We Age.  Ballantine Books, New York.
(2)   M. Leslie.  2016.  ‘Undead’ Genes Come Alive Days after Life Ends.  Science, 22 June 2016.   http://www.sciencemag.org/news/2016/06/undead-genes-come-alive-days-after-life-ends
(3)   A. E. Pozhitkov et al.  2016.  Thanatotranscriptome: Genes Actively Expressed After Organismal Death.  bioRχ, 11 June 2016. http://www.biorxiv.org/content/early/2016/06/11/058305
(4)   R. D. Truog and F. G. Miller.  2008.  The Dead Donor Rule and Organ Transplantation. The New England Journal of Medicine, 14 August 2008 (359:674-675).  http://www.nejm.org/doi/full/10.1056/NEJMp0804474
(5)   G. Kolata.  2015.  Brain Cancers Reveal Novel Genetic Disruption in DNA.  The New York Times, 23 December 2015. http://www.nytimes.com/2015/12/24/health/brain-cancers-reveal-novel-genetic-disruption-in-dna.html
(6)   W. A. Flavahan et al.  2016.  Insulator Dysfunction and Oncogene Activation in IDH Mutant Gliomas.  Nature 529(7584):110-114. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831574/

 

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