Darwin’s Fishing Net: Manipulating Complex Ecosystems

Darwin’s Fishing Net: Manipulating Complex Ecosystems

by Guest Blogger,
Tyler Kokjohn, Ph.D.

Darwins net2In an effort to protect fisheries, laws and treaties require trawlers to use nets with a mesh big enough to allow smaller, presumably young fish, to escape.  The basic idea is simple; capture and eat the big fish, but let the young ones live to reproduce and replenish the stock.  That is logical, but the evidence suggests that practice is not only failing, but in combination with overfishing it is doing something perverse; fish are growing more slowly, reaching sexual maturity earlier and, due to smaller sizes, producing fewer eggs (1).

Picture Darwin’s fishing net capturing the big ones, but always letting the little fish escape.  Using it over and over again, perhaps to a point of overfishing, is a powerful un-natural selection which leaves a fish population with proportionately more small fish.  Some escapees may be young, growing fish, but some might be small sized adults.  Do this enough and over a long period of time the net effect could favor small fish reproduction to the point that waters become populated with significantly smaller fish.  Scientists hoping to conserve fisheries may have unwittingly engineered declines in the average body size and condition of commercially harvested species.

Living systems are dynamic, more than a little mysterious and unpredictable.  We often discover how complex living systems really work by observing them in action or perturbing them with sometimes disastrous consequences.  Consumption of methylmercury present in food can produce a severe neurological disease syndrome (2).  Methylmercury present in aquatic environments increases in concentration (bioaccumulated) as it flows up the food chain, sometimes reaching toxic levels as was the case with Minamata disease.  Named for the geographic locale of first recognition in Japan, this horrific disease outbreak was the result of disposing mercury-laden industrial waste into the bay that served as an important source of seafood for nearby residents.

There are some good reasons why we do not fully grasp how natural ecosystems work.  Part of the problem is we do not exactly know what is in them.  Microbiologists examining natural environments using gene probe methods that can reveal bacteria without having to grow (culture) them discovered only a small proportion of the microbial universe is known to science (3) a situation scientist David Stahl likened to going into the Amazon Basin for the first time.  The majority of microbes, the entities that control the most fundamental aspects of ecosystem function on our planet, are unknown to us.  The fact is we do not understand life on our planet and cannot produce even a rudimentary roster of the critical players.  Assumptions, predictions and extrapolations do not always survive when theory is confronted with the complex realities of living systems.

Gene drives, constructions that are able to automatically spread themselves and cargo DNA throughout entire populations of organisms, have created concern because of the possibility they might damage ecosystems.  However, no one knows how well gene drives will actually perform in natural environments.  And there could be factors such as spontaneously arising mutations that might inhibit their activities (4, 5).   The idea that future ecosystem engineers might capitalize on factors impairing gene drive activity to keep them under firmer control is interesting.  In theory, if damping factors are effective they might help defuse objections to releasing gene drives, a strange situation where it becomes permissible to use a devicebecause it won’t work well for long.  It remains to be seen if using impaired gene drive methods to achieve public health goals like halting mosquito-borne virus disease for example would be practical or economically sustainable.

It is important to note that gene drive technology has immense promise but is still hypothetical.  So is the concept of drive damping.  Scientists are now eagerly sorting out the realities as to how gene drives work and perhaps fail to work.  Given the limitations in our knowledge and the fact that complex living systems are often unpredictable and surprising and we should perturb ecosystems with care.


(1)   B. Borrell.  2013.  A Big Fight Over Little Fish.  Nature, 31 January 2013.   http://www.nature.com/news/ocean-conservation-a-big-fight-over-little-fish-1.12325
(2)   K. M. Rice et al.  2014.  Environmental Mercury and Its Toxic Effects.  J. Prev. Med. Public Health 47(2):74-83. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988285/
(3)   R. F. Service.  1997. Microbiologists Explore Life’s Rich, Hidden Kingdoms.  Science, 21 March 1997, [275(5307):1740]. http://science.sciencemag.org/content/275/5307/1740.full
(4)   T. H. Saey.  2016.  Seeing the Upside in Gene Drives’ Fatal Flaw.  Science News, 15 July 2016.  https://www.sciencenews.org/article/seeing-upside-gene-drives-fatal-flaw
(5)   R. L. Unckless et al.  Evolution of Resistance Against CRISPR/Cas9 Gene Drive.  bioRχiv11, June 2016.  http://biorxiv.org/content/biorxiv/early/2016/06/11/058438.full.pdf



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.



(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


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


(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