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.
(2)   Gina Kolata.  2013.  Mice Fall Short as Test Subjects for Some of Humans’ Deadly Ills.  The New York Times, 11 February 2013.
(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].
(4)   E. Callaway.  2016.  HIV Overcomes CRISPR Gene-editing Attack.  Nature, 7 April 2016.
(5)   S. Reardon.  2014.  Gene-editing Method Tackles HIV in First Clinical Test.  Nature, 5 March 2014.
(6)   S. Reardon.  2016.  First CRISPR Clinical Trial Gets Green Light From U.S. Panel.  Nature, 22 June 2016.
(7)   The Editorial Board.  2016. Gene-therapy Trials Must Proceed With Caution.  Nature, 28 June 2016 (534:590).
(8)   S. G. Stolberg.  1999.  The Biotech Death of Jesse Gelsinger.  The New York Times, 28 November 1999.



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