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The CRISPR-Cas9 Trilogy, CRISPR 101 Part 3: The Questions We Face

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April 12, 2016

10:39 AM

It has been said that the 19th century was the “century of physics,” the 20th was that of chemistry, and the 21st will be remembered as the “century of biology.” In this discussion of CRISPR-Cas9, it becomes reasonable to expect that this prediction will play out. However, whether or not the “century of biology” will be one of benefit or destruction is a harder question to answer preemptively, but one can say that it will be determined by the conversations and reflections that occur in the scientific community right now.

CRISPR-Cas9 is powerful in its universality: this system will work in virtually any cell with a genome. Some cells have a much greater impact on a species than others, and that difference occurs between ‘somatic’ and ‘germ’ cells. Essentially, you are your somatic cells: they make up your organs, muscles and every other tissue in your body. When you die, your somatic cells die with you. Germ cells on the other hand, are the cells that contain the genetic information that is passed on to an organism’s offspring, otherwise known as sperm or egg cells. Any changes made to germ cell DNA will be passed on to future generations. Herein lies the great ethical debate surrounding CRISPR-Cas9: we now have a system that can permanently change the genome of the human species, do we, as a species, have the willpower and foresight to exercise that power wisely?

CRISPR-Cas9 is powerful in its universality: this system will work in virtually any cell with a genome.

The consensus of the more vocal faction of the genomics community, made up of the opinions of George Church (Massachusetts Institute of Technology), Francis Collins (National Institutes of Health), Debra Matthews (Johns Hopkins University), Gang Bao (Rice University) and others, is that we certainly need to hold off on germline editing right now. Some of these experts even recommend an international ban on the procedure. These sentiments have intensified after the first demonstration of germline editing that occurred in China by a team headed by Junjiu Huang at Sun Yat-sen University in Guangzhou in spring 2015.

Huang himself falls on the side against performing germline editing with our current technology and understanding. His experiment showed that the success rate of performing CRISPR-Cas9 in human embryos is too low to be ethically permissible: about four in 54 (it should be mentioned that the embryos used in his research were non-viable and obtained from a fertility clinic).

His experiment showed that the success rate of performing CRISPR-Cas9 in human embryos is too low to be ethically permissible.

It follows that one of the many arguments against germline editing is that it is statistically impossible to reduce the probability of error to zero, anything above which should be considered too high to risk on a potential human life. Harvard University psychology professor Steven Pinker states that we should approach CRISPR-Cas9 germline editing like any other medical treatment: with a cost/benefit analysis. His conclusion is that we shouldn’t ban CRISPR-Cas9 simply out of a “nebulous terror” that may preclude the exploration of other useful applications of this technology, but that in this instance the likely cost of producing a sick or unviable child is too great to justify the potential benefit of a more “desirable” genome.

Further, in consideration of all of human history, how successful have we ever been at identifying a universal definition of “desirable”? What is an “improvement,” genetically speaking? CRISPR-Cas9 has been heralded as a cure-all for genetic diseases, but one cannot ignore that this praise is often presented in the shadow of the ominous “designer baby” warning. This is a natural and valid progression of the argument against performing germline editing: are the benefits of endowing one’s children with blue eyes or a preferred hair color so valuable as to merit the risks inherent to gene editing? What does that say about the value of eye colors that aren’t blue? Additionally, is it wise to grant parents such a high level of control over their children’s’ future? What will follow if the genomes of subsequent generations are as commodified as the personalized specifications of a new car? Will we begin to view our children as symbols of our preferences as opposed to autonomous individuals? Some argue that we already perform this kind of selection when we choose our sex partner, but I think that there is a significant difference between preferring and deliberately ensuring the traits with which our children are born. Finally, if we are to thoroughly treat this technology as any other medical treatment, we need to consider the aspect of consent. Any medical treatment should be performed with some level of consent, and it is impossible to obtain that from future generations.

The likely cost of producing a sick or unviable child is too great to justify the potential benefit of a more “desirable” genome.

Fortunately, for the time being at least, this particular debate is one which will remain theoretical. The unrefined specificity of CRISPR-Cas9, coupled with our limited understanding of the genetic “constellations” which produce a multi-faceted trait like eye color, make genetic edits like this very unrealistic in the foreseeable future.

The only vaguely “realistic” edits that we could make in the meantime concern “monogenic” illnesses, or genetic ailments that arise out of an error in one gene only. There are 3600 known monogenic illnesses, all extremely rare, which present themselves as the logical, not-quite-as-ethically-charged application of germline editing. Embryos that will inherit homozygous recessive deafness, for example, stand out as the immediate hypothetical beneficiaries of this treatment.

The only vaguely “realistic” edits that we could make in the meantime concern “monogenic” illnesses.

In the hype that surrounds the great potential of CRISPR-Cas9, it becomes easy to conflate its ability to cure a disease with simply reducing susceptibility to a disease. Consider multigenic illnesses, like multiple sclerosis, diabetes and cancer, which arise out of certain configurations of multiple genes as well as environmental factors. CRISPR-Cas9 could only address one piece of an intricate genetic mosaic that confers a specific illness.

In both of these “more realistic” applications of germline CRISPR-Cas9 we are again faced with the fundamental dilemma of whether the risk of producing a sick child is worth sparing him or her from an illness or susceptibility to one. How can we possibly evaluate which outcome would be worse: living with a genetic illness or suffering from the residual, unpredictable errors left in the wake of a flawed CRISPR-Cas9 system?

In a recent Nature article, Jennifer Doudna, the lead researcher who first observed and duplicated the CRISPR-Cas9 system, outlines five steps that should be taken by the scientific community to ensure the most responsible use of this technology in its present form, without enacting a total ban:

“First, safety: the global community of scientists and clinicians needs to adopt standard methods for measuring genome-editing efficiency and off-target effects, so that researchers find it easier to compare and evaluate the results of different experiments for clinical relevance. Second, communication: the December [2015] summit should stimulate further forums in which experts from the genome-editing and bioethics communities provide information and education for the public about the scientific, ethical, social and legal implications of human-genome modification. Third, guidelines: there should be international cooperation by policymakers and scientists to determine a shared path forward and to provide clear guidance about what is and is not ethically acceptable research. Fourth, regulation: out of this cooperation, appropriate oversight should be organized and applied to laboratory work that aims to evaluate the efficacy and specificity of genome-editing technologies in the human germ line. And fifth, caution: human-germline editing for the purposes of creating genome-modified humans should not proceed at this time, partly because of the unknown social consequences, but also because the technology and our knowledge of the human genome are simply not ready to do so safely.”

Doudna, Jennifer. “Perspective: Embryo Editing Needs Scrutiny.” Nature 528.7580 (2015). Web.

As knowledge of the CRISPR-Cas9 system proliferates beyond the scientific community it is important to be aware of the “danger of metaphor,” described by Eleonore Pauwels of the Science and Technology Innovation Program at the Wilson Center in Washington, D.C. When explaining the CRISPR-Cas9 mechanism, it’s intuitive to relate the process (as I did) to straightforward “snipping” and “pasting” of genes using “nanoscissors.” This illustrates a much simpler, neater picture than what actually happens on a molecular level. Of course, explaining scientific phenomena in metaphors is ubiquitous in any teaching setting, but for something as profound, yet error-prone as the CRISPR-Cas9 system it’s important to stress a critical reality of this development: that it is uncertainly successful and certainly irreversible. It isn’t like using the spellcheck function on a word processor. Our genes are more multidimensional and interconnected than we can, reasonably, ever expect to fully understand, and it would be foolhardy to assume that we could predict the downstream effects of the kind of permanent change that CRISPR-Cas9 could enact.

It is uncertainly successful and certainly irreversible.

Doudna, naturally, was right to emphasize both safety and caution moving forward. I hope that these remarks are echoed in future discussions on an international level. As demonstrated by Huang’s lab, even if the U.S. decides to hold off on using CRISPR-Cas9 to change the germ line, it may be unlikely that the rest of the world will come to the same conclusion. As long as there is a continuous global conversation about the significance of influencing the germ line, one that transcends the clean, naive simplicity of “nanoscissors,” then the chances of this technology being used only to avoid death or suffering become higher. I’m going to end this series with a few apt words that characterize the question we face moving forward, from Francis Collins, the head of the National Institutes of Health:

“Evolution has been working toward optimizing the human genome for 3.85 billion years. Do we really think that some small group of human genome tinkerers could do better without all sorts of unintended consequences?”

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  • Carly Martin