Rewriting All the Rules – The Arrival of Genomic Editing
Tyler A. Kokjohn, Ph.D.
Humans are poised to become far more powerful. Scientists are perfecting new tools to alter our own genomes and possibly those of all generations to come. And it won’t stop there. Genome editing techniques extended to other organisms and combined with strategies to disseminate modified genes through the environment will enable future genetic authors to literally re-write the DNA scripts that run entire ecosystems.
Genome editing has tremendous potential to alleviate disease and suffering. Because scientists are still learning how genomes function, our raw engineering prowess now far outstrips any ability to predict the ultimate consequences that might follow the use of these new tools. That leaves us in the uncomfortable situation of seeing how using genetic editing technology could provide potentially enormous benefits while recognizing going forward demands we must both court unknown risks and resolve explosive ethical dilemmas. Appreciating the imminent intersection of issues, a group of scientists has called for informed and open discussions to ensure the coming genome engineering capabilities are used wisely and ethically (http://www.sciencemag.org/content/348/6230/36.long).
The genetic engineering technology raising the most concern is known by the cryptic designation of ‘CRISPR-Cas9′.* Although the functional details of the system can be confusing (http://www.sciencemag.org/content/341/6148/833.full), its amazing implications are easy to grasp; human beings will soon be able to engineer their own heredity. For example, today persons inheriting certain rare mutations in the presenilin gene are doomed to suffer early-onset dementia and death. CRISPR-Cas9 technology may make it possible to erase the bad genetic information in that gene and change it to that found in the normal (healthy) form. Perhaps it will ultimately become acceptable to edit the germ cells of persons to correct disease-causing mutations and thereby preempt all future problems by passing only the good gene copies on to future generations. Such efforts and the experiments needed to reach these goals will spark intense ethical debates.
Gene editing technology can be harnessed to produce ‘guided gene drives’ (http://www.ncbi.nlm.nih.gov/pubmed/25035423) which could be deployed to modify the genetic traits of wild organisms. In essence, this would bestow unprecedented powers to genetic engineers and allow them to restructure entire ecosystems to suit human specifications. Perhaps editing technologies and guided gene drives will be used in the future to control or eliminate scourges like malaria by modifying mosquito vector populations. Assessing the environmental risks associated with such manipulations will be challenging. Although (in principle) a second guided gene drive might be employed to reverse a previously released gene drive producing undesirable impacts, undoing any consequential ecological damage may be impossible (http://www.sciencemag.org/content/345/6197/626.long).
This camel already has his nose well inside the tent and we will not have to wait long for a brave new world to arrive. Genomic editing technology (for research purposes) is already available commercially and biotechnology companies like Editas Medicine (http://editasmedicine.com/) have been formed to develop and exploit the fast-emerging opportunities. The tools are being perfected quickly and persistent, vague speculations that human embryos are already being modified (http://www.nature.com/news/mini-enzyme-moves-gene-editing-closer-to-the-clinic-1.17234) feeds the perception that events are literally racing forward.
Scientists, perhaps sensing an urgent need to get ahead of quickly emerging results, are calling for open dialog and meticulous investigation of safety and efficacy of gene editing in advance of its widespread use (http://www.sciencemag.org/content/348/6230/36.long). In addition, aware that some nations prohibit or restrict germ cell engineering while others are more permissive, these experts are explicitly discouraging all efforts to modify human germline cells until the complete spectrum of issues, including ethical concerns, have been fully considered.
The pressure to use genome editing technology will be immense. The audacious notion that human beings might re-write the book of heredity and direct their own evolution will produce intense controversy. Perhaps the coming storm will be severe enough to halt efforts to modify human genetics except for carefully prescribed purposes. However, it is important to remember that gene editing technology has implications that extend much further than directly manipulating human heredity. The tools can be applied to other organisms in ways that will probably not offend sensitivities to the same degree. Once the capacity to modify the genomes of target non-human organisms is perfected, it may be very difficult to rationalize not utilizing it. For example, if scientists are able to modify mosquito species to prevent malaria carriage or transmission (http://www.sciencemag.org/content/345/6197/626.long), the potential benefit to human health is obvious. However, what if the best approach to malaria eradication is altering or inactivating genes in ways that makes mosquito reproduction fail? Will we then proceed to drive some species to extinction to improve the environment? A justification for immediate use based on the idea of safeguarding human health will be compelling. In addition, precedents on such matters would seem to have been set a long time ago. When humans modify the environment to suit their purposes, the fate of other organisms sharing the ecosystems we exploit is sometimes given scant concern. In fact, through the broadcast of chemical agents like DDT we can be downright indiscriminately murderous in our quest to manage the environment. The problem is that is extremely difficult to predict the full implications of human-initiated environmental tinkering because ecosystems are complex, interconnected and dynamic entities whose functions are only dimly understood. As an example of the complexities, think of the Monarch butterfly of North America. A series of changes to improve agricultural economics and environmental esthetics had the unintended consequence of decimating the once vast populations of migratory Monarch butterflies (http://www.washingtonpost.com/news/energy-environment/wp/2015/02/09/the-monarch-massacre-nearly-a-billion-butterflies-have-vanished/). The great annual migrations of this large orange and black butterfly from Canada to Mexico and back may become a thing of the past. It is unclear whether it will be possible to reverse a tragic trend and restore the Midwestern Monarch butterfly populations to safely sustainable levels. Are changes which have collectively driven Monarch butterflies to extinction an improvement? The scientists who issued an urgent call to dialog and debate the development and future implementation of genomic editing technologies noted their extraordinary potential to reshape the biosphere. The tools are powerful and if used, must be applied with the utmost of caution. These technologies and capacities may ultimately impact the health and wellbeing of everyone and everything on our planet.
Clearly, the future discussions addressing the use of genome editing technology must involve experts. Much of the discussion will necessarily be highly technical, but every one of us is a legitimate stakeholder in the outcome and you don’t have to be an expert to ask useful questions and influence the process. Rather than be intimidated by the technology and conceding these far reaching decisions entirely to the authorities, recognize how your perspectives could provide critical and unbiased input to the process. Many of the people who will elbow their way to the table are likely to have a vested interest in the use of the new technology. You do not need a Ph. D. to know whether you value Monarch butterflies more than ensuring high fructose corn syrup will be a few cents cheaper and your perspectives on such matters may be equally as insightful and important as those with advanced degrees. Remember, scientists are truly expert in a narrow range of subjects. A few might well be the world’s leading authorities on creating the guide RNA components for CRISPR-Cas9 nucleases, but may never have chased a Monarch butterfly through a meadow when they were children or ever give any thoughts to such trivial matters let alone assign them an intrinsic value. When it comes to the type of world you want for the next generation, you are the world authority.
I hope you will follow the Twitter feed of the key scientific journals, Science (@sciencemagazine) and Nature (@NatureNews), to stay informed about new developments being disseminated to the scientific community. Be ready to post comments to those articles and the follow-on reports in the newspapers. If you belong to any organizations engaged in conservation issues or ecological protection, ask the leaders what they are doing about this situation. Genomic editing and gene drives are about to become reality. How, when and where genomic modification of humans, other organisms and our biosphere is permissible will soon be under discussion. Take part in the conversation and ensure your part of this story gets written.
D. Baltimore et al., 2015. A Prudent Path Forward for Genomic Engineering and Germline Gene Modification. Science 348:36-38. http://www.sciencemag.org/content/348/6230/36.long
E. Pennisi. 2013. The CRISPR Craze. A Bacterial Immune System Yields a Potentially Revolutionary Genome-editing Technique. Science 341:833-836. http://www.sciencemag.org/content/341/6148/833.full
K. M. Esvelt et al. 2014. Concerning RNA-guided Gene Drives for the Alteration of Wild Populations. eLife. http://www.ncbi.nlm.nih.gov/pubmed/25035423
K. A. Oye et al. 2014. Regulating Gene Drives. Regulatory Gaps Must be Filled Before Gene Drives Could be Used in the Wild. Science 345:626-628.
H. Ledford. 2015. Mini Enzyme Moves Gene Editing Closer to the Clinic. Discovery Expands Potential CRISPR Toolbox for Treating Genetic Diseases in Humans. Nature 520:18. http://www.nature.com/news/mini-enzyme-moves-gene-editing-closer-to-the-clinic-1.17234
D. Fears. 2015. The Monarch Massacre: Nearly a Billion Butterflies Have Vanished. The Washington Post, 9 February 2015. http://www.washingtonpost.com/news/energy-environment/wp/2015/02/09/the-monarch-massacre-nearly-a-billion-butterflies-have-vanished/
*CRISPR-Cas9 – CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats which were originally discovered as peculiar repeated DNA sequence patterns in some bacterial genomes. These repeats are part of a system designed to bind specific target DNA sequences and break apart the molecules which harbor them. The CRISPR genes are believed to form a bacterial immune system, a way for cells to remember the viruses that have infected them in the past and destroy them if they try to return. Cas9 is CRISPR associated gene 9, the protein that actually cuts DNA at specific places in the genome. CRISPR-Cas9 allows engineers to open genomic DNA at precisely selected locations and edit the nucleotide base sequences, thereby changing the product of that gene. In principle this technology could be used to alter germ cells to allow engineered changes to be passed to the future generations. It is believed that all organisms which undergo sexual reproduction will be modifiable by CRISPR-Cas9 methods.