CWR Sister Renee Mirkes 9-25-17
If you’ve been following science headlines, you know that the CRISPR revolution is a real speedboat, clipping along at a breakneck pace. The aim of this essay is to equip this CRISPR ship with moral ballast before it runs afoul of ethical hazards (Part Two). To do that, we have to first school ourselves in facts and concepts about genetic engineering in general and CRISPR-Cas9 in particular (Part One).
Part One: Getting the Facts
What is genetic engineering?
For thousands of years we’ve been genetically engineering plants and animals through selective breeding. We became very good at it, but without understanding how it worked. But then, in 1953, Francis Crick and James Watson discovered the double helix structure of DNA, the blueprint for every living organism. Deoxyribonucleic acid is a complex molecule within the nucleus of every cell consisting of four chemical bases—Adenine (A), Cytosine (C), Guanine (G), and Thymine (T)—that are paired (A with T and C with G). The 3 billion bases in humans are arranged differently for the different information that needs to be transmitted. The different sequences, or genes, contain a genetic code carrying instructions that guide the growth, development, function, and reproduction of every organism. Change the instructions—rewrite the code—and you change the organism.
Once scientists understood its structure they began to do just that: to modify DNA and to engineer genes, not in the former hit and miss fashion, but much more precisely. In 1974, they produced the first genetically modified mouse, making mice the animal of choice for research. In 1994, the first genetically modified plant—the Flavr Savr tomato—was on sale in U.S. supermarkets, thanks to researchers who gave it an extra gene that suppresses the rotting enzyme. In the 1990s, mitochondrial replacement, an in vitro treatment for female infertility, was the first example of human genetic editing, producing babies that have three genetic parents: the cytoplasmic egg donor (the mitochondrial genetic mother), the nuclear egg donor (the nuclear genetic mother), and the father.
Each of the plant, animal, and human genetic engineering examples just cited were expensive, complicated, and time-consuming. With the advent of CRISPR-Cas9 and the gene editing revolution that followed in its wake, all that changed. Jennifer Doudna, University of California, Berkeley; Emmanuelle Charpentier, Max Planck Institute, Berlin; and Feng Zhang, Broad Institute of Harvard and MIT renovated CRISPR into a more standardized, user-friendly system that can be programmed to locate any DNA sequence in any species inexpensively, easily, and quickly.i Anyone with basic knowledge of molecular biology and access to a lab could use it.
How does CRISPR gene editing work?ii
CRISPR/Cas9 is a complex molecule consisting of a guide RNA molecule and a DNA-cutting enzyme called Cas9. CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats and refers to a sequence of base pairs found on the DNA of bacteria that acts like a DNA archive. From the dawn of time, viruses have been trying to destroy bacteria. Lacking their own reproductive cells, viruses invade bacteria and insert their DNA into bacterial cells in an effort to take them over and use them as viral factories. Bacteria, for their part, use their CRISPR archive to store DNA from a viral invader the first time it attacks. When the virus attacks again, the bacterium quickly makes an RNA copy of the viral DNA archived in CRISPR and then discharges its secret weapon, an enzyme called Cas9. “Cas9” stands for “CRISPR-associated protein 9”. The RNA molecule, acting like the Search feature of Word, guides Cas9 to the archived viral DNA so that it can scan the inside of the bacterium for signs of the viral invader, comparing every bit of DNA it finds to the viral sample from its CRISPR archive. When it locates a perfect match to the invader DNA, CRISPR unzips the twisted DNA strands and cuts out the targeted viral sequence, rendering the viral DNA useless and the bacterium victorious.
The CRISPR revolution began when Doudna, Charpentier and Zhang, realized that the bacterium CRISPR system is programmable, that is, it can be customized to locate and then edit—disable, repair, or augment—any gene in any species: microorganisms, plants, animals and humans. In sum, the designable CRISPR-Cas9 is revolutionary in giving scientists and clinicians the ability to wield unparalleled control over the human genome with the singular result of a radical facelift for genetic research and genomic medicine.
CRISPR-Cas9 stands on the shoulders of advanced DNA sequencing technology that has successfully identified the genetic mutations behind diseases that currently have no cure. As a result, CRISPR could make specific and efficient changes that correct these genetic mutations in enough cells to cure the associated diseases. Dr. Francis Collins, director of the NIH, agrees: “CRISPR is an empowering technology with broad applications in both basic science and clinical medicine. It will allow us to tackle problems that for a long time we probably felt were out of our reach.”iii
How could CRISPR-Cas9 be used in humans?
Since CRISPR has cut the HIV virus out of living cells in the lab, it could be effective in curing patients with HIV and other retroviruses. This editing tool could seek out and destroy viruses like herpes that hide inside human DNA and that multiply while concealing themselves. Similarly, CRISPR technology could find and destroy cancer cells that perform the same way: refuse to die and continue to multiply all the while concealing themselves.
And then there’s the panoply of genetic diseases. Over 3,000 genetic disorders are caused by a single incorrect nucleotide or letter (an A, C, G, or T). Cas9 could be programmed to change just a single incorrect letter in all the patient’s cancer cells and to replace it with the correct letter, thereby curing the patient of the genetic disease.
The human uses just described constitute what’s called somatic genetic editing. The genetic changes in the CRISPR’d cells are limited to the patient and die with him. In other words, CRISPR’s edits would not be passed on to any of the patient’s progeny.
But that changed when Chinese and U.S. researchers used CRISPR-Cas9 to edit disease-causing mutations out of in vitro embryos—human embryos in a petri dish in a lab. While it is true that, if transferred to a woman’s uterus and brought to term, these CRISPR’d embryos would transfer their healthy genetic alterations to their descendants, it is also true that, over generations, they could introduce unhealthy genetic changes that would alter the human genome irrevocably.
Here, I focus on the ethics of two current human applications of CRISPR technology. The first showcases Dr. Carl June, an immunologist who works out of the cancer lab at the University of Pennsylvania.iv As you read this, he is leading researchers from three institutions in the first preclinical CRISPR trial. June has enrolled approximately 18 terminal cancer patients in this Phase-1 study, comprising the most extensive manipulation of the human genome to date. In this first-ever U.S. CRISPR trial involving patients, June and his team are treating the patients’ cancers—multiple myeloma, myeloma, and sarcoma—with CRISPR-edited cells. First, they extract the patients’ T cells (cells that play a central role in their immune systems). Second, they use CRISPR to augment three genes in those cells turning them into turbo-charged T cells that are better able to target cancer cells and prevent their recurrence. And, third, they reinfuse these revved up T cells into the patients. The hope, of course, is that these genetically augmented T cells will seek and destroy the patients’ tumors and prevent their cancers from returning, giving them a new lease on life. Whether or not it cures these terminal patients of their cancers, the trial will, in June’s words, be “about two things: safety and feasibility . . . and will yield critical information, paving the way for eventual new treatment options that are more targeted, less brutal and far smarter against tumors than system-wide chemotherapy will ever be.”v
The second focus of our moral analysis is the first research study in the U.S. to use CRISPR to cure a genetic disease in human embryos. This past July, Shoukhrat Mitalipov, Director of the Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, led a team of researchers in hopes of improving results gathered from previous CRISPR embryo experiments in China.vi Mitalipov wanted to test the theory that, once CRISPR snips the DNA in the right place and cuts outs the mutation, the cell’s natural repair system would step in to repair the injury by inserting the proper code—much the way Word’s autocorrect feature fixes spelling mistakes.
Mitalipov and his team programmed CRISPR-Cas9 to target the MYBPC3 gene mutation that can cause hypertrophic cardiomyopathy (HCM), a disease infamous for causing sudden death in young athletes. Then they produced 58 lab embryos by co-injecting CRISPR and sperm from a man who carried one copy of the mutant gene into the cytoplasm of each donor egg. Study results showed that CRISPR efficiently targeted the MYBPC3 gene mutation in 72.2% of the embryos. Second, 42 of the CRISPR’d embryos corrected the majority of the targeted mutations by copying the normal gene from the egg donor. And, third, all of the CRISPR’d embryos showed no off-target cuts and developed normally to their morula stage. This data suggested to Mitalipov et al that human embryonic CRISPR therapy, if it should ever meet the mountain of future safety, reliability, and ethical standards, could someday be used “to reduce the burden of [an] heritable disease [like HCM] on the family and eventually the human population.”vii
It’s important to note that Mitalipov and his team were forbidden by federal regulations to transfer any of the CRISPR’d embryos to a woman’s uterus. So, from the outset of the experiment, the researchers intended to destroy the human embryos. As the final segment of their study, the researchers did just that. They dismantled—disaggregated the individual cells of—the 3 day-old human embryos, including the 58 CRISPR’d embryos and the 19 non-CRISPR’d (control) embryos, so as to compare and contrast results in their individual cells.
Part Two: Determining the Moralityviii
Many researchers and doctors are consequentialists. By that I mean the individual scientist or clinician chooses and carries out his or her medical or research choices based on a fundamental consequentialist principle: the optimization of consequences. The flaws of doing so will become clear as I apply both a virtue ethics assessment—based on the moral good, and a consequentialist analysis—based on technical benefits, to June’s preclinical trial and Mitalipov’s research study.
Dr. Carl June’s preclinical CRISPR trial
If Dr. June were to judge whether to conduct the preclinical CRISPR trial from a virtue ethics perspective, he would have to assess its morality by asking:
What would I be doing in conducting this trial? Or, more specifically, what would I be intending (willing, wanting, desiring or striving for) in conducting this trial? and (2) What kind of a person would I become—what would my moral identity be—based on what I intend, desire or will to do?
And he would have to respond:
What I would intend in freely choosing and intentionally conducting the CRISPR trial (the objective moral content of my action) would be the moral good of giving each cancer patient participating in the trial what is his just due: therapy that could cure or mitigate his cancer, providing the patient with more time on earth with his family and friends. I would offer other cancer patients not participating what is their due: the possibility of a cure for their disease and a longer, heathier life. Finally, I would desire the moral good of giving what I, in justice, owe to myself: allegiance to my oath to do only what is beneficent for my patients.
Since what I would be doing in choosing to conduct the trial is intentionally related to justice, to the good for me and my patients and their families (and, conversely, is not intentionally related to what is bad or unjust for me or for those involved), I know heading up the trial would be an objectively good act.
I also understand that by freely choosing and intentionally doing the just or good thing I would not only make the world a more just place but I—the one choosing and acting to satisfy basic human needs and to realize basic human goods—would be or become a good, just, or moral person. Furthermore, were I to habitually choose to act justly in my dealings with others, I would acquire the virtue of justice, empowering me to act justly in every situation of my daily life readily, consistently, and with a sense of satisfaction. Which is to say, based on the unity of the moral virtues as exemplifications of the various aspects of reason, I would become a reasonable person were I to conduct the clinical trial. My moral identity would be that of someone who does just deeds prudently, courageously, and temperately.
Because doing the trial would be an objectively good action and in doing the trial I would become a good person, I conclude I should conduct the CRISPR preclinical trial.
If Dr. June were to judge his action from a consequentialist perspective (and based on press reports, that is the way he seems to justify conducting the trial), he would need to focus on the following question:
Is conducting the CRISPR trial the right thing for me to do? And he would reply: The CRISPR trial will realize a foreseeable complex of technically beneficial consequences. It will advance the safe and efficient use of CRISPR in the clinical setting. It will provide a last chance treatment for terminal patients struggling with multiple myeloma, myeloma and sarcoma. It will improve the probability that CRISPR could be used safely and efficiently to treat and cure all kinds of other cancers, including those caused by multi-gene mutations, to treat and cure thousands of genetic diseases, as well as all varieties of viral diseases like HIV and herpes. It will open up curative options for cancer patients that are far superior to those currently available, whether surgery, radiation, chemotherapy, or immunotherapy. Conducting this Phase I clinical trial will encourage other genetic engineers to experiment with CRISPR-Cas9 with an eye to improving its use in the clinical setting. It will attract investors who want to commercialize CRISPR to treat diseases that have no cure. This trial will provide long-term treatment follow-up standards. These will be valuable in monitoring future CRISPR’d patients, once the therapy is finally approved for clinical use.
At the same time, the CRISPR trial yielding all of these technical benefits will minimize its predictable technical deficits: not curing or mitigating the targeted diseases or possibly causing off target or unintended health deficits.
Therefore, I conclude, conducting the Phase I clinical CRISPR trial for patients with myeloma, multiple myeloma and sarcoma is the right thing for me to do.
Dr. Shoukhrat Mitalipov’s CRISPR experiment
Should Shoukhrat Mitalipov judge whether to conduct the CRISPR embryo experiment from a virtue ethics perspective, he would need to ask:
What would I be doing in conducting this research? Or, more specifically, Is what I would want (intend, desire or will) to do in conducting this CRISPR experiment on human embryos, in itself, a good action? And (2) What kind of a person would I become—what would my moral identity be—based on what I would intend, desire or will in this research?
He would have to respond:
What I would intentionally be doing in this experiment is to pursue the technical benefit of increased CRISPR safety and efficiency by a means that is unjust or evil. I would deny each of the 78 human embryos what is their just due: I would deprive them of their right to be conceived within a loving act of their parents’ bodily union. I would destroy rather than protect their life. I would reduce them to mere experimental objects, mere means to my research goals. In short, I would use them rather than love them as persons in their own right who deserve my respect and love. And, in striving for my research goals in this CRISPR experiment, I would deny what I, in justice, owe myself: professional commitment to placing my genetic engineering experiments at the service of human life. Since the morality of what I would be doing in choosing to conduct this study would be intentionally unjust—morally bad for me and for the 78 embryonic human beings involved—I judge doing the CRISPR research would, objectively, be an immoral or evil act.
I also judge that by freely choosing and intentionally doing these injustices to myself and others I would not only make the world a more unjust place but I—the one choosing and acting against what is good for man—would become a proportionately unjust, that is, an immoral person. Even more, if I would habitually choose to act unjustly in my dealings with others, I would acquire the vice of injustice, a disposition of character that would dispose me to do unjust acts easily, consistently, and with a sense of satisfaction in the concrete actions of my daily life. Which is to say, based on the unity of the moral virtues as exemplifications of the various aspects of reason, were I to consistently choose to do the unjust or bad thing in the concrete actions of my daily life, I would be, or become a person who acts against reason, someone who does unjust acts imprudently, cravenly, and intemperately.
Because doing the CRISPR research on human embryos would be an evil act, and because in doing it I would become, in proportion to the evil, a bad person, I conclude I should not conduct the CRISPR experiment.
Should Shoukhrat Mitalipov judge the morality of conducting the CRISPR embryo experiment from a consequentialist perspective (which popular reports suggest he does) he would have to ask:
Is conducting the CRISPR research on embryos the right thing for me to do? And he would reply: I foresee that the research will realize a complex of technically beneficial consequences. It will advance the safe and efficient use of CRISPR on human embryos. It will encourage further CRISPR embryo research with an eye to perfecting the technology. It will accelerate the development of the treatment to the point where it will eventually conclude with the transfer of a disease-free embryo to a woman’s uterus. It will bring the medical community one step closer to curing genetic and other diseases at their root, guaranteeing the descendants of the CRISPR’d embryo will not inherit these diseases and, over time, the entire human population will not suffer their ravishes.
However, I also foresee some technically problematic outcomes. First, it’s difficult to predict and therefore difficult to prevent untoward genetic alterations from being introduced into the human genome by CRISPR’d embryos who come to term. What we do not know and therefore cannot forecast is whether interaction between the individual’s CRISPR’d genes and those unaltered will produce harmful modifications in the individual’s genome and, over multi-generations, in the health of the entire human genome. Second, embryonic CRISPR therapy in its most advanced stages could be used by parents to design their baby. On the simple end, to designate their child’s eye or hair color, and on a complex level, to increase the child’s physical or intellectual capacities. But this would have eugenic implications, producing an engineered super class against a non-engineered underclass. Third, it will be difficult to adequately regulate the use of embryonic CRISPR treatment and, therefore, equally difficult to prevent it from falling into the wrong hands. Rogue doctors could precipitously use embryonic CRISPR for pregnancy, before it is proven, beyond a reasonable doubt, to be safe and efficient. Rogue national leaders could use it to produce super-strong military to carry out nefarious, megalomaniac political ends.
Therefore, I judge that in order to eventually be able to optimize outcomes brought about by CRISPR embryonic research, the right thing for me to do is to lead my team of scientists in this first U.S. CRISPR experiment on human embryos.
Exposing errors of a consequentialist justification for using CRISPR on humans
The preceding analyses illustrate that someone following virtue ethics, in his recognition of objective moral good, is able to identify the good in what he does, in what he becomes as a person, and in what he does to other human beings. In direct contrast, the consequentialist analysis, as it focuses on the optimization of physical outcomes and technical benefits, remains on the non-moral level. Even more, the consequentialist principle allows the agent to become immoral by destroying other human beings as a means of optimizing consequences. Only optimal outcomes have meaning, not the morality of one’s respective actions.
In other words, Drs. June and Mitalipov bracket both the objective moral content of their respective actions and the moral goodness or badness he is or becomes in choosing to conduct the trial or to do the research. Each concludes, instead, that the rightness of conducting the CRISPR trial or leading the CRISPR research depends on whether it optimizes consequences, that is, brings about more physical, technical benefits (outcomes, states of affairs) than bad. And since June concludes that doing his trial does optimize foreseeable consequences and Mitalipov believes doing his research will eventually help to optimize its predictable states of affairs, both conclude that their respective action is the right thing to do.
The source of their ethical error is this: June and Mitalipov (and the legion of scientific and medical consequentialists they represent) reduce the moral order to the technical. The pathos and danger of doing so is that a consequentialist like Dr. June is not only oblivious of the moral goodness or justice of doing his CRISPR trial, with its moral implications for the medical world. He’s also unmindful of the morally good or just character he acquires in conducting the trial, with its morally constructive implications for the medical community.
Similarly, Dr. Mitalipov, for his part, is not only ignorant of the moral evil or injustice of doing his CRISPR research with its negative implications for the science world. He’s also insensible to the unjust character he acquires in doing it, with all its morally negative implications for the research community. In sum, their consequentialist leanings prevent both June and Mitalipov (together with their consequentialist colleagues) from knowing and doing what is truly good for themselves and others.
Only genetic engineers who understand and act from a classical virtue ethics are capable of adding moral ballast to the fast-moving ship of CRISPR technology. Because only they can distinguish, and therefore actively pursue, genetic editing that is truly good for them and their fellow human beings.
iAlice Park, “The CRISPR Pioneers,” Time, December 19, 2016; Jennifer Doudna, “Genome-editing revolution: My whirlwind year with CRISPR,” 22 December 2015.
iiSteven Novella, “CRISPR and the Ethics of Gene Editing,” Science-Based Medicine, December 2, 2015; Alice Park, “Life, the Remix,” Time, July 4, 2016.
iiiCRISPR Pioneers, 120.
iv“First CRISPR Clinical Trial in Humans Is Approved by Federal Regulators,” STAT News, June 22, 2016; Arvind Suresh, “Does CRISPR clinical trial on humans proposal bring more questions than answers?”Genetic Literacy Project June 24, 2016.
vCRISPR Pioneers, 120.
viShoukhrat Mitalipov et al., “Correction of a pathogenic gene mutation in human embryos,” Nature, July, 2017; Heidi Ledford, “CRISPR fixes disease gene in viable human embryos,” Nature News, 2 August 2017; Steve Connor, “First Human Embryos Edited in U.S.,” Technology Review, July 26, 2017; Jessica Berg, “Editing human embryos with CRISPR is moving ahead – now’s the time to work out the ethic,”Cosmos Magazine, August 3, 2017; Tina Hesman Saey, “Gene editing of human embryos yields early results,” Science News, March 29, 2017; Shannon Palus, “The Ethics of Editing Human Embryos,”Discover Magazine, November 30, 2015. Jennifer Doudna, “CRISPR germline editing reverberates through biotech industry,” Nature Biotechnology, Volume 33, Number 5, May 2015; Marilyn Marchione, “In US First, Scientists Edit Genes of Human Embryos” AP, July 27, 2017.
viiVictoria Allen, “Ethical concerns over dawn of the designer baby,” Daily Mail, August 2017.
viiiHere I am indebted to the precise analyses of Father Martin Rhonheimer that compare a classical virtue ethics and its theory of the moral act to that of a consequentialist ethic. The Perspective of Morality [The Catholic University of America Press: Washington, DC], especially Chapter IV, pp. 372-421.