Science / CRISPR

The Brave New World of Gene Editing

Since its conception in the early 1970s, genetic engineering has been the enigmatic subject of science fiction, haunting the part of the societal mind that ponders humanity’s power over its future. Until 2012, however, meddling with genomes has been difficult and expensive, so the possibility of effective gene editing seemed too distant to necessitate meaningful contemplation. Overlooking this possibility would be a mistake now.

The future of genetics depends on “Clustered Regularly Interspaced Palindromic Repeats,” or CRISPR. First noted in 1987, CRISPR were described as short “blurbs” of mysterious DNA interspersed within the genomes of E. coli bacteria. The scientists who originally discovered these blurbs were unsure of what function they served, and they brushed them off as unimportant. CRISPR went under the radar for thirteen years, a scientific millennium, until scientists found that the same genetic blurbs were common to many different species of bacteria. This prevalence hinted at the importance of the blurbs, but their true significance still evaded the scientific community. In 2007, scientists working for the Danish laboratory Danisco discovered that the mysterious DNA interspersed within the bacterial DNA actually belonged to a number of various viruses, and they offered experimental evidence supporting the idea that the mysterious DNA somehow aids cell immunity.

Understanding how viruses work is important for understanding why bacteria might benefit from storing viral DNA. Viruses, which lack the faculties needed to reproduce on their own, will hijack a bacterial cell, insert their DNA into the nucleus, and force the enslaved bacterium to build copies of the virus. These new viruses will eventually erupt from the cell like an alien chestburster, often killing the host in the process. The clever hand of evolution has bestowed upon the bacteria the ability to use the virus’s own DNA against it. In 2012, French-born Dr. Emmanuelle Charpentier and American Dr. Jennifer Doudna discovered the mechanism for this immune defense, and subsequently began to manipulate its powers.

When a virus infects a cell, the cell attempts to defend itself. The invaders defeat the bacterium most of the time, but in the rare event that a viral infection does not kill the host, the bacterium will store bits of the viral DNA in its genome in a CRISPR pattern, which the bacterium can pass down to future generations. These bits of DNA within the bacterial genome act as an ID badge to help identify a dangerous virus. Bacterial RNA (DNA’s older, primitive cousin) and a protein called Cas9 work in conjunction with the stored viral DNA to identify and eradicate each virus before it has the chance to take over the cell. By carefully studying the viral ID badges and scanning any new genetic information within the cell, the RNA quickly picks out any sequence that it recognizes as dangerous, and then, like a molecular military commander, sends a Cas9 protein to physically cut out that specific sequence from the invading viral DNA. The virus, now missing a considerable amount of information, is unable to hijack the cell. In a sense, the Cas9 slays the beast of illness.

What Charpentier and Doudna noted in their research was the accuracy with which the RNA and Cas9 executed their operations: the fantastic molecular duo could pick out any specific sequence and cut it out with surgical precision, which in the realm of genetics was nearly unheard of. It was here that the two women saw opportunity. With ingenuity and patience, Charpentier and Doudna invented a method to reprogram the CRISPR in a way that allowed them to replace viral DNA with any gene sequence they wanted so that the corresponding Cas9 protein would cut and remove that desired gene. They realized that by removing a specific gene, they could go about replacing it with a different gene, which is not as difficult as one might think. When a DNA strand is damaged, the cell seeks to repair it. If a gene comparable in length and content to the recently extirpated one is floating around in the general vicinity of the damaged area, the DNA-associated proteins will grab the new gene and pop it into the place of the old one. Essentially, the scientists discovered a way to swap a bad gene for a better one. Editing made easy.

The rest is up to the imagination. This new technology has enormous potential in medicine, especially for treating inherited illness. For example, sickle cell anemia is a debilitating genetic disease that manifests itself in the blood. The sickle cell mutation results in misshapen blood cells that are not only incapable of carrying oxygen around the body but are also prone to severe clotting. Patients afflicted with sickle cell anemia require regular, expensive blood transfusions along with other therapies, and even then they are affected throughout their entire lives. Using CRISPR technology, scientists could potentially expose a patient’s bone marrow (where blood cells are produced) to RNA and Cas9 proteins programmed to target the gene that causes the disease. After the removal of the defective gene, doctors could plug the healthy gene into the empty spot so that the patient would be able to produce healthy blood cells on his or her own. In principle, the disease could be fully corrected. Sickle cell anemia is only one of hundreds of genetic diseases that CRISPR could help cure, and some scientists hypothesize that they could even use it to treat cancer.

Animal testing has already begun. At the Lab of Neuroenergetics in Lausanne, Switzerland, scientists are using CRISPR and Cas9 technology to treat mice with Huntington’s disease. The currently incurable disease is caused by a single faulty gene that results in the production of toxic proteins. These proteins impair neurons in the brain and cause neurodegeneration in humans starting at around age thirty or forty. Patients experience early onset of dementia, loss of motor skills, and ultimately death around twenty years after diagnosis. In Lausanne, Huntington’s-infected mice were treated with the engineered Cas9 proteins. After only three weeks of therapy, the Cas9 treatment inhibited 90 percent of the toxic protein production within the mice, an astonishingly promising result. Other global labs using mice to research different diseases are coming up with similar results.

Charpentier, along with a group of other scientists and investors, patented the technology and founded “CRISPR Therapeutics” in 2013. They have already raised nearly $90 million for research and development. The technology shows huge promise, and CRISPR has proven to be an untamable force in the hands of science. But Charpentier and Doudna quickly realized that their research was headed towards serious ethical concerns.

This concern comes from the fact that the most efficient way to treat genetic disease is to perform CRISPR editing on embryos. Therapy can be very effective on a living adult, but targeting millions of mature cells is difficult and requires complicated delivery systems. Embryos are appealing because scientists would only need to modify a few cells, and those few cells would then reproduce the edited genomes on their own. The most significant benefit of modifying an embryo is the therapy’s permanence. Embryos are comprised of undifferentiated stem cells, like blank slates, that will develop into every kind of cell in the body. Many of these blank cells eventually become gametes. If a modified embryo develops into an adult organism, that organism will have modified egg or sperm cells, meaning that it will be incapable of producing offspring with the mutation for which it was modified. In other words, if an embryo known to have the gene for Huntington’s disease were treated with CRISPR technology, the adult, be it a mouse or a human, would not only not develop Huntington’s, but the adult would also not pass the disease onto its children. The disease is thus eliminated from the genetic line, eradicated from existence.

Photo courtesy of James Duncan Davidson/TED

Photo courtesy of James Duncan Davidson/TED

Doudna, though not a part of CRISPR Therapeutics, gave a TED talk earlier this year pleading the scientific community to give a moratorium on embryonic experimentation, in order to give ethicists the time to determine how to navigate a technology so far ahead of its time. Doudna hypothesized that F.D.A.-approved therapies for adults will likely be available in as little as ten years and asserted that human embryo modification is undoubtedly on the horizon. CRISPR Therapeutics also released a similar statement, denouncing the practice explicitly:

[We are committed to] refraining from directly modifying germline cells, including sperm, egg or embryonic tissue, or developing any clinical applications of germline gene editing. We are dedicated to discovering and developing gene editing-based treatments for serious diseases using only non-germline somatic cells. This is the greatest area of patient need, where the benefits and risks are best understood, and where the ethical support is unambiguous.

Charpentier and her associates have clearly distanced themselves from the idea of embryo modification, electing to leave the stone unturned in favor of ethical security. But many in the global scientific community disagree with their stance and have already begun experimentation on human embryos.

In 2015, at Sun Yat-sen University of Guangzhou, Chinese scientist Junjiu Huang attempted to use CRISPR technology to correct the β-thalassaemia gene, which causes a potentially fatal blood disorder, using non-viable human embryos. Tensions and hopes were high, but to the dismay of Huang’s team, the study ended up being an utter failure. Of the eighty-four embryos Huang manipulated, only four carried the desired mutations. The rest either did not survive or carried erroneous genetic mutations as a result of faulty CRISPR cuts. Some of the embryos developed into genetic patch-quilts containing the corrected genes in some cells and the original DNA in others, mutated beyond recognition. Huang claims the failure is a testament to the technology’s youth, but he is not ready to give up. Other scientists have suggested that some of the errors might be a result of the embryos themselves; defective embryos were selected in an effort to circumnavigate legal constrictions, but perhaps their abnormality affected the their tolerance of CRISPR therapy. The next logical step is to start research on healthy human embryos, but some ethicists and scientists argue that there will never be justification for the genetic manipulation of a viable embryo.

A significant argument against using CRISPR on human embryos is that it is impossible to understand the long-term consequences of gene modification until the embryo has grown into a living human. If complications arise during development or adulthood, the patient will suffer from the results of a procedure that took place without his or her consent. Can a parent give consent on behalf of a person that does not yet exist? Errors during CRISPR modification could even result in new genetic diseases, given that the corrupted genes would be passed on, which is antithetical to the purpose of CRISPR therapy. DNA is an incredibly sensitive medium—any faulty cut could result in a crippling mutation. And even if CRISPR works flawlessly, the members of our society that are financially capable of abusing the technology could do so.

Anyone vaguely familiar with the plot of “Gattaca” (1997) does not need to strain his or her imagination to picture how the hyper-privileged could abuse CRISPR. Modified children could be healthier, smarter, and stronger than the children whose genetic makeup is left to the apathetic hand of chance. The phrase “designer baby” is tacky, but admittedly not unrealistic, and the practice of altering a genome for cosmetic reasons raises its own set of ethical questions. Will highly-desirable genes one day be patented? In a racially segregated society with beauty ideals that favor European (white) features, will physical appearance come to indicate socioeconomic standing? If a human is born with a desirable mutation, should they be able to sell their own genome? If genes are simply a string of nucleotides, why not forge new ones? Will there be a scientific enterprise dedicated to the creation of new genes, never expressed in nature before? It is not unreasonable to believe that one day, much sooner than natural selection would have it, we as a species might not be able to recognize ourselves. We are using our own hands to reshape them into better ones. David, having grown tired of his babyface, picks up Michelangelo’s chisel.

When CRISPR technology improves, as all technologies eventually do, defining legal barriers will become increasingly important. Although CRISPR is new, the idea of gene editing is not, and a significant proportion of the first world has already made up its mind on these issues. Canada, Sweden, Australia, and the majority of western Europe have explicit bans on the alteration of human embryos and gametic cells. In China, where Dr. Huang’s experiments were conducted, scientists working with CRISPR are technically banned from doing so. But Huang’s laboratory was able to carry through with the experiments because the bans are strangely unenforceable, since they are based on guidelines rather than strict legislation. While U.S. regulations are even more ambiguous than Chinese ones, the F.D.A. and N.I.H. have placed, for now, a moratorium on embryonic alteration using CRISPR. Scientists are not sure how long it will last, and they are even more uncertain about how quickly CRISPR will develop relative to our society’s ability to process it. The concern is that many other countries, especially Russia, have ambiguous regulations regarding CRISPR technology and human germline editing. The Space Race begins anew: whoever masters CRISPR technology first will be the one who holds its power, especially economically. People will be willing to pay huge sums of money for CRISPR. Will CRISPR therapy be outsourced to the countries whose lax regulations allowed them to perfect it first? Will there be a black market for the financial elite in the United States who want to secure their children’s futures by making them smarter and otherwise more adept at existence? Will CRISPR have an Achilles’ heel that prevents it from being useful on a large scale, as so many technologies in the past have? It is impossible to say. Although many of these ideas are radical, we cannot close the door on CRISPR therapy because it makes us uncomfortable.

The incorporation of CRISPR technology into modern, culturally acceptable medicine is imminent, and we need to plan accordingly. The use of CRISPR, if we are to avoid dystopic genetic segregation, needs to be highly regulated. Given that the embryonic manipulation is tied to the costly procedure of in vitro fertilization (for the time being, therapy can only be delivered to embryos outside the womb), perhaps the government should financially support CRISPR programs so that people could receive equal access to medical treatment regardless of socioeconomic or racial background. Universal healthcare, expanded to cover the costs of preemptive genetic therapy, would be much cheaper than the tens of thousands of dollars required to treat an adult with a fully manifested genetic disease. At this point, however, it is impossible to tell how the general public will respond to these possibilities. In the past, some religious groups have been opposed to the tampering with of embryonic cells or the regulation of human births at all. It is naive to believe that it will be easy to allocate taxpayer money for something as morally ambiguous as gene editing.

Although there will be much debate regarding the finer points of CRISPR, most people agree that manipulating a human embryo for cosmetic purposes is inherently wrong and could potentially exacerbate an already deep socioeconomic divide by giving the elite the ability to make themselves physically better than those below them on the societal totem pole. Forceful, unmerciful laws banning these practices will be absolutely necessary. But some might argue that if we have the ability to eradicate debilitating genetic diseases on a global scale, we are morally obligated to do so. The discomfort and confusion we feel about our newfound power should be outweighed by the fact that CRISPR has the potential to profoundly improve the lives of millions of people. CRISPR could one day become so involved with health care that it is seen as nothing more than a vaccine against the crippling genetic ailments that pervade our species.

Everyone knows people who are acutely affected by a genetic disease. We have seen their struggle and their pain and wished it away. Now the technology to do away with their suffering is here—will we really push it away because we fear the unknown? For those who might want to ban research with CRISPR altogether, it is important to keep in mind that CRISPR will not only be used on embryos: as mentioned, CRISPR Therapeutics is already constructing a new industry for the treatment of adults with genetic diseases. These treatments will be the first to reach the market, and they will surely be life changing to those who are lucky enough to receive them. Understanding the benefits of CRISPR for adults will help to keep our minds open when it inevitably comes down to debating the ethical permissibility of the altering of embryos.

The immediate future is something to be excited about, not feared. Our responsibility now is to stay informed, and think about what it means to have this technology.