Gene editing is an everyday reality—the 2020 Nobel Prize in chemistry was awarded to biochemist Jennifer Doudna and microbiologist Emmanuelle Charpentier for their pivotal work in identifying the ability of a particular CRISPR system to snip designated genes. The real-life impacts of this gene-editing mechanism range from necessary applications like improved crops and potential cancer treatments to more ethically ambiguous advancements like “designer babies.” Renowned science writer Kevin Davies weaves the intricate story of CRISPR—a tale of competing ideas, rivalrous scientists, and a biological technology with the edge to alter life in a single cut.

CRISPR: It’s the stuff of a science fiction nightmare. Yet, it’s found in something as small as bacteria. First discovered in the immune system of bacteria in 1987, CRISPR is (thankfully) short for Clustered Regularly Interspaced Short Palindromic Repeats, and it operates as a weapon that bacteria use to combat invading viruses. Now this mechanism is applied to the cells of plants, animals, and even humans as an efficient form of gene editing.

CRISPR’s ability to identify and splice DNA targets is due to something called the CRISPR-Cas system. Put simply, this naturally occurring system is composed of two parts. The first part is called the CRISPR array, an alternating sequence of repeat and spacer DNA. While the repeat segments of the array are all the same, the spacer segments are different from each other. The spacer segments operate as a kind of photo album or encoded memory of past enemy DNA segments, and they’re referred to as CRISPR RNA (crRNA). When combined with trans-activating CRISPR RNA (tracrRNA), the mechanism that holds those squirming enemy DNA segments in place, crRNA creates a guide RNA (gRNA). The verbiage is highly technical, but the idea is simple. The guide RNA works as a metal detector to identify and uncover familiar threats.  

This is where the second part of the CRISPR-Cas system comes in—the Cas protein part. The most helpful kind of Cas proteins are called nucleases, which are enzymes that slice DNA segments. Remember that guide RNA? Well, it’s function is pretty clear now—the RNA memory guides the Cas nuclease to incoming threats. The Cas nuclease then uses this guide RNA to match and identify potential invaders; if the segment fits the target, then both strands of the DNA are cut. Once the strands are cut, the damaged DNA fixes itself in a rather imperfect process called non-homologous end joining (NHEJ). The results aren’t always great, but there’s another process called homology-directed repair that replaces the severed segment with a healthy DNA segment more effectively. 

Scientists have taken the astounding, natural CRISPR-Cas9 system and the process it executes, and adapted them to human ends, harvesting the tool from particular kinds of bacteria. This nature-inspired CRISPR process now undergirds a majority of developments in gene editing. Discoveries were slow-going at first, but they eventually led to an incredible breakthrough, one that placed a Nobel into the hands of two brilliant scientists.

This is where things get pretty sci-fi. Following the gradual discovery of  CRISPR-Cas systems’ ability to cut particular, targeted sections of DNA, a few researchers had a thought: If there’s a way to input a particular gene to replace a faulty one, then scientists will be able to develop treatments for afflictions as varied as blindness, cancer, schizophrenia and bipolar disorder. In 2012,  the collective work of Jennifer Doudna and Emmanuelle Charpentier proved that what seemed like fiction was indeed fact. Their work showed that a particular CRISPR-Cas system, CRISPR-Cas9, maintained the ability to cut any kind of DNA. 

This ability was harnessed through the combination of the two parts of the guide RNA—the crRNA and the tracrRNA. This combination created yet another form of RNA called the single guide RNA (sgRNA). But this one isn’t your standard guide RNA that leads the Cas protein to the enemy DNA to perform a quick and unpredictable cut. Rather, the single guide RNA allows scientists to input the sequence of the particular gene they wish to snip. Here we have the creation of modern-day gene editing technology.

With this finding cemented firmly into eons of science textbooks, other researchers forged ahead to see if there was any way to cut and replace a particular segment with an improved section of DNA. The rest was history—quite literally. The summer in which Doudna’s and Charpentier’s paper on the CRISPR-Cas9 system  received publication is dubbed “the CRISPR Craze.” Their findings incited a widespread increase in new research and documentation. With the potential to impact life on Earth dramatically, CRISPR drew scientists, researchers, institutions, and academic journals to recognize the 2012 discovery as a huge milestone in both molecular biology and contemporary science as a whole.

Earth-shattering scientific research doesn’t always lead to worldwide academic prestige. Sometimes discoveries get buried beneath a pile of other research documents or refused by renowned journals altogether. The three most prominent names in the field of CRISPR right now are that of Jennifer Doudna, a Berkeley professor and researcher at Howard Hughes Medical Center; Emmanuelle Charpentier, a professor and head of the Max Planck Unit for the Science of Pathogens; and Feng Zhang, a professor and researcher at the Broad Institute of MIT and Harvard. These highly-decorated and distinguished scientists stand at the helm of advancements in molecular biology and biotech, but CRISPR took many hands to unearth.

CRISPR was first discovered in the cells of bacteria as far back as 1987, and it received its name in 2001 when molecular biologist Francisco Mojica identified repeating segments in bacteria found in the nearly uninhabitable environment of Alicante, Spain. On November 21, 2001, toiling over what to call the strange thing he just uncovered, Mojica sought the advice of friend and fellow scientist Ruud Jansen, who not long after named what history will forever call CRISPR. It took nearly two years for Mojica to get his findings published, which unfortunately, is a familiar story.  It took several more years for CRISPR to achieve the acclaim it deserved. The previously mentioned 2012 paper published by Doudna and Charpentier is the fuel that launched a worldwide academic recognition of CRISPR through its research into the CRISPR-Cas9 system. Before that time, it was incredibly difficult to receive publication for any research on CRISPR; it simply wasn’t taken seriously. Despite this, there were still brilliant scientists and researchers spearheading research into CRISPR that would go on to shape the world.

Inspired by his childhood love for the film Jurassic Park, Feng Zhang channeled his CRISPR interest into a project with microbiologist Luciano Marraffini, in which they applied the mechanism to the cells of mammals. The goal was to pair Cas9 with a tailored guide RNA in order to locate and cut particular segments of DNA. He sought to expand on the work of Doudna and Charpentier and the various other impactful scientists that came after them. The holy grail of CRISPR was close at hand. Not long after their successful work with the cells of mammals, Zhang and his team, along with acclaimed geneticist George Church, applied CRISPR to human cells in a petri dish. Not surprisingly, it worked. This new method successfully cut and then replaced the areas of DNA the team had targeted. This finding was ironically huge in the realm of microscopic molecular biology, and the race to the Nobel was on. 

For good reason, the “CRISPR Craze” attracts some of society’s most brilliant and creative scientific minds inspired by the simple joy of discovery—Nobel prizes and tenure aside, science is at its best when it’s curious, selfless, and free.

Victoria Gray lived with sickle cell disease until a personally and scientifically monumental day in July 2019. In conjunction with pharmaceutical executive Rodger Novak and investor Shaun Foy, Charpentier launched a booming biotech company called CRISPR Therapeutics. They became the first company to execute a medical trial to cure a genetic disease in the United States, removing some of Gray’s bone marrow cells and applying CRISPR to them. Once this was accomplished, scientists reimplanted her cells and awaited the outcome. Fortunately, the results were staggering. Even after 9 months, 80% of Gray’s genetically-modified cells exhibited the correct gene edit. Similar CRISPR successes are cropping up everywhere now. In 2020, a group at the University of Pennsylvania Abramson Cancer Center employed the mechanism to help treat cancer patients, an achievement lauded by Science as the “Human CRISPR.” Researchers applied CRISPR-Cas9 to three patients’ T-cells in order to determine whether or not such a treatment is even safe. Thankfully, gene editing apparently had no negative impacts upon the people’s bodies.

With so much proven potential, biotech companies are moving quickly to conquer new methods, and of course, acquire that lucrative patent. In 2020, the three most well-known biotech companies (Editas Medicine, CRISPR Therapeutics, and Intellia Therapeutics) racked up an astonishing market cap of $10 billion. The evolution of CRISPR from the gene-slicing device documented by Doudna and Charpentier in 2012 to the human genome-editing tool featured in Zhang’s 2013 findings is contentious. The development muddies the question of when and where exactly CRISPR was born. Though various scientists documented discoveries of CRISPR prior to 2012, Doudna and Charpentier’s work set the course for the gene-splicer’s future. As the discoverers of the cutting mechanism of CRISPR-Cas9, they felt entitled to the patent. Apparently, they weren’t the only ones. Shortly after their team (a group dubbed CVC) applied for the patent in 2012, Zhang’s team at the Broad Institute followed suit. Both parties felt that they owned the rights to the CRISPR-Cas9 system. The complication was due to the epistemically complex nature of patent proceedings. Before 2013, patents were determined on the basis of who invented a particular product first, throwing mud into already murky scientific waters.

The decision of the United States Patent and Trademark Office to issue the patent to the Broad Institute in 2016 sparked the beginning of years of meandering biotech battles. Doudna and Charpentier’s group at CVC simply wouldn’t have it, so they took the issue to court. The question at the centerpiece of the proceedings concerned the CVC’s initial discovery and whether or not the team explicitly anticipated the successful use of CRISPR on humans. The results of four years of patent trials brought variable success and failure to both biotech groups. The jury’s still out on this one, unfortunately, with the most recent proceeding taking place in early 2020. But science stops for no one: CRISPR research is still at an all-time high as scientists strategize new ways to use the technology without risking possible legal issues.

These patent disputes present the less appealing other half of scientific discovery, one that’s necessary, but sounds more like an intellectual barroom brawl than an honest quest for academic recognition. On the bright side, it makes an otherwise tedious legal argument into a riveting courtroom plot.

Genetic drama turns to CRISPR crime. Those frazzled-hair, baggy-eyed mad scientists are less fictional than you might think. One of Time Magazine’s 100 Most Influential People of the Year for all the wrong reasons, Chinese scientist He Jianku orchestrated a CRISPR nightmare. Despite valid and already well voiced concerns about the depleting ethics of the progressing CRISPR mechanism, advancements pushed into otherwise dangerous realms of germline editing. This kind of alteration is initiated through the application of gene-editing to the parts of the genome that will be passed down through generations.

One can understand the naive, self-centered enthusiasm of a young scientist researching in the wake of these kinds of developments. Jianku (who goes by the rather ironic nickname JK), fell prey to the CRISPR lure. Growing up in the Henan province of China, JK experienced great poverty and witnessed the way a former underground blood drive infected people with HIV. Citizens of the province lined up to donate their blood for a sum of money and the return investment of a deadly disease. Fueled by the huge impacts of this illness on the poor and his personal idolization of Robert Edwards, the Nobel-winning scientist of in vitro fertilization, JK took CRISPR to the germline. It may sound like this kind of experiment would be concocted in the secret backroom of the scientific community. Though JK’s experiment was indeed secretive, he actually dropped various glaring hints to prominent scientists. Those prestigious researchers and microbiologists paid little heed to JK’s pronouncements and pointed questions concerning the efficacy of editing particular kinds of genes. Understandably, JK took their silence as consent and went ahead with his plan.

In his research leading up to the test, JK discovered that the gene responsible for HIV in humans, CCR5, is also a “protective allele,” meaning that it can receive CRISPR editing with few negative impacts. That’s just what he needed to hear. In the darkness of scientific secrecy, his experiment grew. JK began by recruiting HIV-positive clients. He then applied CRISPR to human embryos to edit out the HIV-stimulating gene and implanted these into female subjects. In 2018, success struck. Two women became pregnant with the world’s first genetically-engineered babies. Later that year, a pair of twins called Lulu and Nana were born, breathing, walking, and living as what we now call “CRISPR babies.” Little is known about the two girls; Lulu and Nana aren’t even their real names. One thing is certain, though—when the discovery of the twins’ birth came about, the scientific community was outraged. JK edited the human race without thinking through the long term implications of such an event, and he did it without explicitly confronting the scientific community. 

One can only imagine the intensity hanging in the air during the 2019 International Summit on Human Genome Ethics held in Hong Kong. Pens poised and fingers flicking the camera button, journalists, reporters, and scientists alike gathered in the aftermath of JK’s experiment. After speaking about his development, JK was met with sparse, slow applause. The scientific community and the Chinese government ruled his actions as unethical and illegal, sentencing him first to house arrest and then to time in prison. The primary concerns voiced by Doudna were that such an instance of germline editing would invoke fear from the public and a widespread apocalyptic attitude towards otherwise ethical science, thus stemming the flow of federal funding. 

Without adequate monetary aid and societal support, progress in science stagnates. Those two little girls strolling along right now in total ignorance of the fact that their identities were tampered with aren't the only ones to be affected by JK’s hands—one man’s hands may have changed the entire flow of scientific advancements for the rest of us as well. 

What do pig organ donors, recreated woolly mammoths, malaria-free mosquitoes, and delicious oranges have in common? CRISPR. The gene-editing and repairing technology of CRISPR is breaking into the realm of the everyday in some unexpected, incredibly helpful ways. On one end of the practicality spectrum, we have the brilliant, imaginative scientist George Church, cofounder of eGenesis, the biotech company that in 2017 removed all viral sequences from the DNA of a pig in order to prepare it to be a future organ donor. This sounds like insane science fiction, but the heart valves and corneas of our pink friends are actually already used in medical operations. Church is also leading developments in something the author calls the “de-extinction revolution,” which aims to recreate the woolly mammoth by applying CRISPR to the similarly-constructed DNA of the Asian elephant. Due to the excellent icy conditions surrounding those mammoth remains, scientists are able to collect the DNA composition of these elephant elders to inject into Asian elephants, potentially creating mammoths anew.

Similarly, CRISPR techniques are being developed to combat diseases and viruses like malaria. In 2014, MIT scientist Kevin Esvelt presented the notion of this kind of gene editing through something termed a CRISPR gene drive. A gene drive involves interrupting the normal progression of genes along the genetic line by disposing one variety of a gene over another one; in Esvelt’s idea, CRISPR is perpetuated along the genetic line as well. While these seem like incredibly positive and welcome scientific advancements, many people are wary of the possible implications. Disrupting the genetic line to such an extent may introduce chaos into the ecosystem, or be used as a kind of biological weapon. The organization Target Malaria has experienced pushback for its work in Africa, with various advocates speaking out concerning its possibly neocolonialist mentality.

In the case of food, the pushback is primarily a mental one. Despite the proven fact that CRISPR is not a GMO, it’s oftentimes categorized as such. Unlike GMOs, CRISPR uses a plant or animal’s present DNA to improve it; it doesn’t add anything new. CRISPR scientist Zhang got together with David Liu and Keith Juong to create the company Pairwise Plants, which aims to develop better and more plentiful agricultural products through CRISPR. Improvements are more necessary than ever in this field where molecular biology meshes and mingles with everyday life. For instance, the population of oranges has decreased by a significant 20-30% in only 10 years due to a disease promulgated by an insect, the Asian citrus psyllid. If biotech researchers and scientists could derive the appropriate gene to protect oranges from this particular disease, then CRISPR may just save the fate of oranges and orange juice everywhere.  

CRISPR invokes a number of oftentimes apocalyptic images which create a stigma surrounding scientific progress. Certainly, the public has a huge reason to be concerned about the possible use of a gene-editing tool in something as necessary as food, but many of these fears are unfounded. We won’t be riding woolly mammoths anytime soon, but maybe we can eat a more nutritious (CRISPR) pear.

The mere mention of gene editing might call to mind a mirage of otherworldly human powers like super strength or disease immunity. The issue with this sci-fi dream is that various human traits in charge of things like size or intelligence are polygenic, or composed of a bunch of genes rather than just one. Theoretical physicist Stephen Hsu is cracking this evolutionary enigma—as creator of the company Genomic Prediction, his team uses government-released data about the human genome to gain knowledge of the polygenic risk scores of various traits, including height and vulnerability to heart disease. We are that much closer to tapping the essence of the intricately woven strands of DNA stitching our identity.

Wouldn’t it be great to harness the genetic power responsible for pain tolerance? Maybe. Maybe not. CRISPR comes with some profound pros and some considerable cons. Without pain intolerance, we would never recognize the need to escape dangerous situations. Similarly, there are a wide range of ethical concerns raised through an enactment of CRISPR. Philosophers at the forefront of this opposition voice concerns about prolonged social and economic inequality, decreased respect for disabled people, and the loss of human choice and identity. Still, scientists at the literal cutting edge of CRISPR developments combat this argument with a parallel ethical claim: Choosing not to touch human DNA isn’t morally greater than tinkering with the genome. Rather, it refuses help to those who desire and deserve a more pleasant life.

Concerns like these were interrupted by the biomedical call of the coronavirus pandemic though, pushing dozens of prominent CRISPR scientists back to their labs in search of a way this gene-splicing mechanism can cut out COVID. CRISPR is a bundle of potentialities—the same nearly dystopian mechanism that may offer to turn your kid’s eyes blue might be the medical answer the world needs to repair its health and splice a new (hopefully maskless) future.