CRISPR explained: the world's most powerful scissors

<span property="schema:name">CRISPR explained: the world's most powerful scissors</span>
IMAGE CREDIT:  A blown-up image of a strand of DNA.

CRISPR explained: the world's most powerful scissors

    • Author Name
      Sean Hall
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    The world of genetics has been equal parts promise and controversy since its entry into the public zeitgeist in the 20th century. Genetic engineering, in particular, has been so mired in seduction and unease as to be considered black magic by some. Prominent individuals of otherwise sound minds frequently declare the intentional alteration of DNA, particularly human DNA, as ethically ersatz. 

    Humans have used genetic engineering for millennia

    Such blanket condemnations reflect a world that has not existed for millennia. The most obvious example is food, specifically of the GMO variety. Those massive, vibrant, succulent Red Delicious apples that fly off grocery shelves are an aberration compared to their pre-human ancestors.

    By crossbreeding specific varieties of apples, humans were able to propagate the genes that led to preferred phenotypes (physical manifestations). More important, selecting for drought-resistant versions of staples such as grain and rice has saved many a great civilization from starvation-induced collapse. 

    Domestic animals provide an even more glaring contrast. Wolves are fierce, territorial predators. They are up to 180 pounds of pure terror with whom few humans could best in a duel. Teacup Pomeranians, by contrast, weigh eight pounds soaking wet, and any human who loses a fight to one is not worthy of passing on his or her genetic material.

    That one of the world's ablest hunters was reduced to a respirating fluffball is a testament to the whole of humanity's love affair with intentionally altering DNA. Common traits society selects among animals include docility, obedience, strength and, of course, tastiness. 

    Yet it's the idea of human DNA alteration that truly leaves jaws agape and knickers in bunches. The lofty ideals of America's early eugenics movement provided a safe haven for the advocacy of racial supremacy, which morphed and reached a terrifying climax in the Third Reich. 

    Nonetheless, the purposeful cultivation of desirable genes is commonplace in liberal society. The most obvious example is abortion, which is legal in most Western societies. It is impossible to argue that humans don't have a preference for certain genomes in a world where approximately ninety percent of fetuses with Down Syndrome are aborted.

    In the United States, courts have deemed genetic-based abortion a constitutional right: Doctors who hide showing genetic disorders among fetuses, fearing the mother will abort, have been sanctioned.

    Intentionally altering an individual's DNA is not the same thing as facilitating certain genes over the course of many generations. Even the once-radical processes of creating GMOs (genetically-modified organisms) merely allow you to insert existing genes into other species as opposed to designing novel ones. However, it is clear that humans prefer certain genes to others and will take drastic measures to make these genes more common. The former merely offers a faster, more precise way of accomplishing the goals of the latter. 

    A method of skillfully altering genetic material has long evaded humanity due to the intense complexity of the biochemical reactions surrounding DNA as well as the paltry range of tools that are effective on such a microscopic scale. Specifically, a method of cutting DNA at exact locations so that small segments can be replaced has been elusive.

    A 2015 breakthrough changed all this; this breakthrough is now allowing humans to shed this long-lasting inadequacy. A world of possibilities awaits and the potential for a large-scale re-ordering of our bodies, our surroundings and even our economies is on deck. 

    CRISPR: The most powerful scissors in history

    (Note: if you can name all the major organelles of a cell and more than three types of RNA off the top of your head, you will probably find the following explanation oversimplified. If you have a basic understanding of what DNA and RNA are, this will be a Goldilocks explanation. If you don’t know what RNA is, think of it as DNA’s older brother who nonetheless ended up as DNA’s errand boy.) 

    This breakthrough goes by the name of CRISPR/CAS9, usually shortened to just CRISPR. This innovative method, pronounced as in "I wish my toast were crisper," is short for Clustered Regularly Interspaced Short Palindromic Repeats. Does this seem like a mouthful? It is. Suck it up. So were "the Theories of General and Special Relativity" as well as "Deoxyribonucleic acid." Trailblazing discoveries often have long names; wearing big boy/big girl pants is advised when dealing with futuristic technology.

    Although the altered DNA is artificial, both components of CRISPR occur naturally. At its core, it takes advantage of the immune system underpinning all living cells. Consider this: the immune system is extremely complex, especially that of a human being, but 99% of the time, a single virus is unable to infect the same person on two different occasions.

    This is because strands of viral DNA are stored and "remembered" within cells after the first encounter. In the twentieth century, scientists discovered that certain forms of bacteria sandwich these DNA fragments in between short, repeating strands of base pairs that are also palindromic: the CRISPRs. Parts of the virus are now permanently embedded into the genome of the bacteria. And you thought you were a good at holding a grudge. 

    Imagine a bacteriophage (a virus that targets bacteria as opposed to multicellular organisms, such as humans) roughs up Barry Bacteria but doesn't kill him. A week later, Phil the Phage comes back for Round 2. Even though Barry sees Phil mugging him, he can't send white blood cells to go beat up Phil because he doesn't have any. The bacterial immune system uses a different approach.

    This is where Cas9, the other half of the CRISPR system, comes into play. Cas9, which stands for CRISPR-associated protein 9, scans the foreign DNA it encounters and checks if any of it matches the viral DNA it has stored between the CRISPRs. If so, Cas9 triggers an endonuclease, also known as a restriction enzyme, to cut off Phil’s arm, or foot, or maybe even his head. Whatever the segment, the loss of such a large part of their genetic code almost always renders the virus unable to execute its predatory intentions.

    Human immune systems win battles against viruses by sending evolution's finest microscopic warriors to do battle, equipped with incredibly accurate descriptions of the enemy's appearance and tactic. The bacterial approach is more akin to intercepting a commander's instructions to his foot soldiers. "Attack the gates at dawn," becomes "Attack the [BLANK] at [BLANK]," and the incursion fails. 

    Eventually, scientists discovered that virtually every living organism has elements of both CRISPR and Cas9. This may seem shocking, but it is actually quite trivial, given that every living thing is descended from bacteria. In these organisms, CRISPRs are akin to an old-timey library that a city has never bothered to tear down, and Cas9 is one of the least important restriction enzymes.

    Nonetheless, they're there, they work, and best of all, they turned out to be very undiscriminating: scientists could feed them sections of DNA that had nothing to do with viruses, and CRISPR would loyally record them and Cas9 would faithfully make incisions. All of a sudden, we had God's scissors in our hands, and they worked on virtually any type of DNA we tried: food, animal, disease and human

    Although the method is being popularized as "CRISPR," it is the combination of both CRISPRs and Cas9 that is so absurdly powerful. As mentioned, there are a number of previously discovered restriction enzymes, or DNA scissors. However, CRISPR is the first method humans have been able to control where the scissors cut with a high degree of precision. 

    Essentially, CRISPRs are short segments of DNA that serve as bookmarks, or as two signs that say “Start cutting here” and “Stop cutting here.” Cas9 is a protein that can read CRISPRs and release an enzyme to cut at both spaces marked by the bookmarks.

    What can CRISPR do?

    Honey, what can’t CRISPR do? There are two main categories of applications for the technology: bad genetic material found in cancer can be replaced with a corrected DNA sequence to eliminate harmful mutations, and it can be applied to improve certain phenotype aspects.

    CRISPR is exciting because it's barely a toddler in age and yet has already jumped from the laboratory to the clinic. The authors of a 2015 study appearing in Nature were able to excise 48% of the genetic material of HIV from HIV-afflicted cells using CRISPR. However, when it comes to cancer, CRISPR has already made the jump from petri dish to humans: in June, the NIH approved the first study of T-cells engineered through CRISPR.

    The trial focuses on preventing the recurrence of cancer. As anyone with friends or family who have battled cancer (which, sadly, is most people) knows, being declared cancer-free is not equivalent to being cured. For the next five to ten years, there is no choice but to wait and see if any minute pockets of cancer escaped treatment and are waiting for a chance to grow back. The CRISPR T-cells have cancerous DNA inserted into their genome, giving them the equivalent of hyper-vision goggles with which to search for the emperor of all maladies.

    HIV and cancer are two of the most formidable Goliaths of pathological medicine. And yet, comparing CRISPR to David is an insufficient metaphor. David was at least an adult, whereas CRISPR is barely a toddler, and this toddler is already taking shots on goal against these most persistent foes of humanity.

    Of course, most humans don't spend their lives constantly lurching between HIV and cancer. More common illnesses with far less complexity, such as colds and flus, will more easily come under the grasp of T-cells on crispy steroids.

    Cutting out bad DNA is good, but it is in the repair of faulty DNA that CRISPR's potential truly lies. Once the DNA is cut in the right place, and the mutated section removed, it becomes fairly straightforward to use DNA polymerases to fuse the correct DNA together.

    The most common genetic afflictions in the United States are hemochromatosis (too much iron in the blood), cystic fibrosis, Huntington’s Disease, and Down Syndrome. Fixes to the disease-causing segments of DNA could prevent massive amounts of human suffering. Furthermore, the economic benefits would be magnificent: fiscal conservatives would delight in saving the $83 million the NIH spends annually on cystic fibrosis alone; liberals would have the opportunity to re-invest these sums in social welfare.

    For those who find the Down Syndrome abortion statistic disturbing, CRISPR modifications could be a suitable compromise, saving the fetus’ life while preserving the mother’s right not to give birth to a severely disabled child.

    The biotechnology world is already being riveted by CRISPR. The GMO food industry alone is already worth billions of dollars a year with methods that are quite rough compared to CRISPR. GMO companies like Monsanto have improved a myriad of foods by inserting whole genes that promote hardiness, size, and tastiness from other foods.

    Now, the gene scavenger hunt is over, and biotech companies can design the perfect gene to insert. It is likely that over the next few decades, the Red Delicious will have to surrender its supremacy to a product along the lines of the Red Orgasm or the Red Spiritual Experience.

    Business and political implications

    CRISPR also has both disruptive and democratizing implications. Gene editing in the 2010s has been like computers in the 1970s. They exist, but they are clumsy and ludicrously expensive. Still, the product is so valuable that the companies big enough to afford them gain a massive market advantage.

    This is why companies like Monsanto have been able to gain near-monopolies in the GMO field. CRISPR is going to do to genetic engineering what personal computers did to software in the 1980s; that is, vastly improve the technology, while making it so cheap that small businesses and individuals can take advantage of them. Whether you’re a biology student, an amateur biohacker or a start-up entrepreneur, you can buy a CRISPR kit on the internet for a few hundred dollars.

    Therefore, CRISPR should make biotech behemoths like Monsanto very nervous. The millions of people who want to undermine or outcompete the company have all been given a dagger.

    Some people oppose Monsanto because they oppose GMOs. Such voices are not given much credence in the scientific community: GMOs are considered quite safe, virtually everyone eats them, and the drought-resistant/harvest-increasing GMOs that underpinned the "Green Revolution" in Africa and India in the 1970s have saved hundreds of millions of people from starvation.

    However, many pro-GMO individuals oppose Monsanto because of its monopolistic business practices and attempts to coerce poor farmers into using its seeds. Before CRISPR, there was little they could do unless they had a spare hundred million dollars lying around to launch a genetic engineering start-up. Their more refined arguments tended to be drowned out by the "GMOs will make your teeth fall out and give your kids autism" crowd, allowing Monsanto to delegitimize its opposition by painting it as unscientific.

    Now, the relative affordability of CRISPR will allow GMOs and the field of genetic engineering to be reclaimed by the democratic-minded, by the young, by the middle class, by those who believe that stringent competition among businesses produces faster progress and a healthier economy than do ossified monopolies.

    Ethics and other issues

    The ethical issues of genetic engineering are potentially massive. The possibility of designing a supervirus that has the ins and outs of the human immune system transcribed in their genome cannot be dismissed. This is a disturbing prospect; it would reverse the normal paradigm, and be akin to a virus being vaccinated against the immune system. “Designer babies” could lead to a resurgence of eugenics and a human arms race in which civilizations are locked in a constant struggle to create the most intelligent, ruthless citizens.

    However, these are issues with the future capabilities of genetic engineering, not with the current realities of CRISPR. For now, none of the main ethical concerns can be realized, mainly due to our limited understanding of our own biology. CRISPR means that if we had a blueprint to create the aforementioned supervirus, we probably could. However, our knowledge of the immune system is far too limited to implement a virus that could circumvent it.

    The worries about designer babies are similarly overblown. First of all, the conflation of genetic engineering with eugenics is dangerous and wrong. Eugenics is garbage science. Eugenics relies on the falsified assumptions that traits such as intelligence and strength are chiefly heritable, as opposed to the nuanced modern consensus that 1) these traits are extremely ill-defined, and 2) they derive from a complex interaction of the genome (not just a few individual genes).

    The obsession of most eugenicists with the promulgation of the white race shows that the movement is nothing more than an attempt to give a pseudoscientific veneer of legitimacy to old racist ideas. After all, the white "race" itself is a social construct, as opposed to a biological reality.

    More importantly, eugenicists have consistently argued for the promotion of "cleaner" genes by force. In 1920s America, this meant sterilizing everyone from the mentally infirm to the sexually promiscuous, and in 1940s Germany, it meant the execution of millions of innocents. Despite the Third Reich's having executed the majority of diagnosed schizophrenics, modern-day Germany shows no deviation in schizophrenia prominence from its neighbors.

    That said, painting genetic engineers as eugenicists smears the good name of scientists working to better the lot of all humans, as well as giving eugenicists a perfect opportunity to mount a comeback by tying themselves to the most exciting invention in science right now. CRISPR engineers don’t endorse crackpot racial theories, and they want to give you more freedom, more choice with which to live your life.

    No, CRISPR will not lead to parents engineering the homosexuality out of their babies. The "gay gene" is a wonderfully apt metaphor for expressing the idea that homosexuality is not a choice. However, as an actual representation of reality, it offers little. Human sexuality is a series of complex, interlocking behaviors that have both genetic and environmental foundations. The fact that homophobic parents don’t abort children who later turn out to be gay proves that there is no “gay gene” simple enough for CRISPR to be able to switch it to heterosexuality.

    Similarly, the reasoning behind the fear of an "embryo intelligence explosion" through CRISPR is flawed. Human intelligence is the crown jewel of the Earth, and quite possibly of the entire solar system. It is so complex and inspiring that a large percentage of humans believes its origins are supernatural. DNA, a biological programming language, does encode it, but in a manner that is currently far beyond our understanding. A world where we understood how to alter our intelligence through CRISPR would be a world where we knew how to represent intelligence in programming language.

    Recalling that DNA is a programming language gives us a useful metaphor to understand the gap between the capabilities of CRISPR and those required to implement people's fears about genetic engineering. The human body is a computer program written in billions of lines of DNA base-pair code.

    CRISPR gives us the ability to alter this code. However, learning how to type does not make you an expert programmer. Typing is obviously a prerequisite to becoming an expert programmer, but by the time an individual is even close to programming proficiency, he or she is long past the discovery of learning how to type.