Kris Keppel
Disclaimer—This paper partially fulfills a writing requirement for first year (freshman) engineering students at the University of Pittsburgh Swanson School of Engineering. Thispaperis astudent, not a professional, paper. This paper is based on publicly available information and may not provide complete analyses of all relevant data. If this paper is used for any purpose other than these authors’ partial fulfillment of a writing requirement for first year (freshman) engineering students at the University of Pittsburgh Swanson School of Engineering, the user does so at his or her own risk.
CRISPR: A REVOLUTIONARY GENE EDITING TOOL
Kris Keppel ()
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Kris Keppel
A POTENTIAL CURE FOR GENETIC DISEASES
In today’s world of medicine, genetic diseases are undoubtedly one of the most central and troublesome problems. Thousands of different diseases have been documented, and, while there are many, such as Down’s syndrome and muscular dystrophy, that are due to a known mutation in one gene, there are plenty others, such as heart disease and Alzheimer’s, that are due to a combination of mutations in hundreds of genes. Regardless of whether the source of the diseasesis understood, the search for a cure for most of these conditions has come up with no answers. Thus, genetic diseases pose two problems: studying them and curing them.
While there have been many attempts with various genetic engineering techniques over the years, few have had much success. That is, until the discovery of CRISPR. Short for “clustered regularly interspaced palindromic repeats,” CRISPR is the most advanced and efficient gene editing tool discovered to date, and has been shown to be able to cut out any particular gene sequence and replace it with a new one. This has immeasurable implications, as it will expedite the process of studying diseases like Alzheimer’s, and also provide an opportunity to cure diseases like Huntington’s. In fact, one specific example of the use of this technology was featured in Sciencemagazine, where it was explained how scientists have been able to successfully cure Duchenne muscular dystrophy in mice [1].
The response from scientists around the world has been one of astonishment and excitement for the all possibilities that come with such a technology. Many seemed especially praiseworthy of the simplicity and efficiency with which CRISPR works, as opposed to past genetic engineering tools. It’s so simple, apparently, that a grad student could master it within sixty minutes, and generate a revised gene within days [2]. Of course, however, there will always be criticism of such a revolutionary idea, and in this case opposition has come from those saying that it’s too risky to genetically alter a human, or that genetic engineering is unethical altogether.
I personally believe that this a once in a generation discovery, and one that can’t be squandered. While I understand and agree that all necessary testing and precautions
must be taken before this tool is tested on humans, I don’t think we should let the small level of risk that will always exist outweigh the incredible rewards that this could produce. This tool has the power to potentially cure diseases we previously thought incurable, and possibly even eradicate them from a person’s germline. That’s why I have selected this technology. I have known far too many friends and family members who have been affected by Alzheimer’s, muscular dystrophy, breast cancer, and numerous other diseases who’s roots lie at the genomic level. I don’t believe anyone should have to go through the suffering that these diseases cause, especially if there is a chance that it could be prevented.
GENETIC DISEASES AND THEIR IMPACT
Stats on Genetic Diseases
When it comes to why genetic diseases should be addressed by engineers, there really should be no need for an explanation. Thousands, even millions, of people are affected by these diseases each year, causing great suffering and sometimes death. According to the Center for Disease Control and Prevention, about 3 to 4% of all babies are born with a genetic disease, and more than 20% of infant deaths are caused by genetic conditions [3]. It’s not just infants that are affected, however, as some genetic disorders, such as Huntington’s disease, usually don’t develop until adulthood. Thus, it should be only human nature that we must try to fix this problem, and consequently help these people.
Why Should Engineers Get Involved?
While it is true that it is the doctor’s job to rehabilitate the patient, the physicians do not necessarily have the best treatments for their patients, or even any treatment at all. This is where the engineers must come in. As engineers, it is our job to problem solve, to think outside of the box and develop more innovative, more efficient solutions. That is what must be done in this situation. Not only do physicians have very little treatments for these types of diseases, but they often don’t even fully understand them because they are so difficult to study. Past experiments would take two years to engineer a mouse with a single mutation, and even that was hardly consistent [2].
At this incredibly slow rate, we would never truly make any progress on diseases such as Alzheimer’s or diabetes that could involve hundreds of different genes [4].
Clearly, something must be done about this issue. There must first be an improved testing procedure, as this will then allow scientists to gather all of the necessary information they need in order to develop cures for the more than 6,000 known conditions. This is where engineers must step in.
A NEW BREAKTHROUGH WITH CRISPR
With the discovery of CRISPR, scientists may finally have found the tool they needed to solve these issues. Before explaining all of the benefits, however, it is important to explain how this new technology actually works.
How CRISPR Works
According to an article published in Science News,CRISPR is essentially a pair of molecular scissors that consists of two major parts [5]. The first major component is the actual CRISPR, which is simply a piece of guide RNA that directs the RNA-enzyme complex to the proper location in the DNA [5]. It’s specific sequence of bases match up to a particular sequence in the DNA, and this enables it to find the exact section of a gene that scientists are targeting [5]. The other half of the CRISPR tool is an enzyme that has been named “Cas9” by its founders [5]. This component is the actual “scissor” part of the complex, as it is the mechanism that cuts the DNA at the desired points [5]. Once the targeted sequence is removed, any other chain of bases may be inserted. Although it may seem almost too simple, that is the reality of CRISPR, and part of what makes it such a fantastic discovery.
The Benefits of CRISPR
Now that the process by which this tool operates is understood, it is quite clear that the benefits of such a device are virtually infinite. Taking it one problem at a time, let’s first examine how CRISPR will improve the ability to study genetic diseases.
Before CRISPR, modifying genes was an incredibly difficult process for multiple reasons, the principal one being the accuracy with which scientists could target a particular gene or sequence. According to Jennifer Duodna, award winning scientist at the University of California-Berkeley who was featured in a New York Times article, it took the injection of approximately one million cells in order to get just one perfect mutation [2]. Precision that poor severely inhibited any progress that could have been made in learning more about these diseases. Another major reason the process was so laborious was because of the amount of time that it took. Producing just a single mouse with the right mutation would often take a full lab team nearly two years, a rate that would never generate much advancement [2]. Lastly, the procedure was problematic because of the limited potential test subjects. Using previous gene editing tools, mice were really the only species that could feasibly be altered [2]. This produced some serious questions as to whether or not even the most successful tactics discovered would translate to success at the human level. Collectively, these three issues greatly hindered the chances for a breakthrough, as echoed by Tom Cech, director of the BioFrontiers Institute, who said, “What most people don’t realize is how limited we were before CRISPR came along. The tools we had were extremely crude,” [2].
As insinuated by Cech, however, all of this has changed since the discovery of CRISPR. All three of these problems have been solved with one astonishing tool. Doudna now says that will CRISPR, it takes the injection of just ten cells to produce that single perfect mutation [2]. Furthermore, the time involved has been cut down exponentially, and CRISPR also appears to work on just about any animal we can find. For example, as explained in an article published by Nature, last October researchers at Harvard were able to simultaneously alter 62 genes in pig embryos in an effort to inactivate a certain virus, and consequently pave the way for pig organ transplants [6]. This shattered the record for most genes altered in a single animal, and made scientists rethink what was possible when it came to genetic testing.
Such progress in the ability to study these diseases has also translated into success in the search for cures as well. As mentioned earlier, one trial at Duke University was able to cure mice suffering from Duchenne muscular dystrophy [1]. The disease is caused by a defect in the gene that produces the muscular protein dystrophin, butwith the use of CRISPR, the team was able to cut out the faulty gene in the mice and replace it with the proper sequence [1]. This partially restored the dystrophin protein expression and greatly improved skeletal muscle function [1]. Similar experiments have corrected errors responsible for sickle-cell anemia, destroyed the receptors used by H.I.V. to infiltrate our immune system, and replaced a mutation that causes cataracts [1]. Now that successful trials have been completed on animals, it is only a matter of time before human trials can begin, which will hopefully culminate in mainstream use to cure such diseases.
Response to CRISPR
Despite producing only success stories so far, CRISPR, like any groundbreaking technology,has generated a huge response from the scientific community, both supportive and critical.
Beginning with the negative reaction, much has stemmed from the worry about what could happen if such a technology ends up in the wrong hands. Even Jennifer Doudna, despite being a huge supporter of CRISPR herself, acknowledged this, and organized a meeting to discuss how to avoid allowing someone to use CRISPR on human embryos before it was fully ready [2]. Additionally, there is still the ongoing debate over whether genetically altering humans in any way is unethical, an idea to which many people still hold true.
Despite this, however, the overall response has been overwhelmingly positive. Developmental biologist Robert Reed of Cornell said, “With CRISPR, literally overnight what had been the biggest frustration of my career turned into an undergraduate side project,” [5]. Feng Zhang, a leading biological engineer at the Broad Institute of Harvard and M.I.T., stated, “This was a finding of mind-boggling importance, and it set off a cascade of experiments that have transformed genetic research” [4]. Furthermore, a member of Zhang’s team, Winston Yan, noted, “I am not sure what a Golden Age looks like, but I think we are in one” [4]. Scientists rarely use such strong words when discussing a technology still in its infancy, but CRISPR truly is that transformative.
As I mentioned earlier, I fully support the development of this technology and its application to as many fields as possible. I believe that it holds the key to unlocking a cure for the thousands of genetic diseases currently plaguing our world, and has the potential to save millions of lives.
USHERING IN A NEW ERA OF GENETICS
Genetic diseases have always been a problem in our society. It wasn’t until the last century that we truly began to understand them, but even then, often times our technology limited our ability to learn as much as we needed to in order to unlock their secrets and find cures. Past gene editing tools made testing extremely tedious, and consequently made developing cures a mere pipe dream. The discovery of CRISPR, however, has changed everything. Simple and incredibly efficient, it has exponentially improved testing procedures and already begun to lead to cures for diseases such as sickle-cell anemia and muscular dystrophy.
Merely discovering it is not enough, however, as engineers must continue to work through extensive testing and trials to improve this device until it is completely safe to use on humans. There is still much work to be done on this front, but I believe that this is a worthy cause, and one that should undoubtedly be the focus of bioengineers for the foreseeable future. I firmly believe in this new technology, and hope that one day I will be lucky enough to have the opportunity to work with CRISPR, and play a part in ushering in this new era of genetics.
SOURCES
[1] C. Nelson. et al. “In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy.” Science. 1.22.2016. Accessed 10.28.2016.
[2] J. Kahn. “The Crispr Quandary.” The New York Times Magazine. 9.09.2015. Accessed 10.27.2016.
[3] “Data and Statistics.” Centers for Disease Control and Prevention. 9.21.2016. Accessed 10.28.2016.
[4]M. Specter. “The Gene Hackers.” The New Yorker. 11.16.2015. Accessed 10.27.2016.
[5] T. Saey. “CRISPR inspires new tricks to edit genes.” Science News. 8.24.2016. Accessed 10.27.2016.
[6] S. Reardon. “Gene-editing record smashed in pigs.” Nature. 8.06.2015. Accessed 10.29.2016.
ACKNOWLEDGEMENTS
I would like to thank my father for the inspiration for this essay, as it was his Science News magazine that first introduced me to this topic and caught my interest. I would also like to thank my Sutherland West floor mates for making it extremely difficult to stay focused while writing this paper and aiding in my procrastination. Lastly, I would like to thank my writing instructor Josh Zelesnick and Professor Newborg for their help and guidance.
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