Beyond CRISPR: The Genome Editing Dilemma

The new genome scissors are already considered the great panacea in the fields of Biology and Medicine. Although the acronym CRISPR is revolutionizing the scientific world, it has rekindled the eternal debate of the ethical limits of how far humans are willing to go to change an organism’s DNA.

Imagine you were alive back in the 1980s and were told that computers would soon take over almost every aspect of our lives: from shopping and dating to the stock market. You were told that billions of people would be connected via the web and that you would own a handheld device, thousands of times more powerful than supercomputers. Then, it all happened and science fiction became today’s reality. It would not be a rash remark to say that the world is at a similar point today with genetic engineering.

Biotechnology is currently experiencing an outstanding revolution through which scientists may be close to finding solutions to many congenital diseases. ‘Genome editing has become a household phrase fairly quickly; however, most people, either affected or not by these pathologies, have no clue of what is being cooked in the laboratories. Last month, the Royal Swedish Academy of Sciences awarded Emmanuelle Charpentier and Jennifer Doudna for “the development of a method for genome editing”. This brief motivation hides a whole universe of research and researchers who have contributed to the finding and development of CRISPR/Cas9.

The word is the acronym for ‘Clustered Regularly Interspaced Short Palindromic Repeats’. The CRISPR/ Cas9 system is a self-defense or ‘adaptive immunity mechanism used by some bacteria to protect themselves against the attack of viruses or plasmids. In other words, the ‘wild type’ CRISPR (the one that is present in nature) exists as a defense mechanism for bacteria (prokaryotic organisms) against external pathogens that try to introduce their genetic material into them (mainly viruses). Bacteria that survive the attack recognize and incorporate certain exogeneous repetitions of DNA from the attacking virus as an acquired immunity, just like vaccines. This way, next time a virus attacks they will neutralize it by recognizing the latter sequences of the invader’s DNA to degrade them. All this is carried out by a protein called Cas9 that acts like little scissors.

This natural and precise mechanism of selecting, cutting and pasting a string of genetic code was restructured to use it as a biotechnological tool of genetic engineering. For this Charpentier and Doudna were granted the award, but the story is not limited to them. Under the name The Heroes of CRISPR, a 2016 article published in the journal ‘Cell’ by Eric Lander, director of the Broad Institute of the Massachusetts Institute of Technology (MIT), reviews the trajectory of twelve key scientists in its development. Among them is Francisco Juan Martínez Mojica (Elche, 1963) who is now a professor of microbiology at the University of Alicante. Everything started with him.

The father of CRISPR

Yes, the father and precursor of the in-vogue method is a Spanish scientist. Francis Mojica, as he likes to call himself, discovered the sequence back in 1993. In 2003 he recognized that the sequences he discovered were not disparate and had a common set of features that are now known as the hallmarks of CRISPR. He coined the term, and in 2005 he published the first paper reporting that it was an adaptive immune system. The community owes Francis the discovery in 1993, the name of CRISPR that is on everyone’s lips today, and his intuition over its function as an immune system of bacteria; however, the academy decided not to award him. «What I am going to say is pure speculation,» said Lluis Montoliuto El País, a researcher at the National Center for Biotechnology (CNB — CSIC) and a member of the Spanish Network for Research on Rare Diseases (Red Española de Investigación de Enfermedades Raras). «We will not know the actual nominations until 2070, and many of us will no longer be there to interpret them. I have had the opportunity to help, providing reasons that justify the award to Francis Mojica. I don’t know if, as a country, we could have done more. But we have missed a historic opportunity, and it will cost us the pain of being as close to a Nobel Prize as Mojica has been this year.»

It was eight years ago that Charpentier and Doudna came up with the idea that would grant them the Nobel Prize of Chemistry. They proposed that the system discovered by Mojica could be used as a genome-editing tool. Although it was Mojica who proved their hypothesis a year later, the patent war had been served and the dispute lingers to this day among scientists in the field.

The bright side

Although each one affects a small percentage of the population, as a whole, the nearly 7,000 documented rare diseases affect 7% of the world’s population. Its low frequency is especially hard on patients due to the difficulties in its diagnosis and treatment, in addition to its low visibility. Between 75–80% of these diseases have a genetic origin; consequently, the treatments, if they exist, are not curative but usually palliative chronic treatments focused on alleviating the symptoms and/or slowing down the progress of the illness. However, recent advances with CRISPR/Cas9 genetic modification technology Juan Martínez Mojica in the laboratories of the University of Alicante carried out by different companies spread optimism for the future treatment of these diseases because of its ability to modify DNA with unprecedented precision and safety.

CRISPR cannot only target rare diseases and ancient pathologies, it is also being used to fight COVID-19. Amid the pandemic, Montoliu and other Spanish researchers set out to use these tools to attack the sars-CoV-2 genome and thus prevent its spread. If they manage to make the coronavirus disappear or decrease in cell cultures they would begin to experiment with animals and finally carry out clinical trials on people. Concerning how long the whole process can take until reaching the clinical trial with humans, the researcher details that he would be “satisfied” if the funded project, which focuses on the cellular part, validates his hypothesis in one year. «So we could apply for funding to do the same with animals. This would take at least another year, then we couldn’t think of clinical trials with people until 2022 or 2023. As much as we want to run, it is better to go step by step.»

The scary side

Curious enough, CRISPR Therapeutics has a strong remark on its web page stating they ‘do not use human germline modifications, which could be passed from parents to children supporting the current recommendations of the International Society for Stem Cell Research.’ This recommendation comes almost two years after the regrettable international scandal that made this technology famous. In late 2018 the world discovered that a Chinese scientist had used CRISPR to edit the genome of two babies. He Jiankui has claimed (without any evidence to date) to have used it to create the first babies genetically modified to be immune to HIV, smallpox, and cholera. The scientific community, including its creator, has shown a unanimous rejection of the genetic manipulation of human embryos. The technology is so recent that there are still no guarantees that its use will not cause inadvertent edits in unwanted regions of the genome, but the debate on the streets is served.

The potential of CRISPR has influenced public and social perception. In the middle of 2016, the Nuffield Council on Bioethics in the UK noted that editing the heritable genome could be “ethically acceptable in some circumstances”. Meanwhile, a report published in late July of 2018 by the Pew Research Center showed that 72 percent of Americans think that modifying the DNA of an unborn child to treat a serious disease is an appropriate use of gene editing.

But beyond the health dangers, having technology capable of modifying the DNA of an embryo before it is born poses one of the biggest ethical dilemmas of science soon. If CRISPR were to be improved and its unlimited use approved, could society end up divided into different classes based on genetics, as envisioned in the 1997 film Gattaca? An era of à la carte babies, whose characteristics have been predefined before birth, separating advantageous from disadvantageous. «Germline modifications are unethical because of the possibility of them being used for military purposes or as weapons» Hernández claims. «I think everyone who is on scientific research is on it for the sake of leaving a positive mark on humanity as we are at CRISPR Therapeutics, but as I said, it all costs money, and the probability of creating profitable biological weapons with this technology is high.»

The scientific community is clear in this regard. In a recent 200 pages report an international consortium of scientists stated that the only use of CRISPR whose benefits outweigh the risks would be to eliminate the mutations inherited from both parents from the genome of future babies; mutations that would translate into a life surrounded by incurable diseases. No taller kids, no smarter kids, no stronger kids. CRISPR possibilities might be limited by scientific regulations, but as the genome editing revolution advances the ethical dilemma surrounding the new tool that edits the code of life gets even more entangled.