CRISPR-Cas9: Becoming a superman, but at what cost?

What is CRISPR and how does it work?

Let’s say you have an appointment with your doctor today. You show up, he greets you and casually explains that you have a cancerous tumor. Is it concerning? Of course not, the doctor is just going to extract some of your cells, modify them and inject everything back in your body. It is simple, cheap, fast, and almost painless. Cancer has become a minor inconvenience.

This might be our near future if CRISPR-Cas9 delivers all its promises. This revolutionary gene-editing tool is now used and enhanced by many actors in the pharmaceutical industry. And curing diseases is only a small part of what gene editing can do to change our lives.

What is CRISPR-Cas9 ?

A close up of a map

Description automatically generated Marie Minet, a PHD student at the Institute of Human Genetics, Saarland University, Germany explains CRISPR-Cas9 as such: Cas9 is a specific enzyme found in bacteria and archaea; this enzyme induces breaks in the DNA following the instructions of CRISPR. The cell machinery then repairs the DNA. In short, Cas9 is a DNA-breaking tool guided by CRISPR.

https://www.vox.com/2018/7/23/17594864/crispr-cas9-gene-editing

Editing genomes can sound complicated at first, but the technology behind CRISPR-Cas9 is surprisingly simple. CRISPR (clustered regularly interspaced short palindromic repeats) are DNA sequences in the genomes of prokaryotic organisms such as bacteria. They are able to find and suppress DNA from similar bacteriophages during infections. Cas9 is an enzyme that uses CRISPR sequences as a guide to recognize and cleave specific strands of DNA that are complementary to the CRISPR sequence.

Together, CRISPR-Cas9 becomes a powerful tool to edit genes in a living organism, including humans. It is a molecular “scissor” that we can use with incredible precision to cut a part of the DNA and replace it by another sequence of our choice.

Historical review

            Other tools allowing gene editing already existed before CRISPR-cas9. Since the 1970s, different methods were developed to add genetic elements to living organisms. Up to this day, no method is 100% effective and the randomness of the insertion of the DNA in the genome makes it hard to find a reliable way of doing it. CRISPR is a true revolution in this domain, as it is a cheap and quite reliable way of editing genes. It is about four times more efficient than TALENS, the previous best genome-editing tool.

Biohackers

The low price of CRISPR made for the first time a powerful and reliable tool for gene edition accessible to the public. With little equipment and a really strong interest in biology and chemistry, basically anyone can experiment DNA modification. This gave birth to an online network of self-taught scientists who call themselves “Biohackers”. From all around the world, they share their experiments through social media as well as advice and materials. The movement first started at MIT about 15 years ago and exploded around 2016, reaching more and more fellows found of science, mainly under the impulse of Josiah Zayner (who since then became the CEO of The Odin).
We’ve come to meet ‘Rick’, a student in chemistry and biohacker since 2016, who used to make a personal lab out of a room of his apartment. As he lives in France – where gene editing is illegal, unlike in the US where most biohackers live – he asked us to use this nickname to preserve his anonymity.  Even though he admits that it can be pretty dangerous to play with science, he is really proud of what he learned throughout his experiments.

What are the possible applications it could have?

            It is difficult to realize the number of applications this tool can have. Curing diseases is one of the most discussed ones, as many genetic diseases could be eradicated. Cancer, AIDS, muscular dystrophy, blood disorders and even some cases of blindness might be curable thanks to CRISPR. But this is only a small part of what this tool is capable of. Anything with a DNA can be modified using CRISPR.

What the biohackers did

Photo credit : David Ishee

           Rick modified bacteria to make it resistant to a certain antibiotic, as an experiment. He also managed to turn some yeast, grown in a petri dish, into a bioluminescent version of itself by modifying its gene sequence thanks to CRISPR-cas9. He admits that it wouldn’t have been possible without the help of the community, especially his “sensei” (Japanese word for instructor) David Ishee. The members share the progress of their even more ambitious projects; making a bioluminescent plant, or even a dog. As scary as it sounds, Rick assures that no wrong is done to any animal nor human, as the people who do this kind of experiment only work with embryo cells and the bioluminescent feature is absolutely painless. They also work for the purpose of learning and make science evolve without all the restrictions that are imposed in the research world. Some of them even go as far as modifying their own genes, to help muscle grow by itself or regenerate their skin cells for example.

What could be done

            Turning yourself into a superhero is also a promise CRISPR should deliver. Keeping some resistance to a disease like Alzheimer’s, getting rid of lactose intolerance or even modifying mosquitoes’ DNA to make females become sterile and thus eradicating malaria might give a better future for the next generations. According to Rick the possibilities of CRISPR-Cas9 are limitless in the future. He gives us the following examples ;

– Using the gene knockout technic to switch on and off the genes expressions to study their roles in the cells

– Inserting more copies of P53 protein into human DNA when it is at the embryo stage resulting in more human resistance to cancer

– Removing Myostatin or Inserting Follistatin to cattle for a better metabolism ; more muscle and less fat

– Designing better crops (Increasing RuBisCo CO2 fixation efficiency or vitamin nutrition)

– Reactivating telomerase in the old multicellular cells resulting in younger cells, increasing life expectancy for humans and animals

– Designing an embryo to make a baby immune to disease, taller, stronger, or even smarter

If we go a bit further, it is quite easy to imagine a society where parents can choose exactly what their children will look like. The personalization of our children, like video-games characters, might become the norm in future societies.

“The question is not what we “could” but what we “should” or “should not” ’ 

– Rick

Which ethical questions should it imply?

https://www.dna.fr/

This does raise ethical questions. But in a way, the Pandora box is already open, and there is little we can do about it. The biohacker community is raising, and tests on humans have already taken place in regular laboratories in a view to treat advanced cancers.
Which mother is going to refuse to edit genes on their child during pregnancy if it is the only way to save it from being still-born or handicapped? This topic will probably be debated extensively in many countries, which could force some governments to keep gene editing illegal, as it currently is in France.  Some will say it is not ’natural’, others will argue that we cannot decide of fundamental changes for future generations. Even more concerning: if we reach total control over the appearance and the personality of newborns, aren’t we going to lose the diversity that defines humanity? 

Marie Minet shares the most widespread ethical state of mind in the scientific field. She indeed thinks that the tools to modify DNA are too openly available and it broadens the possibility of misuses, especially when it comes to human genetics. Dr. Jiankui’s case (see later) is the perfect example of something which can be interpreted as a misuse because he chose to undergo a procedure on embryos without a genetic disease at a time where all the consequences couldn’t all be known. What Mrs. Minet calls for is an improvement and clarification in the legislation surrounding CRISPR-Cas9 regarding embryos and germinal cells.

“Given that we do not know all the consequences of such modifications of human embryos, and that we know that the CRISPR-Cas9 system produces off-targets (modifications of the DNA that were not intended), I believe it necessary to implement an embargo on the modification of germinal cells (cells producing oocytes or sperm cells) and of embryos destined to implantation in future mothers.”

– Marie MINET

The regulations she advises are targeted at the major ethical conundrum CRISPR-Cas9 poses, but she does not believe that such a strong regulation should be applied to all uses of CRISPR-Cas9: indeed, allowing the clinical experiments of the modification of somatic cells (i.e. not germinal cells) in the case of gene therapies could be beneficial, particularly if it becomes available to a broader public.

Regarding this last aspect, Rick, our biohacker who claims to be in favor of the democratization of CRISPR rather than its regulation, perceives the fear of the public and the scientific community as a conservatist behavior. He mentions how humans actually already performed genetic engineering throughout history, like the agricultural selection for decades and the random mutations caused by radiations or termination of pregnancy in case of trisomy 21.

“Those are also genetic engineering techniques just like CRISPR.”

– Rick

The Chinese experiment

The Chinese researcher He Jiankui claimed to have used gene editing in an embryo before implanting it into the mother´s womb. The aim of this experiment was to make babies resistant to HIV infection. This action took place in 2018, and the twins were born in November of the same year.

Dr. He’s experiment consisted in recruiting couples where the man was infected with HIV, modifying the embryos with Crispr-Cas9 and finally introducing them by in-vitro techniques. The aim was to create human embryos that were resistant to the virus that causes AIDS. The success arrived when two twins were born and there were no visible side effects on other genes. Later, in an interview with the Associated Press, Dr. He explained himself.  “I feel a strong responsibility that it’s not just to make a first, but also make it an example. […] Society will decide what to do next.”. Jiankui was not supported by his colleagues and by the hospital where he made his experience. Dr. Mitalipov (director of the Center for Embryonic Cell and Gene Therapy at Oregon Health and Science University) stated that there are different ways of treating HIV infection in newborns. Furthermore, Shenzhen Harmonicare denied being involved and giving permission to carry out the research. In addition, Jiankui’s attached University (Southern University of Science and Technology), claimed that Dr. He´s work “is a serious violation of academic ethics and academic norms,” according to the state-run Beijing News.  

Regarding legal background, it is not forbidden in China to do so, but only for “non-reproductive purposes”, even though researchers in this country are against these techniques. Nevertheless, by the end of 2019, Shenzhen Court sentenced Dr. He to three years in prison for « illegally carrying out the human embryo gene-editing intended for reproduction”. Two of his colleagues had also been sentenced. The controversy has not ended yet, as Xinhua news agency claims that a third gene-edited baby was born, as a result of He´s experiment. The agency finally stated that the researchers acted « […] in the pursuit of personal fame and gain […] » and seriously « […] disrupted medical order […] ».

Another risk is linked to the entities controlling this tool. Giving even more control over our lives to governments like the Chinese one is concerning to say the least. The Chinese government already had a birth control program for a few decades. What if they impose some DNA sequences to new children, to make sure the sex-ratio is preserved? What if they want to keep a unified population and thus impose a certain DNA to Uighur populations in order to tackle communities? These ideas might seem extreme, but past events show that a tool giving so much control over births is dangerous. Just thinking about what Hitler could have done with such tools to accomplish his Arian dream sends shivers down your spine.  


Crispr in the epidemic crisis of today

In the near future, CRISPR and other gene-editing tools will probably be harshly criticized and rejected by the population. These are scary and quite technical tools, closer to sci-fi movies than to real life. Among others, the fear of a hidden disease induced by these techniques is emphasized by the recent COVID-19 pandemic.

Right now, CRISPR is making a name of itself again, as it could be helpful to fight against the Corona-virus. According to Le Monde (28 March 2020), a new test, made to detect the COVID-19, is based on CRISPR. Scientists were adapting their methods to collect samples of DNA attacked by the virus. This could lead us to sequence accurately the virus, but more importantly instantly, and therefore improve our knowledges about it. According to the National Public Radio (NPR, 17th April 2020), CRISPR is the solution to do faster, cheaper and easier tests. This test, developed by the San Francisco Medical School and Mammoths Bioscience, is self-contained and can be used from anywhere, without any medical equipment.

The ethical dilemma around CRISPR is only at its beginning, as this tool is already powerful and will inevitably continue improving. Every day, a new experiment is made and new targets are edited. Who is authorized to decide the path forward for drastically altering human life, and on what ground? For Dr. He, only his colleagues and the government were involved. Public dialogue led by scientists and bioethicists seeks to affirm scientific experts as the legitimate arbitrators of scientific and technical ethics, and delegates decision-making to those doing the experiences. Yet it is important to expand the number of people in the debate to establish a future with gene editing being beneficial for us all.

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