CRISPR cas9 – are designer babies our future?

Lidia Czajkowska
Oct 30, 2022
6 min read

This story starts in 2012 when two amazing women Jenifer Doudna and Emannuelle Charpentier published the results of their research that changed the science that we know forever. They noticed the powerful defence tool that bacteria use against viruses. They realised we can apply this system to us, humans, in order to precisely change the genome of not only somatic cells but also (as the research in China a few years ago showed) germline cells. CRISPR Cas9 is not only a much cheaper but also a much more effective and precise way of modifying our DNA. Editing germline cells also allows scientists not only to make changes in individuals but also to influence whole generations. After 8 years of working on making the method better and doing more research, Jennifer and Emannuelle won The Noble Prize in Chemistry (2020).

CRISPR cas9 – what is it and how does it work?

CRISPR editing schema

”CRISPR" stands for Clustered Regularly Interspaced Short Palindromic Repeats and it is the defense system of prokaryotic organisms from exogenic genetic elements (e.g. parts of viral DNA). "Cas", on the other hand, stands for a CRISPR-associated protein and it is the nucleic acid that cuts our DNA like “molecular scissors”. It naturally occurs in bacteria like the well-known E.coli and acts like an adaptive immune response. It remembers how viruses attacked them in the past and keep a little bit of the viral DNA to use later. Thus, if the same species of virus infects the bacteria again, it will be able to respond more quickly and in a more effective manner. The first thing that happens (in the pair of enzymes- cas1 and cas2) is the part of the virus's DNA called "protospacer" is cut and stuck to the part of the bacterial chromosome called "CRISPR array". Protospacer then becomes a spacer in the CRISPR array which consists of repeat DNA (identical DNA fragments) and spacers between them. After adding a new spacer at the beginning (5’), a new part of repeat DNA is added to the array, making it complete.

But how does cas find and cut useful parts of DNA so precisely? It makes it happen by looking for the Protospacer Adjacent Motif (PAM) which is a motif occurring next to the actual spacer - it can be any nucleotide, followed by two guanines. Cas cuts up the strain which leaves our molecular scissors with a precisely sliced spacer (20-26 bases long).

Sometimes it will happen that an RNA polymerase will transcribe this CRISPR region (a new spacer) into RNA molecules also called pre-CRISPR RNA (pre-crRNA). The single RNA molecule contains both repeats and spacers but also, unlike in the CRISPR array, unprocessed tracrRNA. Those unprocessed fragments of tracrRNA are transcribed from another gene in the cell and stuck to the repeats of DNA. Later in the process, an RNA molecule is cut by the RNA, leaving us with crRNA, spacer RNA, and some processed tracrRNA - we can refer to it as cr:tracrRNA - which is picked up by an enzyme called cas9. Cas9 in 6 different regions (HNC nuclease domain, REC2, REC1, bridge helix, RuvC nuclease domain, and PI PAM interacting domain) identifies PAM, cuts DNA, and holds guide RNA in place. Meanwhile, cas9 finds DNA spacers, then identifies the PAM region (nGG), opens the DNA, and checks if the guide RNA, that it holds, is complementary to the sequence of bases (note: it is not the strand which detected nGG;- it is the opposite one). If it matches, cas9 cuts the DNA on both strains (3 or 4 bases next to the PAM) and leaves the DNA causing it to double the strain break (DSB). After the process is done, cas9 leaves the DNA looking for other PAMs and the process never ends.

But how is cas9 able to tell the difference between bacterial and viral DNA If they are identical? There is NO PAM (nGG) in bacteria, so cas9 won't even look if it matches. It will only look at viral DNA.

How can it be applied to humans?

There are two main approaches in applying CRISPR cas9 mechanism in order to edit the human genome: Non-homologous and joining and Homology directed repair. First (NHEJ), works like a broken glass vase that you want to glue back together. It means that it doesn’t need other parts of DNA to act as a template - much more simple, but at the same time less ideal and precise. The second one (HDR) is based on the DNA having two same base sequences (that’s why even though this approach is much more ideal, it is not always possible to conduct but that’s the problem in bacteria). Fortunately for us, humans, we have 2 pairs of chromosomes, meaning we have an identical copy that can be used in that process: double strain breaks (DSB).

Bioethics

“Bioethics - the study of what is right and wrong in new discoveries and techniques in biology, such as genetic engineering and the transplantation of organs”

- Cambridge dictionary

Genes determine our whole existence as humans. From simply deciding about our eye colour (it's not as simple as it seems) or personality to genetic diseases that we inherit.

Scientists usually don’t consider ethical implications of editing DNA for improving humans health, discussion starts when we want to interfere in one’s intelligence, looks etc.

The question is where we should draw the line?

Imagine a situation where thanks to genetic engineering you are smarter than all of your friends (who aren’t genetically modified), you are taller, you are more beautiful; but not only that, you are also resistant to any disease, lowering your costs of hospitalization. It sounds amazing, right? It appears nearly ideal, but in reality, it carries certain consequences that may be considered unethical. The first and one of the most important ones is the possibility of errors in modifying the human genome, especially in the germline cell, which could cause problems that would be passed on for many generations. We need to acknowledge that it is still a relatively new technique and while testing it is natural to make mistakes but when human life is taken into account, you cannot afford ANY slips. It must be flawless. If one thing goes wrong, the entire field that is so powerful and promising could be damaged. The next consideration that is vital is using designer babies in politics. Governments could start using those improved human beings in e.g. wars. They could also push their agendas and force people to modify their children in a way that they are easier to manipulate or created to do something specific (maybe even unnatural from today's perspective). Designer babies could also become a kind of trend. They could be considered fashionable, posted on social media like a new kind of celebrities, erasing the real aim of genetic engineering. Biotechnologists want to make us, humans, better and make our life easier.

The question is: what is actually better when talking about human beings?

So are designer babies our future?

For those of you who are fans of sci-fi and would like to see designer babies in real life just like in movies, unfortunately, it is not as simple as just using CRISPR Cas9. Scientists are on the right path to cure many diseases and they see the potential possibility to be able to “design“ babies in the future, but it will be only possible when they know each gene responsible for each feature in our body. The truth is, even if they knew it, there is still the possibility of failure. CRISPR Cas9 is an amazing opportunity that may change our lives for the better, but it is not perfect. For those who dream about it being a reality, think about the ethical concerns I pointed out and don’t be disappointed. We should be grateful and amazed by great minds that have allowed us to even dream about this being possible. Thank you, Jenifer Doudna and Emannuelle Charpentier for changing science forever.