genome-editing

In recent years, a real revolution is ongoing in the molecular biology field. This revolution roots back to the 60’ and 70’ years of last century, when all the scientists around the world began to daydream about the possibility of curing diseases by manipulating the human genome taking advantage of the rising methodologies of recombinant DNA. Sometimes dreams come true and, nowadays, genomic manipulation is reality thanks to a newly discovered technique that allows us to specifically and accurately modify our DNA.

CRISPR/Cas9 is a microbial immune system that utilizes RNA molecules for cutting foreigner pieces of DNA into the cell. With our most advanced biotechnological techniques, we are now able to control and design this system in a simple, quick and economic way. Theoretically, it is easily possible to remove target genes for functional studies or exchanging mutated gene copies with normal and functional ones. This biomedical revolution could change not only our means in facing human diseases, but also the entire relationship existing between human beings and nature.

Since several years we are discussing these issues at the borders between Ethics and science fiction. This dated discussion fluctuates from our hope of potentially curing several maladies to the eugenic manipulation of our genome putting aside the slow path designed by Mother Nature. The ongoing fiery debate led several researchers to wonder which will be the first country authorizing clinical applications of genome editing techniques and where in the world could the first CRISPR baby be born.

nature-crispr-map-inline
Ledford, Nature News 2015

 

 

So, after a first work done in China on non-vital embryos (Liang et al 2015, Protein and Cell), the HFEA (Human Fertilisation and Embryology Authority) have been granted permission to edit human genome embryos. The approved application by the developmental biologist Kathy Niakan, at the Francis Crick institute in London, implies the use of CRISPR/Cas9 system in order to study genes involved in the first stages of embryo development. Each experiment will be stopped after seven days and the embryos destroyed.

This landmark decision by the UK national regulatory authority, lead the way for all the groups of research that in the next months will apply to their national regulatory bodies for using similar genome editing strategies.

At this juncture, there are two main questions that we must ask ourselves before undertaking any slippery and dangerous path:

  • Are we scientifically ready to control this technology?
  • Are we ethically and morally ready to regulate and exploiting it?

 

Scientifically, this technique improves day to day. Indeed, what worries researchers most is the possibility of off-target effects namely, stochastic modifications throughout the genome that cannot be predicted a-priori and can create collateral damages to the cells. However, only few months ago, a new paper has shown the possibility of designing a new kind of CRISPR/Cas9 system with no detectable off-target effects (Kleinstiver et al, Nature 2016). Obviously, the system sensitivity is not at the single-event level; nevertheless this great step forward makes us closer to our goal of having targeted genomic modifications without any collateral damage. Nonetheless, there are several doubts on the horizon given that we still do not know how and if this system interacts with other cellular process (we are not aware about all the interactions that happen between every cellular component). Also, the quickness with which the entire process evolved, raise up questions because we did not have the time to accurately define a risk assessment. Unfortunately, nowadays everything is driven by economic reasons. Every item acquires a real value just when it becomes able to generate an economic flux, and it is a matter of fact that now science is completely dependent by economy. Scientific aims are mutated in time: the ultimate goal is not represented anymore by the knowledge itself, but being faster than the others in discovering something and utilize your work to easily get more research foundlings and fame. This hurry to discover, speeds up every process and risks to become a double-edged sword that might lead us to commit unacceptable evaluation mistakes in matters regarding new technologies that could perhaps change the history of mankind and Earth (not by chance some researchers have proposed to rename Anthropocene the era we live in).

It is a matter of fact that HFEA did not approve any clinical studies; nevertheless, permitting work on human embryos is a huge step forward that could have been more carefully weighted. Less than just one year ago, a Chinese research group has faced a barrage of criticisms for using CRISPR/Cas9 system on non-vital human embryos (Liang et al 2015, Protein & Cell). The authors even declared that this paper has been rejected by Nature and Science in part because of ethical reasons (both journals declined to comment on the claim). Still, as soon as a similar situation happens in the UK where we believe probably with prejudice that research works are more controlled, the same technique even used on vital human embryos is widely accepted by scientific community and embolden dozens of scientists to submit similar research application.

Here some example about the two above mentioned situations:

 

About Liang et al paper:

George Daley, stem-cell biologist at Harvard medical School in Boston:

“I believe this is the first report of CRISPR/Cas9 applied to human pre-implantation embryos and as such the study is a landmark, as well as a cautionary tale. Their study should be a stern warning to any practitioner who thinks the technology is ready for testing to eradicate disease genes.”

 

Edward Lanphier, president of Sangamo BioSciences in Richmond, California:

“It underlines what we said before: we need to pause this research and make sure we have a broad based discussion about which direction we’re going here.”

 

About HFEA approval on human embryo research:

Again George Daley:

“it’s an important first. The HFEA has been a very thoughtful, deliberative body that has provided rational oversight of sensitive research areas, and this establishes a strong precedent for allowing this type of research to go forward”.

 

Tetsuya Ishii, Bioethicist at Hokkaido University in Sapporo, Japan:

“This step in the UK will stimulate debate on legal regulation of germline gene editing in clinical settings”. Moreover, he noticed that in some countries reproductive applications are not explicitly prohibited.

 

Robin Lovell-Badge, biologist at Crick Institute, even claimed:

“This decision will give scientists confidence to either apply to their national regulatory bodies, if they have them, or just to go ahead anyway”.

 

Clearly, regulation of this field through an important regulatory body gives hope that borders are traced carefully between research and clinical applications. And it is clear that researcher’s widespread enthusiasm is supported by the importance of beginning a discipline process of such important and complicated matter. All that being said, it is perhaps not justified those discrepant reactions at the same problem (just one year after) and underlines how are we quickly moving toward a difficult to interpret Limbo where “just to go ahead anyway” is not an acceptable option. Before undertaking any important decision, what happened to the “desirable broad based discussions”?

On the other hand, one must say that we should avoid the panic generated in the seventies of last century because of the raising molecular biology methods. At that time, scientists aware of the intrinsic dangers originating by these techniques convened the famous meeting in Asilomar (1975) that afterward led the American regulatory body NIH (National Institutes of Health) to approve tight guidelines that hindered scientific progress for years. Closed systems are strongly discouraged because may times history taught us that progress cannot be stopped: we can just try to bring it on the way toward common good.

And here comes our second question: are we ready for this revolution?

This kind of technology has unlimited biomedical power. For example, we now know that some genetic polymorphisms protect from HIV infection. It has already been proven that human blood stem cells editing through this system is possible (Mandal et al 2014, Cell Stem Cell) and in a near future we might be even able to cure HIV-infected people infusing modified immune cells resistant to the virus. This would represent an unimaginable progress; still, major concerns remains about potential application involving germinal cells that are those who can give rise to an entire organism and can be hereditary transmitted. It follows that the real problem lies on those changes involving not a single individual (as in the case of HIV treatment) but the ones that will affect next generations descending from that person.

Are we willing to taking on responsibility about changing the basis of our own nature? And at this point the discussion should move from science to ethic ground: are we today in 2016 able to manage this great power?

The biggest problem is represented by this ensemble of science and economy. It is normal these days that great discoveries are patented to gain profits every time someone takes advantage of them. Many times we witnessed long legal battles where big pharma or small biotech companies laid claim to intellectual and commercial properties of some scientific discoveries. The same type of battles, are usually avoided in academic field simply because institutions decide to share the benefit deriving from the discovery. This attitude is logic and normal if we assume that academic philosophy should mainly reflect that old dedication toward knowledge. Only in second instance an acquired knowledge could be then used to generate a profit. In our “new world”, this order is completely mutating especially because of funding shortage in academic settings. As a consequence, we are facing now an unexpected fight between academies regarding the CRISPR/Cas9 system. This battle roots back to 2012 when the first research group led by biologists Jeniffer Doudna of University of California, Berkeley, and Emmanuelle Charpentier, now affiliated at Max Planck Institute in Berlin, published the first results regarding this technique and file a patent application in March 2013. Since then, other groups used and improved the techniques, especially the group led by Feng Zhang, Broad Institute and MIT, that filed a patent application in October 2013 through an expedited program. This application was granted in April 2014, and other followed by then from the same group. Oddly, the first application filed by Doudna and Charpentier, is still under review. Things got out of hand when in 2015 Berkley team asked to the US Patent and Trademark Office (USPTO) to determine which team invented first the technique. From this point on the unusual academic fight begins: this situation will definitely leave important aftermath and exacerbates the clear scientific moral shifting toward ruthless competition.

The previous question is now renewed: after this long analysis can we say to be ready or not?

It is just impossible to have an answer, however only one thing seems extremely clear in this entire story. Whatever is in store for us in the future we have a real important duty to fulfill; striving and working hard in order to not take any rash decision on one hand, but also do not behave like Holy Inquisition halting every progress on the other. A fine-tuned balance between all the forces that rule our world is necessary, and more importantly we should take these decisions with our intellect, free from any economical or religious influence. All of this represents a duty that every citizen and scientist owe to the next generation that, for better or worse, will truly pay the price of our actions.

Davide Mangani

 

 

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