Every year, the leading scientific journal Science selects its “breakthrough of the year.” The gene-editing tool CRISPR-Cas9 was the runner up in 2013 and 2014, but it finally broke through and earned the title in 2015. The bacterial immune system turned genetic toolbox is changing the world of molecular biology at breakneck speed, and the technology is now starting to show how it will change our world. With all the possibilities and applications CRISPR-Cas9 has to offer, an important question is raised: how do we use this new technology in a way that is ethically sound? The debate became unavoidable once CRISPR-Cas9 was used to modify human embryos, an act which could have long-lasting consequences.
Some scientific advances have such a profound impact on society that it changes how we see the world. Think about the general distribution of electricity or the ongoing digitalization of our daily lives. These scientific revolutions sometimes raise questions on how we use novel technologies in an ethical way. This has been the case over the course of the twentieth century, as the progression of physics allowed us to harness the energy of nuclear fission while at the same time blasting down the door that led to mass destruction with the atomic bomb.
Today, the new genome-engineering tool CRISPR-Cas9 has put us in a comparable position. The technology has revolutionized the process of DNA modification, expanding its potential applications beyond what was previously deemed possible. But this also challenges us, as a society, to think about the consequences of such applications.
From bacterial defense to DNA-cutting tools
The CRISPR-Cas9 system, when it was first discovered, was a bacterial immune system that protected against viral infections. When a bacterium survives a viral infection, it stores a segment of the viral DNA within its own DNA. If the same type of virus tries to infect the bacterium again, the stored viral DNA is transcribed to RNA and loaded onto the Cas9 endonuclease. The RNA then guides Cas9 to the infecting viral DNA, which is then shredded by Cas9. In this way, CRISPR-repeats in the bacterial genome, where the viral DNA is stored, serve as the molecular memory of previous infections.
In 2012, Jennifer Doudna and Emmanuelle Charpentier, the discoverers of the mechanism, showed that Cas9 could be loaded with synthetic RNA molecules for sequence specific DNA cleavage. In doing so, they had developed a tool that could cut DNA at any desired location, using complementary RNA to guide the enzyme to the desired site. Moreover, the system was much more accurate than any of the previous DNA-editing tools were. For their discovery of the CRISPR-Cas9 mechanism and for its development into a DNA-editing tool, it is expected that Doudna and Charpentier will see a Nobel Prize coming their way in the near future.
The Ford Model T of genetic engineering
But why is CRISPR-Cas9 so groundbreaking? DNA recombination has been around since the 1970s, and technologies preceding CRISPR-Cas9, such as zinc finger nucleases and TALENs, allowed for specific gene targeting and editing. Why then is CRISPR-Cas9 the science breakthrough of the year?
Bioethicist Hank Greely uses a fitting analogy to underline the impact that CRISPR-Cas9 can have on society. He compares CRISPR-Cas9 to the Ford Model T: far from the first automobile, but its simplicity, production process, and affordability transformed society. The main change that CRISPR-Cas9 has brought to the table is that it has made genomic engineering cheaper and easier than ever before. Scientists are calling it “the democratization of gene targeting.” CRISPR-Cas9 circumvents the low efficiency and/or cumbersome protocols of previous DNA-modifying technologies, and, as a result, it lowers the threshold for performing modifications.
Because of these traits, CRISPR-Cas9 brings a new scope to the possible applications of gene editing, including those that were impractical, expensive, unusual, or downright impossible with older methods. Take the gene drive, for example. Gene drive is used to stimulate the inheritance of a certain gene by the next generation. This inheritance bias results in the rapid spread of the gene throughout the population. Using CRISPR-Cas9, gene drive can be used to modify DNA sequences in entire populations at a scorching pace. This principle has already been used in a lab to prevent mosquitos from spreading malaria. Disease vectors can be wiped out quickly, resistance traits can be spread through food crops, and population control becomes quick and easy for any organism, all through the gene drive/CRISPR-Cas9 combination.
The concept of transplanting animal organs into humans, called xenotransplantation, also becomes more realistic with CRISPR-Cas9. A common fear with xenotransplantation is that retroviruses in animal genomes might reactivate and harm patients who receive the transplants. CRISPR-Cas9 has now been used to cut 62 copies of retroviral DNA from the pig genome all at once. These virus-free pig organs could drastically reduce the waiting lists for organ transplantations. Despite this progress, other hurdles still need overcoming to make pig-men a reality.
The CRISPR-Cas9 earthquake also shook the realm of plants. Traditionally, plant DNA has been altered using bacterial T-DNA. The new GMO plant variety is defined by the presence of this foreign DNA, and it must follow strict GMO regulations. CRISPR-Cas9 can, however, modify the genetic code without leaving any foreign DNA; by doing so, it can avoid the regulatory maze surrounding GMOs. In December, the Swedish Board of Agriculture confirmed for the first time that a plant variety modified with CRISPR-Cas9 was, in fact, not a GMO according to European legislation.
Designer babies and super humans
The most controversial feat of CRISPR-Cas9 is, without a doubt, the modification of human embryos. Back in April, a team of Chinese researchers reported the results of its studies. In an effort to cure the genetic blood disease β thalassemia, they modified human embryos using CRISPR-Cas9. Though they used leftover, non-viable embryos from a fertility clinic, their research sparked a lively debate on the ethics of DNA modification. The team, led by Junjiu Huang, showed that while genetic defects could be fixed using CRISPR-Cas9, the technology at the time was too imprecise to be used in clinical practice. The authors also later emphasized that, with their publication, they wanted to show that CRISPR-Cas9 was not ready for such applications. It served as a warning to anyone who might attempt such procedures outside of a lab.
Modifying embryos would also result in the modifications being inheritable by the offspring of these individuals. It remains difficult to predict how this might influence human genetics, but in any case, such actions would have long-lasting consequences. Many scientists and ethicists are also worried that human DNA alteration is a slippery slope that leads to applications beyond the clinic, resulting in enhanced humans. The scientific world has unanimously agreed that too little is known about the relation between genes and human traits to mess with it. However, CRISPR-Cas9 has pulled these ethical discussions from the abstract realm of science fiction into our concrete reality.
Yes, we can! But should we?
The use of CRISPR-Cas9 has exploded since its first application as a gene-editing tool, in 2012, and after the Chinese publication last year, it has become clear that the need for ethical debate on this matter is urgent. A scientific summit was held in Washington, D.C. at the beginning of December to discuss regulations, and even a temporary ban, on human CRISPR-Cas9 research. Not only scientists but also politicians, ethicists, and historians were present at the summit, reflecting the fact that CRISPR-Cas9 is no longer solely a scientific tool but rather a socio-political implement that affects us all.
Central to the summit was the matter of germline editing, in which DNA modifications affect the progeny of the modified individual. The editing of human embryos has the potential to eradicate rare genetic disorders, if allowed. Currently, embryos from IVF can be screened for genetic defects, and healthy embryos can thus be selected for implantation. With this in mind, Nobel Prize laureate David Baltimore asked the million-dollar question: “Is it more ethical to edit embryos or to screen many and throw most of them away?”
As the debate raged on, the summit attendees also witnessed an emotional testimonial from audience member Sarah Gray. Gray had given birth to a son with anencephaly, a genetic defect that caused him to suffer seizures for 6 days before dying. The heartbroken mother’s plea was compelling: “If you have the skills and the knowledge to eliminate these diseases, then freaking do it.”
The summit ended with the conclusion that, for the time being, altering the DNA of human embryos is unacceptable and should be condemned. However, the council supported further research into the possible risks and benefits of CRISPR-Cas9 and acknowledged its enormous potential as a research tool. They also agreed that an ongoing forum should be held on the use and progress of CRISPR-Cas9 to keep a finger on the pulse of its development and intervene when necessary.
In any case, the evolution and use of CRISPR-Cas9 will be an interesting facet of science to keep an eye on in the future.
(Image courtesy: NIH (heading), Andy Langager - malaria (right), Ed Hutman - human embryo (left),