Human beings are such a mystery. They can be breathtakingly smart and unbelievably stupid. Scientists can often demonstrate both of these traits simultaneously. Throughout history they have made amazing discoveries thanks to brilliant insights and very hard work, while completely overlooking how their creations could end up being detrimental to mankind. Robert Oppenheimer felt terrible remorse after creating the A-bomb. All of the computer scientists in the documentary I mentioned last week were embarrassed and apologetic about their part in creating unbridled social media platforms. They simply did not foresee the terrible costs individuals and societies would eventually pay as a result of the algorithms they created.
There is a relatively new technology which has recently been created in biochemistry called CRISPR which could very well lead to untold problems. CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeat, and it refers to a form of DNA peculiar to microbes. DNA in most living things lives on long strands, but the DNA in microbes occurs in short fragments which are repeated many times at regular intervals, hence the term CRISPR. This sort of DNA sequence had never been seen before its initial discovery in the late 1990’s.
CRISPR cells were interesting to scientists not just because of the recurring sequences but also because of the pieces of code which lay between these repeats. Researchers called these “spacers”, and unlike the DNA strands they separate, spacers are all unique. Scientists began to question what the purpose of spacers might be and, as with many advances in science, the answer was discovered accidentally. A researcher at Danisco, a company which sells microbes to food manufacturers, was trying to figure out how to beat viruses that kill the bacterial cultures necessary to make yogurt. A virus is a very simple cell with one function – to find a host, drop in its genetic material, and overrun it. It hijacks the cell and uses it as a factory for its own reproduction, thereby killing the cell. In all viral attacks, however, there are some cells in the host which do not succumb to the disease.
Danisco scientists decided to look at the DNA of cells which survived viruses, hoping to discover the key to their resistance. What they found was that the DNA sequence in these cells had changed – they now contained a new spacer which had not existed before. What’s more, the new spacer had an identical sequence to that of the virus. Somehow this made the cell immune, offering scientists a clue that they could investigate. They conducted several experiments wherein they took a strand of viral DNA and intentionally made it into a spacer in a microbe, and without fail that cell would then became resistant to the disease. Conversely, when they took that new spacer away, the cell was immediately overrun by the virus. Scientists concluded that CRISPR spacers of this kind were actually part of an adaptive immune response. In other words, bacteria have memory and can recognize invaders and kill them.
Enter Jennifer Doudna, a Biochemist working at UC Berkeley. Biochemists study chemical processes within and relating to living organisms. Doudna was very excited when she learned in 2007 that bacterial cells had a built-in defence against viruses. Somehow microbial cells stored copies of viral sequences and reproduced them when they were attacked, but it was unclear how the new spacer know exactly where to cut the DNA chain to stop the virus. Doudna and her team discovered a new protein she called Cas9 which was responsible for putting the defensive spacer in exactly the right spot. Cas9 polices the cell’s DNA, bringing with it a copy of the invader’s code for reference. If it discovers the virus, it then cuts the host’s DNA where the virus has attached itself, ending the invader’s ability to reproduce and thereby kill the cell. Doudna and her team were very excited by this discovery, because here was a potentially programmable protein which was able to target and cut DNA at a particular point. It was clearly a tool which had massive potential to alleviate human suffering caused by viruses and genetic diseases alike, and could also be used to aid other animals and to improve agricultural outcomes. The scientific paper announcing the discovery of Cas9 concluded with the observation that this new protein had “…considerable potential for gene-targeting and genome-editing applications.” This discovery could change our relationship to the entire biosphere.
Cas9 was an absolute game changer. Scientists already knew where many genetic diseases lived in human DNA, but what they didn’t know was how to change the code. Even if they could figure that out, they had no idea how they could possibly ensure that any new code would be placed in exactly the right spot on the incredibly long DNA chain. CRISPR and Cas9 provided the answers. RNA and DNA communicate using the same four letters- A, T, C, and G – with RNA acting as the chemical messenger between DNA and the proteins it forms. RNA sequences can easily be made in labs, and scientists realized that it might therefore be possible to place manmade RNA sequences into Cas9 molecules which could then cut DNA at a desired point and rewrite the code in a beneficial way. In other words, as Doudna puts it, scientists had discovered a tool which allows us to “…change our relationship to nature. It actually allows us to change human evolution if we want to. It’s that profound.” Powerful stuff.
Let’s look at this technology as it could apply to one deadly genetic disease – Sickle Cell Anaemia, or SCA. This is a blood disorder inherited from one’s parents which is predominantly seen in individuals of African descent. The disease changes normal round red blood cells into a crescent shape, hence the word “sickle” in the name. These malformed cells inhibit and eventually stem the natural flow of red blood cells, thus depriving the body of oxygen and leading to a host of unpleasant symptoms such as pain, anemia, swelling in the hands and feet, bacterial infections, and stroke. Most people with this affliction live a maximum of 40 years, and until now the only known treatment was to periodically swap-out diseased blood cells with healthy ones in a transfusion.
Scientists have long known what the genetic mutation causing SCA looks like, and have tried releasing re-written RNA into the system of individuals suffering from the disease. They were never able to target this cure, and consequently only about 1-2% of affected cells received the newly coded information. Now they can put manmade RNA in a Cas9 protein which will search out the same sequence in every cell and cut the code in exactly the right spot. Use of this technique has resulted in the disease being corrected in 50-80% of SCA cells in test subjects. This is a very promising outcome which speaks to the potential of CRISPR and Cas9 technology eventually being capable of curing a whole host of diseases at the genetic level. Experiments into its potential to cure Muscular Dystrophy and cancer are underway right now.
So much CRISPR research is being done, in fact, that there are now companies whose sole purpose is to produce customized CRISPR edits. This means labs working on genome engineering can focus solely on their experiments while a whole other entity creates the RNA sequences they need to further their research. Many scientists are studying the use of this technology for the betterment of humankind. For example, a lab called ReGenesis has recently received a very large grant to figure out how to make pig organs compatible with humans. The ReGenesis lab is using CRISPR to implant desired genetic changes in their animals subjects, as well as to cut out unwanted porcine DNA. In this way they hope to engineer swine which will grow organs that human bodies will not reject. I am a meat eater so I can’t really complain about the ethical implications of killing an animal, but I do have to say that the idea of changing the genetic code on such a large scale makes me uncomfortable.
I am not the only person feeling this unease. Many learned people have concerns about where this technology might lead, and how quickly it could outstrip our ethics. Scientists already know where to make a change on the DNA strand to make us more muscular, to allow us to get by on only four hours of sleep, and to completely inhibit feelings of pain. There is a single gene which is responsible for making the protein which relays pain signals from the body to the brain. People missing this gene experience no pain whatsoever, and CRISPR could easily be used to remove this single letter from a person’s DNA strand. Imagine excising a single gene and completely eradicating pain. How revolutionary for chronic pain sufferers, not to mention end-stage cancer patients whose pain is off the charts. There are so many ways this targeted gene editing could be used humanely, but what about its misuse? Do we really want to enable aggressive governments to create special forces soldiers who are immune to pain?
The long and horrible history of eugenics makes scientists very wary about making genetic changes to embryos. There is an international understanding in their community that such things are not allowed, but a doctor in China has already stepped over that line. He knocked out CCR5, the receptor to HIV, from twin-girl embryos. While it may seem like a good idea to make humans HIV resistant, the worry is that furthering this branch of bio-medicine may lead in time to tailor-made babies. John Zhang runs the 3rd biggest fertility clinic in America and he recently started a company called Darwin Life. Zhang himself has said of the company, “Everything we do is a step toward designer babies. With nuclear transfer and gene editing, you can really do anything you want.”
Antonio Regalado is a reporter for the MIT Technology Review. He managed to get hold of a taped shareholders meeting held by OvaScience, another well known bio-fertility company. On the tape the CEO baldly states, “We will be able to correct mutations before we generate your child. And that may not be in 50 years, that may be in 10 given the way things are going.” Let’s pause a moment to parse that first sentence. The word ‘mutations’ concerns me. What does he mean when he says ‘mutations’? Is he talking about genetic diseases or malformed limbs, or could that term be applied just as easily by some people to traits like brown skin or average intelligence? What about the way he says they will ‘generate’ a child? Such a cold, industrial term. As though humans, in his estimation, are just products. Just widgets that can be designed to meet the purchasers’ requirements. I find this whole statement extremely chilling.
Scientists recognize the potential for harm in this technology and therefore have placed an international moratorium on using CRISPR on germ lines. Every part of our bodies – organs, tissue, blood, etc. – is made up of somatic cells. Any genetic changes made to these cells are fine as they are contained within an individual’s body and die with them. Cells in sperm and ova are called germ line cells, and changes to these will be passed down through the genetic code. There is simply no knowing what ancillary harm such a change could produce in subsequent generations, and once an edit is made on a germ line, it is impossible to put the genie back in the bottle.
As for designer babies, Alta Charo, a Bioethicist at the University of Wisconsin-Madison, notes that science is a long way from being able to produce babies with exceptional patience or a good sense of humour or increased intelligence. They do not know what the code for any of these traits looks like, making it impossible for them to design it in a lab. Many fears about this technology are overblown, says Charo, and besides, humans have always found ways to commit horrible acts without it. Eugenics, discrimination, and genocide all flourished well before CRISPR was discovered. It is just the latest scientific tool, and whether it produces laudable or despicable outcomes is completely dependent on the user.
Stephen Hsu is an example of a scientist who feels he is using CRISPR for good. He is co-founder of a company called Genomic Prediction which specializes in providing advanced genomic testing for in-vitro fertilization. They use pre-implantation genetic sequencing on embryos to identify those which are most likely to improve newborn health outcomes. In other words, like all IVF facilities, they often produce many viable embryos, and their machines do genetic tests on each candidate to determine which is the best one to implant. Right now there are only a handful of genetic traits they can definitively identify, but the science is moving so quickly that before too long they may well be able to learn pretty well everything genetics can reveal. It may be that our understanding of DNA will be so comprehensive in the future that IVF facilities can produce a single viable embryo and then make lots of edits to just that one. Procreation would no longer be a lottery, and genetic diseases could be eradicated.
Part of the problem with this technology is the cost. Clearly only rich people have enough money to pay for the services of companies like Hsu’s. While they can ensure their children are genetically primed to thrive, people of lesser means will continue to roll the dice when they procreate. This could lead to a class of people who not only have the advantage of wealth but also of excellent health and longevity. The negative implications on society of such a scenario are frightening, and rather put me in mind of the dystopian future described in “Brave New World”.
Certainly we need to be cautious about the applications of this technology. It opens up the possibility of alleviating much human suffering, but in the wrong hands could be used to interfere in natural processes in a tremendously detrimental way. I tend to fall on the more optimistic side of the debate, and feel that overall CRISPR will turn out to be a boon for humanity. I also believe that the fears about creating a super-race are exaggerated. Stephen Hsu often gives public talks about the future of embryonic genetic testing, and he notes that the comments he receives afterwards from listeners vary widely depending on which member of the audience is speaking. Aryan-looking people expect that everyone will opt for their child to be tall and blond, nerds predict parents will all want kids with high intelligence, and jocks assume the most sought after trait will be athleticism. As long as people have different priorities, even pre-determined genetic traits will remain varied. If we can have that while getting rid of the genes which predispose a person to developing breast cancer or early-onset Alzheimer’s, then I say hurray for CRISPR.