CRISPR: Intro and Ethics

source: Shutterstock // image description: close-up of a DNA double-helix strand

By SydneyBlu Garcia-Yao

Part One: What is CRISPR Cas9?

CRISPR (Cas9 - more on that later) is a gene editing tool. Standing for Clustered Regularly Interspaced Short Palindromic Repeats, it was first mentioned in a 1987 paper written by Yoshizumi Ishino and colleagues. They were at Osaka University in Japan studying E. Coli when they discovered, and were confused by, the five repeated sequences in between longer sequences that were all unique. 

So, how did we get from E. Coli to superhuman babies?

What Ishino had done was accidentally cloned CRISPR. The next mention was in the Netherlands in 1992 when researchers published two papers on interrupted direct repeats in bacteria. CRISPR still wasn't moving very fast. It wasn't until 2005 when scientists finally turned their attention away from the repeated sequences. Instead,they discovered that the unique sequences in between matched with virus DNA. This discovery started the breakthrough of CRISPR.

It was very surprising to find virus DNA in bacteria. You wouldn't expect fly DNA in humans, would you? Yet it makes sense. Eugene Koonin, an American-Russian biologist was the first to figure out why it was there - as a defense mechanism. Every day, 40% of bacteria is killed by viruses, but there's a small percentage that were able to defeat the virus and survive. When this happens, new enzymes clean up the virus DNA and cut it up and insert it into the bacteria's own DNA, with some repeated sequence as spacer. This way, the next time the same virus attacks, the bacteria can recognize it by comparing it to the sequence that it stored; if it matches, the bacteria can then use molecular "scissors" to kill the virus. 

On to the Cas9

CRISPR doesn't actually do anything - it's just the name of the natural phenomenon. The gene editing and replacement is done by Cas9, an enzyme, along with some of the body's other natural functions. Besides Cas9, the second most popular is Cas13, but typically the Cas9 part is assumed. In most cases, when only CRISPR is used while referring to gene editing, it really means CRISPR Cas9, but it's abbreviated CRISPR. 

This understanding of CRISPR Cas9 fundamentally changed what we thought was possible in gene editing. For the first time, it allows us to find, cut, and replace just about any DNA sequence, cheaply and reliably. In the past, we were very limited on the types of edits we could make and still it was prone to errors. With CRISPR, we just need to "program" the enzyme with the target sequence we are looking for, inject it into the cell and it locates target gene and cuts it; then the cell's natural DNA repair mechanism automatically kicks in and fixes it with the correct gene. CRISPR is only $75 to use, a far cry from the previous $5000. It's also much faster, only taking a few hours. 

CRISPR is an exploding field with more than 14000 publications in 2017, compared to less than 100 just 6 years ago in 2011. With its wide and profound potential applications, it is no surprise that the title of "who owns it" is a subject of intense dispute. The patent has been litigated for years between  Feng Zhang at the Broad Institute and Jennifer Doudna at UC Berkeley, and it has been awarded to the former as of now.

Part Two: CRISPR Ethics and Designer Babies

Designer Babies???

Recently, CRISPR has been all over the news. A Chinese scientist, He Jiankui, is said to have created the first CRISPR babies, a set of two twin girls whose embryos were modified. While he has yet to publish a peer-reviewed article so we have no verification on any claims, He claims that a third CRISPR baby is on its way. The twins are edited for the purpose of preventing disease. The father of the supposed twins had HIV, so He used the CRISPR Cas9 system to make sure they wouldn't get it. 

He studied at Stanford and now resides in the Shenzhen city of China. Before this he used to be an associate professor teaching at the Southern University of Science and Technology. He didn't go through any of the normal paths when publishing studies like in scientific journals. It was also self funded. This isn't the first time China has been blamed for breaking the unspoken rules of ethics around CRISPR. A couple of years ago Chinese scientists used In Vitro Fertilization and edited human embryos. 

But it's also not just Chinese scientists doing things that might be questionable. Harvard researchers are using CRISPR in sperm DNA, though not intended for an actual pregnancy. Now you may think that's ethical because they go through all the right routes and are approved, but others may still feel that it's too dangerous. 

The issue with what He did, besides the fact that he didn't use the proper channels, is that the possible negative effect outweighs the possible benefits. CRISPR could fail if the edit was in the wrong place causing off-target edits. Mosaicism could occur when some cells are edited, but others aren't. CRISPR isn't particularly risky, but in ethics, like I mentioned earlier, the risk is measured to the benefit and in this case, HIV is preventable. 

Was it ethical to create the CRISPR babies?

There's no real way to know for sure whether or not it was ethical. It just depends on how you stand since there are great arguments on either side. Sure, for the supposed twin girls, arguably the risk outweighs the benefits. But for the future of CRISPR, one could argue it's a lot more beneficial, considering all the genetic diseases that are not preventable and have no cure. If we want the technology to go far, we can't just sit around and wait. 
One of the largest debate regarding  ethics in CRISPR is germline editing. You cannot ask all future generations if they consent to editing. Similarly, you cannot ask a baby if they want to be born either. While babies have been born regardless, whether we can get around the ethics of CRISPR is a different story. Besides the decision of whether or not you consent to be born (which is shaky at best since your parents didn't pick you of all the possible babies they could've had), you also don't get to consent to your family, socioeconomic status, eye color, hair color, intelligence, height and outside influences. Of course, it isn't the same as deliberate editing, but it puts CRISPR more into context. 

A lot of countries have taken steps to either ban or discourage research on germline editing. The NIH (National Institutes of Health) does not fund any research for editing human embryos. As of now, the idea of editing on a living human is unthinkable. 

If we can't have super babies, what about just healthy babies?

If both parents are homozygous (meaning they both have the condition), the child will also inherit the condition definitively, so using CRISPR to prevent the child from having a life-threatening or debilitating disease could be ethical. Scientists are trying to reverse mutations like Huntington's disease and cystic fibrosis or mutations that lead to breast and ovarian cancers. CRISPR can also be used in CAR-T Cell therapy by modifying immune cells to attack cancer cells more effectively. CRISPR could even be helpful with treating bacteria infection especially since they're getting resistant to antibiotics and creating new ones is expensive. There's just one issue: if things go wrong, no one wants to be held accountable and it would tarnish CRISPR reputation. 

Additionally, once CRISPR is shown to be safe, easy and effective for medical purposes, what's stopping it from shifting to enhancement purposes? The line between medical and enhancement is very blurry. If you were smarter maybe you would get a better job with less stress and be healthier. If you were more athletic then maybe you'd work out more often. Of course, these are just some examples, and I'm sure no one fully understands the extent of CRISPR yet. 

Let's imagine what CRISPR could do

In many ways, CRISPR could be the new agriculture. The technology seems to have come out of a comic book. It's hard not to imagine life with super babies. It's hard not to imagine this dystopian world where everyone is the same or as smart/fast/tall/etc. as the amount of money they have. The Olympics would be defunct unless they could figure out a way to trace it, but that's hard, if not impossible. The gaps in wage between poor and middle class would be huge, with the gap to upper glass being even larger. What class you're in could be determined by the quality of genome editing. 

Let's say we hold back from exploring the world of CRISPR in humans and instead focus on other plants and animals. We could make crops more resilient and nutritious make wooly mammoths by splicing elephant DNA and inserting woolly mammoth DNA. Korean researchers are trying to create bananas resistant to a deadly fungal disease and cows without horns so we don't have to take them off. Those are a lot of good that CRISPR can do without the threat of ethics concerns.

Now what?

The possibilities of CRISPR are endless and we really have no idea where it'll go. So we'll all be holding our breaths, waiting to see what happens next.