"Here be dragons."
Those words, included on uncharted territory of a globe made in the 16th century, underscore how people have historically associated danger with the unknown. This fear also often manifests itself with major new technological advances. Some were afraid of automobiles, airplanes, and computers when the innovations first appeared. Now another relatively new technology -- gene editing -- is stoking fears.
Is gene editing actually dangerous? Possibly. Risks of gene editing include:
- Potential unintended, or "off-target," effects
- Increased likelihood of developing cancer
- Possibility of being used in biological attacks
- Unintended consequences for future generations
However, these risks shouldn't scare investors away from considering a technology that could revolutionize healthcare. Here's a brief intro to gene editing, followed by four things every investor should know about the potential dangers of gene editing.
What is gene editing?
Just as gaining a better knowledge of world geography helped explorers centuries ago know which dangers were real and which were imagined, learning more about gene editing will help investors better understand the risks. Gene editing, which is also known as genome editing, involves the insertion, deletion, or replacement of DNA (deoxyribonucleic acid) in a gene.
DNA is where all genetic information is stored in the body. You've probably seen a picture or model of the DNA double helix, which looks similar to a ladder that has been twisted. The steps in this twisted ladder are DNA base pairs. Each base pair is made up of a combination of two chemical bases -- either adenine and thymine or cytosine and guanine. The sequences of these DNA base pairs provide instructions for how proteins are built, which in turn dictate how the body develops and functions.
In effect, gene editing is like using molecular scissors to cut specific sequences of DNA base pairs. But the actual process of gene editing is more complicated than just using scissors. In fact, there are several different methods that can be used to edit genes.
Zinc finger nuclease (ZFN) technology has been used longer than any other gene-editing method. First developed in the 1990s, this approach involves the binding of a pair of ZFNs to a DNA target. ZFNs are engineered proteins that are made up of two parts: (1) a chain of zinc modules that look like fingers and seek out specific DNA sequences, and (2) an enzyme known as a nuclease that can split DNA. You can think of ZFNs like two bookends that search for certain books on a library shelf and then knock the books off the shelf. The DNA sequence between two ZFNs is cut, which causes the cell to begin to repair the break. The ZFN approach can either insert a new DNA sequence into the space where DNA has been cut out, or totally remove the original DNA sequence.
In 2009, a different but similar gene-editing method called transcription activator-like effector nuclease (TALEN) was developed. TALENs are produced by a common type of plant bacteria. Like ZFNs, TALENs bind to and cut targeted DNA sequences. A key advantage the TALEN gene-editing method holds over ZFN is that engineering TALENs is simpler than using ZFNs.
Probably the biggest development in gene editing was the discovery of clustered regularly interspaced short palindromic repeats (CRISPRs). While research on CRISPRs began as early as 1993, the first scientific paper detailing the use of CRISPR to edit genes was published in early 2013. The CRISPR method uses bacterial enzymes to target and cut specific sections of DNA. CRISPR is simpler and cheaper than earlier gene-editing methods.
1. How worrying are off-target effects of gene editing?
One of the primary risks usually mentioned when the topic of gene editing arises is the potential for unintended, or off-target, effects. The goal of gene editing is to modify specific DNA sequences, resulting in target mutations (desired changes in gene structure). There's a possibility, though, that DNA sequences other than the target ones could also be changed.
Are these off-target DNA changes akin to minor side effects of taking a prescription drug? It's possible. But they could be much worse. Imagine going into surgery for a tonsillectomy and accidentally having a kidney removed also. That's a simplistic analogy for what happens with off-target effects of gene editing. This is definitely a scary prospect.
How big is this issue? Off-target effects have been experienced with all three types of gene editing, and it's not yet clear how big of a deal they are. The rapid rise of CRISPR, especially CRISPR-Cas9 (Cas9 stands for CRISPR-associated system 9), has caused any problems with off-target effects to receive special attention.
For example, an article published in Nature Methods in May 2017 raised serious concerns about CRISPR-Cas9. The scientists who wrote the article reported that using CRISPR-Cas9 to edit genes could cause hundreds of unintended mutations. As you might imagine, this news shook investors who had bought shares of biotechs focused on CRISPR gene editing. It definitely highlighted a danger for investors in such an early-stage technology.
That wasn't the end of the story, though. Many in the scientific community, including researchers working for the biotechs pioneering CRISPR gene editing, didn't agree with the article's findings. As it turned out, their skepticism was warranted.
In March 2018, the original article was retracted, and an error correction was posted to a scientific website. The initial research was flawed. Instead of CRISPR-Cas9 producing hundreds of unintended mutations, the scientists stated that the gene-editing approach "can precisely edit the genome at the organismal level and may not introduce numerous, unintended, off-target mutations."
Does this huge mistake mean we don't have to worry about off-target effects? No. However, the problem doesn't appear to be nearly as significant as some fear it will be. Scientists are fully aware of the conerns and are taking steps to minimize these issues.
David Liu, a biochemist with Harvard University and the Broad Institute and a pioneer in CRISPR gene editing, stated earlier this year that "progress is being made at a pretty stunning rate." Liu thinks new tools will enable scientists to use CRISPR gene editing in ways that don't produce unintended mutations.
2. Is the possibility that gene editing increases the risk of cancer a showstopper?
A more recently identified potential danger of gene editing is potentially increasing the risk of cancer. On June 11, 2018, two separate papers were published in Nature Medicine that raised concerns that CRISPR-Cas9 could elevate the likelihood of cancer cells developing.
Scientists at Cambridge University and the Karolinska Institute in Sweden reported that CRISPR-Cas9 gene editing can induce a response in cells that attempts to protect against DNA damage. This response involves activation of the p53 gene, which tries to repair the DNA break or cause the cell to self-destruct.
The problem isn't in the response itself. Instead, it's that CRISPR-Cas9 doesn't work well in the cells with the p53 gene response, but it does work in cells that have a dysfunctional p53 gene. And cells with p53 gene mutations are much more likely to cause cancer.
A similar report was also published in Nature Medicine on the same day by scientists with the Novartis Research Institute. This team also found that CRISPR-Cas9 worked more effectively in human pluripotent stem cells -- which can form any other kind of cell -- with dysfunctional p53 genes.
Is the potential for increasing the risk of cancer a showstopper for CRISPR-Cas9? No. There are four factors to keep in mind.
First, CRISPR-Cas9 can be used for deletion of a DNA sequence (referred to as gene disruption) or deletion of a DNA sequence combined with insertion of a new DNA sequence (referred to as gene correction). The papers published in Nature Medicine could point to problems with gene correction, but gene disruption using CRISPR-Cas9 should still work without increasing the risk of cancer.
Second, these results are preliminary. Remember that the early report finding that CRISPR-Cas9 caused hundreds of unintended mutations ended up not being the problem many thought it was after additional research was performed. More studies are needed before it is known how serious the p53 response issue really is.
Third, even if CRISPR-Cas9 is found to increase cancer risk, it's not the only method for gene editing. It's not even the only method for using CRISPR in gene editing. There are CRISPR-associated system enzymes that can be used to edit genes that potentially won't have the same problems as Cas9.
Fourth, workarounds could be identified. The lead researcher on the Cambridge team, Jussi Taipale, said in a statement released along with the publication of the article in Nature Research that his team wasn't claiming that CRISPR-Cas9 was dangerous. Taipale maintained that the gene-editing approach is "clearly going to be a major tool for use in medicine," adding that ways to overcome the potential problems identified in his team's research could be found.
3. Could gene editing be used in biological attacks?
When you think about weapons of mass destruction (WMD), nuclear bombs and chemical warfare probably come to mind. But in 2016, the then-director of National Intelligence, James Clapper, added another item to the WMD list: gene editing.
Clapper mentioned gene editing as a new global danger in his testimony to the Senate Armed Services Committee in addition to listing the technology as a potential weapon of mass destruction. Why? Gene editing could be used to genetically engineer bacteria or viruses to be used in biological attacks against humans, or to cause widespread crop damage.
These might sound like far-fetched plots from books and movies, but the advent of CRISPR makes the prospects of gene editing being used in biological attacks greater than ever. Unlike previous gene-editing approaches, CRISPR-Cas9 is inexpensive and relatively easy to use, which could make it appealing to terrorist organizations or rogue states.
The United States military is taking the threat seriously. Last year, the U.S. Defense Advanced Research Projects Agency (DARPA) gave contracts worth a total of $65 million to seven teams to study gene editing. In particular, this research is targeting gene drives -- genetic changes that rapidly sweep through an entire population. Some of the DARPA-funded teams are working on ways to interfere with harmful gene drives.
4. Could gene editing change the human genome forever?
Perhaps the biggest fear of all about gene editing is that it could be used to change what it means to be human. It's one thing to cut out sequences of DNA that cause genetic diseases, but making genetic changes that are passed down to all later generations is another thing altogether.
Germline editing involves making changes to the human genome that is inherited. The name comes from germ cells, which include egg and sperm cells that combine to form an embryo. Other cells in the body that aren't related to reproduction are called somatic cells. Editing somatic cells doesn't impact offspring like germline editing does. Many countries, including the U.S., have regulations in place to restrict germline editing.
Some concerns about germline editing are more scientific and practical. For example, Rice University professor of bioengineering Gang Bao told online healthcare journal STAT in 2015 that he thought the potential for the off-target effects discussed earlier make it far too risky to contemplate editing human germlines.
Others have ethical problems with germline editing. Francis Collins, director of the National Institutes of Health and leader of the team that first mapped the human genome, is concerned that modifying the DNA of human embryos to fit the preferences of parents -- creating "designer babies" -- could change society's view of human life. Collins worries that children could be seen as "commodities" instead of as "precious gifts."
But not everyone shares these concerns. John Harris, professor emeritus in science ethics at the University of Manchester, argues that permanently modifying the human genome to eradicate genetic diseases is something that should be done. Harris acknowledges that more needs to be known about the risks of editing genes in human embryos. However, he also stated in a 2016 National Geographic article, "But when the suffering and death caused by such terrible single-gene disorders as cystic fibrosis and Huntington's disease might be averted, the decision to delay such research should not be made lightly."
One of the pioneers of CRISPR, Jennifer Doudna, has changed in her views on germline editing. Doudna wrote in her book A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution that she first thought about permanently editing the human genome as "unnatural and wrong." However, she said that her "views on the ethics of germline editing continue to evolve." Doudna's perspective now is that "above all else, we must respect people's freedom to choose their own genetic destiny and strive for healthier, happier lives."
Jennifer Doudna's view, though, brings up another concern: Germline editing takes away the ability for future generations to choose their own genetic destiny. Francis Collins has noted that germline editing prevents unborn children from being able to give consent to genomic changes.
Debra Mathews, with the Johns Hopkins Berman Institute of Bioethics, takes a pragmatic view. Mathews told STAT that "regardless of what we decide to do in the United States, germline editing for reproductive purposes will be done somewhere in the world."
What these risks mean to investors
There are certainly risks and dangers associated with gene editing. But how do they affect investors? It depends on the specific risk -- and where you invest.
Below are four top gene-editing stocks along with their respective market caps and the types of gene-editing method used by each biotech.
Type(s) of Gene Editing
CRISPR Therapeutics (NASDAQ:CRSP)
Editas Medicine (NASDAQ:EDIT)
Intellia Therapeutics (NASDAQ:NTLA)
Sangamo Therapeutics (NASDAQ:SGMO)
All of these biotechs could face some risks associated with off-target effects of gene editing. Sangamo Therapeutics arguably could have a lower risk than the others because it's the only company so far to have advanced to a phase 1 clinical trial of a gene-editing therapy in humans.
All of the other biotechs are in pre-clinical testing. CRISPR Therapeutics and partner Vertex Pharmaceuticals have applied to the U.S. Food and Drug Administration (FDA) to begin a phase 1 study, but all testing has been placed on clinical hold until the companies answer more questions for the agency.
What about the increased risk of cancer? Again, Sangamo is least impacted. The research identifying a potential link between gene editing and cancer risk only involved CRISPR-Cas9. Sangamo's gene-editing therapies use ZFN instead.
But recall that the published articles appeared to only point to a potential increased risk of cancer in gene correcting therapies. The lead candidate for CRISPR Therapeutics, CTX-001, targets use of CRISPR-Cas9 in gene disruption -- not correction -- in treating genetic blood disorders beta-thalassemia and sickle cell disease.
It's a similar story for Editas Medicine and Intellia Therapeutics. Editas' lead candidate, EDIT-101, only deletes targeted DNA to treat Leber congenital amaurosis, the top cause of genetic blindness in children. The biotech also uses another gene-editing approach, CRISPR-Cpf1, that hasn't yet been linked to increased risk of cancer. Intellia's lead candidate targeting rare genetic disease transthyretin amyloidosis also uses gene disruption rather than gene correction.
However, all three of these CRISPR-focused biotechs have other pipeline programs that do rely on gene correction.
The other two risks associated with gene editing don't present specific threats to any of these biotechs. None of the companies are researching germline editing. And, of course, none of them are doing anything that's related to the use of gene editing as a weapon.
Still, there is perhaps a sliver of a chance that those gene-editing dangers could hurt CRISPR Therapeutics, Editas, Intellia, and Sangamo. If gene editing was used to conduct a biological attack that affected a large number of people, there could be a groundswell of support to completely halt all research based on gene editing.
Likewise, suppose that it is discovered that germline editing had been done with horrible unintended consequences. It's possible that such an event could lead to public demand that the government ban gene-editing research. Again, though, these are pretty far-fetched scenarios.
A risk that's not a danger
So far, we've looked at risks of gene editing that are also dangers. However, there's at least one risk for the technology that isn't itself a danger: Gene editing simply might not be effective in humans.
In January 2018, a paper posted on biology website bioRxiv (pronounced "bio-archive") caused a minor panic for some gene-editing biotech stocks by stating that humans could have immune responses to CRISPR-Cas9 that interfere with use of the gene-editing method. The problem stems from the fact that the Cas9 enzyme comes from Staphylococcus aureus (S. aureus) and Streptococcus pyogenes (S. pyogenes) bacteria, both of which have infected humans for a long time. And humans have developed immune responses to the bacteria.
How big is this risk? Not nearly as big as the initial hoopla over the findings. A lead author of the paper (and one of the scientific co-founders of CRISPR Therapeutics), Matthew Porteus, called the potential issue "a bump" rather than a roadblock.
It's not certain yet whether or not human immune responses actually do interfere with CRISPR-Cas9 gene editing. Even if this does happen, several alternatives exist to get around the problem. The issue would only impact gene-editing therapies that are done "in vivo" (inside the body). Several of the current CRISPR programs, including CRISPR Therapeutics' lead candidate, are done ex vivo (outside the body).
But what about therapies like Editas Medicine's EDIT-101, which is administered through a local injection into the retina (in vivo)? Again, it's not known yet if there really is a problem. It's also possible to either use CRISPR enzymes from bacteria for which humans don't have immune responses, or to modify Cas9 so the human immune system doesn't attack quickly enough to interfere with the gene editing.
The flip side of risk
It's also important to remember that in investing, risk is just one side of the coin. The flip side of the coin is the opportunity for reward.
More than 10,000 diseases are caused by mutations in one gene, according to the World Health Organization. The vast majority of these genetic diseases don't have an approved treatment. CRISPR Therapeutics, Editas, Intellia, and Sangamo together are currently targeting the use of gene editing to treat -- and potentially cure -- 14 of these diseases.
The rare disease drug market is already huge, totaling around $125 billion last year, according to market research firm EvaluatePharma. This market is projected to grow more than twice as fast as the overall prescription drug market over the next seven years, reaching $262 billion by 2024. Biotechs focusing on gene editing could claim a nice chunk of this rapidly expanding market within a few years.
Is gene editing potentially risky and dangerous? Yep. But so were (and are) automobiles, airplanes, and computers. But like these other game-changing technologies, there are a lot of rewards that come along with the risks. And sometimes, where we think there are dragons, there's really just opportunity.