The Promise and Perils of Gene Editing

An experimental genetic science that can be used on people is quietly becoming widely available
March 5, 2020 Updated: March 5, 2020

With little public discussion, a new technology with unknown potential to change the very building blocks of a human being is operating in a weakly regulated grey zone.

While proponents hope gene editing can revolutionize the future of medicine, the implications of the technology remain largely unknown. Scientists say that with just a few tweaks to our genome, we may one day be able to treat or cure diseases.

The problem with CRISPR is the problem with all potent medical interventions. It’s inevitably the case that side effects don’t reveal themselves for some time and turn out to be more serious than was first known. Drugs like NSAIDs, Lipitor, and opioids are some of the most recent or devastating examples.

The tool helping to realize these developments is called CRISPR-Cas9. CRISPR stands for “clustered regularly interspaced short palindromic repeats.” and CRISPR-Cas9 takes advantage of this mechanism to change genes. It may sound complicated, but what sets this current CRISPR gene-editing tool apart from earlier tools is that it makes the procedure of altering a particular gene cheaper and easier than ever before.

Unfortunately, it may be too easy. The scientific community recoiled in horror in 2018 when a Chinese physicist, with no formal training in medicine or clinical trials, announced the creation of the world’s first CRISPR-edited babies.

The name of the disgraced scientist is He Jiankui (or JK). Experts say JK’s work reveals a lack of vital information about gene science, and an ignorance (or disregard) of basic patient consent procedures. JK’s aim was to create children resistant to HIV infection, but his gene adjustments may have inadvertently given these babies several genetic drawbacks, such as increased susceptibility to the flu and West Nile virus, and a propensity to early death.

To date, JK’s work is considered one of the biggest medical ethics fiascos of the 21st century.

Dr. Kiran Musunuru weighs in on this question in his new book, “The CRISPR Generation: The Story of the World’s First Gene-Edited Babies.”

Gene editing is a subject close to Musunuru’s heart. He’s an assistant professor in Harvard’s Department of Stem Cell and Regenerative Biology and a cardiologist at Brigham and Women’s Hospital.

Musunuru’s book is both a celebration of this cutting edge science and a warning of how bad things can turn if we handle it poorly.

“The work we’re doing does have consequences,” Musunuru said. “It’s not happening isolated in a laboratory. Increasingly, the work that we’re doing has implications for human health and well-being, and when used irresponsibly can cause harm. The scientific community needs to be more mindful of that.”

Musunuru compares CRISPR gene editing to fire. Use it right and it can be very helpful. But cross the line and you can spark a raging inferno.

It’s a vivid comparison, but not entirely accurate. We have an extensive history of handling fire, but very little with gene editing.

Plant and animal breeding have long been used to encourage desirable traits, and weed out the unwanted. But it’s only been in the last few decades that scientists have developed a game-changing level of genetic influence. Instead of simply encouraging genetic traits through a natural process, we can now change specific genes in ways nature would never allow.

Since the discovery of DNA in the 1950s, we’ve learned a lot about how to tinker with the genetic code of life in a relatively short period of time.  It took $2.5 billion and 15 years starting in 1990 to chart the entire human genome. Today, we can map one person’s unique genetic blueprint—all 6.4 billion letters of it—in less than 24 hours for a few hundred bucks.

Yet for all this new knowledge, Musunuru says there is still a mountain of mystery that remains.

“The problem is interpreting those letters; interpreting the genome, so to speak,” he said. “We’re pretty bad at that. It’s going to take a long time before we have the mastery of that information. We’re in a mode now where we’re making a lot of guesses.”

This is a big reason why JK’s experiment was so egregious, and why most gene scientists discourage experimentation on human embryos. The term “gene editing” suggests a very clear and precise procedure—like fixing an obvious punctuation or spelling error. CRISPR gene editing certainly makes the process more precise than it used to be, but there is still so much that can go wrong. And when you’re talking about a human embryo unable to consent to such a risky procedure, that’s a gamble on another person’s life with a huge margin of error.

Although JK focused on just one gene with the intention of warding off HIV (and it’s not clear if this goal was actually achieved), he caused several unintentional alterations known as “off-target mutations” in the babies born from his experiment. We don’t know exactly what traits these changes will give the twin girls created from this process, but they will likely endure the results forever, and could even pass them to their offspring if they’re able to procreate.

Evaluating Risk

No scientific endeavor conjures the trope of the mad scientist quite like gene editing. And several experiments born from this technology help solidify the comparison. Some recent examples include pig-monkey hybrids and tiny robot frogs, both created from stem cells.  Although cringeworthy, scientists justify these abominations as necessary steps toward building a better future.

When it comes to animal experiments with gene editing, scientists try just about anything the technology might allow. But when it comes to gene editing human subjects, ethical concerns restrict most from tinkering too much. Scientists are already applying CRISPR gene editing techniques on people, but Musunura explains that they typically come with serious consideration of the risk-reward ratio of a particular patient.

A major fault of JK’s experiment is that his risk-reward ratio was pretty lousy from the beginning. While HIV was a veritable death sentence over 30 years ago, the treatment available today allows HIV positive people to lead a relatively symptom-free life of average length. Plus, HIV is an easily preventable infection. Altering an embryo for this trait, even if the treatment is successful and otherwise harmless, doesn’t bring much to the table.

The strongest argument made for CRISPR-based therapy is found in tackling debilitating genetic disorders, such as sickle cell anemia, muscular dystrophy, or cystic fibrosis. Compared to other ailments, gene-based diseases are clearly determined by a specific mutation. This means that there’s a lot less guesswork about which target gene needs to be altered. And even if the procedure produces unintended consequences, the promise that it can alleviate suffering means patients and doctors are more willing to take a chance.

“You’re willing to take on the risk because, chronically, it can’t get much worse,” Musunuru said. “If there are only upsides and benefits, then it might make sense to undertake therapy, even if we haven’t perfected the technology.”

But gene scientists are not content to merely focus on genetic diseases. These disorders are pretty rare compared to most of what doctors see, and CRISPR’s power to edit the building blocks of people is too enticing to keep in such a small box. Drug companies, in particular, are eager to find a gene-altering treatment that can apply to a wider population.

But it’s a lot harder to make a case for these types of treatments. In common diseases— like cancer and heart disease, for example— genetics play a role, but so do many other factors, like lifestyle and environment. Even if your genetics are perfect, a poor diet, smoking, and a lack of exercise can still lead to disease.

But what if there was a treatment that could give everyone a genetic advantage to guard against heart disease? That’s the goal behind a vaccine Musunuru is working to develop. Unlike a traditional vaccine that triggers antibodies to protect against a virus, a genetic vaccine uses CRISPR to permanently alter genes. In a 2014 study looking at genome editing in mice, Musunuru and his team were able to show that with a single injection, cholesterol levels could be permanently reduced.

There’s a lot of buzz about these gene vaccines, but human trials are still at least a decade away, and a marketable treatment is even further into the future. Just like embryo editing, this technique also causes off-target mutations, and the risk-reward ratio is not yet clear.

A Foolish Quest for Certainty

To understand the limits of gene editing, you have to respect the element of risk. And this can be difficult because we tend to think in terms of black and white. People like the security of certainty—especially when it comes to things like science and health.

However, mutations usually suggest a propensity toward (or protection against) a particular disease, not a clear yes or no. For example, a mutation in the BRCA1 or BRCA2 genes are known to substantially increase the risk of breast cancer. So when some women discover they have a mutation in one of these genes, they go to extraordinary lengths to avoid this disease. The most publicized example is actress Angelina Jolie, who had a preventive double mastectomy in an effort to dodge her higher than normal cancer risk.

But Musunuru says it’s a specific mutation in the BRCA1 and BRC2 genes that carry this elevated risk. Some mutations in these genes have absolutely no cancer risk at all, while others are still a mystery, but patients may still overreact if they find an issue with a gene they’ve only heard bad things about.

“I worry that if there’s a lot of uncertainty in a particular patient’s scenario, they might choose an extreme option. If the information changes and they realize they actually didn’t have as high a risk as they thought, they’re going to regret a double mastectomy on the basis of imperfect information,” Musunuru said.

Another fantasy of certainty with respect to gene editing is found in something called enhancements— a desirable non-medical trait. Enhancements include things like choosing your child’s hair or eye color, granting them improved intelligence, athletic ability, or some other gene-based advantage that was previously only bestowed by nature.

Genetic enhancements promise a future where you can select a perfect child of your own design, and avoid the imperfect and unpredictable results of creating offspring in a conventional manner. But Musunuru says such enhancements are difficult or perhaps even impossible to achieve. However, if regulations are lax, and there are enough parents with money who are willing to take the risk, there’s not much that can be done to stop fertility clinics from offering a menu of options.

“We see a modern-day parallel with stem cell printing. In principle, they are using unproven technology. Some of them run afoul of the FDA, but because it’s so new and it doesn’t quite fit into the older regulations, they’re operating in this grey zone, and they’ve gotten away with offering services to patients,” Musunuru said. “Patients who are desperate feel like they don’t have other options, and some of them have suffered harm as a result of this.”

While genetic experts have a much clearer understanding of the limits of this science, they are not immune to the pursuit of certainty and control. There’s a strong belief among CRISPR gene editor that, with enough regulation, we can still claim the benefits while avoiding the pitfalls of genetic tampering.

When it comes to powerful technologies that feature a hefty downside, gene editing certainly isn’t alone. Nuclear energy, for example, has disastrous minuses that come with its enticing plusses. That’s why strict laws govern its use.

But where do you draw the line on something like editing the human genetic code? While scientists and drug companies see big potential for exciting new therapies, the technology also threatens to change the human genome in disastrous and perhaps irreversible ways. When you’re tinkering with something as complex and mysterious as the code of life, such unintended consequences and unforeseen circumstances may still slip through even the tightest regulations. And there may be no way to fix it once the damage is done.

Despite all the dangers gene editing invites, scientists are intent on preserving the use of this power for all the supposed benefits it promises. The World Health Organization and the International Commission on the Clinical Use of Human Germline Genome Editing have been working to identify the scientific, medical, and ethical requirements necessary to craft regulations on CRISPR gene editing.

Committee reports are expected by the end of this year to guide governments toward regulatory frameworks regarding how CRISPR can be used to edit DNA. But even with legal limits in place, the possibilities this technology offers may be too enticing for some scientists to ignore. Despite JK’s cautionary tale, Musunuru believes more CRISPR-edited babies are part of an inevitable future.

“Whether it happens this year, next year, or five years from now, the technology is there and it’s going to be used by someone sooner or later,” he said.

Follow Conan on Twitter: @ConanMilner