CRISPR gene editing technology, which burst on the scientific scene over the past several years, is creating scientific breakthroughs at a seeming breakneck pace. This, the last week of July, 2017, was certainly no exception. Earlier this week it was reported by MIT's Technology Review that a scientific lab in Oregon has done gene editing on human embryos . Technology Review reported, "Until now, American scientists have watched with a combination of awe, envy, and some alarm as scientists elsewhere were first to explore the controversial practice. To date, three previous reports of editing human embryos were all published by scientists in China. Now [Shoukhrat] Mitalipov [the lead researcher] is believed to have broken new ground both in the number of embryos experimented upon and by demonstrating that it is possible to safely and efficiently correct defective genes that cause inherited diseases." Certainly very promising, but many, maybe most, people are justifiably concerned about where this is heading. Should this type of research be encouraged, or should we press the brakes?
CRISPR (an acronym for clustered regularly interspersed short palindromic repeats), is a naturally occurring defense mechanism that has evolved over millions of years to help bacteria gain protection against attacking viruses. Scientists have adapted this naturally occurring process as a means to edit genetic information, much as one would edit computer software. In her recently published book, A Crack in Creation, Professor Jennifer Doudna of the University of California Berkeley and co-author Sam Sternberg note that CRISPR has both incredible promise but also tremendous peril. The authors have called for scientists, ethicists, religious leaders and others to study the risks of CRISPR before launching into certain types of research, especially with respect to human cells. While CRISPR shows tremendous promise of treating, even preventing, terrible diseases that have afflicted humankind, the same technology can also be used to create "designer babies". The caution of Doudna and others has largely been heeded, but not universally.
The ethical problems of "designer babies" aside, CRISPR poses other serious potential risks, and two in particular stand out. The first has to do with the risk of editing "the germline". Humans, as well as animals, plants and other organisms have two types of cells – somatic and germline. A somatic cell is one that can divide, but the DNA in the cell can't be passed on to the next generation. Most of the cells in our bodies are of this type. Conversely, a germline cell is one that can be passed along to your children, grandchildren and all posterity. If a somatic cell is edited using CRISPR, the "editing" will be passed along to other somatic cells in the organism, but not to offspring. In a germline cell, however, all the changes, both good and bad, intended and unintended, are passed on to posterity.
If the change induced by CRISPR is good, that means that a genetic error could be fixed in one person, but also the risk of passing the genetic error on to subsequent generations would be eliminated. For example, if the DNA of a person who suffers from Sickle Cell Disease is edited in the right way, not only would the person no long suffer from this terrible disease, but he or she would no longer pass the bad genes on to subsequent generations. Sounds great, but what if a mistake is made? It will be passed on to subsequent generations, too. Maybe the mistake will be caught quickly and fixed, but what happens if the editing mistake is made in very fast reproducing species such as bacteria or viruses? Lots of potential for unintended consequences.
The second problem with CRISPR is that as a byproduct of gene editing, sometimes unintended gene edits occur. Further, sometimes the desired edits are passed along to other cells, but sometimes they arent't. This is a problem called "mosaicism". As described above, it's one thing for errors to occur for one individual, but what happens if these errors occur in the germline and the error passes to all subsequent generations? Pretty scary stuff! The risks of mosaicism, as well as incorrect edits in the germline, are causing CRISPR researchers and others considerable pause. We need to be very careful!
Despite the caution of Doudna and others, certain researchers are "pushing the envelope" on CRISPR research. Perhaps no scientific researcher fits that mold better than Shoukhrat Mitalipov, the lead researcher in Oregon mentioned earlier. Mitalipov perfectly embodies both the potential, but also peril, of CRISPR.
Mitalipov hails from Kazakhstan, one of the former republics of the Soviet Union. He reportedly is of Uighur ancestry, the Uighurs being an oppressed minority group from northwest China. Mitalipov earned a PhD from a prestigious school in Moscow, but then emigrated to the USA. At present, he is with the Oregon Health Sciences University. His career suggests that he enjoys "pushing the envelope." Consider two of his research accomplishments:
- In 2007, he was involved in creating the world's first cloned monkey;
- He also developed what is called the "spindle transfer" technique. This involves removing the nucleus from a human egg, then placing that nucleus in another egg. If the latter egg is fertilized, it has three parents;
These are important accomplishments, along with this week's announcement, but I think what he did in 2013 is truly emblematic: developing a technique to create human stem cells from skin cells. It was lauded as one of the Top 10 scientific accomplishments in 2013 by numerous prestigious scientific publications. This was certainly a great scientific accomplishment, but what has made it especially important is that it resolved a dilemma: how to obtain stem cells without destroying a fetus. Recall that much research in this field almost ground to a halt because many people, particularly the religiously inclined, objected to the destruction of human tissue that was the byproduct of abortions. When limits were placed on using human stem cells, many felt that scientific research was being unnecessarily limited. Many also believed that the hands of scientists in countries such as the USA would be tied, but scientists in other countries would proceed without fetter, putting American scientists at a serious disadvantage.
To the rescue came Shoukhrat Mitalipov. By developing a way to create human stem cells from skin cells, Mitalipov found a way to permit scientific advances with stem cells without having to rely upon fetal tissue. Everyone could win: the concerns of religious conservatives could be met, and scientific research could proceed. The seeming "zero sum game" turned out to be a false dichotomy. Mitalipov's experience of creating human stem cells from skin tissue could serve as a great model of how to move forward with CRISPR:
- As a first step, limits should be placed on CRISPR research involving human cells, just as limits were placed on the use of human tissue in stem cell research;
- As a second step, however, researchers such as Mitalipov should be encouraged to "push the envelope": figure out ways to develop "unexpected solutions", much as Mitalipov did when he found a way to create human stem cells without relying upon aborted fetal tissue;
- Enterprising scientists such as Mitalipov, should be able to figure out ways to address the clear risks of CRISPR, particularly on human germline cells, even if significant restraints are placed on the scientists now.
Of course, there's no guarantee that the "stem cells from skin cells" model can be replicated in this case, or that it can be done in a timely manner. CRISPR research is happening at breakneck pace, and funding is plentiful. Moreover, researchers are increasingly mobile. Restrictions on CRISPR research may be place on laboratories in the USA, Canada, Europe, and other developed Western countries, but there may not be similar restrictions in places like China. There is already some evidence that China has taken a fairly aggressive approach in CRISPR research. It's been reported that several Chinese scientists have already attempted to do CRISPR editing on human cells.
The other problem is how great the restrictions on research should be. We already have a pretty idea about the risks of too few restrictions, but what about the risks of too many constraints? Very likely, if too many restrictions are placed in the USA, for example, scientists will simply decamp to research institutions in these other countries. The restrictions will be overlooked, and the type of risky research that Jennifer Doudna is frightened of might still occur anyway. In a certain sense, this is a Goldilocks problem.
Maybe … but maybe not. I agree with Professor Doudna, it's worth being very cautious about CRISPR research, and encouraging scientists to be the same. So how might that be done in practice? First, do whatever is possible to encourage other countries to impose the same types of restrictions on dangerous research. As much as possible, develop an international scientific consensus about the risks, then encourage collective restraint. Not easy, and there won't be assurance of desirable outcomes, but the alternative is potentially much worse. That appears to be in progress.
Second, while imposing lots of restrictions, make sure there is plenty of research funding available. Moreover, make sure there are plenty of incentives to encourage scientists to continue working in countries and labs that are encouraging reckless, dangerous research.
Third, utilize the experience of the "stem cells from skin cells" case as a guide.
Encourage CRISPR scientists to look for what I'll call "Mitalipov solutions". A "Mitalipov solution" is one that produces a "human stem cells from skin cells" type solution: out of the box thinking that solves a problem in a unique way that avoids ethically questionable, and potentially safety compromised, projects.
CRISPR continues to hold tremendous promise, but also tremendous peril. Professor Doudna is absolutely right: we need to be very careful. Yes, some scientists may pack up and head for jurisdictions with lax restrictions, but that should not deter us from encouraging caution. Scientists are going to continue to "push the envelope". We likely can't stop that, but in a certain way, we should welcome scientists like Shoukhrat Mtalipov, and encourage them to "push the envelope" in ways that will help achieve positive outcomes while simultaneously avoiding the ethical and other risks. The irony of "pushing the envelope" is that it may be the very best way for us to protect ourselves against the unintended consequences of CRISPR.
