Jun 04 2019

New Information on the CRISPR Babies

Last year a Chinese researcher, Dr. He Jiankui, announced that he had altered the germ line DNA of two babies using the relatively new and powerful gene-editing technique known as CRISPR. Dr. He is back in the news because of a new study looking at the effect of a mutation similar to the one Dr. He created on the life expectancy of those with the natural variant. The study finds that those who are homozygous for the gene variant (the delta 32 mutation of the CCR5 gene) have a 21% greater all cause mortality than those without the variant. What this means for the two children is unclear, but does raise concern.

Dr. He took it upon himself, without proper oversight or approval, to use CRISPR to alter the CCR5 (C-C chemokine receptor type 5) gene of embryos he then used for IVF (in-vitro fertilization) on his patient. The father who donated the sperm for fertilization (the patient’s husband) is HIV positive, so He sought to make a genetic change to the eggs to prevent HIV infection from the father. CCR5 is a protein on white blood cells that is used by HIV as an important gateway into the cell. Without it HIV infection becomes much less likely. There are other gateways, so it is not perfect immunity, but those with the naturally-occurring delta 32 mutation of CCR5 seem to be immune to HIV as a result.

He’s plan was to alter the CCR5 gene in the embryos in a way similar to, but not identical to, the delta 32 mutation. This was apparently successful in preventing HIV infection in the resulting babies. He announced what he had done after their live and apparently healthy birth.

He received widespread criticism for what he did for several legitimate reasons. First and foremost is his unsanctioned use of CRISPR on humans. He essentially conducted illegal human research. Human research is carefully regulated, with international standards, in order to protect the rights of people from harm and exploitation. He bypassed these regulations and was acting as a rogue researcher. That in and of itself is a career-ender.

Further, the specific application that He chose was not necessary. There are already effective proven treatments to minimize the chance of HIV infection from infected sperm used in IVF. Using an experimental treatment instead of a proven standard treatment is also considered unethical.

Finally the gene alterations He made were in the germ line. This means that they would be carried into future generations – they don’t end with the individuals. So He introduced a new mutation into the human genepool. I am not saying that we should never do this, or that the results are necessarily bad, but the world has not yet decided to move forward with such changes. Scientists are appropriately cautious about making changes they can’t take back, and that have the potential to reverberate through the future of humanity. He was way out of bounds in what he did, and China was justified in censuring him and condemning his actions (I am not going so far as to say I agree with whatever they did – just that He deserved to be sanctioned for his actions).

So what does the new study show? Not surprisingly, the common variant of the CCR5 gene on white cells, an important part of the immune system, has a normal function. The protein is not there just for the HIV, of course, but rather the virus is exploiting the protein which serves a purpose in immunity. Of course we are all mutants – there are variants of most genes (some are so critical that they really can’t be altered at all and still function adequately). Some variants are neutral, some bestow an advantage, some carry a disadvantage, and some are a trade-off with some benefits and some harms.

For example, there is the sickle-cell mutation in hemoglobin, the oxygen carrying molecule in our red blood cells. If you have one copy of this mutation (we all have two copies of every gene), which is called heterozygous, then you are resistant to malaria. If you have two copies (homozygous) then you have sickle cell disease. So there is a trade-off in having the mutation. You and many of your descendants will be protected from malaria, but some of your descendants will have sickle cell disease. This trade-off is also context dependent, and is only worth it in parts of the world where malaria is endemic.

Similarly the CCR5 delta 32 mutation appears to be a trade-off, at least now that HIV is in the world (I don’t know if other viruses are also affected). Having the variant confers resistance to HIV, but the new study shows that it also makes the host more susceptible to certain kinds of infections. This is not surprising, as the most common variant of CCR5 has likely already been optimized by evolution, and so altering it is likely to reduce its primary function. It’s still possible a new mutation might improve its function, change its function without losing the benefits, or simply alter its function for a new role. But the odds are pretty good that any random mutation will reduce it’s primary function.

That is what the new study shows. Those with two copies of the delta 32 mutation had a 21% increase in all-cause mortality. This is partly from an increased risk of dying from the flu.

However, we cannot say, as is being erroneously reported by some outlets, what this means exactly for the two girls that are the result of He’s manipulation. There are several reasons for this. First, the alteration in the CCR5 gene he made is not identical to the delta 32 mutation. So the effects may be different. Mutation can alter functions in many ways. They may reduce the function of a protein, but also the mutated protein may have a direct deleterious effect. So harm may come not only from the protein not properly doing its job, but doing something new and harmful. Therefore not every mutation that alters the protein to make it resistant to HIV will necessarily have the same effect. It may – we just don’t know.

But further, not everyone with the delta 32 mutation had a shortened life. The study, which looked at over 400,000 people, was calculating averages. Some people with the homozygous mutation lived normal life spans. Perhaps they were just lucky and didn’t get the flu. Or perhaps they have other genetic variants that compensated for the deleterious effects of delta 32 on immune function. Any single mutation always has to be put into the context of the overall organism, including all other gene variants.

So the bottom line is that we don’t know that He’s CRISPR children will have shortened life expectancies. They may, but we can’t conclude that from the current study, although it does raise this possibility as a legitimate concern. This is a good reason why it was risky for He to target CCR5 – it is an important protein for optimal function of the immune system. There was no guarantee that changing it would not have harmful effects.

Despite all this, I do think there is tremendous potential for using some version of CRISPR to treat human genetic disease. I fear that Dr. He’s ethical violations will ultimately have a harmful effect on this research. Dr. He’s actions may ultimately have a negative effect on the very technology he hoped to usher in. It shouldn’t. There are ethical and scientifically valid ways to carefully proceed with this technology, as I think it will. For example, we can treat patients without altering the germ line. We can target diseases where the benefit is more clear, and there are no alternatives. We can carefully study the effects of the gene alteration prior to using it as a treatment.

And of course we need to make the CRISPR technology as safe as possible. It is still rapidly advancing, and the indications are that it can and will be a powerful tool. But there is the potential of “off target” gene alterations, and we need to get a good handle on their scope, and how to control and minimize them. Given the progress already made, and despite Dr. He’s unfortunate actions, it seems likely that we’ll get there.

 

 

 

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