We Must Be Very Careful With Human Genetic Engineering

The gene editing tool CRISPR allows scientists to remove a damaged part of DNA and replace it with a healthy one. (Ernesto del Aguila III/NHGRI)

Our geneticist, Dr. Barry Starr, weighs in on the current debate surrounding the latest gene-editing technique.

Ever since we've been able to alter DNA, there have been discussions about what this means for the human race. In some far off future, when we can make wholesale changes to human DNA, what will these changes do to each of us? And to society at large?

It turns out that the far off future isn’t so far off any more. With a new tool called CRISPR, we are on the cusp of being able to easily change the DNA of a human embryo so the changes can be passed on to the next generation. We are so close in fact, that a group of scientists has advocated that we stop and take a deep breath before we add any altered DNA to our gene pool.

Part of the reason for this pause is because the technique has not been widely tested yet. It has only been around for a few years and so we definitely need to spend some time studying it. For example, what other changes happen elsewhere in the DNA when we make the selected change? How can we make sure any changes we make are in all of the cells not just some of them? These are just two of the potential questions for which we don’t yet have good answers.

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Despite issues like these, there is a real temptation to just barrel ahead and start using CRISPR to cure genetic diseases because it is such a powerful and easy technique. We need to resist that temptation until these technical issues have been resolved.

But even with a resolution, other problems will arise. Like the ethical concern over whether we should be tampering with human DNA at all. I leave the bioethicists to debate that one.

Some genetic engineering decisions are obviously bad ones. (Wikimedia Commons)
Some genetic engineering decisions are obviously bad ones. (Wikimedia Commons)

Assuming the safety problem has been resolved and we decide, as a society, that changing human DNA is sometimes acceptable, the next issue will be what DNA to change. This is a more difficult discussion than you may think.

To me, a few changes are pretty obvious. If we can safely do it, we should change the DNA of an embryo that would die a terrible death after birth. For example, fixing a DNA difference in the HEXA gene that leads to Tay Sachs--a genetic disorder that is fatal--seems like an obvious choice.

And of course at the other end of the spectrum there are changes that make most people squeamish. Examples of these might be changing an embryo’s DNA so he grows up to have blue eyes or red hair or some other physical trait. This smacks of eugenics and rightly makes people uncomfortable.

But there are a whole lot of DNA edits in between these that are much less obvious. And some, like Huntington’s disease, seem like Tay Sachs but if done incorrectly could have unexpected consequences.

Beware of Unknown Unknowns

Huntington’s disease (HD) is a really awful genetic disease (click here to see what it looks like in the later stages). It initially causes subtle personality changes, usually when a person is in his or her 30’s or 40’s. After that there is an inevitable decline in muscle control and a descent into various psychiatric disorders and dementia. Usually someone with HD is dead within 20 years of their first symptoms although it can happen much more rapidly in some cases.

We have a very good understanding of how HD works genetically. Certain changes in the HTT gene lead to the disease. But these changes are different than you might think.

Here is an image of the three categories of HTT genes you can have:

HTTgene

In this image, the blue rectangle is the HTT gene. The green, yellow and red boxes represent something in the gene called CAG repeats. Basically, the DNA letters CAG are repeated the number of times listed in the box. So the green box has 10-35 repeats, the yellow has 36-39 and the red has 40 or more.

As you can see, only people with more than 35 of these repeats are at risk for HD. People with 36-39 repeats may or may not get the disease and most everyone with 40 or more ends up with HD.

So an obvious use of CRISPR would be to edit the HTT gene of embryos like this:

httCRISPR

Now this embryo won't develop HD. And because we reduced the number down to 10, his kids and grandkids probably won't be at risk for HD either because they are safe from something called anticipation.

In anticipation, the number of repeats can increase from one generation to the next. So someone with 34 repeats might have a child with 40 or more which means that child will probably develop the disease. Lowering the repeats to 10 makes it much less likely any future kids will get HD. But it might also decrease the chances of the child being a genius.

Recent research reviewed here suggests that the more repeats you have, the more likely you are to do well on tests that are supposed to gauge intelligence. In protecting future generations from the risk of HD, we may be toying with their intelligence.

The reverse of this situation is even worse. Imagine we first discovered that extra repeats make it more likely someone will be clever. Now parents are adding repeats to their kids’ HTT genes with the end result that most of that generation comes down with HD!

This isn’t the only case like this either. As discussed here, studies showed that a certain version of the SERT gene leads to an increased risk of depression. With CRISPR you might be tempted to correct this gene. Which may be a mistake.

Later studies showed that this version of SERT is only an issue if the child is raised in poor conditions. Under the right conditions, this gene version actually increases the chances a person will be creative. Editing this gene might have consequences no one expected.

If the second set of studies had never been done, we wouldn’t know about the positive effects of this DNA difference. We would simply have fewer creative people in humanity’s future.

These are just a couple of the genes we know about. There are many others where we may not yet know the effects of genetic engineering.

To Edit or Not to Edit

If we decide that changing human DNA is acceptable, then sickle cell anemia is an obvious candidate. (NHGRI)
If we decide that changing human DNA is acceptable, then sickle cell anemia is an obvious candidate. (NHGRI)

None of this necessarily means we should never change human DNA. Some genetic diseases like sickle cell anemia or cystic fibrosis served a useful role in the past but are now just terrible, terrible diseases. It is hard to think of the downside of eliminating these DNA differences from the gene pool.

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The bottom line is that if we decide it is OK to repair genetic problems in a way that can be passed down to the next generation, we need to be very careful and selective about which problems we fix. And in how many people we fix them in.

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