08/04/2017

A Promising And Still Uncertain Future For Human Gene Editing

17:24 minutes

CRISPR, via Shutterstock

CRISPR-Cas9 is making headlines again this week. A group of researchers at Oregon Health and Science University have used the gene editing technology to fix a mutation in human embryos. The embryos were developed in a lab dish and destroyed after a few days—researchers had no intention of implanting them in a uterus. Still, it’s an important first step towards a day when we can prevent certain deadly or debilitating diseases from being passed onto future generations.

[Just how easy is it to edit DNA?]

Dr. Shoukhrat Mitalipov, director of the Center for Embryonic Cell and Gene Therapy at Oregon Health and Science University, joins Ira to discuss the new research. And Kelly Ormond, Professor of Genetics at Stanford University School of Medicine and faculty member at the Stanford Center for Biomedical Ethics, talks about the promising and uncertain future of human gene editing.


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Segment Guests

Shoukhrat Mitalipov

Shoukhrat Mitalipov is the director of the Center for Embryonic Cell and Gene Therapy at the Oregon Health and Science University. He’s based in Portland, Oregon.

Kelly Ormond

Kelly Ormond is a professor of Genetics at Stanford University School of Medicine. She’s also a faculty member for the Stanford Center for Biomedical Ethics. She’s based in Stanford, California.

Segment Transcript

IRA FLATOW: This is Science Friday. I’m Ira Flatow.

You may have heard that our old friend CRISPR is back in the headlines again this week. This time, researchers from Oregon Health and Science University used this gene editing technology to fix a genetic mutation in human embryos.

Now, this isn’t designer babies. We’re talking about using CRISPR to swap out a mutated gene inherited from one parent for a healthy gene from the other parent. But the impact of just this small change could be huge.

Imagine a day where we could eliminate certain deadly or debilitating diseases from future generations by just swapping out one little piece of a gene. Of course there are scientific challenges and regulations. And most importantly, ethical concerns to address before we get there.

Joining me now is one of the co-authors of the new study, Shoukhrat Mitalipov, he is director of the Center for Embryonic Cell and Gene Therapy at Oregon Health and Science University. Welcome to Science Friday.

SHOUKHRAT MITALIPOV: Thank you. Thanks for having me.

IRA FLATOW: What did you and your colleagues set out to do in this study? Is this basically a proof of concept idea?

SHOUKHRAT MITALIPOV: Yes. So one of the main goals of our center is to develop and study technologies that would allow us to basically replace mutant genes in early embryos, or even in gametes. It’s called germline because humans actually carry many of these kind of germ limitations that have been passed from parents.

We have about 10,000 or so mutant genes that are causing greater diseases. And the idea was if we can allow some of the parents to have children without wanting to pass this mutation.

And in this particular case, this was one of the types of mutation that caused disease even if there is only one copy of the mutant gene transmitted. As you know, we have in most our genes, we have two copies, one comes from mom, one from dad.

And there are some mutations when you have to have both copies mutated, then there would be no normal protein made.

But this case that we’ve been working on, this is actually one mutant copy is enough to cause disease.

IRA FLATOW: And then what I find– this was this was a heart disease. And what I find interesting about this, a lot of different things, but in particular, you tried a couple of different ways. First, you tried delivering CRISPR and the external replacement gene together into a fertilized embryo, and then got a different result with an unfertilized embryo.

SHOUKHRAT MITALIPOV: Yes. So the idea of using CRISPR or some other gene-editing tools is that they mainly give you just access to gene and they induce actually damage, the cut. So the good thing is you can program and tell these CRISPR which gene you’re targeting and where to make a cut. But that’s all they do.

But we need to fix the mutation, not just to make damage additional to this gene. And that’s when the cells own kind of SOS or repair mechanism come in place. Every cell has this DNA repair mechanism. They always survey integrity, and once they find that there is a breakage there, they immediately start to basically glue it together.

So we sometimes provide a kind of a small synthetic gene, which we call an external template, that we hope will be used to repair this gene and hopefully remove mutation, as well.

And then, yes, when we provided these to embryos, and saying that this is a normal gene, then we would like you to use this when you repair this breakage.

Embryos actually refuse to use this synthetic gene. But the good thing is, as I mentioned, this mutation is heterozygous, meaning they only– one of the parents would provide this mutant gene, whether the second parent, in this case maternal side, would be normal.

So the embryos always chose that maternal normal gene as a blueprint to repair the damaged paternal gene.

So this was quite different than expected. We actually tried to use this CRISPR was patients skin cells and some other cell types, which we considered as a somatic, basically, body cells. And their body cells, they actually responded a bit differently, and the DNA repair system appears to be quite different, when the embryos actually like to do this job very well.

It’s been known that the– because it’s a germline, which is very important for survival of species, and maintaining integrity of DNA is quite different than most stringent in the germline.

IRA FLATOW: Does this mean that you don’t need to provide the external repair gene for this to work?

SHOUKHRAT MITALIPOV: Oh, so that we– at least with this study, it didn’t make any difference. So embryos would always refuse it. But the good thing is, as I said, we had another normal gene that seems like will take over.

But we’ve been now thinking, as I mentioned, there are mutations or gene mutations that have to be in two copies. And there are diseases like that, say, cystic fibrosis. Or when both parents would pass this mutant gene, that would be that both of them would be the same, then mutant.

So if we instruct to cut down and repair both genes, then what the copy will be served as a template, and then we would have to provide a third synthetic gene, but we have to figure out the way how– to embryos– to use this template to repair both copies.

IRA FLATOW: So you haven’t gotten that far, yet.

SHOUKHRAT MITALIPOV: No. We are still working. So this is actually the next project we were working on and we’re looking at so-called homozygous mutations. And find a way now to repair or at least help the embryo self-repair and give them right instructions to do it.

IRA FLATOW: Does this suggest that adding external genes to the embryos is going to be tougher than you expected?

SHOUKHRAT MITALIPOV: Yeah. At this point, it seems like, you know, it’s– you would have to do something differently if you want to insert some extra piece of DNA, and the embryo seems likely to refuse it.

IRA FLATOW: I want to bring on another point of view about this, because news of this research has sparked many reactions from stakeholders, including the American Society of Human Genetics, which published a policy statement on human germline genome editing this week. I want to bring on one of the authors of that report. Kelly Ormond, professor of genetics at Stanford School of Medicine, and faculty at Stanford Center for Biomedical Ethics. Welcome to Science Friday.

KELLY ORMOND: Thanks so much for having me, Ira.

IRA FLATOW: Do you have any fear about the results of this experiment?

KELLY ORMOND: You know, it’s a really exciting study and scientific development. And we actually started writing our position paper two years ago, I think with the fear that we need to be cautious about how this research moves forward. And all of the press about designer babies really exemplifies that. That makes people quite nervous.

And we also don’t know what the medical and scientific risks and benefits of these sorts of procedures are. So I think the main point of our statement was that basic science research like this at quite early stages is appropriate if it’s done in a regulated manner with good oversight and transparency. But we shouldn’t be leaping from this straight to having it implanted into a woman’s uterus and seeing those babies born.

IRA FLATOW: That’s still illegal, is it not?

KELLY ORMOND: Yes.

IRA FLATOW: And no one is talking about taking that step yet, but we’re just talking about to see if it might work in these early experiment.

KELLY ORMOND: Yeah. And I think the main issue is that not every country in the world has the same sorts of regulations or the same ability to enforce regulations. And so we really felt quite strongly with our statement, which was signed by 11 international organizations across five continents that we need to get everybody around the globe talking about this. So that it happens in parallel with the science that’s going on. So that in five years we’re not all of a sudden surprised by what’s happening and caught off guard with no policies.

IRA FLATOW: Dr. Mitalipov, do you basically agree with this line of reasoning?

SHOUKHRAT MITALIPOV: Yeah. Absolutely. So when we actually going through a review on this paper and several reviewers actually brought up these issues, saying, well, of course this is basic study, none of these embryos we intend, and we are not even thinking that we have a way of going to transfer these embryos. But how are you going to control this kind of unregulated IVF clinics that may just use it.

The example is in parallel, we’ve been working on this mitochondrial gene replacement also in the idea of replacing mutant mitochondria. Which works a little bit different, unfortunately CRISPR doesn’t work there. But the data studies and technologies were progressing really well in academic institutions and then in the labs. But all suddenly, private clinics took it and then the children already born in very poorly regulated studies or clinical trials that actually, you know, doesn’t seem like these private clinics are actually equipped to do clinical trials.

And that was the concern. And I think that having many of these societies, scientific, expressing the view is that, yes, basic science and in vitro studies must go on, but it’s too early to move to clinical applications.

IRA FLATOW: I have a tweet coming in from James. Says, “How do you know when you’re cutting the gene that you’re not removing something helpful by accident?”

SHOUKHRAT MITALIPOV: That’s a good question. And as we mentioned, the CRISPR may recognize some slightly similar sequences around the genome. And we have a particular genome. The only way to know it is to do very thorough screen on every embryo or biopsied cell from the embryo. And look for this potential of a so-called off target mutations.

So far, we didn’t detect anything wrong. And looks like this particular C CRISPR construct was very faithful. But you cannot say that this will be for every other target gene, because the CRISPR will be designed a little bit different. And I guess this off target has to be screened, and has to be a part of the PGD before we say that there is no harmful, unintended mutations.

IRA FLATOW: Dr. Ormond, you were talking about the ethical problems of using this technique but what about the flip side of this, the ethical problems of not using this technique, which might save thousands of lives of people who come down with a genetic disease.

KELLY ORMOND: Absolutely. Everybody wants to see individuals and families who are faced with genetic disease get treatments or cures. And no one who is experiencing those is going to say, gosh, I think we shouldn’t be considering this at all. But I do want to be really clear there are also many other options for doing it. And one is to use this in a somatic way on the affected cells in an individual’s body. So you’re not changing an embryo or changing that person’s germline and what they would pass on to future generations.

So those future generations would still have to be dealing with it. But you can also think about the currently available techniques of prenatal diagnosis and genetic testing. As well as IVF and PGD.

So when we’re really thinking about people who would use this down the line, it probably is going to be pretty rare situations. And the times when you wouldn’t otherwise be able to have a biologically related child using one of those other techniques. Or as Dr. Mitalipov’s group has said in their paper, people who feel uncomfortable with doing PGD and discarding embryos after that testing is performed.

So those are the potential times when it might actually be useful. And that’s going to be a small number of cases.

IRA FLATOW: I’m Ira Flatow. This is Science Friday from PRI, Public Radio International. Talking about this new CRISPR headline this week, about fixing a genetic defect in human embryos which we should repeat, these embryos were never brought to term, were never implanted, they were just done in a dish. Correct, doctor?

SHOUKHRAT MITALIPOV: Yes. Yes. So we recovered gametes and sperm and egg, and all the fertilization was done in a Petri dish. And then we have a small window, about four or five days when these embryos can develop. It’s still a small group of cells, hardly visible in the microscope.

Then there was, of course, never intention of using these embryos to transfer an establishing pregnancy. This was very strictly said in consent forms to donors who donated the gametes, but also to the regulations locally. They only allow us to do this in vitro work.

Going further, for example sometimes in the future, and if transplanting embryos back into a patient. That where, federal regulatory agencies would regulate it. Unfortunately at this point, we still don’t have any way of going forward just because the FDA, who is supposed to be regulating, actually they step forward many years ago saying this is gene therapy even in the germline, and we would like to regulate it as gene therapy. But unfortunately, our most recent restriction to funding from a Congress to FDA wouldn’t allow them even to review and work on INGs.

So this is where we’re kind of still unclear because there is no clear ban on transplanting, but it seems like the FDA is not allowed to regulate. So this is kind of a very strange situation that needs to be a problem resolved.

IRA FLATOW: But Dr. Ormond, as you pointed out, it doesn’t prevent other countries where these bans may not be.

KELLY ORMOND: Yeah. That’s correct. Other countries can certainly take this up. And in England there is a group called HFEA which looks at this kind of research. But right now it’s really a funding issue in the United States. And our statement actually did go so far as to recommend reconsideration of that ban on funding around embryo research.

We said that because we think that federal research actually undergoes a different level of oversight and regulation. And it’s more transparent. And for something as controversial as this, if it’s going to be happening in the United States, we really would encourage our Senate and our House to consider this and the potential importance.

IRA FLATOW: Dr. Mitalipov, are you going to be moving forward with the next step on this?

SHOUKHRAT MITALIPOV: I think we still have a lot more to look in the basic science, as I mentioned. There are so many different mutations. We have our work cut out, of course, to do in vitro work without ever transplanting these embryos. Particularly improving efficiency. So this repair does occur, with I would say majority of the embryos, but not all. And for germline, this may not be efficiency, may not be high enough. And so we still have ways to improve it.

But of course, the intention of doing research on human embryos is, it has to be for sake of future treatments. And we would be happy to do move forward and work with the FDA particularly, because defining what the next step and the safety, efficacy studies that needs to be done, are usually FDA usually regulates it. And at this point, since they are not in the place, we wouldn’t know how to move forward.

IRA FLATOW: All right. We’ll be watching closely both the FDA, the USA, and other parts of the world. I want to thank Dr. Shoukhrat Mitalipov, director of the Center for Embryonic Cell and Gene Therapy at Oregon Health and Science University.

Kelly Ormond, professor of genetics at Stanford School of Medicine. Faculty of the Stanford Center for Biomedical Ethics.

Thank you both for taking time to be with us today.

KELLY ORMOND: Thank you.

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