Huntington’s Disease Makes Its Mark Early On

IRA FLATOW: This is Science Friday. I’m Ira Flatow. Huntington’s disease is a devastating neurological disorder caused by a genetic mutation. If you have the gene for Huntington’s, your chance of having the disease is 100%. But even though the gene is there since birth, the symptoms of Huntington’s disease don’t start showing up until later in life. Why is that?

My next guest also found this curious. Why do people with a genetic mutation only show signs of illness decades after they are born? Well using a technique for growing human embryos from stem cells in the lab, he discovered that even before people with Huntington’s disease show outward signs of the disease the mutation makes invisible changes much sooner, in the earliest stages of embryonic development. Doctor Ali Brivunlou– Brivanlou, I’m sorry, Professor of Molecular Embryology and Stem Cell Biology at Rockefeller University, is with us today. Welcome to Science Friday.

ALI BRIVANLOU: Thank you for having me.

IRA FLATOW: Now you were able to see what the Huntington’s mutation was doing in the embryo by using the CRISPR tool, right. What did you do?

ALI BRIVANLOU: Exactly. So as you mentioned correctly, Huntington is a disease that is due to a mutation in a single gene, one of the two copies that we have for every single gene. And it really represents an insertion of DNA. And it creates, with 100% penetrance, all the symptoms that the patients go to the doctor for, which includes jerky movements and, ultimately, loss of brain neurons and dementia.

So I’m an embryologist at the Rockefeller University. And my job is to try to figure out how do you generate all the structures from a single fertilized egg. And that includes, of course, the formation of the brain. We were a little bit surprised by the fact that putting this [? express ?] in the first cell actually manifest its mutant effect late in life, when people are in their middle age. And so, I wanted to ask if we can find the origins of it. And yes, we did use CRISPR Cas9 in embryonic stem cells to model the disease, and we came up with discoveries that were recently published.

IRA FLATOW: And your discoveries, you looked at two otherwise identical embryos. And what was different about the one with Huntington’s?

ALI BRIVANLOU: So we noticed very quickly that as neurons emerge and differentiate there is some serious abnormalities in the two lines that are otherwise identical genetically, except for that one mutation. And that generated giant, multinucleated neurons that we had never seen before. So usually, as you know, a neuron had a single nuclear use and axon and dendrite and projections to establish circuitry.

In this particular case, while the normal non-HD, not Huntington line displayed normal neurons, in every single one of the lives that were mutated for Huntington we discovered this giant, nucleated neurons. And, amazingly, the number of neurons, abnormal neurons, was going up the worse the DNA insertion was. In other words, the longer the DNA insertion, the more frequent those multinucleated neurons were.

IRA FLATOW: So even though you can see the beginnings right there in the embryo, does it give you any clue to why it doesn’t manifest– it takes decades for itself to manifest itself?

ALI BRIVANLOU: Well, I think for the first time we’re witnessing the origin of the disease. And so is a little bit like this giant dominoes that you probably see in TV or in Southeast Asia TV. Mostly what you’d generate is labyrinths of dominoes. And then you push the first one, and then sometimes a few minutes later the last one falls and it unveils a pattern, maybe a flower or a leaf or something like that. We think the same thing is happening here in Huntington. And the first symptoms, which are very, very early during development, that is when the first domino is pushed. And then the last one falls decades after birth and creates the symptoms that is recognized as the disease.

And, of course, there are consequences about this discovery, I think. One of the most important one is what we’re doing probably in clinic right now, is that we’re treating the symptoms of the disease and not the cause. And if we were to be serious about attacking the cause, we should be intervene much, much earlier. Perhaps as early as during embryologist– embryological time.

IRA FLATOW: Are you saying you could do something while the person was still in an embryo stage and intervene right there?

ALI BRIVANLOU: Well, hopefully as soon as possible. As you know, Huntington patients also have access to IVF. So you can go to any in vitro fertilization clinic and generate fertilized embryos and eliminate, by the DNA sequencing, those that carry the mutation. And implant those that do not have the mutation. And this is usually what is done in families that actually can afford this kind of treatment. Because, as you know, IVF is still not covered by insurance, is not publicly funded, and it requires private fund to execute this kind of intervention.

And so it is not accessible to everybody. That would be, of course, the best way to go if one could do it. But for the majority of the people with the disease in the world, or in the US– and I know that in the US is one in 10,000 Americans suffer from this disease. For those who cannot afford that kind of technology, I think the sooner the intervention, the better. And yes, there are cases where one can intervene relatively quickly. We still can get couple of dominoes fall, but we cannot let go through all the way to the last one. So anywhere, as early as possible, the better.

IRA FLATOW: You think– you think it could be– are you talking about genetic intervention? Or what kind of intervention as quickly as possible?

ALI BRIVANLOU: So, I think both the gene therapy and drugs are on the table. For gene therapy, we’re now starting to see what is the consequences at the genetic level, at the global level, when these neurons have so many different sets of DNA because of so many nuclei. Some of them can go up to 12 nuclei. It looks a little bit like birthday balloons that you take to somebody’s house and they’re attached by the string. And that means that the chromosomes are still connected among these different nucleus.

Any intervention that helps resolve this conflict between the chromosomes of different nuclei will be a good start, as far as we’re concerned. And yes, gene therapy is going to be one of the easiest approach. But I do not exclude the possibility of doing drug screens in the embryos that we have generated to find the one that rescues this mutated neurons back to normal.

IRA FLATOW: Thank you very much, very interesting. Dr. Ali Brivanlou, Professor of Molecular Embryology and Stem Cell Biology at Rockefeller University. Thank you, and good luck to you.

ALI BRIVANLOU: Thank you very, very much. I will need some. Talk to you soon.

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