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Home » Ancient Puzzles, Genomic Canaries, Medical X: Ting Wu at TEDxBeaconStreet (Transcript)

Ancient Puzzles, Genomic Canaries, Medical X: Ting Wu at TEDxBeaconStreet (Transcript)


I’m here to talk about genetic disease, which is diseases that have some basis in your genetic material. And that dry definition, I know, does nothing to capture the suffering that genetic diseases cause.

I’m sure also many of you’ve asked: Why has it taken researchers so long to come up with treatments for genetic disease? And the answer is that these diseases are extremely clever. They are clever in the way they manifest themselves, clever in the way they hide. They can spring up spontaneously in your body, and they can morph. And so it really is a battle of wits. So, know your enemy.

And what I’d like to do, is tell you today about four categories of genetic diseases, they are not the only categories, but they are major ones. And to do that, I’d like to start off by introducing you to chromosomes, which contain the majority of your genetic material. And the one thing that’s important for us today, is that, except for the X and Y chromosomes, they come in pairs. So remember that all right.

What are the four categories of genetic diseases? Well, they are — they share the fact that they change the structure of the genome. Some are associated with deletions in which genetic material is lost. Some are associated with duplications. So, segments duplicate themselves, colored here for you. Some take a segment of a chromosome, excise it, flip it around, reinsert it in the wrong order.

And the fourth category are those that combine two different chromosomes, exchange material, and generate two hybrid chromosomes. All right. Now, how often does this happen? We used to think not very often, but actually it happens incredibly often. There are papers coming out now showing, that, in some of your tissues, up to 10% or more of your cells have done one of these things. Are they bad? Always bad? Probably not.

We’re beginning to think that many of these rearrangements are just fine. Some of them may be advantageous. But nestled among them are those that are bad and that will lead to disease, diseases such as cancer. Now here’s the catch. Because they can happen, in real time, as you’re developing, many times, a cell that has a bad rearrangement, will be nestled among good ones.

And, so, the trick is to try and find that bad cell in order to treat it. Also, as you age, you continually pick up these rearrangements. So, the older you are, the greater the chance you have for picking up a bad rearrangement. Now, what do researchers do? Well, first they have to find, sort out the bad rearrangements from the good ones. Then they have to use that information to identify the genes that they think may be responsible for the disease.

When they’ve found the gene — it can be a very sophisticated guessing game — they have to study that gene to understand how it affects your body, and only then, can they start to work on treatment. And this is a long, long process. Except in some miracle cases, it can take years, decades, a lifetime, or more lifetimes. It’s extremely frustrating. I can tell you, in the research world, although we celebrate our wins in this battle, no one wants it to last as long as it does.

So, the question is: Is there a shortcut? And, I’m here, because in the spirit of “solve for x”, we think there is. Why do we need a shortcut? Because currently, we attack diseases one at a time, gene by gene. And it is just painfully, painfully slow and expensive. Now, here I’m joined in our shortcut venture, by Ruth McCole, who’s actually in the audience, Chamith, Adnan, and Charleston. And I could tell you what they’ve been thinking.

So, what is the Achilles heel for these genetic diseases? The Achilles heel for the ones that are associated with rearrangements, is simply the fact that they’ve rearranged the genome. And our strategy is to not try and address these diseases one at a time, and then work backwards, but to actually focus on the fact that they all have a rearrangement, and start there. If we can get cells to recognize that they have a bad rearrangement, and fight that rearrangement, we may be able to skip diagnosis altogether. Alright, but cells don’t have dotted lines, and colors, and arrows. If we got rid of those things, rearrangements would just vanish into the background.

But remember I said that chromosomes come in pairs? So, our strategy, what we like to do, is to pair up chromosomes. Because a deletion ends up creating a buckle. And a duplication? Creates a buckle. And an inversion creates an open buckle, and translocations, if you’ll permit me, I’m going to call that a buckle too. Now, if we can get cells to induce buckles, and eliminate the rearrangements, we’d be in a good shape.

But they also have to distinguish bad from good. What is the key? I think the key may be these elements called ultraconserved elements. They are widely recognized as perhaps some of the most mysterious things to have come from genome sciences. We do not know how they got there, what they do. They are in all of you, there are 100’s, if not 1000’s, of them.

And the most interesting thing about them, is that they have not changed — essentially remained unchanged for 300 to 500 million years. Every other part of your genome has changed over time, and those changes are responsible for why you are not a chimpanzee or not a chinchilla. But these sequences, for reasons we cannot explain, have managed to resist that change. Alright, there are many theories out there for how they do that, ours is definitely not the prevailing one, but we really like our model. And what we’re proposing, is that, once a generation, these ultraconserved elements, of which there are two copies, one from your biological mom, one from your biological dad, come together and they compare themselves.

And if they see a difference between them, or one is missing, or one is duplicated, and a buckle has been created, then that signal tells a cell or the individual carrying that cell, to either die, or to have loss of fitness in terms of stability. Alright So, this model can explain ultraconservation, in that, it does not permit changes to persist. Therefore, the only thing that remains, are things that have been unchanged. In addition to explaining ultraconservation, we think this model gives us the engine to bring chromosomes to the point where they compare themselves and look for buckles.

The question is: Can this mechanism which we think exists in all of you and is very active, distinguish between bad rearrangements and good rearrangements? Well, the fact that you all have hundreds, if not thousands, of those rearrangements in you, and are generally well and healthy and sitting in the audience, tells us that this mechanism, if it exists, certainly does allow these good rearrangements to persist. It’s a benevolent mechanism. Alright. The most exciting thing we found, Ruth found, recently, is that we think this process might happen in cells in real time. So, doing this through indirect evidence, but I think very compelling ones, we can see this sorting out of the bad — what we think are cells containing bad rearrangements — right within the Petri dish.

Alright. So, if UCE’s are so good at making sure the genome doesn’t change too much in regions that are important, why do we have genetic disease to begin with? Well, we think, unfortunately, every once in a while, there’s a bad rearrangement that escapes this surveillance system. And when it escapes, it can take over a tissue. And when it takes over that tissue, it can lead to disease, tumors, malformations of the brain, you name it. So, here is our proposal.

We’d like to understand how these UCE’s work. And then, we’d like to induce it in our bodies. So, the tissues that have cells that have somehow forgotten how, or have not yet managed to create the pairing-induced buckles to get rid of bad rearrangements, can do so. Now, we think this strategy will be quite general. Chromosome rearrangements are not specific for a certain disease, for many diseases will share the fact that they are rearranged.

We think it will be quite efficient, because it may permit us — by focusing on rearrangements, it may permit us to actually skip diagnosis and look for specific treatments that address only a certain gene. And then we are very happy because we think it’s all natural It runs in your cells all the time. Alright then So, I’ll end with the summary here.

The huge problem in the “solve for x” spirit is diseases. And there are thousands of them, and many, many genes. And we are getting tired of studying these diseases, disease by disease, and gene by gene. The radical solution, we think, is to skip the disease-specific strategies, and go for these rearrangements, and help the cells recognize when they’ve made a bad rearrangement. And our technology is actually something that’s been in you and honed, and has been honed, for 100’s of millions of years, ultraconserved elements.

Now, I know there’s a brainstorming session coming up, so I thought I’d throw this question out. If we can get this mechanism to work, and, you know, scientists, we take risks all the time, and I think we feel that the community hopes that we take these risks on your behalf. So, we’ll take this risk, see if UCE’s work the way we think they work, but if they do, the question that I would love to ask you is: How far should we take this, and how far can we take it? And then I finally would like to thank my lab I have an amazingly fun lab. It’s the sort of place where you can come up with all kinds of ideas and talk for hours — I know Ruth’s lab meetings on her work last for hours.

And then I’d like to thank our collaborators and our funding source. So, thank you very much.

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