[Script Info]
Title: 
[Events]
Format: Layer, Start, End, Style, Name, MarginL, MarginR, MarginV, Effect, Text
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,[MUSIC]
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,So, in many ways a broken car is not so different from a disease,
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,when the engine is smoking and the lights don't come up.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,There's a fundamental difference, however, between humans and cars.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,If I can get my car to a mechanic, I can be pretty certain that they can fix it,
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,which is much more than we can say about many of our diseases today.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,So what can a mechanic, with much less education and much less bucks than a doctor,
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,fix our car, while our doctors often let us go with diseases persisting in our body?
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,Well, there are actually a number of things that a mechanic has that our doctor doesn't have right now.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,First of all, it's got a parts list.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,It has a blueprint telling us how the pieces connect together.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,It has diagnostics tools to figure out where the components, which is broken and which is healthy.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,It has the means, essentially, to replace the parts.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,Now let's think about it. Which of these components are available to our doctor today?
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,Well, the good news is that they've finally got the parts list.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,That was the output of the human genome project.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,And when the human genome was actually mapped about ten years ago, we thought
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,It's going to be easy from now. From the parts, we will have essentially the world bonanza that we need to fix humans, us.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,But of course reality sinks in. We also realize that these many pieces will eventually give us many drugs.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,In 2001, or 2000, the year before the genome project was unveiled, the FDA approved about a hundred drugs a year.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,We thought this number could only go up.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,It could only just increase.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,Yet the reality just sinks in.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,The number of new drugs in just the last ten years, went from a hundred before the genome, to about twenty per year.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,In hindsight, the reason is pretty clear.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,It's not enough to have the parts list.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,We also need to actually figure out how the pieces fit together.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,That is, we should not look at this picture, but rather we should be looking at how the wiring diagram of the car should look like.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,How the wiring of ourselves actually look like.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,How the genes and the proteins and the metabolites link to each other, forming a conistent network.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,Because this network, with I am going to try to tell you today, is really the key to understanding human diseases.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,Now, the problem is that if you look at this map, you soon realize that it looks completely random.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,Randomness certainly has the upper hand.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,But down the line, it is not. I believe there is a deep order behind this wiring diagram.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,And understanding that order is the key to understand human diseases.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,Now, I am a physicist, and the conventional wisdom is that as a physicist, I should be studying very large objects:
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,stars, quasars, or very tiny ones like the Higgs boson or quarks.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,Yet about a decade ago, my interest has turned to a completely different subject: Complex systems and networks.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,And that's because our very existence depends on the successful functioning of systems and networks behind us.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,And I also believe the scientific challenges behind complex systems and networks are just as [???] as behind quarks or quasars.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,So I started looking at the structure of th Internet.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,Telling us how many, many computers are linked together by various cables.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,I looked at the structure of the social network, telling us how do societies wire together through many friendship and other linkages.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,And eventually I started looking at the structure of the cell.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,Telling us you our genes and proteins link to each other into a coherent network.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,And through that path, I arrived at human diseases.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,A path that is rarely taken by physicists.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,Now, the fundamental question that really comes up from that is:
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,How do we think about diseases in the context of these of these very very complicated networks?
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,And from that, let me turn to a map that we all understand, probably the most famous map out there, which is the map of Manhattan.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,Now, in many ways, Manhattan is structured different from a cell.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,But let's for a moment carry with me and let's believe together that it's not a map of Manhattan but a map of a cell.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,Where the intersections showing us nodes are the genes and the proteins.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,And the street segments that connect them corresponds to the interactions between them.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,Now, down the line, this is not so different from what happens in our cells.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,The busy life of Manhattan very easily maps into the crowded life of the cell where molecules interact with each other,
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,and recombine and transport and so on.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,So there's lots of similarities on the surface between them.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,And if we look at Manhattan, we also realize that action is not uniformly spread within the cit.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,If you want to go, for example, to the theater, you don't go to any parts of Manhattan, you would go to the theater district.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,Because that's where most of the theaters are, that's where the shows are.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,You want to buy an artwork. You will not actually be going anywhere in the city, but you would be going to the gallery district.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,Because there is one small region in the town that has most of the high-end galleries, and that's where most of the artwork is for sale.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,The same is true in the cell.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,Its functions are not spread uniformly within the network.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,But there are other pockets within the network that are responsible for particular functions,
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,and their breakdown potentially leads to disease.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,So the way to think about disease in the context of the network is to think that
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,there are different regions that correspond to different diseases on this map.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,So, for example, you could say that cancer stays somewhere around Wall Street
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,[AUDIENCE LAUGHTER]
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,And bipolar disease would be somewhere around Times Square.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,[AUDIENCE LAUGHTER]
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,And you know asthma, a respiratory disease, it would be somewhere up near the Washington Bridge.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,Where Washington brings the people and cars into New Jersey and The Bronx.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,[AUDIENCE LAUGHTER]
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,Now, under normal conditions
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,Manhattan is full of traffic.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,And that's how the cell looks like normally.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,But if we had defects, some genes breaking down, that corresponds to some of the intersections now working, and
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,soon enough we would get a very typical Manhattan disease: A traffic jam.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,This is not so different from what happens in our cells.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,Because there are many different ways you can get the same phenotype.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,In the same way, there are many different ways you can get a disease.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,For example, there was a famous study by Burt [???]'s group which sequenced about 300 individuals who all had colo-rectal cancer.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,They had the same phenotype.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,Therefore the expectation was that all of them would have probably the same mutations in the same genes.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,Yet, the study showed that not only did they not have the same set of mutations, but the mutations were all in different genes.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,There were no two individuals who would actually have the same genes exactly the same group of genes' defect.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,The only way to understand how it's possible that many different genes broken down in different combinations linked to the same disease,
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,is to think in terms of Manhattan.
Dialogue: 0,9:59:59.99,9:59:59.99,Default,,0000,0000,0000,,If you think in terms of disease module and to really have the wiring diagram of the disease module,