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  • Translator: Joseph Geni Reviewer: Morton Bast

  • So let me ask for a show of hands.

  • How many people here are over the age of 48?

  • Well, there do seem to be a few.

  • Well, congratulations,

  • because if you look at this particular slide of U.S. life expectancy,

  • you are now in excess of the average life span

  • of somebody who was born in 1900.

  • But look what happened in the course of that century.

  • If you follow that curve,

  • you'll see that it starts way down there.

  • There's that dip there for the 1918 flu.

  • And here we are at 2010,

  • average life expectancy of a child born today, age 79,

  • and we are not done yet.

  • Now, that's the good news.

  • But there's still a lot of work to do.

  • So, for instance, if you ask,

  • how many diseases do we now know

  • the exact molecular basis?

  • Turns out it's about 4,000, which is pretty amazing,

  • because most of those molecular discoveries

  • have just happened in the last little while.

  • It's exciting to see that in terms of what we've learned,

  • but how many of those 4,000 diseases

  • now have treatments available?

  • Only about 250.

  • So we have this huge challenge, this huge gap.

  • You would think this wouldn't be too hard,

  • that we would simply have the ability

  • to take this fundamental information that we're learning

  • about how it is that basic biology teaches us

  • about the causes of disease

  • and build a bridge across this yawning gap

  • between what we've learned about basic science

  • and its application,

  • a bridge that would look maybe something like this,

  • where you'd have to put together a nice shiny way

  • to get from one side to the other.

  • Well, wouldn't it be nice if it was that easy?

  • Unfortunately, it's not.

  • In reality, trying to go from fundamental knowledge

  • to its application is more like this.

  • There are no shiny bridges.

  • You sort of place your bets.

  • Maybe you've got a swimmer and a rowboat

  • and a sailboat and a tugboat

  • and you set them off on their way,

  • and the rains come and the lightning flashes,

  • and oh my gosh, there are sharks in the water

  • and the swimmer gets into trouble,

  • and, uh oh, the swimmer drowned

  • and the sailboat capsized,

  • and that tugboat, well, it hit the rocks,

  • and maybe if you're lucky, somebody gets across.

  • Well, what does this really look like?

  • Well, what is it to make a therapeutic, anyway?

  • What's a drug? A drug is made up

  • of a small molecule of hydrogen, carbon,

  • oxygen, nitrogen, and a few other atoms

  • all cobbled together in a shape,

  • and it's those shapes that determine whether, in fact,

  • that particular drug is going to hit its target.

  • Is it going to land where it's supposed to?

  • So look at this picture here -- a lot of shapes dancing around for you.

  • Now what you need to do, if you're trying to develop

  • a new treatment for autism

  • or Alzheimer's disease or cancer

  • is to find the right shape in that mix

  • that will ultimately provide benefit and will be safe.

  • And when you look at what happens to that pipeline,

  • you start out maybe with thousands,

  • tens of thousands of compounds.

  • You weed down through various steps

  • that cause many of these to fail.

  • Ultimately, maybe you can run a clinical trial with four or five of these,

  • and if all goes well, 14 years after you started,

  • you will get one approval.

  • And it will cost you upwards of a billion dollars

  • for that one success.

  • So we have to look at this pipeline the way an engineer would,

  • and say, "How can we do better?"

  • And that's the main theme of what I want to say to you this morning.

  • How can we make this go faster?

  • How can we make it more successful?

  • Well, let me tell you about a few examples

  • where this has actually worked.

  • One that has just happened in the last few months

  • is the successful approval of a drug for cystic fibrosis.

  • But it's taken a long time to get there.

  • Cystic fibrosis had its molecular cause discovered in 1989

  • by my group working with another group in Toronto,

  • discovering what the mutation was in a particular gene

  • on chromosome 7.

  • That picture you see there?

  • Here it is. That's the same kid.

  • That's Danny Bessette, 23 years later,

  • because this is the year,

  • and it's also the year where Danny got married,

  • where we have, for the first time, the approval by the FDA

  • of a drug that precisely targets the defect in cystic fibrosis

  • based upon all this molecular understanding.

  • That's the good news.

  • The bad news is, this drug doesn't actually treat all cases of cystic fibrosis,

  • and it won't work for Danny, and we're still waiting

  • for that next generation to help him.

  • But it took 23 years to get this far. That's too long.

  • How do we go faster?

  • Well, one way to go faster is to take advantage of technology,

  • and a very important technology that we depend on

  • for all of this is the human genome,

  • the ability to be able to look at a chromosome,

  • to unzip it, to pull out all the DNA,

  • and to be able to then read out the letters in that DNA code,

  • the A's, C's, G's and T's

  • that are our instruction book and the instruction book for all living things,

  • and the cost of doing this,

  • which used to be in the hundreds of millions of dollars,

  • has in the course of the last 10 years

  • fallen faster than Moore's Law, down to the point

  • where it is less than 10,000 dollars today to have your genome sequenced, or mine,

  • and we're headed for the $1,000 genome fairly soon.

  • Well, that's exciting.

  • How does that play out in terms of application to a disease?

  • I want to tell you about another disorder.

  • This one is a disorder which is quite rare.

  • It's called Hutchinson-Gilford progeria,

  • and it is the most dramatic form of premature aging.

  • Only about one in every four million kids has this disease,

  • and in a simple way, what happens is,

  • because of a mutation in a particular gene,

  • a protein is made that's toxic to the cell

  • and it causes these individuals to age

  • at about seven times the normal rate.

  • Let me show you a video of what that does to the cell.

  • The normal cell, if you looked at it under the microscope,

  • would have a nucleus sitting in the middle of the cell,

  • which is nice and round and smooth in its boundaries

  • and it looks kind of like that.

  • A progeria cell, on the other hand,

  • because of this toxic protein called progerin,

  • has these lumps and bumps in it.

  • So what we would like to do after discovering this

  • back in 2003

  • is to come up with a way to try to correct that.

  • Well again, by knowing something about the molecular pathways,

  • it was possible to pick

  • one of those many, many compounds that might have been useful

  • and try it out.

  • In an experiment done in cell culture

  • and shown here in a cartoon,

  • if you take that particular compound

  • and you add it to that cell that has progeria,

  • and you watch to see what happened,

  • in just 72 hours, that cell becomes,

  • for all purposes that we can determine,

  • almost like a normal cell.

  • Well that was exciting, but would it actually work in a real human being?

  • This has led, in the space of only four years

  • from the time the gene was discovered to the start of a clinical trial,

  • to a test of that very compound.

  • And the kids that you see here

  • all volunteered to be part of this,

  • 28 of them,

  • and you can see as soon as the picture comes up

  • that they are in fact a remarkable group of young people

  • all afflicted by this disease,

  • all looking quite similar to each other.

  • And instead of telling you more about it,

  • I'm going to invite one of them, Sam Berns from Boston,

  • who's here this morning, to come up on the stage

  • and tell us about his experience

  • as a child affected with progeria.

  • Sam is 15 years old. His parents, Scott Berns and Leslie Gordon,

  • both physicians, are here with us this morning as well.

  • Sam, please have a seat.

  • (Applause)

  • So Sam, why don't you tell these folks

  • what it's like being affected with this condition called progeria?

  • Sam Burns: Well, progeria limits me in some ways.

  • I cannot play sports or do physical activities,

  • but I have been able to take interest in things

  • that progeria, luckily, does not limit.

  • But when there is something that I really do want to do

  • that progeria gets in the way of, like marching band

  • or umpiring, we always find a way to do it,

  • and that just shows that progeria isn't in control of my life.

  • (Applause)

  • Francis Collins: So what would you like to say to researchers

  • here in the auditorium and others listening to this?

  • What would you say to them both about research on progeria

  • and maybe about other conditions as well?

  • SB: Well, research on progeria has come so far

  • in less than 15 years,

  • and that just shows the drive that researchers can have

  • to get this far, and it really means a lot

  • to myself and other kids with progeria,

  • and it shows that if that drive exists,

  • anybody can cure any disease,

  • and hopefully progeria can be cured in the near future,

  • and so we can eliminate those 4,000 diseases

  • that Francis was talking about.

  • FC: Excellent. So Sam took the day off from school today

  • to be here, and he is — (Applause) --

  • He is, by the way, a straight-A+ student in the ninth grade

  • in his school in Boston.

  • Please join me in thanking and welcoming Sam.

  • SB: Thank you very much. FC: Well done. Well done, buddy.

  • (Applause)

  • So I just want to say a couple more things

  • about that particular story, and then try to generalize

  • how could we have stories of success

  • all over the place for these diseases, as Sam says,

  • these 4,000 that are waiting for answers.

  • You might have noticed that the drug

  • that is now in clinical trial for progeria

  • is not a drug that was designed for that.

  • It's such a rare disease, it would be hard for a company

  • to justify spending hundreds of millions of dollars to generate a drug.

  • This is a drug that was developed for cancer.

  • Turned out, it didn't work very well for cancer,

  • but it has exactly the right properties, the right shape,

  • to work for progeria, and that's what's happened.

  • Wouldn't it be great if we could do that more systematically?

  • Could we, in fact, encourage all the companies that are out there

  • that have drugs in their freezers

  • that are known to be safe in humans

  • but have never actually succeeded in terms

  • of being effective for the treatments they were tried for?

  • Now we're learning about all these new molecular pathways --

  • some of those could be repositioned or repurposed,

  • or whatever word you want to use, for new applications,

  • basically teaching old drugs new tricks.

  • That could be a phenomenal, valuable activity.

  • We have many discussions now between NIH and companies

  • about doing this that are looking very promising.

  • And you could expect quite a lot to come from this.

  • There are quite a number of success stories one can point to

  • about how this has led to major advances.

  • The first drug for HIV/AIDS

  • was not developed for HIV/AIDS.

  • It was developed for cancer. It was AZT.

  • It didn't work very well for cancer, but became

  • the first successful antiretroviral,

  • and you can see from the table there are others as well.

  • So how do we actually make that a more generalizable effort?

  • Well, we have to come up with a partnership

  • between academia, government, the private sector,

  • and patient organizations to make that so.

  • At NIH, we have started this new

  • National Center for Advancing Translational Sciences.

  • It just started last December, and this is one of its goals.

  • Let me tell you another thing we could do.

  • Wouldn't it be nice to be able to a test a drug

  • to see if it's effective and safe

  • without having to put patients at risk,