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Annotated captions of Jay Bradner: Open-source cancer research in English

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I moved to Boston 10 years ago, from Chicago,

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with an interest in cancer and in chemistry.

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You might know that chemistry is the science of making molecules --

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or to my taste, new drugs for cancer.

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And you might also know that, for science and medicine,

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Boston is a bit of a candy store.

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You can't roll a stop sign in Cambridge

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without hitting a graduate student.

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The bar is called the Miracle of Science.

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The billboards say "Lab Space Available."

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And it's fair to say that in these 10 years,

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we've witnessed absolutely the start

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of a scientific revolution -- that of genome medicine.

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We know more about the patients that enter our clinic now

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than ever before.

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And we're able, finally, to answer the question

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that's been so pressing for so many years:

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why do I have cancer?

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This information is also pretty staggering.

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You might know that,

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so far in just the dawn of this revolution,

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we know that there are perhaps 40,000 unique mutations

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affecting more than 10,000 genes,

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and that there are 500 of these genes

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that are bona-fide drivers,

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causes of cancer.

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Yet comparatively,

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we have about a dozen targeted medications.

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And this inadequacy of cancer medicine

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really hit home when my father was diagnosed

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with pancreatic cancer.

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We didn't fly him to Boston.

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We didn't sequence his genome.

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It's been known for decades

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what causes this malignancy.

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It's three proteins --

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Ras, Myc and P53.

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This is old information we've known since about the 80s,

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yet there's no medicine I can prescribe

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to a patient with this

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or any of the numerous solid tumors

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caused by these three horsemen

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of the apocalypse that is cancer.

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There's no Ras, no Myc, no P53 drug.

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And you might fairly ask: why is that?

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And the very unsatisfying, yet scientific, answer

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is it's too hard.

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That for whatever reason,

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these three proteins have entered a space in the language of our field

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that's called the undruggable genome --

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which is like calling a computer unsurfable

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or the Moon unwalkable.

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It's a horrible term of trade.

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But what it means

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is that we fail to identify a greasy pocket in these proteins,

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into which we, like molecular locksmiths,

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can fashion an active, small, organic molecule

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or drug substance.

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Now as I was training in clinical medicine

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and hematology and oncology

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and stem cell transplantation,

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what we had instead,

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cascading through the regulatory network at the FDA,

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were these substances --

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arsenic, thalidomide

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and this chemical derivative

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of nitrogen mustard gas.

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And this is the 21st century.

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And so, I guess you'd say, dissatisfied

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with the performance and quality of these medicines,

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I went back to school in chemistry

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with the idea

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that perhaps by learning the trade of discovery chemistry

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and approaching it in the context of this brave new world

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of the open-source,

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the crowd-source,

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the collaborative network that we have access to within academia,

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that we might more quickly

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bring powerful and targeted therapies

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to our patients.

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And so please consider this a work in progress,

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but I'd like to tell you today a story

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about a very rare cancer

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called midline carcinoma,

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about the protein target,

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the undruggable protein target that causes this cancer,

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called BRD4,

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and about a molecule

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developed at my lab at Dana Farber Cancer Institute

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called JQ1, which we affectionately named for Jun Qi,

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the chemist that made this molecule.

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Now BRD4 is an interesting protein.

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You might ask yourself, with all the things cancer's trying to do to kill our patient,

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how does it remember it's cancer?

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When it winds up its genome,

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divides into two cells and unwinds again,

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why does it not turn into an eye, into a liver,

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as it has all the genes necessary to do this?

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It remembers that it's cancer.

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And the reason is that cancer, like every cell in the body,

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places little molecular bookmarks,

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little Post-it notes,

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that remind the cell "I'm cancer; I should keep growing."

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And those Post-it notes

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involve this and other proteins of its class --

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so-called bromodomains.

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So we developed an idea, a rationale,

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that perhaps, if we made a molecule

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that prevented the Post-it note from sticking

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by entering into the little pocket

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at the base of this spinning protein,

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then maybe we could convince cancer cells,

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certainly those addicted to this BRD4 protein,

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that they're not cancer.

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And so we started to work on this problem.

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We developed libraries of compounds

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and eventually arrived at this and similar substances

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called JQ1.

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Now not being a drug company,

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we could do certain things, we had certain flexibilities,

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that I respect that a pharmaceutical industry doesn't have.

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We just started mailing it to our friends.

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I have a small lab.

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We thought we'd just send it to people and see how the molecule behaves.

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And we sent it to Oxford, England

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where a group of talented crystallographers provided this picture,

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which helped us understand

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exactly how this molecule is so potent for this protein target.

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It's what we call a perfect fit

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of shape complimentarity, or hand in glove.

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Now this is a very rare cancer,

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this BRD4-addicted cancer.

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And so we worked with samples of material

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that were collected by young pathologists at Brigham Women's Hospital.

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And as we treated these cells with this molecule,

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we observed something really striking.

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The cancer cells,

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small, round and rapidly dividing,

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grew these arms and extensions.

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They were changing shape.

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In effect, the cancer cell

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was forgetting it was cancer

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and becoming a normal cell.

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This got us very excited.

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The next step would be to put this molecule into mice.

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The only problem was there's no mouse model of this rare cancer.

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And so at the time that we were doing this research,

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I was caring for a 29 year-old firefighter from Connecticut

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who was very much at the end of life

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with this incurable cancer.

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This BRD4-addicted cancer

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was growing throughout his left lung,

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and he had a chest tube in that was draining little bits of debris.

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And every nursing shift

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we would throw this material out.

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And so we approached this patient

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and asked if he would collaborate with us.

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Could we take this precious and rare cancerous material

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from this chest tube

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and drive it across town and put it into mice

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and try to do a clinical trial

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and stage it with a prototype drug?

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Well that would be impossible and, rightly, illegal to do in humans.

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And he obliged us.

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At the Lurie Family Center for Animal Imaging,

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my colleague, Andrew Kung, grew this cancer successfully in mice

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without ever touching plastic.

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And you can see this PET scan of a mouse -- what we call a pet PET.

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The cancer is growing

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as this red, huge mass in the hind limb of this animal.

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And as we treat it with our compound,

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this addiction to sugar,

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this rapid growth, faded.

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And on the animal on the right,

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you see that the cancer was responding.

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We've completed now clinical trials

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in four mouse models of this disease.

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And every time, we see the same thing.

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The mice with this cancer that get the drug live,

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and the ones that don't rapidly perish.

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So we started to wonder,

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what would a drug company do at this point?

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Well they probably would keep this a secret

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until they turn a prototype drug

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into an active pharmaceutical substance.

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And so we did just the opposite.

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We published a paper

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that described this finding

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at the earliest prototype stage.

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We gave the world the chemical identity of this molecule,

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typically a secret in our discipline.

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We told people exactly how to make it.

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We gave them our email address,

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suggesting that, if they write us,

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we'll send them a free molecule.

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We basically tried to create

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the most competitive environment for our lab as possible.

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And this was, unfortunately, successful.

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(Laughter)

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Because now when we've shared this molecule,

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just since December of last year,

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with 40 laboratories in the United States

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and 30 more in Europe --

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many of them pharmaceutical companies

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seeking now to enter this space,

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to target this rare cancer

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that, thankfully right now,

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is quite desirable to study in that industry.

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But the science that's coming back from all of these laboratories

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about the use of this molecule

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has provided us insights

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that we might not have had on our own.

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Leukemia cells treated with this compound

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turn into normal white blood cells.

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Mice with multiple myeloma,

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an incurable malignancy of the bone marrow,

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respond dramatically

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to the treatment with this drug.

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You might know that fat has memory.

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Nice to be able to demonstrate that for you.

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And in fact, this molecule

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prevents this adipocyte, this fat stem cell,

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from remembering how to make fat

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such that mice on a high fat diet,

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like the folks in my hometown of Chicago,

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fail to develop fatty liver,

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which is a major medical problem.

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What this research taught us --

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not just my lab, but our institute,

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and Harvard Medical School more generally --

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is that we have unique resources in academia

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for drug discovery --

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that our center

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that has tested perhaps more cancer molecules in a scientific way

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than any other,

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never made one of its own.

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For all the reasons you see listed here,

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we think there's a great opportunity for academic centers

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to participate in this earliest, conceptually-tricky

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and creative discipline

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of prototype drug discovery.

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So what next?

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We have this molecule, but it's not a pill yet.

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It's not orally available.

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We need to fix it, so that we can deliver it to our patients.

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And everyone in the lab,

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especially following the interaction with these patients,

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feels quite compelled

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to deliver a drug substance based on this molecule.

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It's here where I have to say

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that we could use your help and your insights,

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your collaborative participation.

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Unlike a drug company,

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we don't have a pipeline that we can deposit these molecules into.

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We don't have a team of salespeople and marketeers

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that can tell us how to position this drug against the other.

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What we do have is the flexibility of an academic center

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to work with competent, motivated,

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enthusiastic, hopefully well-funded people

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to carry these molecules forward into the clinic

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while preserving our ability

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to share the prototype drug worldwide.

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This molecule will soon leave our benches

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and go into a small startup company

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called Tensha Therapeutics.

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And really this is the fourth of these molecules

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to kind of graduate from our little pipeline of drug discovery,

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two of which -- a topical drug

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for lymphoma of the skin,

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an oral substance for the treatment of multiple myeloma --

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will actually come to the bedside

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for first clinical trial in July of this year.

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For us, a major and exciting milestone.

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I want to leave you with just two ideas.

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The first is

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if anything is unique about this research,

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it's less the science than the strategy --

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that this for us was a social experiment,

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an experiment in what would happen

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if we were as open and honest

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at the earliest phase of discovery chemistry research

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as we could be.

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This string of letters and numbers

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and symbols and parentheses

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that can be texted, I suppose,

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or Twittered worldwide,

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is the chemical identity of our pro compound.

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It's the information that we most need

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from pharmaceutical companies,

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the information

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on how these early prototype drugs might work.

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Yet this information is largely a secret.

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And so we seek really

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to download from the amazing successes

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of the computer science industry two principles:

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that of opensource and that of crowdsourcing

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to quickly, responsibly

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accelerate the delivery of targeted therapeutics

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to patients with cancer.

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Now the business model involves all of you.

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This research is funded by the public.

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It's funded by foundations.

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And one thing I've learned in Boston

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is that you people will do anything for cancer -- and I love that.

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You bike across the state. You walk up and down the river.

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(Laughter)

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I've never seen really anywhere

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this unique support

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for cancer research.

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And so I want to thank you

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for your participation, your collaboration

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and most of all for your confidence in our ideas.

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(Applause)