TEDxBoston 2011
Jay Bradner: Open-source cancer research
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How does cancer know it's cancer? At Jay Bradner's lab, they found a molecule that might hold the answer, JQ1. But instead of patenting it and reaping the profits (as many other labs have done) -- they published their findings and mailed samples to 40 other labs to work on. An inspiring look at the open-source future of medical research.
Jay Bradner - Research scientist
In his lab, Jay Bradner, a researcher at Harvard and Dana Farber in Boston, works on a breakthrough approach for subverting cancer .. and he’s giving the secret away. Full bio
In his lab, Jay Bradner, a researcher at Harvard and Dana Farber in Boston, works on a breakthrough approach for subverting cancer .. and he’s giving the secret away. Full bio
Double-click the English transcript below to play the video.
00:15
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)
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ABOUT THE SPEAKER
Jay Bradner - Research scientistIn his lab, Jay Bradner, a researcher at Harvard and Dana Farber in Boston, works on a breakthrough approach for subverting cancer .. and he’s giving the secret away.
Why you should listen
A doctor and a chemist, Jay Bradner hunts for new approaches to solving cancer. As a research scientist and instructor in medicine at Harvard and Dana Farber Cancer Institute, he and his lab are working to subvert cancer's aggressive behavior by reprogramming the cell's fundamental identity. A molecule they're working on, JQ1, might do just that. (And he’s giving it away in order to spur faster open-source drug discovery.) If you're a researcher who'd like a sample of the JQ1 molecule, contact the Bradner Lab.
Jay Bradner | Speaker | TED.com