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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,

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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
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
of a scientific revolution --

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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, 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
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 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
what causes this malignancy.

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It's three proteins: ras, myc, 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
or any of the numerous solid tumors

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caused by these three ...

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Horsemen 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 is:

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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've failed 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 or drug substance.

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Now, as I was training
in clinical medicine

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and hematology and oncology
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,

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thalidomide,

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and this chemical derivative
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,

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dissatisfied 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 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 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
called midline carcinoma,

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about the undruggable protein target
that causes this cancer,

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called BRD4,

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and about a molecule developed at my lab
at Dana-Farber Cancer Institute,

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called JQ1,

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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: 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 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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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 exactly
how this molecule is so potent

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for this protein target.

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It's what we call a perfect fit
of shape complementarity,

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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 and 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,

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the cancer cell
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
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
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,
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
at a stage that with a prototype drug,

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well, that would be, of course, impossible

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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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our 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 the prototype drug

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into an active pharmaceutical substance.

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So we did just the opposite.

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We published a paper
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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(Laughter)

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We basically tried to create
the most competitive environment

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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, 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
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
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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I'll nicely demonstrate that for you.

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(Laughter)

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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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(Laughter)

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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, which has tested
perhaps more cancer molecules

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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 bioavailable.

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We need to fix it so 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
to deliver a drug substance

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based on this molecule.

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It's here where I'd 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,
we don't have a pipeline

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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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to 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
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 start-up company
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

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of drug discovery,

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two of which -- a topical drug
for lymphoma of the skin

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and an oral substance for the treatment
of multiple myeloma --

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will actually come to the bedside
for the first clinical trial

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in July of this year -- 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: if anything is unique
about this research,

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it's less the science than the strategy.

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This, for us, was a social experiment --

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an experiment in "What would happen
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
from pharmaceutical companies,

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the information 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, to download

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from the amazing successes
of the computer-science industry,

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two principles -- that of open source
and that of crowdsourcing --

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to quickly, responsibly 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 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,

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for your confidence in our ideas.

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(Applause)