0:00:10.768,0:00:14.061
I moved to Boston[br]10 years ago from Chicago,

0:00:14.085,0:00:16.680
with an interest in cancer[br]and in chemistry.

0:00:17.173,0:00:20.468
You might know that chemistry[br]is the science of making molecules

0:00:20.492,0:00:21.808
or, to my taste,

0:00:21.832,0:00:23.463
new drugs for cancer.

0:00:23.779,0:00:26.576
And you might also know that,[br]for science and medicine,

0:00:26.600,0:00:29.008
Boston is a bit of a candy store.

0:00:30.607,0:00:35.230
You can't roll a stop sign in Cambridge[br]without hitting a graduate student.

0:00:35.254,0:00:37.429
The bar is called the Miracle of Science.

0:00:37.833,0:00:40.695
The billboards say "Lab Space Available."

0:00:40.896,0:00:43.055
And it's fair to say[br]that in these 10 years,

0:00:43.079,0:00:47.386
we've witnessed absolutely the start[br]of a scientific revolution --

0:00:47.410,0:00:48.889
that of genome medicine.

0:00:49.575,0:00:52.305
We know more about the patients[br]that enter our clinic now

0:00:52.329,0:00:53.488
than ever before.

0:00:53.512,0:00:55.736
And we're able, finally,[br]to answer the question

0:00:55.760,0:00:58.124
that's been so pressing for so many years:

0:00:58.148,0:01:00.104
Why do I have cancer?

0:01:01.215,0:01:03.336
This information[br]is also pretty staggering.

0:01:03.755,0:01:06.848
You might know that, so far,[br]in just the dawn of this revolution,

0:01:06.872,0:01:10.598
we know that there are perhaps[br]40,000 unique mutations

0:01:10.622,0:01:13.233
affecting more than 10,000 genes,

0:01:13.257,0:01:16.620
and that there are 500 of these genes[br]that are bona-fide drivers,

0:01:16.644,0:01:18.540
causes of cancer.

0:01:19.634,0:01:20.829
Yet comparatively,

0:01:20.853,0:01:23.615
we have about a dozen[br]targeted medications.

0:01:24.512,0:01:26.774
And this inadequacy of cancer medicine

0:01:26.798,0:01:30.908
really hit home when my father[br]was diagnosed with pancreatic cancer.

0:01:32.750,0:01:34.411
We didn't fly him to Boston.

0:01:34.435,0:01:35.966
We didn't sequence his genome.

0:01:36.347,0:01:39.489
It's been known for decades[br]what causes this malignancy.

0:01:40.903,0:01:44.950
It's three proteins: ras, myc, p53.

0:01:46.377,0:01:49.075
This is old information[br]we've known since about the 80s,

0:01:49.099,0:01:51.019
yet there's no medicine I can prescribe

0:01:51.043,0:01:54.606
to a patient with this[br]or any of the numerous solid tumors

0:01:54.630,0:01:56.322
caused by these three ...

0:01:57.281,0:01:59.590
Horsemen of the Apocalypse that is cancer.

0:01:59.979,0:02:02.415
There's no ras, no myc, no p53 drug.

0:02:02.796,0:02:05.050
And you might fairly ask: Why is that?

0:02:05.749,0:02:08.582
And the very unsatisfying[br]yet scientific answer is:

0:02:08.606,0:02:09.764
it's too hard.

0:02:10.320,0:02:11.590
That for whatever reason,

0:02:11.614,0:02:15.107
these three proteins have entered[br]a space, in the language of our field,

0:02:15.131,0:02:17.331
that's called the undruggable genome --

0:02:17.355,0:02:19.645
which is like calling[br]a computer unsurfable

0:02:19.669,0:02:20.925
or the Moon unwalkable.

0:02:20.949,0:02:23.057
It's a horrible term of trade.

0:02:23.081,0:02:24.239
But what it means

0:02:24.263,0:02:27.485
is that we've failed to identify[br]a greasy pocket in these proteins,

0:02:27.509,0:02:29.779
into which we, like molecular locksmiths,

0:02:29.803,0:02:34.895
can fashion an active, small,[br]organic molecule or drug substance.

0:02:35.474,0:02:37.907
Now, as I was training[br]in clinical medicine

0:02:37.931,0:02:41.392
and hematology and oncology[br]and stem-cell transplantation,

0:02:41.416,0:02:43.289
what we had instead,

0:02:43.813,0:02:48.696
cascading through the regulatory[br]network at the FDA,

0:02:48.752,0:02:50.185
were these substances:

0:02:50.209,0:02:51.518
arsenic,

0:02:51.542,0:02:52.707
thalidomide,

0:02:52.731,0:02:56.088
and this chemical derivative[br]of nitrogen mustard gas.

0:02:56.112,0:02:58.721
And this is the 21st century.

0:02:59.245,0:03:00.491
And so, I guess you'd say,

0:03:00.515,0:03:03.652
dissatisfied with the performance[br]and quality of these medicines,

0:03:03.676,0:03:05.949
I went back to school, in chemistry,

0:03:07.549,0:03:12.898
with the idea that perhaps by learning[br]the trade of discovery chemistry

0:03:12.932,0:03:15.805
and approaching it in the context[br]of this brave new world

0:03:15.829,0:03:18.041
of the open source,

0:03:18.065,0:03:19.493
the crowd source,

0:03:19.517,0:03:22.822
the collaborative network[br]that we have access to within academia,

0:03:22.846,0:03:27.124
that we might more quickly bring[br]powerful and targeted therapies

0:03:27.148,0:03:28.510
to our patients.

0:03:28.891,0:03:31.991
And so, please consider[br]this a work in progress,

0:03:32.015,0:03:34.032
but I'd like to tell you today a story

0:03:34.056,0:03:37.257
about a very rare cancer[br]called midline carcinoma,

0:03:38.059,0:03:42.273
about the undruggable protein target[br]that causes this cancer,

0:03:42.297,0:03:43.825
called BRD4,

0:03:44.149,0:03:47.994
and about a molecule developed at my lab[br]at Dana-Farber Cancer Institute,

0:03:48.018,0:03:49.170
called JQ1,

0:03:49.194,0:03:51.416
which we affectionately named for Jun Qi,

0:03:51.440,0:03:53.479
the chemist that made this molecule.

0:03:54.409,0:03:57.105
Now, BRD4 is an interesting protein.

0:03:57.129,0:04:00.810
You might ask: with all the things[br]cancer's trying to do to kill our patient,

0:04:00.834,0:04:02.422
how does it remember it's cancer?

0:04:02.446,0:04:03.877
When it winds up its genome,

0:04:03.901,0:04:06.272
divides into two cells and unwinds again,

0:04:06.296,0:04:08.533
why does it not turn[br]into an eye, into a liver,

0:04:08.557,0:04:10.938
as it has all the genes[br]necessary to do this?

0:04:10.962,0:04:12.524
It remembers that it's cancer.

0:04:13.388,0:04:16.476
And the reason is that cancer,[br]like every cell in the body,

0:04:16.500,0:04:18.476
places little molecular bookmarks,

0:04:18.500,0:04:19.878
little Post-it notes,

0:04:19.902,0:04:22.885
that remind the cell, "I'm cancer;[br]I should keep growing."

0:04:23.500,0:04:27.513
And those Post-it notes involve this[br]and other proteins of its class --

0:04:27.537,0:04:28.853
so-called bromodomains.

0:04:29.432,0:04:32.100
So we developed an idea, a rationale,

0:04:32.124,0:04:34.273
that perhaps if we made a molecule

0:04:34.297,0:04:36.590
that prevented[br]the Post-it note from sticking

0:04:36.614,0:04:38.273
by entering into the little pocket

0:04:38.297,0:04:40.153
at the base of this spinning protein,

0:04:40.177,0:04:42.233
then maybe we could convince cancer cells,

0:04:42.257,0:04:45.058
certainly those addicted[br]to this BRD4 protein,

0:04:45.082,0:04:46.399
that they're not cancer.

0:04:47.118,0:04:49.341
And so we started to work on this problem.

0:04:49.365,0:04:51.667
We developed libraries of compounds

0:04:51.691,0:04:54.476
and eventually arrived[br]at this and similar substances

0:04:54.500,0:04:55.682
called JQ1.

0:04:56.277,0:04:57.841
Now, not being a drug company,

0:04:57.865,0:05:00.959
we could do certain things,[br]we had certain flexibilities,

0:05:00.983,0:05:03.817
that I respect that a pharmaceutical[br]industry doesn't have.

0:05:03.841,0:05:06.091
We just started mailing it to our friends.

0:05:06.583,0:05:07.736
I have a small lab.

0:05:07.760,0:05:11.165
We thought we'd just send it to people[br]and see how the molecule behaves.

0:05:11.189,0:05:12.639
We sent it to Oxford, England,

0:05:12.663,0:05:15.885
where a group of talented[br]crystallographers provided this picture,

0:05:15.909,0:05:19.006
which helped us understand exactly[br]how this molecule is so potent

0:05:19.030,0:05:20.196
for this protein target.

0:05:20.220,0:05:23.156
It's what we call a perfect fit[br]of shape complementarity,

0:05:23.180,0:05:24.330
or hand in glove.

0:05:25.027,0:05:26.648
Now, this is a very rare cancer,

0:05:26.672,0:05:28.476
this BRD4-addicted cancer.

0:05:28.901,0:05:31.132
And so we worked with samples of material

0:05:31.156,0:05:34.730
that were collected by young pathologists[br]at Brigham and Women's Hospital.

0:05:34.754,0:05:37.127
And as we treated these cells[br]with this molecule,

0:05:37.151,0:05:39.190
we observed something really striking.

0:05:39.500,0:05:40.706
The cancer cells --

0:05:40.730,0:05:42.797
small, round and rapidly dividing,

0:05:42.821,0:05:45.174
grew these arms and extensions.

0:05:45.198,0:05:46.562
They were changing shape.

0:05:47.020,0:05:48.347
In effect,

0:05:48.371,0:05:51.678
the cancer cell[br]was forgetting it was cancer

0:05:51.702,0:05:53.210
and becoming a normal cell.

0:05:54.776,0:05:56.133
This got us very excited.

0:05:57.541,0:06:00.129
The next step would be to put[br]this molecule into mice.

0:06:00.153,0:06:03.548
The only problem was there's no[br]mouse model of this rare cancer.

0:06:03.572,0:06:06.295
And so at the time[br]we were doing this research,

0:06:06.319,0:06:09.892
I was caring for a 29-year-old[br]firefighter from Connecticut

0:06:09.916,0:06:11.798
who was very much at the end of life

0:06:11.822,0:06:13.678
with this incurable cancer.

0:06:14.321,0:06:17.771
This BRD4-addicted cancer[br]was growing throughout his left lung.

0:06:17.795,0:06:20.960
And he had a chest tube in[br]that was draining little bits of debris.

0:06:20.984,0:06:23.945
And every nursing shift,[br]we would throw this material out.

0:06:23.969,0:06:25.736
And so we approached this patient

0:06:25.760,0:06:27.772
and asked if he would collaborate with us.

0:06:28.415,0:06:32.114
Could we take this precious[br]and rare cancerous material

0:06:32.138,0:06:33.737
from this chest tube

0:06:33.761,0:06:35.980
and drive it across town[br]and put it into mice

0:06:36.004,0:06:39.645
and try to do a clinical trial[br]at a stage that with a prototype drug,

0:06:39.669,0:06:41.693
well, that would be, of course, impossible

0:06:41.717,0:06:43.550
and, rightly, illegal to do in humans.

0:06:43.574,0:06:44.827
And he obliged us.

0:06:45.706,0:06:49.453
At the Lurie Family Center[br]for Animal Imaging,

0:06:49.522,0:06:53.137
our colleague, Andrew Kung,[br]grew this cancer successfully in mice

0:06:53.161,0:06:54.851
without ever touching plastic.

0:06:55.175,0:06:58.591
And you can see this PET scan[br]of a mouse -- what we call a pet PET.

0:06:58.615,0:07:00.171
The cancer is growing

0:07:00.195,0:07:03.100
as this red, huge mass[br]in the hind limb of this animal.

0:07:03.521,0:07:05.744
And as we treat it with our compound,

0:07:05.768,0:07:07.376
this addiction to sugar,

0:07:07.400,0:07:08.991
this rapid growth, faded.

0:07:09.015,0:07:11.058
And on the animal on the right,

0:07:11.082,0:07:13.093
you see that the cancer was responding.

0:07:14.169,0:07:16.376
We've completed, now, clinical trials

0:07:16.400,0:07:18.376
in four mouse models of this disease.

0:07:18.400,0:07:20.249
And every time, we see the same thing.

0:07:20.273,0:07:22.978
The mice with this cancer[br]that get the drug live,

0:07:23.002,0:07:25.298
and the ones that don't rapidly perish.

0:07:27.400,0:07:28.829
So we started to wonder,

0:07:28.853,0:07:30.957
what would a drug company[br]do at this point?

0:07:30.981,0:07:33.030
Well, they probably[br]would keep this a secret

0:07:33.054,0:07:34.939
until they turn the prototype drug

0:07:34.963,0:07:37.107
into an active pharmaceutical substance.

0:07:37.663,0:07:39.104
So we did just the opposite.

0:07:39.484,0:07:42.319
We published a paper[br]that described this finding

0:07:42.343,0:07:44.319
at the earliest prototype stage.

0:07:45.113,0:07:48.021
We gave the world the chemical[br]identity of this molecule,

0:07:48.045,0:07:49.942
typically a secret in our discipline.

0:07:49.966,0:07:51.942
We told people exactly how to make it.

0:07:52.639,0:07:54.307
We gave them our email address,

0:07:54.331,0:07:55.982
suggesting that if they write us,

0:07:56.006,0:07:57.608
we'll send them a free molecule.

0:07:57.632,0:07:58.720
(Laughter)

0:07:58.744,0:08:01.641
We basically tried to create[br]the most competitive environment

0:08:01.665,0:08:02.825
for our lab as possible.

0:08:02.849,0:08:04.791
And this was, unfortunately, successful.

0:08:04.815,0:08:05.839
(Laughter)

0:08:05.863,0:08:07.868
Because now, we've shared this molecule,

0:08:07.892,0:08:10.295
just since December of last year,

0:08:10.319,0:08:12.574
with 40 laboratories in the United States

0:08:12.598,0:08:14.376
and 30 more in Europe --

0:08:14.400,0:08:16.249
many of them pharmaceutical companies,

0:08:16.273,0:08:17.868
seeking now to enter this space,

0:08:17.892,0:08:20.941
to target this rare cancer[br]that, thankfully right now,

0:08:21.796,0:08:24.409
is quite desirable[br]to study in that industry.

0:08:26.662,0:08:29.731
But the science that's coming back[br]from all of these laboratories

0:08:29.755,0:08:31.589
about the use of this molecule

0:08:31.613,0:08:34.785
has provided us insights[br]we might not have had on our own.

0:08:34.809,0:08:36.787
Leukemia cells treated with this compound

0:08:36.811,0:08:39.227
turn into normal white blood cells.

0:08:39.876,0:08:41.657
Mice with multiple myeloma,

0:08:41.681,0:08:44.716
an incurable malignancy[br]of the bone marrow,

0:08:45.740,0:08:47.717
respond dramatically

0:08:47.741,0:08:49.456
to the treatment with this drug.

0:08:50.216,0:08:52.192
You might know that fat has memory.

0:08:53.264,0:08:55.240
I'll nicely demonstrate that for you.

0:08:55.264,0:08:56.295
(Laughter)

0:08:56.319,0:08:57.871
In fact, this molecule

0:08:57.895,0:09:01.295
prevents this adipocyte,[br]this fat stem cell,

0:09:01.319,0:09:04.188
from remembering how to make fat,

0:09:04.212,0:09:06.580
such that mice on a high-fat diet,

0:09:06.604,0:09:08.718
like the folks[br]in my hometown of Chicago --

0:09:08.742,0:09:09.750
(Laughter)

0:09:09.774,0:09:11.782
fail to develop fatty liver,

0:09:11.806,0:09:13.629
which is a major medical problem.

0:09:14.820,0:09:16.392
What this research taught us --

0:09:16.416,0:09:18.676
not just my lab, but our institute,

0:09:18.700,0:09:20.772
and Harvard Medical School[br]more generally --

0:09:20.796,0:09:23.057
is that we have unique[br]resources in academia

0:09:23.081,0:09:24.415
for drug discovery;

0:09:24.439,0:09:27.622
that our center, which has tested[br]perhaps more cancer molecules

0:09:27.646,0:09:28.803
in a scientific way

0:09:28.827,0:09:29.978
than any other,

0:09:30.002,0:09:31.477
never made one of its own.

0:09:32.445,0:09:34.612
For all the reasons you see listed here,

0:09:34.636,0:09:37.375
we think there's a great[br]opportunity for academic centers

0:09:37.399,0:09:41.223
to participate in this earliest,[br]conceptually tricky

0:09:41.247,0:09:43.177
and creative discipline

0:09:43.201,0:09:44.983
of prototype drug discovery.

0:09:47.772,0:09:48.922
So what next?

0:09:49.249,0:09:51.629
We have this molecule,[br]but it's not a pill yet.

0:09:51.653,0:09:54.247
It's not orally bioavailable.

0:09:54.271,0:09:57.466
We need to fix it so we can[br]deliver it to our patients.

0:09:57.490,0:09:59.074
And everyone in the lab,

0:09:59.098,0:10:01.899
especially following the interaction[br]with these patients,

0:10:01.923,0:10:04.248
feels quite compelled[br]to deliver a drug substance

0:10:04.272,0:10:05.470
based on this molecule.

0:10:05.994,0:10:07.405
It's here where I'd say

0:10:07.429,0:10:09.644
that we could use your help[br]and your insights,

0:10:09.668,0:10:11.530
your collaborative participation.

0:10:12.481,0:10:16.162
Unlike a drug company,[br]we don't have a pipeline

0:10:16.186,0:10:18.193
that we can deposit these molecules into.

0:10:18.217,0:10:20.614
We don't have a team[br]of salespeople and marketeers

0:10:20.638,0:10:23.349
to tell us how to position[br]this drug against the other.

0:10:23.373,0:10:26.041
What we do have is the flexibility[br]of an academic center

0:10:26.065,0:10:28.001
to work with competent, motivated,

0:10:28.041,0:10:30.946
enthusiastic, hopefully well-funded people

0:10:30.970,0:10:33.263
to carry these molecules[br]forward into the clinic

0:10:33.287,0:10:36.985
while preserving our ability[br]to share the prototype drug worldwide.

0:10:38.074,0:10:40.715
This molecule will soon leave our benches

0:10:40.739,0:10:43.789
and go into a small start-up company[br]called Tensha Therapeutics.

0:10:43.813,0:10:46.749
And, really, this is the fourth[br]of these molecules

0:10:46.773,0:10:49.020
to kind of "graduate"[br]from our little pipeline

0:10:49.044,0:10:50.498
of drug discovery,

0:10:50.522,0:10:54.878
two of which -- a topical drug[br]for lymphoma of the skin

0:10:55.797,0:10:58.908
and an oral substance for the treatment[br]of multiple myeloma --

0:10:58.932,0:11:02.170
will actually come to the bedside[br]for the first clinical trial

0:11:02.194,0:11:05.717
in July of this year -- for us,[br]a major and exciting milestone.

0:11:07.149,0:11:09.172
I want to leave you with just two ideas.

0:11:09.196,0:11:13.530
The first is: if anything is unique[br]about this research,

0:11:13.554,0:11:15.911
it's less the science than the strategy.

0:11:15.935,0:11:18.357
This, for us, was a social experiment --

0:11:18.381,0:11:23.646
an experiment in "What would happen[br]if we were as open and honest

0:11:23.670,0:11:26.186
at the earliest phase[br]of discovery chemistry research

0:11:26.210,0:11:27.657
as we could be?"

0:11:27.681,0:11:30.022
This string of letters and numbers

0:11:30.046,0:11:32.061
and symbols and parentheses

0:11:32.085,0:11:33.704
that can be texted, I suppose,

0:11:33.728,0:11:35.155
or Twittered worldwide,

0:11:36.448,0:11:38.950
is the chemical identity[br]of our pro compound.

0:11:38.974,0:11:43.056
It's the information that we most need[br]from pharmaceutical companies,

0:11:43.080,0:11:47.794
the information on how these early[br]prototype drugs might work.

0:11:48.188,0:11:50.312
Yet this information is largely a secret.

0:11:50.982,0:11:53.861
And so we seek, really, to download

0:11:53.885,0:11:57.004
from the amazing successes[br]of the computer-science industry,

0:11:57.028,0:12:01.407
two principles -- that of open source[br]and that of crowdsourcing --

0:12:01.431,0:12:07.425
to quickly, responsibly accelerate[br]the delivery of targeted therapeutics

0:12:07.449,0:12:08.956
to patients with cancer.

0:12:09.617,0:12:12.736
Now, the business model[br]involves all of you.

0:12:12.760,0:12:14.736
This research is funded by the public.

0:12:15.085,0:12:16.463
It's funded by foundations.

0:12:16.487,0:12:18.217
And one thing I've learned in Boston

0:12:18.241,0:12:21.315
is that you people will do anything[br]for cancer, and I love that.

0:12:21.339,0:12:24.236
You bike across the state,[br]you walk up and down the river.

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(Laughter)

0:12:26.390,0:12:28.716
I've never seen, really, anywhere,

0:12:28.740,0:12:31.983
this unique support for cancer research.

0:12:32.007,0:12:33.764
And so I want to thank you

0:12:33.788,0:12:37.085
for your participation, your collaboration

0:12:37.109,0:12:38.270
and most of all,

0:12:38.294,0:12:40.228
for your confidence in our ideas.

0:12:40.252,0:12:45.753
(Applause)