0:00:00.968,0:00:04.261
I moved to Boston[br]10 years ago from Chicago,

0:00:04.285,0:00:06.880
with an interest in cancer[br]and in chemistry.

0:00:07.373,0:00:10.668
You might know that chemistry[br]is the science of making molecules

0:00:10.692,0:00:12.008
or, to my taste,

0:00:12.032,0:00:13.663
new drugs for cancer.

0:00:14.179,0:00:16.976
And you might also know that,[br]for science and medicine,

0:00:17.000,0:00:19.408
Boston is a bit of a candy store.

0:00:20.507,0:00:25.130
You can't roll a stop sign in Cambridge[br]without hitting a graduate student.

0:00:25.154,0:00:27.329
The bar is called the Miracle of Science.

0:00:27.733,0:00:30.595
The billboards say "Lab Space Available."

0:00:31.396,0:00:33.555
And it's fair to say[br]that in these 10 years,

0:00:33.579,0:00:37.886
we've witnessed absolutely the start[br]of a scientific revolution --

0:00:37.910,0:00:39.389
that of genome medicine.

0:00:39.775,0:00:42.505
We know more about the patients[br]that enter our clinic now

0:00:42.529,0:00:43.688
than ever before.

0:00:43.712,0:00:45.936
And we're able, finally,[br]to answer the question

0:00:45.960,0:00:48.324
that's been so pressing for so many years:

0:00:48.348,0:00:50.304
Why do I have cancer?

0:00:51.415,0:00:53.536
This information[br]is also pretty staggering.

0:00:53.955,0:00:57.048
You might know that, so far,[br]in just the dawn of this revolution,

0:00:57.072,0:01:00.798
we know that there are perhaps[br]40,000 unique mutations

0:01:00.822,0:01:03.433
affecting more than 10,000 genes,

0:01:03.457,0:01:06.820
and that there are 500 of these genes[br]that are bona-fide drivers,

0:01:06.844,0:01:08.740
causes of cancer.

0:01:09.834,0:01:11.029
Yet comparatively,

0:01:11.053,0:01:13.815
we have about a dozen[br]targeted medications.

0:01:14.712,0:01:16.974
And this inadequacy of cancer medicine

0:01:16.998,0:01:21.108
really hit home when my father[br]was diagnosed with pancreatic cancer.

0:01:22.950,0:01:24.611
We didn't fly him to Boston.

0:01:24.635,0:01:26.166
We didn't sequence his genome.

0:01:26.547,0:01:29.689
It's been known for decades[br]what causes this malignancy.

0:01:31.103,0:01:35.150
It's three proteins: ras, myc, p53.

0:01:35.677,0:01:38.375
This is old information[br]we've known since about the 80s,

0:01:38.399,0:01:40.319
yet there's no medicine I can prescribe

0:01:40.343,0:01:43.906
to a patient with this[br]or any of the numerous solid tumors

0:01:43.930,0:01:45.622
caused by these three ...

0:01:46.581,0:01:48.890
Horsemen of the Apocalypse that is cancer.

0:01:49.279,0:01:51.715
There's no ras, no myc, no p53 drug.

0:01:52.096,0:01:54.350
And you might fairly ask: Why is that?

0:01:55.049,0:01:57.882
And the very unsatisfying[br]yet scientific answer is:

0:01:57.906,0:01:59.064
it's too hard.

0:01:59.620,0:02:00.890
That for whatever reason,

0:02:00.914,0:02:04.407
these three proteins have entered[br]a space, in the language of our field,

0:02:04.431,0:02:06.631
that's called the undruggable genome --

0:02:06.655,0:02:08.945
which is like calling[br]a computer unsurfable

0:02:08.969,0:02:10.225
or the Moon unwalkable.

0:02:10.249,0:02:12.357
It's a horrible term of trade.

0:02:12.381,0:02:13.539
But what it means

0:02:13.563,0:02:16.785
is that we've failed to identify[br]a greasy pocket in these proteins,

0:02:16.809,0:02:19.079
into which we, like molecular locksmiths,

0:02:19.103,0:02:24.195
can fashion an active, small,[br]organic molecule or drug substance.

0:02:24.774,0:02:27.207
Now, as I was training[br]in clinical medicine

0:02:27.231,0:02:30.692
and hematology and oncology[br]and stem-cell transplantation,

0:02:30.716,0:02:32.589
what we had instead,

0:02:32.613,0:02:36.128
cascading through the regulatory[br]network at the FDA,

0:02:36.152,0:02:37.585
were these substances:

0:02:37.609,0:02:38.918
arsenic,

0:02:38.942,0:02:40.107
thalidomide,

0:02:40.131,0:02:43.488
and this chemical derivative[br]of nitrogen mustard gas.

0:02:43.512,0:02:46.121
And this is the 21st century.

0:02:46.145,0:02:47.391
And so, I guess you'd say,

0:02:47.415,0:02:50.552
dissatisfied with the performance[br]and quality of these medicines,

0:02:50.576,0:02:52.849
I went back to school, in chemistry,

0:02:54.049,0:02:58.708
with the idea that perhaps by learning[br]the trade of discovery chemistry

0:02:58.732,0:03:01.605
and approaching it in the context[br]of this brave new world

0:03:01.629,0:03:03.841
of the open source,

0:03:03.865,0:03:05.293
the crowd source,

0:03:05.317,0:03:08.622
the collaborative network[br]that we have access to within academia,

0:03:08.646,0:03:12.924
that we might more quickly bring[br]powerful and targeted therapies

0:03:12.948,0:03:14.310
to our patients.

0:03:14.691,0:03:17.791
And so, please consider[br]this a work in progress,

0:03:17.815,0:03:19.832
but I'd like to tell you today a story

0:03:19.856,0:03:23.057
about a very rare cancer[br]called midline carcinoma,

0:03:23.859,0:03:28.073
about the undruggable protein target[br]that causes this cancer,

0:03:28.097,0:03:29.625
called BRD4,

0:03:29.649,0:03:33.494
and about a molecule developed at my lab[br]at Dana-Farber Cancer Institute,

0:03:33.518,0:03:34.670
called JQ1,

0:03:34.694,0:03:36.916
which we affectionately named for Jun Qi,

0:03:36.940,0:03:38.979
the chemist that made this molecule.

0:03:39.709,0:03:42.405
Now, BRD4 is an interesting protein.

0:03:42.429,0:03:46.110
You might ask: with all the things[br]cancer's trying to do to kill our patient,

0:03:46.134,0:03:47.722
how does it remember it's cancer?

0:03:47.746,0:03:49.177
When it winds up its genome,

0:03:49.201,0:03:51.572
divides into two cells and unwinds again,

0:03:51.596,0:03:53.833
why does it not turn[br]into an eye, into a liver,

0:03:53.857,0:03:56.238
as it has all the genes[br]necessary to do this?

0:03:56.262,0:03:57.824
It remembers that it's cancer.

0:03:58.688,0:04:01.776
And the reason is that cancer,[br]like every cell in the body,

0:04:01.800,0:04:03.776
places little molecular bookmarks,

0:04:03.800,0:04:05.178
little Post-it notes,

0:04:05.202,0:04:08.185
that remind the cell, "I'm cancer;[br]I should keep growing."

0:04:08.800,0:04:12.813
And those Post-it notes involve this[br]and other proteins of its class --

0:04:12.837,0:04:14.153
so-called bromodomains.

0:04:14.732,0:04:17.400
So we developed an idea, a rationale,

0:04:17.424,0:04:19.573
that perhaps if we made a molecule

0:04:19.597,0:04:21.890
that prevented[br]the Post-it note from sticking

0:04:21.914,0:04:23.573
by entering into the little pocket

0:04:23.597,0:04:25.453
at the base of this spinning protein,

0:04:25.477,0:04:27.533
then maybe we could convince cancer cells,

0:04:27.557,0:04:30.358
certainly those addicted[br]to this BRD4 protein,

0:04:30.382,0:04:31.699
that they're not cancer.

0:04:32.418,0:04:34.641
And so we started to work on this problem.

0:04:34.665,0:04:36.967
We developed libraries of compounds

0:04:36.991,0:04:39.776
and eventually arrived[br]at this and similar substances

0:04:39.800,0:04:40.982
called JQ1.

0:04:41.577,0:04:43.141
Now, not being a drug company,

0:04:43.165,0:04:46.259
we could do certain things,[br]we had certain flexibilities,

0:04:46.283,0:04:49.117
that I respect that a pharmaceutical[br]industry doesn't have.

0:04:49.141,0:04:51.391
We just started mailing it to our friends.

0:04:51.883,0:04:53.036
I have a small lab.

0:04:53.060,0:04:56.465
We thought we'd just send it to people[br]and see how the molecule behaves.

0:04:56.489,0:04:57.939
We sent it to Oxford, England,

0:04:57.963,0:05:01.185
where a group of talented[br]crystallographers provided this picture,

0:05:01.209,0:05:04.306
which helped us understand exactly[br]how this molecule is so potent

0:05:04.330,0:05:05.496
for this protein target.

0:05:05.520,0:05:08.456
It's what we call a perfect fit[br]of shape complementarity,

0:05:08.480,0:05:09.630
or hand in glove.

0:05:10.327,0:05:11.948
Now, this is a very rare cancer,

0:05:11.972,0:05:13.776
this BRD4-addicted cancer.

0:05:14.201,0:05:16.432
And so we worked with samples of material

0:05:16.456,0:05:20.030
that were collected by young pathologists[br]at Brigham and Women's Hospital.

0:05:20.054,0:05:22.427
And as we treated these cells[br]with this molecule,

0:05:22.451,0:05:24.490
we observed something really striking.

0:05:24.800,0:05:26.006
The cancer cells --

0:05:26.030,0:05:28.097
small, round and rapidly dividing,

0:05:28.121,0:05:30.474
grew these arms and extensions.

0:05:30.498,0:05:31.862
They were changing shape.

0:05:32.320,0:05:33.647
In effect,

0:05:33.671,0:05:36.978
the cancer cell[br]was forgetting it was cancer

0:05:37.002,0:05:38.510
and becoming a normal cell.

0:05:40.076,0:05:41.433
This got us very excited.

0:05:42.841,0:05:45.429
The next step would be to put[br]this molecule into mice.

0:05:45.453,0:05:48.848
The only problem was there's no[br]mouse model of this rare cancer.

0:05:48.872,0:05:51.595
And so at the time[br]we were doing this research,

0:05:51.619,0:05:55.192
I was caring for a 29-year-old[br]firefighter from Connecticut

0:05:55.216,0:05:57.098
who was very much at the end of life

0:05:57.122,0:05:58.978
with this incurable cancer.

0:05:59.621,0:06:03.071
This BRD4-addicted cancer[br]was growing throughout his left lung.

0:06:03.095,0:06:06.260
And he had a chest tube in[br]that was draining little bits of debris.

0:06:06.284,0:06:09.245
And every nursing shift,[br]we would throw this material out.

0:06:09.269,0:06:11.036
And so we approached this patient

0:06:11.060,0:06:13.072
and asked if he would collaborate with us.

0:06:13.715,0:06:17.414
Could we take this precious[br]and rare cancerous material

0:06:17.438,0:06:19.037
from this chest tube

0:06:19.061,0:06:21.280
and drive it across town[br]and put it into mice

0:06:21.304,0:06:24.945
and try to do a clinical trial[br]at a stage that with a prototype drug,

0:06:24.969,0:06:26.993
well, that would be, of course, impossible

0:06:27.017,0:06:28.850
and, rightly, illegal to do in humans.

0:06:28.874,0:06:30.127
And he obliged us.

0:06:31.006,0:06:33.198
At the Lurie Family Center[br]for Animal Imaging,

0:06:33.222,0:06:36.837
our colleague, Andrew Kung,[br]grew this cancer successfully in mice

0:06:36.861,0:06:38.551
without ever touching plastic.

0:06:38.575,0:06:41.991
And you can see this PET scan[br]of a mouse -- what we call a pet PET.

0:06:42.015,0:06:43.571
The cancer is growing

0:06:43.595,0:06:46.500
as this red, huge mass[br]in the hind limb of this animal.

0:06:46.921,0:06:49.144
And as we treat it with our compound,

0:06:49.168,0:06:50.776
this addiction to sugar,

0:06:50.800,0:06:52.391
this rapid growth, faded.

0:06:52.415,0:06:54.458
And on the animal on the right,

0:06:54.482,0:06:56.493
you see that the cancer was responding.

0:06:57.569,0:06:59.776
We've completed, now, clinical trials

0:06:59.800,0:07:01.776
in four mouse models of this disease.

0:07:01.800,0:07:03.649
And every time, we see the same thing.

0:07:03.673,0:07:06.378
The mice with this cancer[br]that get the drug live,

0:07:06.402,0:07:08.698
and the ones that don't rapidly perish.

0:07:10.800,0:07:12.229
So we started to wonder,

0:07:12.253,0:07:14.357
what would a drug company[br]do at this point?

0:07:14.381,0:07:16.430
Well, they probably[br]would keep this a secret

0:07:16.454,0:07:18.339
until they turn the prototype drug

0:07:18.363,0:07:20.507
into an active pharmaceutical substance.

0:07:21.063,0:07:22.504
So we did just the opposite.

0:07:22.884,0:07:25.719
We published a paper[br]that described this finding

0:07:25.743,0:07:27.719
at the earliest prototype stage.

0:07:28.513,0:07:31.421
We gave the world the chemical[br]identity of this molecule,

0:07:31.445,0:07:33.342
typically a secret in our discipline.

0:07:33.366,0:07:35.342
We told people exactly how to make it.

0:07:36.039,0:07:37.707
We gave them our email address,

0:07:37.731,0:07:39.382
suggesting that if they write us,

0:07:39.406,0:07:41.008
we'll send them a free molecule.

0:07:41.032,0:07:42.120
(Laughter)

0:07:42.144,0:07:45.041
We basically tried to create[br]the most competitive environment

0:07:45.065,0:07:46.225
for our lab as possible.

0:07:46.249,0:07:48.191
And this was, unfortunately, successful.

0:07:48.215,0:07:49.239
(Laughter)

0:07:49.263,0:07:51.268
Because now, we've shared this molecule,

0:07:51.292,0:07:53.695
just since December of last year,

0:07:53.719,0:07:55.974
with 40 laboratories in the United States

0:07:55.998,0:07:57.776
and 30 more in Europe --

0:07:57.800,0:07:59.649
many of them pharmaceutical companies,

0:07:59.673,0:08:01.268
seeking now to enter this space,

0:08:01.292,0:08:04.341
to target this rare cancer[br]that, thankfully right now,

0:08:05.196,0:08:07.809
is quite desirable[br]to study in that industry.

0:08:10.062,0:08:13.131
But the science that's coming back[br]from all of these laboratories

0:08:13.155,0:08:14.989
about the use of this molecule

0:08:15.013,0:08:18.186
has provided us insights[br]we might not have had on our own.

0:08:18.210,0:08:20.187
Leukemia cells treated with this compound

0:08:20.211,0:08:22.627
turn into normal white blood cells.

0:08:23.276,0:08:25.057
Mice with multiple myeloma,

0:08:25.081,0:08:28.116
an incurable malignancy[br]of the bone marrow,

0:08:28.140,0:08:30.117
respond dramatically

0:08:30.141,0:08:31.856
to the treatment with this drug.

0:08:32.316,0:08:34.292
You might know that fat has memory.

0:08:35.364,0:08:37.340
I'll nicely demonstrate that for you.

0:08:37.364,0:08:38.395
(Laughter)

0:08:38.419,0:08:39.971
In fact, this molecule

0:08:39.995,0:08:43.395
prevents this adipocyte,[br]this fat stem cell,

0:08:43.419,0:08:46.288
from remembering how to make fat,

0:08:46.312,0:08:48.680
such that mice on a high-fat diet,

0:08:48.704,0:08:50.818
like the folks[br]in my hometown of Chicago --

0:08:50.842,0:08:51.850
(Laughter)

0:08:51.874,0:08:53.882
fail to develop fatty liver,

0:08:53.906,0:08:55.729
which is a major medical problem.

0:08:56.920,0:08:58.492
What this research taught us --

0:08:58.516,0:09:00.776
not just my lab, but our institute,

0:09:00.800,0:09:02.872
and Harvard Medical School[br]more generally --

0:09:02.896,0:09:05.157
is that we have unique[br]resources in academia

0:09:05.181,0:09:06.515
for drug discovery;

0:09:06.539,0:09:09.722
that our center, which has tested[br]perhaps more cancer molecules

0:09:09.746,0:09:10.903
in a scientific way

0:09:10.927,0:09:12.078
than any other,

0:09:12.102,0:09:13.577
never made one of its own.

0:09:14.545,0:09:16.712
For all the reasons you see listed here,

0:09:16.736,0:09:19.475
we think there's a great[br]opportunity for academic centers

0:09:19.499,0:09:23.323
to participate in this earliest,[br]conceptually tricky

0:09:23.347,0:09:25.277
and creative discipline

0:09:25.301,0:09:27.083
of prototype drug discovery.

0:09:29.872,0:09:31.022
So what next?

0:09:31.349,0:09:33.729
We have this molecule,[br]but it's not a pill yet.

0:09:33.753,0:09:36.347
It's not orally bioavailable.

0:09:36.371,0:09:39.566
We need to fix it so we can[br]deliver it to our patients.

0:09:39.590,0:09:41.174
And everyone in the lab,

0:09:41.198,0:09:43.999
especially following the interaction[br]with these patients,

0:09:44.023,0:09:46.348
feels quite compelled[br]to deliver a drug substance

0:09:46.372,0:09:47.570
based on this molecule.

0:09:47.594,0:09:49.005
It's here where I'd say

0:09:49.029,0:09:51.244
that we could use your help[br]and your insights,

0:09:51.268,0:09:53.130
your collaborative participation.

0:09:53.481,0:09:57.162
Unlike a drug company,[br]we don't have a pipeline

0:09:57.186,0:09:59.193
that we can deposit these molecules into.

0:09:59.217,0:10:01.614
We don't have a team[br]of salespeople and marketeers

0:10:01.638,0:10:04.349
to tell us how to position[br]this drug against the other.

0:10:04.373,0:10:07.041
What we do have is the flexibility[br]of an academic center

0:10:07.065,0:10:09.417
to work with competent, motivated,

0:10:09.441,0:10:12.346
enthusiastic, hopefully well-funded people

0:10:12.370,0:10:14.663
to carry these molecules[br]forward into the clinic

0:10:14.687,0:10:18.385
while preserving our ability[br]to share the prototype drug worldwide.

0:10:19.474,0:10:22.115
This molecule will soon leave our benches

0:10:22.139,0:10:25.189
and go into a small start-up company[br]called Tensha Therapeutics.

0:10:25.213,0:10:28.149
And, really, this is the fourth[br]of these molecules

0:10:28.173,0:10:30.420
to kind of "graduate"[br]from our little pipeline

0:10:30.444,0:10:31.898
of drug discovery,

0:10:31.922,0:10:36.278
two of which -- a topical drug[br]for lymphoma of the skin

0:10:37.197,0:10:40.308
and an oral substance for the treatment[br]of multiple myeloma --

0:10:40.332,0:10:43.570
will actually come to the bedside[br]for the first clinical trial

0:10:43.594,0:10:47.117
in July of this year -- for us,[br]a major and exciting milestone.

0:10:48.649,0:10:50.672
I want to leave you with just two ideas.

0:10:50.696,0:10:55.030
The first is: if anything is unique[br]about this research,

0:10:55.054,0:10:57.411
it's less the science than the strategy.

0:10:57.435,0:10:59.857
This, for us, was a social experiment --

0:10:59.881,0:11:05.146
an experiment in "What would happen[br]if we were as open and honest

0:11:05.170,0:11:07.686
at the earliest phase[br]of discovery chemistry research

0:11:07.710,0:11:09.157
as we could be?"

0:11:09.181,0:11:11.522
This string of letters and numbers

0:11:11.546,0:11:13.561
and symbols and parentheses

0:11:13.585,0:11:15.204
that can be texted, I suppose,

0:11:15.228,0:11:16.655
or Twittered worldwide,

0:11:17.948,0:11:20.450
is the chemical identity[br]of our pro compound.

0:11:20.474,0:11:24.556
It's the information that we most need[br]from pharmaceutical companies,

0:11:24.580,0:11:29.294
the information on how these early[br]prototype drugs might work.

0:11:29.688,0:11:31.812
Yet this information is largely a secret.

0:11:32.482,0:11:35.361
And so we seek, really, to download

0:11:35.385,0:11:38.504
from the amazing successes[br]of the computer-science industry,

0:11:38.528,0:11:42.907
two principles -- that of open source[br]and that of crowdsourcing --

0:11:42.931,0:11:48.925
to quickly, responsibly accelerate[br]the delivery of targeted therapeutics

0:11:48.949,0:11:50.456
to patients with cancer.

0:11:51.117,0:11:54.236
Now, the business model[br]involves all of you.

0:11:54.260,0:11:56.236
This research is funded by the public.

0:11:56.585,0:11:57.963
It's funded by foundations.

0:11:57.987,0:11:59.717
And one thing I've learned in Boston

0:11:59.741,0:12:02.815
is that you people will do anything[br]for cancer, and I love that.

0:12:02.839,0:12:05.736
You bike across the state,[br]you walk up and down the river.

0:12:05.760,0:12:07.300
(Laughter)

0:12:07.890,0:12:10.216
I've never seen, really, anywhere,

0:12:10.240,0:12:13.483
this unique support for cancer research.

0:12:13.507,0:12:15.264
And so I want to thank you

0:12:15.288,0:12:18.585
for your participation, your collaboration

0:12:18.609,0:12:19.770
and most of all,

0:12:19.794,0:12:21.728
for your confidence in our ideas.

0:12:21.752,0:12:27.253
(Applause)