WEBVTT 00:00:00.968 --> 00:00:04.261 I moved to Boston 10 years ago from Chicago, 00:00:04.285 --> 00:00:06.880 with an interest in cancer and in chemistry. 00:00:07.373 --> 00:00:10.668 You might know that chemistry is the science of making molecules 00:00:10.692 --> 00:00:12.008 or, to my taste, 00:00:12.032 --> 00:00:13.663 new drugs for cancer. 00:00:14.179 --> 00:00:16.976 And you might also know that, for science and medicine, 00:00:17.000 --> 00:00:19.408 Boston is a bit of a candy store. 00:00:20.507 --> 00:00:25.130 You can't roll a stop sign in Cambridge without hitting a graduate student. 00:00:25.154 --> 00:00:27.329 The bar is called the Miracle of Science. 00:00:27.733 --> 00:00:30.595 The billboards say "Lab Space Available." NOTE Paragraph 00:00:31.396 --> 00:00:33.555 And it's fair to say that in these 10 years, 00:00:33.579 --> 00:00:37.886 we've witnessed absolutely the start of a scientific revolution -- 00:00:37.910 --> 00:00:39.389 that of genome medicine. 00:00:39.775 --> 00:00:42.505 We know more about the patients that enter our clinic now 00:00:42.529 --> 00:00:43.688 than ever before. 00:00:43.712 --> 00:00:45.936 And we're able, finally, to answer the question 00:00:45.960 --> 00:00:48.324 that's been so pressing for so many years: 00:00:48.348 --> 00:00:50.304 Why do I have cancer? 00:00:51.415 --> 00:00:53.536 This information is also pretty staggering. 00:00:53.955 --> 00:00:57.048 You might know that, so far, in just the dawn of this revolution, 00:00:57.072 --> 00:01:00.798 we know that there are perhaps 40,000 unique mutations 00:01:00.822 --> 00:01:03.433 affecting more than 10,000 genes, 00:01:03.457 --> 00:01:06.820 and that there are 500 of these genes that are bona-fide drivers, 00:01:06.844 --> 00:01:08.740 causes of cancer. NOTE Paragraph 00:01:09.834 --> 00:01:11.029 Yet comparatively, 00:01:11.053 --> 00:01:13.815 we have about a dozen targeted medications. 00:01:14.712 --> 00:01:16.974 And this inadequacy of cancer medicine 00:01:16.998 --> 00:01:21.108 really hit home when my father was diagnosed with pancreatic cancer. 00:01:22.950 --> 00:01:24.611 We didn't fly him to Boston. 00:01:24.635 --> 00:01:26.166 We didn't sequence his genome. 00:01:26.547 --> 00:01:29.689 It's been known for decades what causes this malignancy. 00:01:31.103 --> 00:01:35.150 It's three proteins: ras, myc, p53. 00:01:35.677 --> 00:01:38.375 This is old information we've known since about the 80s, 00:01:38.399 --> 00:01:40.319 yet there's no medicine I can prescribe 00:01:40.343 --> 00:01:43.906 to a patient with this or any of the numerous solid tumors 00:01:43.930 --> 00:01:45.622 caused by these three ... 00:01:46.581 --> 00:01:48.890 Horsemen of the Apocalypse that is cancer. 00:01:49.279 --> 00:01:51.715 There's no ras, no myc, no p53 drug. NOTE Paragraph 00:01:52.096 --> 00:01:54.350 And you might fairly ask: Why is that? 00:01:55.049 --> 00:01:57.882 And the very unsatisfying yet scientific answer is: 00:01:57.906 --> 00:01:59.064 it's too hard. 00:01:59.620 --> 00:02:00.890 That for whatever reason, 00:02:00.914 --> 00:02:04.407 these three proteins have entered a space, in the language of our field, 00:02:04.431 --> 00:02:06.631 that's called the undruggable genome -- 00:02:06.655 --> 00:02:08.945 which is like calling a computer unsurfable 00:02:08.969 --> 00:02:10.225 or the Moon unwalkable. 00:02:10.249 --> 00:02:12.357 It's a horrible term of trade. 00:02:12.381 --> 00:02:13.539 But what it means 00:02:13.563 --> 00:02:16.785 is that we've failed to identify a greasy pocket in these proteins, 00:02:16.809 --> 00:02:19.079 into which we, like molecular locksmiths, 00:02:19.103 --> 00:02:24.195 can fashion an active, small, organic molecule or drug substance. NOTE Paragraph 00:02:24.774 --> 00:02:27.207 Now, as I was training in clinical medicine 00:02:27.231 --> 00:02:30.692 and hematology and oncology and stem-cell transplantation, 00:02:30.716 --> 00:02:32.589 what we had instead, 00:02:32.613 --> 00:02:36.128 cascading through the regulatory network at the FDA, 00:02:36.152 --> 00:02:37.585 were these substances: 00:02:37.609 --> 00:02:38.918 arsenic, 00:02:38.942 --> 00:02:40.107 thalidomide, 00:02:40.131 --> 00:02:43.488 and this chemical derivative of nitrogen mustard gas. 00:02:43.512 --> 00:02:46.121 And this is the 21st century. 00:02:46.145 --> 00:02:47.391 And so, I guess you'd say, 00:02:47.415 --> 00:02:50.552 dissatisfied with the performance and quality of these medicines, 00:02:50.576 --> 00:02:52.849 I went back to school, in chemistry, 00:02:54.049 --> 00:02:58.708 with the idea that perhaps by learning the trade of discovery chemistry 00:02:58.732 --> 00:03:01.605 and approaching it in the context of this brave new world 00:03:01.629 --> 00:03:03.841 of the open source, 00:03:03.865 --> 00:03:05.293 the crowd source, 00:03:05.317 --> 00:03:08.622 the collaborative network that we have access to within academia, 00:03:08.646 --> 00:03:12.924 that we might more quickly bring powerful and targeted therapies 00:03:12.948 --> 00:03:14.310 to our patients. NOTE Paragraph 00:03:14.691 --> 00:03:17.791 And so, please consider this a work in progress, 00:03:17.815 --> 00:03:19.832 but I'd like to tell you today a story 00:03:19.856 --> 00:03:23.057 about a very rare cancer called midline carcinoma, 00:03:23.859 --> 00:03:28.073 about the undruggable protein target that causes this cancer, 00:03:28.097 --> 00:03:29.625 called BRD4, 00:03:29.649 --> 00:03:33.494 and about a molecule developed at my lab at Dana-Farber Cancer Institute, 00:03:33.518 --> 00:03:34.670 called JQ1, 00:03:34.694 --> 00:03:36.916 which we affectionately named for Jun Qi, 00:03:36.940 --> 00:03:38.979 the chemist that made this molecule. 00:03:39.709 --> 00:03:42.405 Now, BRD4 is an interesting protein. NOTE Paragraph 00:03:42.429 --> 00:03:46.110 You might ask: with all the things cancer's trying to do to kill our patient, 00:03:46.134 --> 00:03:47.722 how does it remember it's cancer? 00:03:47.746 --> 00:03:49.177 When it winds up its genome, 00:03:49.201 --> 00:03:51.572 divides into two cells and unwinds again, 00:03:51.596 --> 00:03:53.833 why does it not turn into an eye, into a liver, 00:03:53.857 --> 00:03:56.238 as it has all the genes necessary to do this? 00:03:56.262 --> 00:03:57.824 It remembers that it's cancer. 00:03:58.688 --> 00:04:01.776 And the reason is that cancer, like every cell in the body, 00:04:01.800 --> 00:04:03.776 places little molecular bookmarks, 00:04:03.800 --> 00:04:05.178 little Post-it notes, 00:04:05.202 --> 00:04:08.185 that remind the cell, "I'm cancer; I should keep growing." 00:04:08.800 --> 00:04:12.813 And those Post-it notes involve this and other proteins of its class -- 00:04:12.837 --> 00:04:14.153 so-called bromodomains. 00:04:14.732 --> 00:04:17.400 So we developed an idea, a rationale, 00:04:17.424 --> 00:04:19.573 that perhaps if we made a molecule 00:04:19.597 --> 00:04:21.890 that prevented the Post-it note from sticking 00:04:21.914 --> 00:04:23.573 by entering into the little pocket 00:04:23.597 --> 00:04:25.453 at the base of this spinning protein, 00:04:25.477 --> 00:04:27.533 then maybe we could convince cancer cells, 00:04:27.557 --> 00:04:30.358 certainly those addicted to this BRD4 protein, 00:04:30.382 --> 00:04:31.699 that they're not cancer. NOTE Paragraph 00:04:32.418 --> 00:04:34.641 And so we started to work on this problem. 00:04:34.665 --> 00:04:36.967 We developed libraries of compounds 00:04:36.991 --> 00:04:39.776 and eventually arrived at this and similar substances 00:04:39.800 --> 00:04:40.982 called JQ1. 00:04:41.577 --> 00:04:43.141 Now, not being a drug company, 00:04:43.165 --> 00:04:46.259 we could do certain things, we had certain flexibilities, 00:04:46.283 --> 00:04:49.117 that I respect that a pharmaceutical industry doesn't have. 00:04:49.141 --> 00:04:51.391 We just started mailing it to our friends. 00:04:51.883 --> 00:04:53.036 I have a small lab. 00:04:53.060 --> 00:04:56.465 We thought we'd just send it to people and see how the molecule behaves. 00:04:56.489 --> 00:04:57.939 We sent it to Oxford, England, 00:04:57.963 --> 00:05:01.185 where a group of talented crystallographers provided this picture, 00:05:01.209 --> 00:05:04.306 which helped us understand exactly how this molecule is so potent 00:05:04.330 --> 00:05:05.496 for this protein target. 00:05:05.520 --> 00:05:08.456 It's what we call a perfect fit of shape complementarity, 00:05:08.480 --> 00:05:09.630 or hand in glove. NOTE Paragraph 00:05:10.327 --> 00:05:11.948 Now, this is a very rare cancer, 00:05:11.972 --> 00:05:13.776 this BRD4-addicted cancer. 00:05:14.201 --> 00:05:16.432 And so we worked with samples of material 00:05:16.456 --> 00:05:20.030 that were collected by young pathologists at Brigham and Women's Hospital. 00:05:20.054 --> 00:05:22.427 And as we treated these cells with this molecule, 00:05:22.451 --> 00:05:24.490 we observed something really striking. 00:05:24.800 --> 00:05:26.006 The cancer cells -- 00:05:26.030 --> 00:05:28.097 small, round and rapidly dividing, 00:05:28.121 --> 00:05:30.474 grew these arms and extensions. 00:05:30.498 --> 00:05:31.862 They were changing shape. 00:05:32.320 --> 00:05:33.647 In effect, 00:05:33.671 --> 00:05:36.978 the cancer cell was forgetting it was cancer 00:05:37.002 --> 00:05:38.510 and becoming a normal cell. NOTE Paragraph 00:05:40.076 --> 00:05:41.433 This got us very excited. 00:05:42.841 --> 00:05:45.429 The next step would be to put this molecule into mice. 00:05:45.453 --> 00:05:48.848 The only problem was there's no mouse model of this rare cancer. 00:05:48.872 --> 00:05:51.595 And so at the time we were doing this research, 00:05:51.619 --> 00:05:55.192 I was caring for a 29-year-old firefighter from Connecticut 00:05:55.216 --> 00:05:57.098 who was very much at the end of life 00:05:57.122 --> 00:05:58.978 with this incurable cancer. 00:05:59.621 --> 00:06:03.071 This BRD4-addicted cancer was growing throughout his left lung. 00:06:03.095 --> 00:06:06.260 And he had a chest tube in that was draining little bits of debris. 00:06:06.284 --> 00:06:09.245 And every nursing shift, we would throw this material out. 00:06:09.269 --> 00:06:11.036 And so we approached this patient 00:06:11.060 --> 00:06:13.072 and asked if he would collaborate with us. 00:06:13.715 --> 00:06:17.414 Could we take this precious and rare cancerous material 00:06:17.438 --> 00:06:19.037 from this chest tube 00:06:19.061 --> 00:06:21.280 and drive it across town and put it into mice 00:06:21.304 --> 00:06:24.945 and try to do a clinical trial at a stage that with a prototype drug, 00:06:24.969 --> 00:06:26.993 well, that would be, of course, impossible 00:06:27.017 --> 00:06:28.850 and, rightly, illegal to do in humans. 00:06:28.874 --> 00:06:30.127 And he obliged us. 00:06:31.006 --> 00:06:33.198 At the Lurie Family Center for Animal Imaging, 00:06:33.222 --> 00:06:36.837 our colleague, Andrew Kung, grew this cancer successfully in mice 00:06:36.861 --> 00:06:38.551 without ever touching plastic. NOTE Paragraph 00:06:38.575 --> 00:06:41.991 And you can see this PET scan of a mouse -- what we call a pet PET. 00:06:42.015 --> 00:06:43.571 The cancer is growing 00:06:43.595 --> 00:06:46.500 as this red, huge mass in the hind limb of this animal. 00:06:46.921 --> 00:06:49.144 And as we treat it with our compound, 00:06:49.168 --> 00:06:50.776 this addiction to sugar, 00:06:50.800 --> 00:06:52.391 this rapid growth, faded. 00:06:52.415 --> 00:06:54.458 And on the animal on the right, 00:06:54.482 --> 00:06:56.493 you see that the cancer was responding. 00:06:57.569 --> 00:06:59.776 We've completed, now, clinical trials 00:06:59.800 --> 00:07:01.776 in four mouse models of this disease. 00:07:01.800 --> 00:07:03.649 And every time, we see the same thing. 00:07:03.673 --> 00:07:06.378 The mice with this cancer that get the drug live, 00:07:06.402 --> 00:07:08.698 and the ones that don't rapidly perish. NOTE Paragraph 00:07:10.800 --> 00:07:12.229 So we started to wonder, 00:07:12.253 --> 00:07:14.357 what would a drug company do at this point? 00:07:14.381 --> 00:07:16.430 Well, they probably would keep this a secret 00:07:16.454 --> 00:07:18.339 until they turn the prototype drug 00:07:18.363 --> 00:07:20.507 into an active pharmaceutical substance. 00:07:21.063 --> 00:07:22.504 So we did just the opposite. 00:07:22.884 --> 00:07:25.719 We published a paper that described this finding 00:07:25.743 --> 00:07:27.719 at the earliest prototype stage. 00:07:28.513 --> 00:07:31.421 We gave the world the chemical identity of this molecule, 00:07:31.445 --> 00:07:33.342 typically a secret in our discipline. 00:07:33.366 --> 00:07:35.342 We told people exactly how to make it. 00:07:36.039 --> 00:07:37.707 We gave them our email address, 00:07:37.731 --> 00:07:39.382 suggesting that if they write us, 00:07:39.406 --> 00:07:41.008 we'll send them a free molecule. NOTE Paragraph 00:07:41.032 --> 00:07:42.120 (Laughter) NOTE Paragraph 00:07:42.144 --> 00:07:45.041 We basically tried to create the most competitive environment 00:07:45.065 --> 00:07:46.225 for our lab as possible. 00:07:46.249 --> 00:07:48.191 And this was, unfortunately, successful. NOTE Paragraph 00:07:48.215 --> 00:07:49.239 (Laughter) NOTE Paragraph 00:07:49.263 --> 00:07:51.268 Because now, we've shared this molecule, 00:07:51.292 --> 00:07:53.695 just since December of last year, 00:07:53.719 --> 00:07:55.974 with 40 laboratories in the United States 00:07:55.998 --> 00:07:57.776 and 30 more in Europe -- 00:07:57.800 --> 00:07:59.649 many of them pharmaceutical companies, 00:07:59.673 --> 00:08:01.268 seeking now to enter this space, 00:08:01.292 --> 00:08:04.341 to target this rare cancer that, thankfully right now, 00:08:05.196 --> 00:08:07.809 is quite desirable to study in that industry. 00:08:10.062 --> 00:08:13.131 But the science that's coming back from all of these laboratories 00:08:13.155 --> 00:08:14.989 about the use of this molecule 00:08:15.013 --> 00:08:18.186 has provided us insights we might not have had on our own. 00:08:18.210 --> 00:08:20.187 Leukemia cells treated with this compound 00:08:20.211 --> 00:08:22.627 turn into normal white blood cells. 00:08:23.276 --> 00:08:25.057 Mice with multiple myeloma, 00:08:25.081 --> 00:08:28.116 an incurable malignancy of the bone marrow, 00:08:28.140 --> 00:08:30.117 respond dramatically 00:08:30.141 --> 00:08:31.856 to the treatment with this drug. 00:08:32.316 --> 00:08:34.292 You might know that fat has memory. 00:08:35.364 --> 00:08:37.340 I'll nicely demonstrate that for you. NOTE Paragraph 00:08:37.364 --> 00:08:38.395 (Laughter) NOTE Paragraph 00:08:38.419 --> 00:08:39.971 In fact, this molecule 00:08:39.995 --> 00:08:43.395 prevents this adipocyte, this fat stem cell, 00:08:43.419 --> 00:08:46.288 from remembering how to make fat, 00:08:46.312 --> 00:08:48.680 such that mice on a high-fat diet, 00:08:48.704 --> 00:08:50.818 like the folks in my hometown of Chicago -- NOTE Paragraph 00:08:50.842 --> 00:08:51.850 (Laughter) NOTE Paragraph 00:08:51.874 --> 00:08:53.882 fail to develop fatty liver, 00:08:53.906 --> 00:08:55.729 which is a major medical problem. NOTE Paragraph 00:08:56.920 --> 00:08:58.492 What this research taught us -- 00:08:58.516 --> 00:09:00.776 not just my lab, but our institute, 00:09:00.800 --> 00:09:02.872 and Harvard Medical School more generally -- 00:09:02.896 --> 00:09:05.157 is that we have unique resources in academia 00:09:05.181 --> 00:09:06.515 for drug discovery; 00:09:06.539 --> 00:09:09.722 that our center, which has tested perhaps more cancer molecules 00:09:09.746 --> 00:09:10.903 in a scientific way 00:09:10.927 --> 00:09:12.078 than any other, 00:09:12.102 --> 00:09:13.577 never made one of its own. 00:09:14.545 --> 00:09:16.712 For all the reasons you see listed here, 00:09:16.736 --> 00:09:19.475 we think there's a great opportunity for academic centers 00:09:19.499 --> 00:09:23.323 to participate in this earliest, conceptually tricky 00:09:23.347 --> 00:09:25.277 and creative discipline 00:09:25.301 --> 00:09:27.083 of prototype drug discovery. NOTE Paragraph 00:09:29.872 --> 00:09:31.022 So what next? 00:09:31.349 --> 00:09:33.729 We have this molecule, but it's not a pill yet. 00:09:33.753 --> 00:09:36.347 It's not orally bioavailable. 00:09:36.371 --> 00:09:39.566 We need to fix it so we can deliver it to our patients. 00:09:39.590 --> 00:09:41.174 And everyone in the lab, 00:09:41.198 --> 00:09:43.999 especially following the interaction with these patients, 00:09:44.023 --> 00:09:46.348 feels quite compelled to deliver a drug substance 00:09:46.372 --> 00:09:47.570 based on this molecule. 00:09:47.594 --> 00:09:49.005 It's here where I'd say 00:09:49.029 --> 00:09:51.244 that we could use your help and your insights, 00:09:51.268 --> 00:09:53.130 your collaborative participation. 00:09:53.481 --> 00:09:57.162 Unlike a drug company, we don't have a pipeline 00:09:57.186 --> 00:09:59.193 that we can deposit these molecules into. 00:09:59.217 --> 00:10:01.614 We don't have a team of salespeople and marketeers 00:10:01.638 --> 00:10:04.349 to tell us how to position this drug against the other. 00:10:04.373 --> 00:10:07.041 What we do have is the flexibility of an academic center 00:10:07.065 --> 00:10:09.417 to work with competent, motivated, 00:10:09.441 --> 00:10:12.346 enthusiastic, hopefully well-funded people 00:10:12.370 --> 00:10:14.663 to carry these molecules forward into the clinic 00:10:14.687 --> 00:10:18.385 while preserving our ability to share the prototype drug worldwide. NOTE Paragraph 00:10:19.474 --> 00:10:22.115 This molecule will soon leave our benches 00:10:22.139 --> 00:10:25.189 and go into a small start-up company called Tensha Therapeutics. 00:10:25.213 --> 00:10:28.149 And, really, this is the fourth of these molecules 00:10:28.173 --> 00:10:30.420 to kind of "graduate" from our little pipeline 00:10:30.444 --> 00:10:31.898 of drug discovery, 00:10:31.922 --> 00:10:36.278 two of which -- a topical drug for lymphoma of the skin 00:10:37.197 --> 00:10:40.308 and an oral substance for the treatment of multiple myeloma -- 00:10:40.332 --> 00:10:43.570 will actually come to the bedside for the first clinical trial 00:10:43.594 --> 00:10:47.117 in July of this year -- for us, a major and exciting milestone. 00:10:48.649 --> 00:10:50.672 I want to leave you with just two ideas. 00:10:50.696 --> 00:10:55.030 The first is: if anything is unique about this research, 00:10:55.054 --> 00:10:57.411 it's less the science than the strategy. 00:10:57.435 --> 00:10:59.857 This, for us, was a social experiment -- 00:10:59.881 --> 00:11:05.146 an experiment in "What would happen if we were as open and honest 00:11:05.170 --> 00:11:07.686 at the earliest phase of discovery chemistry research 00:11:07.710 --> 00:11:09.157 as we could be?" NOTE Paragraph 00:11:09.181 --> 00:11:11.522 This string of letters and numbers 00:11:11.546 --> 00:11:13.561 and symbols and parentheses 00:11:13.585 --> 00:11:15.204 that can be texted, I suppose, 00:11:15.228 --> 00:11:16.655 or Twittered worldwide, 00:11:17.948 --> 00:11:20.450 is the chemical identity of our pro compound. 00:11:20.474 --> 00:11:24.556 It's the information that we most need from pharmaceutical companies, 00:11:24.580 --> 00:11:29.294 the information on how these early prototype drugs might work. 00:11:29.688 --> 00:11:31.812 Yet this information is largely a secret. 00:11:32.482 --> 00:11:35.361 And so we seek, really, to download 00:11:35.385 --> 00:11:38.504 from the amazing successes of the computer-science industry, 00:11:38.528 --> 00:11:42.907 two principles -- that of open source and that of crowdsourcing -- 00:11:42.931 --> 00:11:48.925 to quickly, responsibly accelerate the delivery of targeted therapeutics 00:11:48.949 --> 00:11:50.456 to patients with cancer. NOTE Paragraph 00:11:51.117 --> 00:11:54.236 Now, the business model involves all of you. 00:11:54.260 --> 00:11:56.236 This research is funded by the public. 00:11:56.585 --> 00:11:57.963 It's funded by foundations. 00:11:57.987 --> 00:11:59.717 And one thing I've learned in Boston 00:11:59.741 --> 00:12:02.815 is that you people will do anything for cancer, and I love that. 00:12:02.839 --> 00:12:05.736 You bike across the state, you walk up and down the river. NOTE Paragraph 00:12:05.760 --> 00:12:07.300 (Laughter) NOTE Paragraph 00:12:07.890 --> 00:12:10.216 I've never seen, really, anywhere, 00:12:10.240 --> 00:12:13.483 this unique support for cancer research. 00:12:13.507 --> 00:12:15.264 And so I want to thank you 00:12:15.288 --> 00:12:18.585 for your participation, your collaboration 00:12:18.609 --> 00:12:19.770 and most of all, 00:12:19.794 --> 00:12:21.728 for your confidence in our ideas. NOTE Paragraph 00:12:21.752 --> 00:12:27.253 (Applause)