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TEDxBoston 2011

Jay Bradner: Open-source cancer research

May 26, 2011

How does cancer know it's cancer? At Jay Bradner's lab, they found a molecule that might hold the answer, JQ1 -- and instead of patenting JQ1, 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. (Filmed at TEDxBoston.)

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

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Double-click the English subtitles below to play the video.
I moved to Boston 10 years ago, from Chicago,
00:15
with an interest in cancer and in chemistry.
00:19
You might know that chemistry is the science of making molecules --
00:22
or to my taste, new drugs for cancer.
00:25
And you might also know that, for science and medicine,
00:29
Boston is a bit of a candy store.
00:32
You can't roll a stop sign in Cambridge
00:35
without hitting a graduate student.
00:38
The bar is called the Miracle of Science.
00:40
The billboards say "Lab Space Available."
00:42
And it's fair to say that in these 10 years,
00:46
we've witnessed absolutely the start
00:48
of a scientific revolution -- that of genome medicine.
00:51
We know more about the patients that enter our clinic now
00:54
than ever before.
00:56
And we're able, finally, to answer the question
00:58
that's been so pressing for so many years:
01:00
why do I have cancer?
01:03
This information is also pretty staggering.
01:06
You might know that,
01:08
so far in just the dawn of this revolution,
01:10
we know that there are perhaps 40,000 unique mutations
01:12
affecting more than 10,000 genes,
01:15
and that there are 500 of these genes
01:18
that are bona-fide drivers,
01:20
causes of cancer.
01:22
Yet comparatively,
01:24
we have about a dozen targeted medications.
01:26
And this inadequacy of cancer medicine
01:29
really hit home when my father was diagnosed
01:32
with pancreatic cancer.
01:34
We didn't fly him to Boston.
01:37
We didn't sequence his genome.
01:39
It's been known for decades
01:41
what causes this malignancy.
01:43
It's three proteins --
01:45
Ras, Myc and P53.
01:47
This is old information we've known since about the 80s,
01:50
yet there's no medicine I can prescribe
01:53
to a patient with this
01:55
or any of the numerous solid tumors
01:57
caused by these three horsemen
01:59
of the apocalypse that is cancer.
02:01
There's no Ras, no Myc, no P53 drug.
02:04
And you might fairly ask: why is that?
02:07
And the very unsatisfying, yet scientific, answer
02:09
is it's too hard.
02:12
That for whatever reason,
02:14
these three proteins have entered a space in the language of our field
02:16
that's called the undruggable genome --
02:19
which is like calling a computer unsurfable
02:21
or the Moon unwalkable.
02:23
It's a horrible term of trade.
02:25
But what it means
02:27
is that we fail to identify a greasy pocket in these proteins,
02:29
into which we, like molecular locksmiths,
02:31
can fashion an active, small, organic molecule
02:34
or drug substance.
02:37
Now as I was training in clinical medicine
02:39
and hematology and oncology
02:41
and stem cell transplantation,
02:43
what we had instead,
02:45
cascading through the regulatory network at the FDA,
02:47
were these substances --
02:50
arsenic, thalidomide
02:52
and this chemical derivative
02:54
of nitrogen mustard gas.
02:56
And this is the 21st century.
02:58
And so, I guess you'd say, dissatisfied
03:01
with the performance and quality of these medicines,
03:03
I went back to school in chemistry
03:05
with the idea
03:08
that perhaps by learning the trade of discovery chemistry
03:10
and approaching it in the context of this brave new world
03:13
of the open-source,
03:16
the crowd-source,
03:18
the collaborative network that we have access to within academia,
03:20
that we might more quickly
03:23
bring powerful and targeted therapies
03:25
to our patients.
03:27
And so please consider this a work in progress,
03:29
but I'd like to tell you today a story
03:32
about a very rare cancer
03:34
called midline carcinoma,
03:36
about the protein target,
03:38
the undruggable protein target that causes this cancer,
03:40
called BRD4,
03:42
and about a molecule
03:44
developed at my lab at Dana Farber Cancer Institute
03:46
called JQ1, which we affectionately named for Jun Qi,
03:48
the chemist that made this molecule.
03:51
Now BRD4 is an interesting protein.
03:54
You might ask yourself, with all the things cancer's trying to do to kill our patient,
03:57
how does it remember it's cancer?
04:00
When it winds up its genome,
04:02
divides into two cells and unwinds again,
04:04
why does it not turn into an eye, into a liver,
04:06
as it has all the genes necessary to do this?
04:08
It remembers that it's cancer.
04:11
And the reason is that cancer, like every cell in the body,
04:13
places little molecular bookmarks,
04:16
little Post-it notes,
04:18
that remind the cell "I'm cancer; I should keep growing."
04:20
And those Post-it notes
04:23
involve this and other proteins of its class --
04:25
so-called bromodomains.
04:27
So we developed an idea, a rationale,
04:29
that perhaps, if we made a molecule
04:32
that prevented the Post-it note from sticking
04:34
by entering into the little pocket
04:36
at the base of this spinning protein,
04:38
then maybe we could convince cancer cells,
04:40
certainly those addicted to this BRD4 protein,
04:42
that they're not cancer.
04:45
And so we started to work on this problem.
04:47
We developed libraries of compounds
04:49
and eventually arrived at this and similar substances
04:51
called JQ1.
04:54
Now not being a drug company,
04:56
we could do certain things, we had certain flexibilities,
04:58
that I respect that a pharmaceutical industry doesn't have.
05:01
We just started mailing it to our friends.
05:04
I have a small lab.
05:06
We thought we'd just send it to people and see how the molecule behaves.
05:08
And we sent it to Oxford, England
05:10
where a group of talented crystallographers provided this picture,
05:12
which helped us understand
05:15
exactly how this molecule is so potent for this protein target.
05:17
It's what we call a perfect fit
05:20
of shape complimentarity, or hand in glove.
05:22
Now this is a very rare cancer,
05:24
this BRD4-addicted cancer.
05:26
And so we worked with samples of material
05:28
that were collected by young pathologists at Brigham Women's Hospital.
05:31
And as we treated these cells with this molecule,
05:34
we observed something really striking.
05:37
The cancer cells,
05:39
small, round and rapidly dividing,
05:41
grew these arms and extensions.
05:43
They were changing shape.
05:45
In effect, the cancer cell
05:47
was forgetting it was cancer
05:49
and becoming a normal cell.
05:51
This got us very excited.
05:54
The next step would be to put this molecule into mice.
05:57
The only problem was there's no mouse model of this rare cancer.
06:00
And so at the time that we were doing this research,
06:03
I was caring for a 29 year-old firefighter from Connecticut
06:06
who was very much at the end of life
06:09
with this incurable cancer.
06:12
This BRD4-addicted cancer
06:14
was growing throughout his left lung,
06:16
and he had a chest tube in that was draining little bits of debris.
06:18
And every nursing shift
06:20
we would throw this material out.
06:22
And so we approached this patient
06:24
and asked if he would collaborate with us.
06:26
Could we take this precious and rare cancerous material
06:28
from this chest tube
06:32
and drive it across town and put it into mice
06:34
and try to do a clinical trial
06:36
and stage it with a prototype drug?
06:38
Well that would be impossible and, rightly, illegal to do in humans.
06:40
And he obliged us.
06:43
At the Lurie Family Center for Animal Imaging,
06:46
my colleague, Andrew Kung, grew this cancer successfully in mice
06:48
without ever touching plastic.
06:51
And you can see this PET scan of a mouse -- what we call a pet PET.
06:53
The cancer is growing
06:56
as this red, huge mass in the hind limb of this animal.
06:58
And as we treat it with our compound,
07:01
this addiction to sugar,
07:03
this rapid growth, faded.
07:05
And on the animal on the right,
07:07
you see that the cancer was responding.
07:09
We've completed now clinical trials
07:12
in four mouse models of this disease.
07:14
And every time, we see the same thing.
07:16
The mice with this cancer that get the drug live,
07:18
and the ones that don't rapidly perish.
07:20
So we started to wonder,
07:25
what would a drug company do at this point?
07:27
Well they probably would keep this a secret
07:29
until they turn a prototype drug
07:31
into an active pharmaceutical substance.
07:33
And so we did just the opposite.
07:35
We published a paper
07:37
that described this finding
07:39
at the earliest prototype stage.
07:41
We gave the world the chemical identity of this molecule,
07:43
typically a secret in our discipline.
07:46
We told people exactly how to make it.
07:48
We gave them our email address,
07:50
suggesting that, if they write us,
07:52
we'll send them a free molecule.
07:54
We basically tried to create
07:56
the most competitive environment for our lab as possible.
07:58
And this was, unfortunately, successful.
08:00
(Laughter)
08:02
Because now when we've shared this molecule,
08:04
just since December of last year,
08:06
with 40 laboratories in the United States
08:08
and 30 more in Europe --
08:10
many of them pharmaceutical companies
08:12
seeking now to enter this space,
08:14
to target this rare cancer
08:16
that, thankfully right now,
08:18
is quite desirable to study in that industry.
08:20
But the science that's coming back from all of these laboratories
08:24
about the use of this molecule
08:27
has provided us insights
08:29
that we might not have had on our own.
08:31
Leukemia cells treated with this compound
08:33
turn into normal white blood cells.
08:35
Mice with multiple myeloma,
08:38
an incurable malignancy of the bone marrow,
08:40
respond dramatically
08:43
to the treatment with this drug.
08:45
You might know that fat has memory.
08:47
Nice to be able to demonstrate that for you.
08:49
And in fact, this molecule
08:53
prevents this adipocyte, this fat stem cell,
08:55
from remembering how to make fat
08:58
such that mice on a high fat diet,
09:01
like the folks in my hometown of Chicago,
09:03
fail to develop fatty liver,
09:06
which is a major medical problem.
09:08
What this research taught us --
09:11
not just my lab, but our institute,
09:13
and Harvard Medical School more generally --
09:15
is that we have unique resources in academia
09:17
for drug discovery --
09:19
that our center
09:21
that has tested perhaps more cancer molecules in a scientific way
09:23
than any other,
09:25
never made one of its own.
09:27
For all the reasons you see listed here,
09:29
we think there's a great opportunity for academic centers
09:31
to participate in this earliest, conceptually-tricky
09:34
and creative discipline
09:37
of prototype drug discovery.
09:40
So what next?
09:44
We have this molecule, but it's not a pill yet.
09:46
It's not orally available.
09:48
We need to fix it, so that we can deliver it to our patients.
09:51
And everyone in the lab,
09:54
especially following the interaction with these patients,
09:56
feels quite compelled
09:58
to deliver a drug substance based on this molecule.
10:00
It's here where I have to say
10:02
that we could use your help and your insights,
10:04
your collaborative participation.
10:06
Unlike a drug company,
10:08
we don't have a pipeline that we can deposit these molecules into.
10:10
We don't have a team of salespeople and marketeers
10:13
that can tell us how to position this drug against the other.
10:16
What we do have is the flexibility of an academic center
10:19
to work with competent, motivated,
10:21
enthusiastic, hopefully well-funded people
10:24
to carry these molecules forward into the clinic
10:27
while preserving our ability
10:29
to share the prototype drug worldwide.
10:31
This molecule will soon leave our benches
10:34
and go into a small startup company
10:36
called Tensha Therapeutics.
10:38
And really this is the fourth of these molecules
10:40
to kind of graduate from our little pipeline of drug discovery,
10:43
two of which -- a topical drug
10:46
for lymphoma of the skin,
10:49
an oral substance for the treatment of multiple myeloma --
10:52
will actually come to the bedside
10:55
for first clinical trial in July of this year.
10:57
For us, a major and exciting milestone.
10:59
I want to leave you with just two ideas.
11:03
The first is
11:05
if anything is unique about this research,
11:07
it's less the science than the strategy --
11:10
that this for us was a social experiment,
11:12
an experiment in what would happen
11:14
if we were as open and honest
11:17
at the earliest phase of discovery chemistry research
11:20
as we could be.
11:22
This string of letters and numbers
11:24
and symbols and parentheses
11:26
that can be texted, I suppose,
11:28
or Twittered worldwide,
11:30
is the chemical identity of our pro compound.
11:32
It's the information that we most need
11:35
from pharmaceutical companies,
11:37
the information
11:39
on how these early prototype drugs might work.
11:41
Yet this information is largely a secret.
11:44
And so we seek really
11:47
to download from the amazing successes
11:49
of the computer science industry two principles:
11:51
that of opensource and that of crowdsourcing
11:54
to quickly, responsibly
11:57
accelerate the delivery of targeted therapeutics
12:01
to patients with cancer.
12:04
Now the business model involves all of you.
12:06
This research is funded by the public.
12:09
It's funded by foundations.
12:11
And one thing I've learned in Boston
12:13
is that you people will do anything for cancer -- and I love that.
12:15
You bike across the state. You walk up and down the river.
12:17
(Laughter)
12:20
I've never seen really anywhere
12:22
this unique support
12:24
for cancer research.
12:26
And so I want to thank you
12:28
for your participation, your collaboration
12:30
and most of all for your confidence in our ideas.
12:33
(Applause)
12:36

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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.

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

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