GUY RAZ, HOST:
It's the TED Radio Hour from NPR. I'm Guy Raz. Today on the show, ideas about where we are and where we're headed in the fight against cancer. And one place at the front lines of the battle is a research lab in Boston. It's called the Bradner Lab. And on its website, there's a little tab that you can click. It's up on the right-hand corner, and it just says request probes.
JAY BRADNER: That's right.
RAZ: Yeah. And what does that do?
BRADNER: So the probe request button will trigger a page where scientists around the world can learn about molecules that our lab has created and have made available for open-source drug discovery.
RAZ: Jay Bradner is the guy who makes the probes.
BRADNER: I'm a physician at the Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School.
RAZ: And by probes, we mean molecules - molecules that could act like drugs in the fight against cancer. And after Jay Bradner and his lab develop these molecules, they share them. And in the world of drug development, that's kind of a new thing.
BRADNER: You see, pharmaceutical science is perhaps one of the most secretive fields in technology development, second only perhaps to defense contractors. I think that we're starting to see this change.
RAZ: He described why that change has started to happen just in the past 10 years and what it could mean for the future from the TED stage.
(SOUNDBITE OF TED TALK)
BRADNER: It's fair to say that in these 10 years, we've witnessed absolutely the start of a scientific revolution, that of genome medicine. We know more about the patients that enter our clinic now than ever before. And we're able finally to answer the question that's been so pressing for so many years - why do I have cancer? This information is also pretty staggering. You might know that so far in just the dawn of this revolution, we know that there are perhaps 40,000 unique mutations affecting more than 10,000 genes and that there are 500 of these genes that are bona fide drivers - causes of cancer. Yet comparatively, we have about a dozen targeted medications. And this inadequacy of cancer medicine really hit home when my father was diagnosed with pancreatic cancer. It's been known for decades what causes this malignancy. It's three proteins - Ras, Myc, P53. This is old information we've known since about the '80s, yet there's no Ras, no Myc, no P53 drug. And you might fairly ask why is that? And the very unsatisfying, yet scientific answer is it's too hard.
RAZ: And the reason why it's too hard is because so far, scientists haven't been able to figure out how to switch off or block most of the genes that cause cancer.
BRADNER: To put it simplistically, there's a gene called Myc. This gene is in your body to activate, like the conductor of an orchestra, the five to 15 percent of genes in your genome involved in cell duplication.
RAZ: So Myc, which is one of the most well-studied genes, tells your cells to grow. But cancer...
BRADNER: ...Almost uniformly...
RAZ: Sends Myc into overdrive. It hijacks the genes, tells cells to keep dividing and dividing and dividing and dividing...
BRADNER: You see, if we could inhibit Myc, it would have historic value in the treatment of cancer. But at this moment, this Myc gene, this central conductor of the cancer growth symphony, is considered undruggable.
(SOUNDBITE OF TED TALK)
BRADNER: Which is like calling a computer unsurfable or the moon unwalkable. It's a horrible term of trade. But what it means is that we've failed to identify a greasy pocket in these proteins into which we, like molecular locksmiths, can fashion an active, small, organic molecule or drug substance.
RAZ: So this is actually a very physical problem. Scientists need to know what kind of shape a specific protein has in order to design a drug molecule that can bind to it and then block it or even change it. And in the past couple of years, new technologies have led to huge leaps forward in how scientists are tackling that problem.
BRADNER: Such as the use of three-dimensional pictures that can help to find nooks and crannies where a drug molecule might bind.
RAZ: The place where a drug molecule could bind, by the way, is called the target.
BRADNER: There have been advances in chemistry, a reconsideration of what does a molecule need to look like in order to occupy its target? Imagine reinventing the key.
RAZ: And those advances in chemistry...
RAZ: ...Jay Bradner says...
BRADNER: ...Have created now, I believe, enough examples of molecules targeting undruggable targets that truly nothing is undruggable.
RAZ: Including even the Myc gene.
BRADNER: The Myc gene that turns on the growth program of the human cell, like the conductor of an orchestra.
RAZ: Jay and his team of researchers knew that Myc played a big role in the growth of certain cancers. And they thought that that role might have something to do with a certain protein called BRD4.
BRADNER: BRD4, it does not stand for Bradner. I wish that it did. This BRD4 protein is very important because the Myc gene we hypothesized might require BRD4 as a cofactor or a drinking buddy.
RAZ: BRD4, they guessed, often got Myc into a lot of trouble. So Jay Bradner's idea was...
BRADNER: ...To circumvent the behaviors of the master cancer-causing gene, Myc.
RAZ: They needed a drug molecule specifically designed...
BRADNER: ...To bind to and inhibit BRD4.
RAZ: A molecule like that could basically make cancer cells forget they were cancer.
(SOUNDBITE OF TED TALK)
BRADNER: And so we started to work on this problem. We developed libraries of compounds and eventually arrived at a molecule developed at my lab at Dana-Farber Cancer Institute called JQ1, which we affectionately named for Jun Qi, the chemist that made this molecule. Now, not being a drug company, we could do certain things. We had certain flexibilities that our respective pharmaceutical industry does not have. We just started mailing it to our friends.
BRADNER: I have a small lab. We thought we'd just send it to people and see how the molecule behaves. And we sent it to Oxford, England, where a group of talented crystallographers provided this picture, which helped us understand exactly how this molecule is so potent for this protein target. It's what we call a perfect fit of shape complementarity or hand-in-glove. Now, this is a very rare cancer, this BRD4-addicted cancer. And as we treated these cells with this molecule, we observed something really striking. The cancer cells - small, round and rapidly dividing - grew these arms and extensions. They were changing shape. In effect, the cancer cell was forgetting it was cancer and becoming a normal cell.
RAZ: So what Jay and his team did next was to turn this molecule into a drug. And they began testing it on a group of mice.
BRADNER: About 14 mice.
RAZ: Mice with cancerous tumors.
BRADNER: Seven mice would receive the drug and seven would not. Over the next 14 days, we observed something very striking. All of the mice that received the drug were thriving, and the tumors were no longer even palpable.
BRADNER: The mice that did not receive the drug, unfortunately, had progressed disease and did not survive.
(SOUNDBITE OF TED TALK)
BRADNER: So we started to wonder - what would a drug company do at this point? Well, they probably would keep this a secret until they turned a prototype drug into an active pharmaceutical substance. And so we did just the opposite. We published a paper that described this finding at the earliest prototype stage. We gave the world the chemical identity of this molecule, typically a secret in our discipline. We told people exactly how to make it. We gave them our email address suggesting that if they write us, we'll send them free molecule.
BRADNER: We basically tried to create the most competitive environment for our lab as possible. And this was, unfortunately, successful because now we have shared this molecule, just since December of last year, with 40 laboratories in the United States and 30 more in Europe.
RAZ: And by sharing this molecule far and wide, Jay Bradner gave scientists all over the world a chance to invent drugs based on his original JQ1 molecule. And already, he says, six other molecules have reached human clinical trials.
BRADNER: One of these molecules that looks just like JQ1 and acts just like JQ1 has shown remarkable activity in patients with advanced blood cancers. At least one patient had a complete response to this medication, meaning that where 100 percent of their bone marrow was occupied by leukemia cells, after about 90 days of therapy, there was no evidence of leukemia at all.
RAZ: That's incredible.
BRADNER: It's amazing.
RAZ: Do we - I mean, we often hear, like, oh, we're at the brink of this or that, but, like, are we - like, do you think we're at an inflection point, like, we are at the brink of something really big changing in cancer treatment?
BRADNER: I do believe that we're at an inflection point. I think, again, about the software industry, where source code is freely available on GitHub. But one of the best applications of source code are for computer scientists to bring it back to their garage, to innovate around it, to do something that changes the way that we access the Internet on our telephone or wake up in the morning to your favorite song. But I go to bed at night, I'm very comfortable that there's $1 billion out there for someone who cures cancer because open-source drug discovery will bring many people to this historic challenge.
RAZ: Jay Bradner works at the Dana-Farber Cancer Institute and teaches at Harvard Medical School. You can get your hands on his molecules at bradnerlab.com.
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