Â鶹´«Ã½ÉçÇø

Transcript

Nick Fiore: You’re now At the Lab with Â鶹´«Ã½ÉçÇø. My name is Nick Fiore.

Nick Wurm: I’m Nick Wurm.

Sam Diamond: My name is Sam Diamond.

Marc Persad: I’m Marc Persad.

Sue Weil-Kazzaz: My name is Sue Weil-Kazzaz.

Sara Giarnieri: I’m Sara Giarnieri.

NF: And this week At the Lab we’re running back all of our episodes from Season 1 that focus on Â鶹´«Ã½ÉçÇø’s cutting-edge cancer research.

{Music}

NF: Scientists at Cold Spring Harbor approach cancer from a number of exciting angles: immunology, chemistry, and CRISPR gene editing to name just a few. You’ll hear about each of these and more. But first, let’s kick things off with some good old-fashioned detective work.

{A police siren rings.}

Nick Wurm: In a lot of ways, your immune system is like your body’s personal police force. At the first warning sign of cancer, it’s supposed to dispatch T cells to protect you. You can think of these immune cells as your body’s cancer cops.

NW: LaboratoryAssistant Professor Semir Beyaz takes this analogy a step further.

Semir Beyaz: You can consider [the] lymph node as your local police station. It collects all the information from the neighboring organs and then teaches the immune system that there is something wrong.

NW: With so many cops around, you’d think the lymph node would be the last place cancer would want to go. So then why is it metastatic breast cancer’s first stop?

NW: To crack the case, Beyaz did what any good detective does. He put himself in the mind of a criminal.

SB: Imagine you are like a mob in a neighborhood, and then you go to invade another neighborhood. You are first going to go to the local police station, probably corrupting the officers there, and then going to the next neighborhood. And then you are taking over the whole city.

NW: How does metastatic breast cancer ‘corrupt’ the body’s police force? Beyaz discovered that in mice, this kind of cancer dons the uniform of an immune system molecule called MHC-II.

NW: The disguise is so convincing that when other officers try to report cancer’s inside man, the immune system treats it like a false alarm.

SB: In the breast, we found that when you have MHC-II, it’s actually suppressing the immune response, protecting cancer cells.

NW: In other words, cancer rises through the immune system’s ranks and starts calling the shots.

{Film noir music}

Old-Timey Gangster: Now listen here, copper.

NW: How do you clean up such systemic corruption? According to Beyaz, you have to nip it in the bud. His team found that if they turned off MHC-II production in the breast, the unmasked cancer cells couldn’t set up shop in the lymph node. That allowed the immune system to arrest cancer’s growth.

{A jail cell door closes.}

NW: You can’t end organized crime overnight. Likewise, there’s a long road ahead before this research can lead to new breast cancer treatments. But Beyaz and his team have found important clues. And the investigation continues At the Lab.

{Music}

{Rainforest sounds}

SD: Deep in the jungles of Malaysia, there’s a plant called Tabernaemontana corymbosa. Don’t be surprised if you’ve never heard of it. The plant is so rare it’s on some endangered species lists.

SD: But that’s not the only thing that makes it remarkable. It also produces a chemical called (–)-jerantinine A. You might not have heard of this either. But don’t be surprised if you do in the future. That’s because (–)-jerantinine A has been found to have anticancer properties. To find out more, we met with LaboratoryProfessor John Moses.

John Moses: Nature provided the blueprint. Nature provides many lifesaving molecules, but it doesn’t always provide them in large quantities. But we can now access (–)-jerantinine A from a commercially viable source, which is very inexpensive, and make this precious material.

SD: Moses is a chemist who specializes in something called click chemistry. This set of reactions enables chemists to ‘click’ together two or more molecules, forming new compounds quickly and reliably. The technique was pioneered by Moses’ mentor, Nobel laureate K. Barry Sharpless. And it’s click chemistry that empowered Moses to synthesize (–)-jerantinine A at the lab.

SD: From there, he worked with Cold Spring Harbor biologists to test the synthetic on different diseases, including pancreatic cancer and breast cancer.

JM: From my lab at Cold Spring Harbor, this is the first proper chemical biology study—chemistry for biology. They brought the chemist in to help cross the bridge between chemistry and biology and eventually develop therapeutics and investigate biological pathways. This shows you exactly the power. It shows you the strength of collaboration and communication internally. The fact that I’m there on the ground and we’re swapping ideas—it really is an effective way to make advances.

SD: More work will need to be done before (–)-jerantinine A is ready for clinical trials. However, initial preclinical results look promising. And beyond that, Moses’ work here demonstrates the value of using click chemistry for drug discovery.

SD: Thanks to his team’s efforts, we don’t have to travel across the world or mess with endangered species to get our hands on this rare chemical. Instead, we can make it safely and sustainably right here … At the Lab.

{Music}

Marc Persad: Diseases aren’t cured overnight. It takes years, often decades, for biomedical breakthroughs to materialize. But every now and again there’s a turning point—a moment when years of hard work start to pay off. LaboratoryProfessor Christopher Vakoc may be rounding such a corner.

Christopher Vakoc: We can’t see the future. But every successful drug has its origin story. And studies like this are the soil out of which new drugs are born. It’s a fundamental discovery. It’s learning one of the most important molecules in a disease that kids are dying of.

MP: The disease he’s talking about is rhabdomyosarcoma, or RMS, a form of cancer that mostly occurs in children and teenagers. The molecule is a protein called NF-Y. We’ll return to that shortly. But first, let’s talk about RMS and how the Vakoc lab came to study it.

CV: The name rhabdomyosarcoma refers to the similarity of the tumor to muscle stem cells. There’s not a lot of research dollars directed at this cancer. And that’s a big part of how we got into this. There are families that have lost children or spouses to this disease on Long Island. And they all came together and funded us to try to find a new therapeutic strategy for this disease.

MP: About 10 years ago, the Vakoc lab had a radical idea. If RMS cells are essentially muscle stem cells that never transformed into muscles, maybe they could stop the cancer’s growth by completing the cells’ transformation. It took years to develop the genetic screening tests needed to pinpoint the molecular machinery that would cause RMS cells to change. But finally, NF-Y emerged. Vakoc’s team used CRISPR to target NF-Y inside the RMS cells. And that’s when it happened.

CV: These tumor cells, which can’t contract, now become a muscle cell that has the whole contraction machine. It’s like a fork in the road. The cell has gone down one path, but now it can’t go back to its multiplying state because all of its energy and resources are devoted to contraction.

MP: A fork in the road for RMS cells and just maybe a turning point for RMS research, and it all happened here, At the Lab.

{Music}

Sue Weil-Kazzaz: Anyone who’s ever gone through cancer diagnosis and treatment can attest to how excruciatingly stressful this experience can be.

SWK: Words fail to describe it.

SWK: New research from Laboratoryshows how metastatic cancer can feed off of this stress. The discovery comes from LaboratoryAdjunct Professor Mikala Egeblad and her former postdoc Xue-Yan He. They worked in collaboration with Professors Linda Van Aelst, Christopher Vakoc, and David Spector.

SWK: At the center of their discovery are structures called NETs that are known to promote cancer’s spread. Here’s Professor Egeblad to explain:

Mikala Egeblad: It’s not news that NETs promote metastasis. But it is news that stress increases metastasis. And it can do it from cancer cells that already have spread but are sitting and not really growing. Or it can do it by making the new tissue more susceptible to have a cancer cell come and succeed in forming metastasis.

SWK: NET stands for neutrophil extracellular trap. You can think of NETs as sticky webs made up of immune cells called neutrophils. Normally, neutrophils help us fight off diseases. But Egeblad’s team found that in mice with cancer, the stress hormone glucocorticoid drastically alters this dynamic.

ME: The glucocorticoid is acting on the neutrophils to make them form these NETs. And that is a key factor in causing metastasis in stressed animals.

SWK: The finding could point the way toward future treatments that help stop cancer from metastasizing. But more immediately speaking, it also says something about stress’ role in cancer treatment and prevention—and in human health in general. Here’s Egeblad again, with the final word.

ME: The whole thing starts in the brain with the release of glucocorticoids. So, if you can change the way that you sense stress—if you can make a stressful event less stressful so there’s less release of these stress hormones—that’s yet another approach. And that probably fits very well with some of the epidemiological studies that show that group therapy or a social network, which helps you feel less stressed and more supported, has been shown to increase survival. And that may be potentially why.

{Music}

{A car drives along.}

Sara Giarnieri: If the cells in your body are like cars on the road, then the P53 protein would be akin to the car’s brakes.

{Suddenly, the car comes screeching to a halt.}

SG: It helps to slow cell duplication, keeping the cells from dividing over and over, or driving out of control.

SG: Mutations in the gene that produces P53 are the most common genetic cause of cancer. However, in most cases of glioblastoma, P53 looks just fine. So what gives? How did the brakes get cut in this deadly brain cancer? LaboratoryProfessor Alea Mills may have arrived at an answer. To get there, she had to look beyond genetics.

Alea Mills: It’s not like a genetic mutation affects if a patient lives or dies here. We wanted to search for an Achilles heel of vulnerability—something that’s vital to that tumor being so aggressive and so lethal for these patients. So, if they don’t have genetic mutations, maybe they have epigenetic mutations—not affecting the DNA sequence itself, but something above and beyond the genome.

SG: The Mills lab utilized tools made by LaboratoryProfessor Christopher Vakoc’s team. You might remember from a recent episode how Vakoc’s lab developed a method using CRISPR to screen for proteins that could be implicated in different kinds of cancer. Narrowing their search to the epigenetic machinery that packages our genome, the Mills lab went looking for whatever was cutting the brakes on P53.

AM: We found a new target, and that’s BRD8. Even though P53 is not mutated like it is in lots of other solid tumors, BRD8 is basically annihilating it. So it’s shutting down these brakes, and that’s how it’s maintaining the glioblastoma cells. But you can fix it all.

{Machines toil away in an autobody repair shop.}

AM: We found we can target BRD8 and get reestablished P53. So we’re unleashing P53’s tumor suppressive activity by targeting BRD8.

SG: In other words, it’s like they reconnected the brakes. And that made the brain cancer stop growing in mice and lab-grown tumor cells.

SG: The journey from potential drug discovery to drug development often has many twists and turns. But you can’t get far without a working vehicle. And Mills’ discovery may provide just that. Its starting location: right here, At the Lab.

{Music}

NF: Thanks again for listening. If you like what you heard, be sure to subscribe wherever you get your podcasts and tune in next week as we rewind this season’s neuroscience stories. You can also find us online at Â鶹´«Ã½ÉçÇø.edu. For Â鶹´«Ã½ÉçÇø, I’m Nick Fiore, and I’ll see you next time At the Lab.