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Base Pairs Episode 14.5: Medicine and mad scientists

It’s important to know that a drug works, but knowing how it works can be just as crucial. CSHL Fellow Jason Sheltzer discovered that the hypothesis explaining the action of a new cancer drug was incorrect, indicating that its beneficial effects had to be due to other factors. Hear more from him following up on his discussion in Base Pairs episode 14, “The cancer answer that wasn’t.” Also, in a new pop culture segment, we talk about movie “mad scientists” and how they contribute to misconceptions about the way real science is done.

Brian: Hey everybody. My name is Brian.
Andrea: And I’m Andrea.
Brian: And this is a Base Pairs chat episode.
So for those of you who don’t know we follow up every full episode, kind of our story telling episodes, with what we call a chat episode. So this is the content that we leave on the cutting room floor or interviews that we had wanted to discuss but weren’t able to include in the podcast and then Andrea and I kind of just talk it out.
Andrea: But today we have another person joining us, someone else from our team at Cold Spring Harbor Laboratory, who is our kind of resident pop culture aficionado. Her name is Sara Roncero-Menendez and she’ll be joining us a little later in the show, so look forward to that.
Brian: It’s going to be fun. But first let’s start into what we normally do.
So Andrea, I know in our last episode, which we called The Cancer Answer That Wasn’t, you talked to Jason Sheltzer.
Andrea: Yes. Jason is a CSHL fellow who studies cancer and he and his team kind of stumbled upon this really surprising result, which was that this cancer gene and supposed cancer drug target called MELK, that’s M-E-L-K-
Brian: Right. Not milk, the beverage. Want to make that pretty clear starting out here.
Andrea: No. MELK the cancer gene, or so they thought, because it wasn’t actually a cancer drug target at all. And that was very surprising to them because there was a cancer drug in clinical trials that they thought was targeting MELK. And so that kind of lead us to talking about, how common is this? When researchers know that a drug works, how much do they really know about how it works? And so I’m going to play a little clip about that.
Jason: It’s killing cancer cells, we know that, but the reason that people thought it was killing cancer cells must be totally wrong. And so we think that this drug, which is in clinical trials, it’s effective at killing cancer cells, we can see that very well in our own hands, it just has to have some different mechanism, which we and, to our knowledge no one else, have discovered yet.
Andrea: Right. It’s definitely important to make that point because a lot of people would see drug target invalidated and think, “Oh my gosh, you’re giving this to cancer patients and wasting their time.” But that is not exactly the conclusion to draw from this work.
Jason: There are a lot of cancer drugs out there that have been studied for 20, 30, 40 years and we still have a very incomplete understanding of how they work in the cell. We know that they kill cancer cells and that they’re effective in patients and so there are a lot of drugs that are effective that we have an incomplete understanding of.
Andrea: Right. And that’s not only true of cancer that’s true of other drugs.
Jason: Sure. Psychiatric drugs time a million.
Andrea: Oh yes.
Brian: Times a million. I’m really glad he brought that up because that reminded me immediately of one of our previous episodes. It’s actually one of my favorite episodes, which was episode seven. It was the season finale of our first season, in which we talked about psychiatric drug discovery. And in that episode we talked about kind of the craziest surprising fact that a lot of the drugs that we use today we’ve been using for 20, 40 years and we still don’t fully understand why they work. We just know that they do.
Andrea: Yeah, and I mean, how would we when scientists are so at the beginning of understanding how the brain works, just in general? When you think about it, it’s just totally unrealistic that scientists would not only have cured a disease with this drug but then they also know exactly how it works.
Brian: So it’s not like I come up with an idea, it’s a solution to a problem, and I fully understand every little bit of how I reached that solution and why it works.
Sara: That reminds me of something.
Brian: Welcome Sara. As we mentioned at the top of the episode, this is Sara Roncero-Menendez, a member of our little digital den down at Cold Spring Harbor Laboratory.
Sara: The discussion you guys were having about MELK and not having everything figured out reminds me of a story.
Andrea: Okay, what’s your story?
Brian: Okay, shoot.
Sara: So have you guys ever heard of the ancient Greek mathematician Archimedes.
Brian: It’s ringing a bell, a very tiny bell.
Andrea: Refresh our memory.
Sara: Well, there’s lots of reasons to remember the name but the story I want to tell you guys is about Archimedes and the word Eureka. Now, once upon a time, Archimedes was charged by King Hiero II to figure out a way to detect a fraudulent crown, or in some versions it’s something about a boat not sinking with all the silver on it. The legend varies. And you know how you always get your best ideas in the shower? Well, the ancient Greeks got their best ideas at the public bath. So Archimedes goes to get a good steam, he sits down in the bathtub, realizes that his volume actually creates water displacement and, so excited, he shouts …
Andrea: “Eureka!”
Sara: Exactly. And he’s so jazzed about this idea that he runs out of the public bath naked.
But ever since then, we’ve associated the word Eureka with scientific discovery that happens in an instant. It’s an idea we carry over even to other scientists.
Andrea: Oh yeah, definitely. I mean, the whole Ben Franklin with his key on a kite and figuring out electricity all in one nice neat story.
Brian: Right, or another one where it’s bodily harm triggers genius was the apple falling from the tree, knocking on the head of Isaac Newton.
Sara: Right. And even Mendeleev, the guy who created the periodic table, was said to have thought of it in a dream. But it’s not even just about Eureka in these science legends, but in science fictions too.
Brian: So what do you mean, science fictions?
Sara: So even in movies that we all come to know and love, this Eureka myth persists and is perpetuated over and over again. This has been around since the early days of cinema. I want to introduce you guys to a beloved classic, the 1931 Universal Pictures Frankenstein, starring Boris Karloff.
Frankenstein: Look, it’s moving. It’s alive. It’s alive! It’s alive, it’s moving. It’s alive, it’s alive, it’s alive, it’s alive!
Andrea: Very spooky and dramatic, for sure.
Sara: Right. But we can definitely see that there are some problems here with Victor Frankenstein’s method.
Andrea: Oh yeah. I mean, what did he even really just do?
Sara: Well, for those of you who haven’t seen the movie, he just put a body on top of a slab, pumped it full of thousands of volts of electricity and then watched it’s hand twitch and declared that it was alive.
Brian: That’s a heck of a conclusion to jump to.
Sara: Right. So it’s not like we see Victor Frankenstein running any tests or running a slew of monster models, but rather he becomes horrified by it and lets Frankenstein’s monster destroy a village.
Andrea: I’m very glad that that is not how science is done.
Brian: But that is a very classic mad scientist, right? I’m sure modern Hollywood kind of takes it a little bit easier on scientists.
Sara: Oh, Brian. Well, unfortunately, I am here to ruin some sci-fi classics for you.
Brian: Oh no.
Sara: I’m sure you guys have seen Back to the Future?
Andrea: I wouldn’t be so sure about that, but-
Brian: What?
Andrea: -but this is why we have Sara on the show, to tell me about pop culture.
Sara: Well Andrea, let me get you up to speed.
So Back to the Future is about this total loser named Marty McFly, who’s best friends with a mad scientist named Doc Brown. Now Doc Brown has a dream and he wants to build himself a time machine, which he does, out of a DeLorean.
Doc Brown: What did I tell you? 88 mph! The temporal displacement occurred exactly 1:20 AM and zero seconds.
Marty McFly: Jesus Christ. Jesus Christ Doc, you disintegrated Einstein.
Doc Brown: Calm down Marty, I didn’t disintegrate anything. The molecular structure of both Einstein and the car are completely intact.
Marty McFly: Then where the hell are they?
Doc Brown: The appropriate question is, when the hell are they?
Brian: So for those of you who can’t see the clip, we’ve got this 30-year-old car that you’ll never see driving around today, directed right at this little boy and this old crazy man and there’s a dog driving it. Am I getting this right Sara?
Sara: That’s actually a pretty accurate summary. So as you can see, there are definitely some problems with Doc Brown’s method. The first of it being that he put a dog in a car on his very first test run of this time machine.
Andrea: How is the dog going to report back on what happened even?
Sara: And that’s if the dog comes back at all because Doc Brown doesn’t know that 88 mph is the magic number he needs to achieve time travel.
Brian: Right. Marty here thinks that Einstein, the dog, got disintegrated. And Doc Brown’s just assuming that’s not the case?
Sara: Essentially. He’s so confident that he basically even knows when to tell Marty to move for when the DeLorean comes rushing back onto the scene.
Andrea: Oh my goodness. You really can’t be that confident about your first experiment when you’re doing real science. I mean, first of all, you have to open to being surprised, like when Jason realized that this cancer drug target was not what it was thought to be. You ought to be open to that and if our mad scientist here was open to that, he would have been putting himself in mortal danger.
Brian: Okay, but right now, Sara, we still have two mad scientists. What about Hollywood portrayal of a real scientist, somebody who is-
Andrea: Legit.
Brian: Legit. All right.
Sara: Well, have you guys ever heard of a little movie called Jurassic Park?
Andrea: I have heard of it. Maybe not seen it.
Brian: You’re killing me Andrea. I’ve seen it.
Sara: Well, for those of you who haven’t, just in case, basically the film is about these scientists who find a preserved mosquito that has dinosaur DNA and they use that to make more dinosaurs.
Brian: So far, so good.
Sara: Right. And they even have a fail safe. They make all the dinosaurs female so they can’t reproduce.
Henry Wu: This is really not that difficult. All vertebrate embryos are inherently female anyway, they just require an extra hormone given at the right developmental stage to make them male. We simply deny them that.
Ellie Sattler: Deny them that?
Ian Malcolm: John, the kind of control you’re attempting, it’s not possible. Listen, if there’s one thing the history of evolution has taught us, it’s that life will not be contained. Life breaks free. It expands to new territories and crashes through barriers painfully, maybe even dangerously, but … well, there it is.
John Hammond: There it is.
Henry Wu: You’re implying that a group composed entirely of females will breed?
Ian Malcolm: No, I’m simply saying that life finds a way.
Andrea: I definitely like the sentiment of life finds a way. I’m not as confident as the scientist is that it’s going to go the way he planned.
Sara: Right. They don’t wait a couple of life cycles to see how these dinosaurs are going to work and interact. They don’t check to see if they are able to reproduce due to the amphibian DNA that they used to fix the dinosaurs. They sort of just hope that this project is ready to go public in a year or less.
Andrea: That’s not even enough time to get a drug ready for FDA approval, let alone to unleash dinosaurs on the entire planet.
Brian: But of course, this movie almost seems like a good thing in that it’s portraying a lesson for scientists, where it says, “Hey, if you want to do good science, you have to rigorously check what you’re doing. Otherwise, you get eaten by dinosaurs.”
Andrea: Right. You might think that you know how it all works but you really need to test every little aspect, especially when you might be putting people in danger.
Sara: That’s probably not how most audiences saw it, but maybe they should have.
So the long and short of it ends up being that narratives really love this Eureka moment, and it often overlooks the months and years of hard work and testing and laboratory work that’s necessary to really come up with these real rigorous results, not just quick answers.
Brian: So thanks Sara, for coming in and talking to us about this.
For everybody else out there, we talk to Sara during the production of every podcast episode. She’s kind of always there in the background, giving suggestions and always tying everything into pop culture, so I’m really glad we were able to have her on the show now and share that with you guys. We’re going to be doing this every chat episode. Sara will be her to drop her pop culture knowledge bomb, so look forward to it. Please stay tuned.
Andrea: And we’ll be back in May with another full episode for you all, so stay tuned for that too.
Brian: Thanks a lot guys.
Andrea: We’re coming to you from Cold Spring Harbor Laboratory, a private not-for-profit institution at the forefront of molecular biology and genetics.
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Andrea: I’m Andrea …
Brian: And I’m Brian …
Sara: And I’m Sara.
Andrea: And this is Base Pairs. More science stories soon.