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Cold Spring Harbor Laboratory’s award-winning podcast, Base Pairs, tells stories that convey the power of genetic information—past and present.

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Base Pairs Season 3

Latest episode

Episode 17: Genomes, justice, and the journey here

Mail-order genetic testing—more accurately known as genotyping—has become a growing trend, and these companies can tell a lot from your genetic code. One of the more surprising uses of this data is finding criminals. These investigations make you wonder: how public or private is your genetic data? What could someone tell about you if they had access to your genome?

AA: Hey all, I’m Andrea

BS: And I’m Brian

AA: And this, as you know… is Base Pairs.

BS: But maybe you don’t know about Base Pairs! Maybe you just clicked on this podcast to give us a try, and that’s cool too, because we’re not about to throw you into unfamiliar territory.

AA: Well, we ARE going to talk about a huge trend in genetics in a minute. But we’re going to start with something LOTS of people have been talking about throughout this summer of 2018.

BS: That would be the unmasking – so to speak – of the Golden State killer. The cracking of a decades-old cold case is a subject of wonderment in itself, and we’ll get into the details of that case in a second, but HOW this case was solved… how a notorious serial killer was finally brought to justice… THAT’s very relevant to what we’re going to talk about in this episode… which is about personal genetic testing, and what having that data actually means.

AA: but first, a timeline. And this gets unsettling, so listener discretion is advised.

[archive clip 1978] It’s so warm in Concord tonight that people have their windows and doors open, but Sacramento police are saying “lock up tight.” Sacramento’s east area rapist may still be in town. He raped a 29-year-old housewife near the Agnosio Valley shopping center around 5:30 this morning. Her Husband was tied up nearby and had to listen… [fade]

BS: That’s a clip from 1978 out of ABC 7’s broadcast archives… a clip that describes one of nearly 50 rapes committed between 1976 and 1986. In addition to these abhorrent crimes, Sacramento and the east Bay Area were terrorized by a string of burglaries and murders that could all be tied back to the same assailant – the East Area Rapist – later to be known as the Golden State Killer.

[archive clip 1979] there is a real sense of frustration among women tonight… despite all their locked doors and bolted windows, they are all still very much afraid tonight of the East Area Rapist, and that makes them all in a sense, his victims. [fade]

AA: No one knows exactly why the crimes stopped in 1986, but for the three decades that followed, little more was discovered about the notorious man that had terrorized California.

BS: It was only this year, on April 25, 2018, that an arrest was made, pinning the crimes on 72-year-old Joseph James DeAngelo. He was fired from the Exeter, California police department in 1976, just before the crimes began, and has lived in the Sacramento area ever since. Amazingly, the purportedly damning case against DeAngelo is rooted not in witness testimony, but instead in the DNA from a 37-year-old rape kit.

CR: I didn’t know about it right away. …The first [news report] that came out didn’t mention us at all, and I wondered if we were involved in that. … Then I forgot about it. The next day, they had… another meeting with the press, and in that one, they announced GEDmatch was the big reason why they were able to … find this guy

BS: That’s Curtis Rogers, the co-founder of the open source database called GEDmatch that police used to track down the Golden State Killer through genome matching. When I spoke with him, it was also about to be his birthday.

CR: tomorrow is my 80th birthday. That’s frightening … It just keeps happening! The years keep coming! Anyway, I started GEDmatch– Well, I’ve been in touch with genealogy ever since I was a teenager lightly, but as I got older, I got more involved in it.

BS: Curt had originally been part of the Rogers Surveying Project, for Family Tree DNA – a sort of genealogical scavenger hunt for ancestry that all Rogers family members could access. According to Curt, ancestry is often how a lot of citizens become interested in genealogy.

CR: everyone started writing emails back and forth. “Do you have McGillicutty in your family tree?” “No, but do you have a McCarthy?” “No, but do you have …” Blah, blah, blah. Go on for hours and hours…and I met this guy by computer who is now my partner, John Olson, and… I asked him if we could do a computer comparison of family trees so we wouldn’t have to do all this back and forth, and he came up with it. He came up with a great algorithm, and it was just too much for my little Rogers Project, so based on that, we started GEDmatch…There’s now the criminal thing that we didn’t anticipate at all, but certainly law enforcement’s trying to use it for that.“

AA: It’s incredible that some site dedicated to comparing family trees could be used by the police to track down a killer! How exactly does GEDmatch work? What is it?

BS: Well, I’m sure you know about direct to consumer genome sequencing. Spit in a tube. Send it off. Get a whole bunch of colorful graphs back. That sort of thing.

AA: Sure! You’re describing services like 23andMe, MyHeritageDNA, or AncestryDotCom. A few services have even cropped up exclusively for dog pedigrees!

BS: Right, but when these companies send back their results, they’re working within a limited pool of data. That’s where GEDmatch comes in.

CR: we are not in competition with the testing companies. We are helping them. We are supplementing them.

BS: GEDmatch basically is a hub where anyone can upload their genetic data and cross-compare with results from other services. They even provide a LOT of different tools for amateur and professional genealogists alike. And since Curt and John basically started their site as hobbyists for hobbyists, they’ve left the site entirely open-source. In this way, the family trees its users compile – which are lists of potential relatives based upon similarities in genetic data – are accessible to anyone with a login.

AA: Even law enforcement.

BS: Exactly. While detectives behind the Golden State case have not revealed their exact process, what’s understood is that they uploaded DNA data from that 37 year old rape kit. They located a close match in the GEDmatch database – someone like a first or second cousin – and then they contacted that individual to find out if they had any relatives around a target age who lived in the Sacramento Area between 1976 and 1986.

AA: Ah. And since these genetic results are public domain, investigators didn’t even have to file a warrant. That’s… pretty game-changing.

BS: It’s been estimated that since the Golden State Killer’s case, GEDmatch has been used by law enforcement in eight other criminal cases – ranging from identifying unidentified victims to zeroing in on murderers.

CR: I was really concerned for a long time that, “Is this invasion of privacy? Is it being used for something it shouldn’t?” I came to the conclusion that we really didn’t have a choice… We could put a policy up there, “Hey, we’re only requiring that we get a warrant from the courts before we give up any information.” So what? We would never know. We would never be able to enforce it really. What we did decide is that we really have to educate our users, let them know, give them as much warning as we can of some of the uses and especially of law enforcement.

AA: Well, I can definitely get behind the idea of educating these genome-curious consumers. So let’s talk about what exactly this genetic information they’re uploading CAN actually be used for. And to do that, we need to talk about what the data we’re discussing really is.

BS: What it really is? What do you mean? It’s information in your genetic code—the sequence of letters in your DNA.

AA: You do get information about your genetic code, but there’s an important distinction here: most direct-to-consumer tests don’t exactly sequence your genome. Sequencing means going along the DNA and reading out every letter along the way—either all 3 billion of them or some subset—and that’s still relatively expensive.

BS: If they don’t sequence the whole genome, then how are the direct-to-consumer testing companies figuring out what’s in people’s DNA?

AA: For the most part, these consumer companies use a faster, more economical approach called genotyping.

DM: Genotyping looks at some hundreds of thousands of spots in the genome…

AA: That’s CSHL Professor Dick McCombie.

DM: …and you can infer a lot from that, because DNA, parts of the chromosome tend to go in chunks.

BS: So, genotyping involves looking at particular spots in the genome that you’ve decided you’re interested in and then trying to fill in the blanks based on genome sequences that researchers already have from other people.

AA: Yeah, that’s part of how these testing companies like 23andMe are able to make their tests so affordable.

BS: They don’t have to sequence a person’s entire genome, because they can look at existing human genome sequences and figure out some of the most important or interesting spots to check.

AA: Dick didn’t have that luxury, though, when he was getting his career started back in the 1980s.

AA [in clip]: Where was genome sequencing technology at when you first started in this field?

DM: I want to say it was a hope, but I’m not even sure it was that.

BS: So, this was before the Human Genome Project had even started—the historic effort to put together the first full human genome sequence.

AA: It was. Dick is one of the sequencing pioneers who was involved in the Human Genome Project from its early days. He was also part of some of the first major discussions about publicly releasing human genetic data.

DM: I was at the original Bermuda meetings back in the mid 90s for open release of data. There were a series of meetings in the mid 90s, I think three of them, in Bermuda, organized by NIH and the Wellcome Trust in England, where 30 people or so got together at each one — and worked out the data release protocols for the Human Genome Project, which were that when we were actually working on the human reference genome, we had scripts on the computers that would go through our directories every Friday and take everything more than a certain size —and automatically submit it to the public repository for public access.

BS: Wow, they not only made all of the genetic data public, but they did it in real time. What made them decide to do that?

AA: One important factor is that the Human Genome Project used genetic data from about a dozen different people—who had all consented to this use, of course—to create a sort of mosaic that could serve as what scientists call a “reference genome.” It essentially serves as a model or template for sequencing and analyzing the genomes of other individuals of the same species.

BS: So, it’s not like they were putting out any one person’s entire genome. They were putting together a more general representation of what a human genome looks like.

AA: Right, and then the really big question was, would each lab get patents on the genes they sequenced and sell them for profit, or would they make all of the data publicly available to advance scientific research?

BS: That is really important.

AA: Access to this first human genome sequence has helped countless scientists conduct human genome studies in their own labs. And yet, when Dick was telling me about how he was a part of these huge discussions about the open release of data, he also told me something that surprised me.

DM: I could say personally, when we were first doing the whole genome sequencing with the new instruments, and the company was giving us free reagents and we were running tests and stuff, I did think about putting some of my own DNA on there and sequencing myself. I decided not to for a variety of reasons.

BS: I’m surprised that someone who’s devoted his career to this genome sequencing hasn’t looked at his own genome.

AA: He’s holding back partially because he knows himself.

DM: I know I worry. There’s 3 billion bases for me to look at and say, “I don’t like that,” but not know what it means.

AA: But he’s also holding off in part because he doesn’t know how other people might use his data, if they were to get access to it.

DM: I’m a big believer in public data access in general. However — I do worry about data privacy a lot. — The example of catching a murderer is a great example, and everyone says, “It’s great they caught a murderer,” including me, but I worry that there’s the possibility of using data like that for inappropriate purposes. By that, I mean totally publicly available data.

BS: Right. Inappropriate purposes like discrimination. Say, a potential employer takes a look at your genome, sees that you have a mutation that causes some terrible disease that will force you to retire early, and doesn’t hire you as a result.

AA: That’s one big concern, and there’s been some progress in protecting against this type of discrimination. There’s legislation known as GINA—the Genetic Information Nondiscrimination Act—that was signed into law in the United States in 2008 and makes it illegal for employers to use genetic information in the way you described. It also prevents health insurance companies from using information from your genome to make decisions about your eligibility for insurance, what you pay, or what you’ll be covered for.

BS: But a lot has changed in the last 10 years. For one thing, I know that I wasn’t hearing about these direct-to-consumer genetic tests nearly as much back then.

AA: There’s still a lot of work to do to make sure that genetic information is used for good.

DM: I think despite the GINA legislation, which I think was a big step forward, the genetic privacy legislation that passed a few years ago, that doesn’t cover everything. — I don’t think it’s a solved issue. It’s one that is evolving hopefully at reasonably close to the same speed as the technology’s evolving, because technology is evolving very, very fast.

BS: This is a conversation that we all need to be having. Genotyping has already made it much easier for people to access a small fraction of their own genetic information, and look at how powerful that information has already proven to be. It allowed law enforcement to crack a cold case that’s over three decades old. I would imagine that as sequencing technology continues to become cheaper, it will be more common, maybe even routine, for people to have their whole genomes sequenced.

AA: I thought that too—that the only reason we aren’t already getting sequenced as a routine part of our healthcare must be that it’s too expensive. But Dick told me that’s not really the issue.

DM: I actually think the biggest hold up isn’t the cost of the sequencing, but the … being able to understand what the sequence means. For instance, radiology has dealt with this issue of, well, what if you do an X-ray for one thing and you see something else? They deal with that every day. Sequencing hasn’t. What if you sequence someone to find out if they have a mutation in this gene, but you find they have a mutation in this [other] gene, and you think it may be bad, but you don’t know what it means. That’s really a problem. I mean, I was actually really sick a few years ago and had multiple MRIs done, and MRIs cost more than a genome sequence I think.

AA: I looked it up, and Dick’s right. While prices vary, an MRI can cost more than a whole genome sequence.

BS: You’re kidding me. I would have never guessed that. But isn’t Dick working on ways to further improve sequencing methods? If the cost is no longer holding back medical use of genetic information, then why is he still working on that?

AA: The motivation behind improving sequencing technologies isn’t just cost. It’s also quality. Dick told me that a key method that researchers have long used to put together sequences tends to miss some really important stuff present in many genomes—and especially in cancer genomes. Sometimes, fairly large chunks of DNA move from one part of a chromosome to another part, or even a to different chromosome. These mutations are called structural variations.

BS: Cancer cells have really screwed up genomes, so it makes sense that they would have more of these big rearrangements.

AA: Moving entire sections of DNA around is problematic. Dick was looking into this with his colleagues, including CSHL Adjunct Associate Professor Michael Schatz—who is also an Associate Professor at Johns Hopkins University—anyway, Dick and Mike knew of a particular breast cancer cell line that had a lot of this rearranging going on.

DM: We picked it because we knew it was a messed-up breast cancer cell line, chromosome wise. It was really rearranged.

AA: They mapped this cancer’s genome using newer sequencing technology and recently published a paper that reveals about 20,000 never before seen structural variations in this breast cancer cell line alone.

BS: 20,000 new structural variations?! Ok, now I’m starting to see why there’s still a need for better sequencing technology. But still, if these are big chunks of the DNA, how are they getting missed?

AA: Before I learned about how DNA sequencing really works, I kind of assumed that it was a lot more straightforward than it actually is. I imagined a machine unwinding the double helix of DNA and reading out the ‘letters’ one by one until it reaches the end of that piece of DNA.

BS: That seems like the easiest way to do it.

AA: While that would be nice, it turns out to be hard to do. Instead, most sequencing machines so far have been able to read only short pieces of DNA at a time.

BS: I’ve heard genome researchers talk a lot about “long reads” and “short reads”—and I know they’re not referring to their summer book list. They’re talking about volumes of the genome.

AA: In the world of literature, a short read refers to something that’s generally quicker to get through, but it has kind of the opposite meaning in genome research. Once scientists get these short or long reads from the sequencing machine, they have to put them in the correct order.

BS: And with long reads they have fewer pieces to manage.

AA: Exactly. It’s just like a puzzle, really.

DM: A puzzle with four pieces versus a puzzle with 400 pieces.

AA: Researchers use software to compare the sequence of each piece to the reference genome—what we were talking about earlier—and then figure out where in the genome it came from. Everyone at least has little variations that make us unique, but the software can work around those. It’s really difficult to figure out where these bigger structural variations are coming from using short reads, however. And that’s partly because they often happen in DNA that’s really repetitive.

BS: Yeah, I’m not sure how many people know it, but our DNA is chock full of sequences of letters that appear several times in a row.

AA: About half of the human genome is repetitive sequences! So it’s problematic that short reads aren’t so good at mapping these areas.

DM: The short reads basically can’t be mapped back uniquely to repetitive regions because they’re all the same. They can’t tell if it’s this repeat on this chromosome, or this one on another chromosome. Whereas the long reads get the repeat, but they also get the flanking regions that are unique, and so you can unambiguously map them back to the genome.

BS: Since long reads are like big puzzle pieces instead of little ones, the software has more context to work with. It can see more of the full picture of the puzzle on that one piece, so it’s easier to figure out where it’s supposed to go—even if it’s like one of those really difficult puzzles where the image is something repetitive, like a big crowd of people at a sports game.

AA: There’s a catch, though.

DM: Unfortunately, a puzzle that’s got four pieces is a lot more expensive. The prices on those keep coming down, though. While it was 100,000 four or five years ago [AA: 100,000 dollars, that is] we’re still trying to figure out exactly what the price is, but it’s probably in the area of 10 to 15,000 now.

AA: Because of the expense, a lot of researchers haven’t yet adopted long read sequencing methods. But the breast cancer findings that Dick and his colleagues recently published really show the benefits of using long reads to sequence the genome.

DM: We want to do two things. One, see what we’re missing, and secondly — we’re trying to do combinations of technology to drive the cost down.

BS: So, this technology is a lot more expensive, but it gives you a higher quality genome sequence and isn’t as laborious to produce.

AA: Right now, Dick and other researchers are working to make it more affordable, and to provide the knowledge necessary to interpret the information within people’s genomes.

BS: And that makes me think we’re headed toward more people getting their whole genomes sequenced – like I said before – and more genetic information seems like it would spell more ethical issues – like the job and healthcare discrimination issues which have already come up with genotyping.

AA: I thought it might too, and I asked Dick about whether he thinks that we need to be even more protective over whole genome sequence information than genotyping data.

DM: I think the issues are the same for either. Both have a lot of information in them that should be handled in a way respectful of reasonable privacy concerns I think. I don’t think that whole genome drastically changes that in most cases.

AA [in clip]: Okay. That’s interesting. In terms of the ethical risks, we kind of, we’re there.

DM: Yeah, yeah. I think we are, yeah.

BS: That makes sense, actually. We need to protect people from having their genetic information used against them, period. If we are careful about that, having access to even more genetic information shouldn’t be an issue. And as sequencing technology continues to improve, there are undoubtedly more benefits to be gained on the medical side, like the discoveries that Dick’s team made in breast cancer.

AA: Plus, the more people who get sequenced and allow their data to be used for research, the better the chances are that researchers will be able to pinpoint which genetic variations contribute to which diseases—even very genetically complicated ones like psychiatric disorders.

DM: In theory, if you sequenced everyone in the world and you have a detailed phenotype of everyone, you could write some computer program and come back 10 years later and it would tell you what it all means. That’s kind of a glib answer, but in general, that’s true. If you could compare lots of, if you looked at — people with schizophrenia say, and say, “These are the regions of the genome that seem to be associated with schizophrenia.”

BS: More genetic information means more ways to learn about yourself and to help reveal new ways to keep everyone healthy. I asked Curtis, the gentleman from GEDmatch who we heard from earlier, about where he saw this personal genetic information thing going in the future.

CR: I suspect that, at some point, everyone is going to have their DNA done. It may be done at birth, and they will then have this to help them health-wise or whatever else purpose they want. There will be this whole genome that they will have. They will own it.

AA: Ownership is an important thing to emphasize. These days, a lot of people have kind of forgotten that their personal information, genetic or otherwise, is something that they own and that is valuable. Billions of people around the world have willingly given intimate personal details to companies like Facebook for free. What will they do with their personal genetic information?

BS: Right. This is just a start for one heck of a deep discussion. It’s going to be important to make sure that consumers understand how powerful their genetic information can be. So talk to your friends, family – really to measure what YOU want to do with this – and this will sound familiar – this “power of genetic information.”

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Episode 16.5: Fuels of the Fuels

Biofuels are the wave of the future, and a small plant called duckweed could be a significant part of that. Professor Rob Martienssen explains how genetic modification and advances in genome mapping technology factor in to the future of fuel. On our pop culture segment, we dive into some cinematic biofuels of the future, both hopeful and dystopian.

BS: Hey everyone, I’m Brian.

AA: I’m Andrea.

SRM: And I’m Sara.

BS: This is Base Pairs, this is one of our chat episodes where we talk about stuff from the previous episode and riff off it from there. So last episode, what was that about Andrea?

AA: Well last episode we talked about biofuel and a very exciting new potential source of biofuel that a plant scientist here named Rob Martienssen is working on. The crop that he wants to use for this biofuel is duckweed, which you’ve probably seen and thought of as just pond scum, it’s all over the place, it’s that tiny, tiny green plant that forms a mat over ponds and he has found a way to, as he puts it, “persuade” duckweed to make oil.

BS: Right, and Rob, if you listen to the episode, you’ll find out Rob has a very charming classical English accent, so he sounds very persuasive, at least to us Americans, every time he says something.

AA: Yeah, Rob can be pretty persuasive but he needs more than his charming accent to get duckweed to make oil. He had to do some genetic tricks to do that and the way that he and his team of researchers made that happen is they actually transferred a gene, a gene called WRINKLED1, from corn into duckweed.

BS: Okay, corn though, really? When I think of corn, I think of corn ethanol, kind of like what we talked about last episode with the different generations of biofuels but in that case, ethanol is not oil, it’s ethanol, it’s alcohol. How the heck is he turning it into oil then?

SRM: Well actually, I just typed it in on my phone and apparently corn oil is a thing. So it’s used as speed stock for biodiesel but it’s also in soaps, salves, paints, rust proofing stuff for metal surfaces, inks, textiles, nitroglycerine and even insecticides.

AA: There you go, yeah corn knows how to make oil and basically Rob and his team just borrowed corn’s method, or at least part of it, for making oil and stuck it into duckweed and it worked. It got duckweed to start making oil.

SRM: But wait, wouldn’t that then make it a GMO?

AA: It would. So since this is a gene coming from corn, pretty much under any definition of a GMO, this would qualify but I was talking to Rob and there is a potential for getting duckweed to make oil without going through this more GMO route, where you’re taking a gene from another organism and sticking it into a new organism. There could be a way of using this newer tool called CRISPR that does something called gene editing, where you’re not taking genetic material from some other species and moving it, but you’re just making a little cut in the DNA, or just making some other chain that essentially looks indistinguishable from what you would see arising naturally, and so-

BS: That’s CRISPR, that’s C-R-I-S-P-R, we’re not talking about potato chips here or anything?

AA: Right, no. So here’s Rob talking about that.

Rob Martienssen: It certainly would yes, there’s no question that it’s a GMO. There are some strategies that we could use perhaps with CRISPR that would make it less … I don’t know, it’s still a debate and I know that it’s been decided pretty much in some parts of the world that it’s … So in the United States, CRISPR is not regarded as GMO, whereas in Europe it almost certainly will be and in Australasia it is. So exactly what’ll happen to that in the future is very hard to say. I think it’s actually made people really think about what they mean by GMO and genetic modification of course is something that’s been practiced by breeders for thousands of years and actually results in changes in the DNA sequence which are indistinguishable from those that are generated by CRISPR.

What we mean by genetic modification is something that needs to be discussed a lot more, I think in a sort of public debate. In truth, I think really high impact climate changing biofuels are probably going to be produced in GMO plants and there’s not much we can do about that.

BS: So here what we’re talking about with the corn genes, this is a transgenic GMO and usually one of the big concerns with that was, “Oh no, what’s it going to do to me if I eat it?” This Frankenstein food.

AA: Right, what if you have an allergy not to what you think that you’re eating but to the gene that was spliced in.

BS: Right, but in this case we’re not eating it, it’s fuel. At least I don’t want you to eat it.

SRM: Well isn’t the other worry about GMO’s that they might get out and sort of infect the native population?

AA: Right, yeah, there’s this concern that if scientists are creating these GMOs to be stronger, better plants in whatever respect, if they get out are they going to out-compete everything around them and destroy ecosystems? That is certainly a concern that you might have about biofuel crops but in the case of duckweed, Rob is less concerned about that, though certainly looking into it for a number of reasons which he told me about.

Rob Martienssen: A big advantage of this sort of indoor growth thing is that it’s all contained and for example, the duckweed producing oil, even if it did escape, would have absolutely no way of competing with anything else because it’s very, very unique niche and one that can only be maintained by humans. Yeah, clearly this is going to be an issue for most biofuels. That is a question that is important to address and so for example, we have a grant from the department of energy now to do this work and part of that is very much … is what they call bio-containment and we have to think about this pretty hard. As I said, most of our engineered strains … the great thing about duckweed in the wild is that it out-competes everything so it’ll certainly out-compete anything that we manage to make in the laboratory.

AA: So Rob and his team were successful in getting duckweed to make oil but there was this unintended consequence of it slowing down the plant’s growth overall.

BS: Right, and we described that a little bit more in the full episode but based off what Rob just said, my impression is that it kind of winds up being a silver lining, at least right now, where these plants are dependent on the people who are making them, but the more we know about the genome, the more scientists could even intentionally do that, right? Where it’s making it so if the plant gets out it’s not going to cause harm because we know exactly what we’re adding to the environment?

AA: Yeah right, the more we know about how these genomes work, the better chance we have of getting these plants to do what we want them to do and not anything that we didn’t expect them to do. That’s a lot easier said than done of course, but it is getting actually significantly easier to the point that a post-doc in Rob’s lab was able to do a lot of the DNA sequencing of these duckweed genomes with a device that looks a lot like a USB stick. Sometimes he would pack it up at the end of the day and take it home to his apartment in Brooklyn.

You mentioned that Evan’s analyzer looked like a USB device somehow?

Rob Martienssen: Yes, exactly things have changed so much. Human genome projects, and I forget exactly how much it cost, but it was in the order of half a billion dollars and took the efforts of thousands of people and it was only 20 years ago. Now, a single person, in my case Evan Ernst who’s a duckweed meister in the lab, also a computer guy and genomics guy was able to do the sequence of two complete different duckweed genomes on his own, using a new technology called Oxford Nanopore which is literally a USB stick-like device where you pipette the DNA onto it and you get these wonderful long reads, it’s just amazing. He did some other things, he did some Illumina and other things as well, but yeah it produced a really beautiful genome.

SRM: So you’re telling me that somebody can map a genome while binge-watching Netflix in their own apartment?

AA: Yes, using the very same device, it’s pretty incredible.

BS: I remember when I first started working here and there was a meeting going on and I got to see one of these things for the first time in person, this little … what I thought at the time was pretty just like an outdated, oversized USB device. I’m like, “What do they use that thing for?”

AA: What’s this piece of junk?

BS: Right and it’s still mind-blowing that somebody is pipe heading just a little bit of plant matter or what have you onto this device and bam, genome.

AA: Yeah, definitely sounds pretty sci-fiesque to me but this is the reality we live in now. Actually speaking of sci-fi, I know that Ssts, our pop culture aficionado has some examples of fuels of the future from the movie world for us.

SRM: Yep, that’s right. Since basically the dawn of sci-fi, people have been really interested in the future of travel and that means the fuels that power it too. Usually it’s really interesting, you can tell how a cultural mindset, or the cultural miasma feels about the future by what fuels are being used. Either they’re hopeful and bright or they’re dark and dismal. So one of the first ones I wanted to bring up is, you guys remember way back in episode 14.5 when we talked about Back To The Future?

AA: Yes. Sara

BS: Mm-hmm (affirmative).

SRM: Doc Brown had to steal that plutonium in order to power the DeLorean.

AA: Right, right, that very old looking car.

SRM: Yes, that very old winged-looking car. Well luckily in Back To The Future 2, he didn’t have to steal any more plutonium from terrorists, instead, he goes all the way to the futuristic year of 2015.

AA: Oh boy.

SRM: And gets himself something called the Mr. Fusion, which we don’t hear much about but we do see it turn a banana peel and some beer into nuclear energy to power the time traveling car.

BS: Wow, so my impression here is it’s basically … it’s not really a biofuel but it’s taking the matter of these organic waste-

SRM: I mean, we don’t 100% know but just imagine waking up in the morning, going over to your car, popping a little hatch and throwing in last night’s leftovers and then being able to drive into work just on that.

AA: Wow, yeah, that sounds pretty ideal though I wonder what kind of efficiency he’s getting, especially out of that old car.

SRM: Yeah.

BS: Right, how many miles per banana peel?

SRM: Right, how many miles per beer can? It’s a very bright future, that’s the same movie that has the infamous hover board that everybody and their mother wants to be a reality and since this movie took place in 2015, it seems we’re lagging a little bit behind. But not all biofuels are portrayed positively. The cyber-punk classic, The Matrix, basically shows us a future where the robots have taken over earth and well, they use human bodies to power their entire mainframe.

Morpheus: Human body generates more bio-electricity than a 120 volt battery and over 25,000 BTUs of body heat. Combined with a form of fusion, the machines had found all the energy they would ever need.

AA: Do the human bodies get to live?

SRM: Well actually, that’s the interesting part. So the humans, without mental stimulation, die. So the robots build this thing called The Matrix, which is basically a sort of virtual reality illusion where people believe that they’re living their lives in the 20th century, when they are in fact plugged into a mass of machines with billions of other people.

BS: As for anyone who hasn’t seen The Matrix, apologies for the extensively broad spoiler that we just threw down there, but it’s not really ruining all that much.

AA: No that’s a pretty grim figure of the future, I think we’d be much better off with some duckweed.

SRM: The last movie I want to talk about is actually a movie series and it looks at a world where we don’t adopt biofuels and rely solely on power sources like gasoline that are not renewable and that’s a pretty famous one that I’m sure you guys have heard of called Mad Max.

BS: Right, Fury Road was one of the best movies I’ve seen in a long time.

AA: Sell it to me because I’ve not seen it.

SRM: Right.

AA: Shocker.

SRM: All right, here we go. So the film, the films excuse me, take place in Australia in a world where all the resources are starting to fall away, gas, water, electricity starts to dwindle down, so people start taking to the roads in these really elaborately made junk cars to fight it out for the last of these super valuable resources, especially gasoline.

BS: Right, to get more gasoline, you got to burn gasoline.

SRM: Exactly, and the more the movies continue with the story, the more you see the earth deteriorating around them until you get to probably one of the most popular entries in the franchise, the very recent Mad Max Fury Road. In this movie, actually probably one of the most heartbreaking portrayals is this character, Furiosa, is trying to get these women to the Green Place, this home where she used to live that was green and lush and beautiful, not the horrible desert where a war lord essentially controls when people have access to important life sources like water and gasoline. In the end, when she finally meets up with people from her old tribe, they tell her that the Green Place is now nothing but an inhospitable, desolate marsh.

Speaker 8: The creepy place with all the crows, the soil.

Speaker 9: We had to get out.

Speaker 8: We had no water and-

Speaker 9: The water was filth.

Speaker 8: It was poisoned, it was sour.

Speaker 10: And then the crows came.

Speaker 8: We couldn’t grow anything.

AA: Hopefully not covered in duckweed.

SRM: No, not covered … unfortunately, maybe it would be better off if it was covered in duckweed?

AA: Yeah it’s true, maybe they would be.

SRM: Yeah but unfortunately it’s just a sad, desolate wasteland of darkness and creepy people on stilts walking around.

AA: Well I think we have an uplifting sequel idea.

SRM: Exactly. Mad Max, accept the biofuels.

BS: Yeah, so I guess that’s it, thanks for listening, apologies for the movie spoilers, but at this point you should have seen these movies, guys.

SRM: You should have seen them.

BS: So thanks again, stay tuned for next month’s episode, what’s that going to be about?

AA: We are going to dive into some of the implications of having access to personal genetic information, what’s in everyday people’s genomes.

BS: And if we know about it what does that mean?

AA: Yeah.

BS: All right, so thanks. Stay tuned.

AA: We’re coming to you from Cold Spring Harbor laboratory, a private, not for profit institution at the forefront of molecular biology and genetics. If you’d like to support the research that goes on here, you can find out how to do that at cshl.edu and while you’re there, you can check out our newsstand which showcases our videos, photos, interactive stories and more.

BS: And if that’s still not enough, you can always pay us a visit. Between our undergraduate research program, high school partnerships, graduate school meetings and courses, and public events, there really is something for everyone.

AA: I’m Andrea.

BS: And I’m Brian.

SRM: And I’m Sara.

AA: And this is Base Pairs, more science stories soon.

SRM: I mean that’s what I would do.

AA: That was perfect.

SRM: I’d get a pipette and watch Buffy the Vampire Slayer. Like boop-boop-Buffy. I’m sorry.

AA: Yay.

BS: All right, let me add that, I’m probably going to include the Buffy the Vampire part by the way.

SRM: Oh no.

Episode 16: Big plans for a tiny plant

Scientists are working to develop solutions as global temperatures rise but one significant hurdle is our dependence on fossil fuels. Researchers are working with a variety of biofuels that can power the future, but one CSHL professor is using something unique: duckweed.

BS: Hey everyone, I’m Brian.

AA: And I’m Andrea.

BS: And today, we’re going to talk about… well… let’s just cut straight to the clips.

Newsreel supercut: “Co2” “Greenhouse gasses” “Record levels” “Rising temperatures” “Global warming.”

BS: All these soundbites, as you can probably guess, feature folks who are very worried about record-climbing levels of greenhouse gases, which scientific consensus says is tied to warmer, worrying shifts in our planet’s climate.

AA: Now, I’ll cut in to say that Base Pairs is not “the podcast about climate change” – this is the podcast about the power of genetic information, and we have a story for you about how diving into the genomes of plants could help in the fight against climate change. But first [pause] some stats:

BS: According to the US Environmental Protection Agency, global greenhouse gas emissions have spiked by about 90% since the 1970s, with emissions from fossil fuel combustion contributing about 78% of the that total increase. And if you’re wondering why burning these fossils fuels might shake up business-as-usual for our climate – put simply – we’re pulling billions of tons of carbon dioxide from out of the earth and releasing it into the air.

AA: The working theory is that high concentrations of greenhouse gases such as carbon dioxide can trap sun-delivered heat, and while a lot of that co2 gets reabsorbed by the processes of photosynthesis –

BS: Thanks, trees! Thanks, algae!

AA: – a lot also contributes to warming our oceans, which melts glaciers and permafrost, raising sea levels and causing some really weird weather.

BS: And that’s why shifting away from fossil fuels is a huge goal of the nations that signed the Paris climate accord.

AA: the Paris Agreement, as it is often called, was first signed by 196 international parties in 2015. Its central aim is keep the global temperature rise in this century well below 2 degrees Celsius — as measured from a baseline of pre-industrial levels.

BS: And according to experts around the world, abandoning fossil fuels in favor of biofuels will be instrumental in keeping that central aim a realistic possibility. The idea is that biofuels, which come from carbon-consuming plants, can be “carbon neutral” – that is to say, the amount of carbon dioxide released by burning them is mitigated by how much those plants absorb before they’re burned. Compare that to burning fossil fuels, which simply releases co2 that was trapped in the earth for millions of years… and you can see why the former would be preferable.

OD: The basic aspect is that biofuels replace fossil fuels. Being renewable, [biofuels] come from plants, they go back to plants or to residues that go back into the soil and so on at some stage, so basically it’s a virtuous cycle… Basically, bioenergy including biofuels are an essential component to achieve our climate change targets.

BS: That’s Olivier Dubois, of the United Nations’ Food and Agricultural organization… and I really hope I got his name right.

OD: some people would call me Olivier Dubious. I said no. I’m not dubious. Dubois. Dubois. Olivier Dubois. Not dubious. [laughter]

BS: (laughing) not dubious at all! In fact, Olivier is one of the FAOs leading experts on biofuel.

OD: I’m a Senior Natural Resources officer in FAO, and I currently coordinate the energy program including on bioenergy and biofuels in FAO… And… if we really want to reach the two degrees limit and even below two degrees from the Paris agreement, we need by 2030, twice as much bioenergy that we have now and four times more biofuels. And when you go to 2060, it’s four times more bioenergy and 10 times more biofuel.

AA: So, two times more bioenergy and four times as much biofuel?! But wait. Brian. It’s 2018. Is Olivier saying that the world is going to have to quadruple our biofuel production within the next decade? That’s a fairly tall order!

BS: It is! But Olivier told me that the UN currently estimates that biofuels only make up five to six percent of all fuel, so it’s not as tall of an order as you might think.

OD: Certainly less than 10% currently. Out of that, less than, much less than 5% are second generation. The bulk of the current biofuel production is basically first generation.

BS: So, apparently there are a LOT of different kinds of biofuel, and you can divide them into three distinct generations.

OD: within the biofuel sphere, you have biofuels produced out of let’s say food crops. You have those from starch like from corn or sugarcane, and then those that are produced from oil such as rapeseed, palm oil, soybeans. These are two major types of biofuels made out of food crops and they are called first generation biofuels.

Then you have another category which is the second-generation biofuels, which are usually considered to be those produced out of either residues from agriculture, food production, whatever biomass residues you have. It can also be from restaurants, reusable waste. and then you have the more advanced which are like from algae and that kind of stuff, which is really currently in research.

AA: Wow! So, what’s holding us back? Why haven’t any of these biofuels already saved the planet, helping us break away from fossil fuels for good?

BS: Well that’s the thing. Each of these generations of biofuels have its drawbacks and limitations. The first generation – corn ethanol for instance – is easy for even undeveloped nations to pick up, but in doing so, they’re left with less cropland for growing foodcrops. Olivier told me that it’s actually rare for this to pose a problem, and really should be looked at on a community-by-community basis. But opponents of first generation biofuels will highlight this food vs fuel dilemma. Likewise, with second generation biofuels –

AA: Those are the fuels made from food industry residues… so hay bales, corn husks, or used cooking oil?

BS: And from grasses and trees, but yes, food industry residues are the source of a lot of second generation biofuels. For them, the potential problems double:

OD: concerning the second generation biofuel which people say, “Well, it’s fantastic. it doesn’t have conflict with food.” Well, no direct, but indirectly you may have conflict because the residues from crops are often used for soil management. It’s the cheapest fertilizer for small scale farmers in developing countries. The straw can protect the soil from rain, for example, and you can also use it a lot as animal feed. From FAO’s work, we know that in developing countries, 30 to 40 percent of the animal feed for small scale herders in developing countries come from the residues from the farm.

BS: So even in this case, you run into the food vs fuel dilemma. The second problem is that lignin – that’s the tough, stringy parts like stalks, husks, and grasses – is SUPER difficult to break down. Doing this sustainably takes a lot of technological investment, limiting cellulosic fuel development to the wealthiest of nations.

AA: Ok but what about the third generation? I heard Olivier mention algae and that sounds promising! I imagine that you can farm algae in places where foodcrops can’t grow, so that at least gets rid of one problem.

BS: You’re right. But then you’re still left with high costs of a different kind:

OD: Normally these advanced biofuels, they require a lot of energy. The algae biofuel requires so much energy that if you do the balance you may use more energy than you produce. the thing is bioenergy… is a very complex and multifaceted topic.

BS: So, those third generation biofuels, while promising, currently require a lot of energy to produce in the first place.

AA: That’s exactly the problem that CSHL Professor Rob Martienssen is working on. His team is searching for a way to make a more efficient, sustainable advanced biofuel not from algae, but from another aquatic plant. And it’s no coincidence that they’re both aquatic—plants that live in or on water have unique features that are useful for making biofuels.

RM: Aquatic plants like to absorb a lot of CO2. Because they live on water, they don’t need to worry about water loss through transpiration [AA: that’s plant sweat, essentially] through their stomata [AA: the pores through which plants both sweat and breathe] and so they can keep their stomata, their guard cells, open all the time and so they can suck in huge amounts of CO2.

BS: Cool! So, what’s this other aquatic plant Rob’s interested in?

AA: Well, when he was telling me about the advantages of aquatic plants for sucking carbon out of the atmosphere, he was actually talking about a plant that lived tens of millions of years ago.

BS: Oh… then how is that going to help us make better biofuels now?

AA: The plant Rob’s team is studying in his lab is has features that are very similar to those of this ancient species of… pond scum, basically, called Azolla. It was a tiny fern that grew on the surface of freshwater, and it seems to have spurred an enormous change in climate. This plant’s impact is thought to have been so dramatic that this climate shift became known as the Azolla Event.

RM: About 50 million years ago roughly, a bit less, during the Eocene, the level of CO2 in the earth’s atmosphere was much, much higher than it is now. — It was about 3,600 ppm.

BS: 3,600 part per million!! Right now, we’re worrying that the level of atmospheric carbon recently exceeded 400ppm.

AA: As you might guess, the climate was way warmer than it is today because of all of that heat-trapping carbon in the atmosphere.

RM: The surface temperature of the Arctic Ocean was something like 13 Celsius, which is extremely high. There were hippopotamuses and palm trees in the Arctic and it was a hot house climate. But the Arctic Ocean was actually surrounded by land at the time, and so it was somewhat fresh water and so could support the growth of these freshwater aquatic plants, which are extremely rapidly growing.

BS: While hippos in the Arctic is one of the more fun effects of warming climates that I’ve heard about, we still need to avoid atmospheric carbon levels getting anywhere near that high again right now. But how do we know that Azolla, this ancient pond scum, should get so much of the credit for reducing the amount of carbon in the atmosphere?

AA: When plants suck carbon out of the atmosphere in the form of CO2, the carbon doesn’t disappear—it gets converted into plant matter. So, all of that CO2 that was in the atmosphere millions of years ago got converted to tons upon tons of Azolla. And a lot of it is still up there in the Arctic.

RM: Geologists went to look at the fossil record by drilling down through the Arctic sea bed and from cores that they dug up there they found, largely from pollen samples, that there were mats of Azolla 8 to 20 meters thick covering the Arctic Ocean for many hundreds of thousands of years. And this was enough to absorb a huge amount of CO2 and actually reduce the level and the temperature of the earth to more or less what it is now. — In a sense, aquatic plants have this capability of changing the climate.

BS: That’s amazing!

AA: It is! But, there’s a big catch.

RM: The time that we have to do this is not as long as was available in the Eocene when it took more than a half a million years to complete this. So, we need obviously to do something with a bit more of an engineered strategy to be able to use aquatic plants in this way, but it is an exciting prospect.

AA: Rob is using a type of aquatic plant very similar to Azolla for his research. It’s called duckweed. Rob’s team has been diving deep into the genomes of various duckweeds to find ways to make them an even better tool for sucking carbon out of the atmosphere and turning it into fuel. Duckweeds are really common—I’m sure you’ve seen them.

RM: Ponds on golf courses are classic examples because of all the fertilizer that’s put on the grass runs off into the pond. — Duckweeds, or the Lemnaceae, are the smallest flowering plants, but also the fastest growing. — Now, although they weren’t actual Lemnaceae, these — Azolla — were aquatic ferns — they grew very similarly as far as we can tell.

BS: I’ve definitely seen duckweed. It is a very modest-looking plant, but being the fastest-growing plant in the world is quite a feat. How do they do it?

AA: They clone themselves.

BS: Really?

AA: Really. For both duckweed and Azolla…

RM: …the clonal reproduction aspect of it is why they grow so fast.

AA: By cloning itself, duckweed is able to double in biomass every two days!

BS: Cloning itself—so this is different from the highly-engineered way that scientists created Dolly the famous cloned sheep, for example. Some plants can naturally sprout clones of themselves. Similarly, some of you may have used cuttings of houseplants to grow new plants. That’s a form of cloning, too.

AA: Duckweed is a plant that clones itself naturally. While the Azolla Event helped inspire Rob to look into duckweed as a potential biofuel, it was clonal reproduction that really got him interested in duckweed. He’s kind of a plant clone enthusiast, and after talking with him, I can see why. Clones offer some huge advantages.

RM: My lab really works on different types of plant reproduction and the genetic and epigenetic mechanisms that underlie it. We actually always had an interest in plants growing from clones and the epigenetic mechanism they have.

AA: When you look at the net amount of energy that various biofuel crops produce, you see that the ones that come out on top are major food crops, which run into the food vs. fuel issues you talked about with Olivier. But they have something else in common, too: the best energy crops are clones.

RM: Right now, the most successful biofuel feedstocks are sugarcane and oil palm—both of which are clonal, by the way, and both of which can produce between five and 10 times as much energy as what you put in.

BS: Those are some impressive numbers! Clonal reproduction makes that big of a difference?

AA: It can. While it’s not the only factor that makes oil palm and sugarcane good biofuel crops, cloning can greatly improve a plant’s yield. One reason for that is when you find one particularly high-yielding plant, you can then make genetically identical copies.

BS: It’s kind of like if the Yankees were able to clone Babe Ruth, except instead of racking up home runs, you get more palm oil or sugar or whatever the crop is. Duckweed has a big advantage, then, as a clonally reproducing plant that isn’t a big food crop. How does duckweed stack up in terms of net energy production?

AA: It’s hard to say exactly, because Rob’s team is still working on making duckweed a better biofuel crop. For example, when duckweed takes up CO2, it mostly uses that carbon to make starch, which requires a lot of processing to turn into fuel. But Rob and his team thought, is there a way that we could get duckweed to make oil instead?

BS: Oil is a much better starting material for biofuel than starch, so that would be a major improvement. But that’s also a pretty big change to make to a plant. How is he going to do that?

AA: One particularly appealing way is to create a whole new chromosome that contains the instructions for making oil using CO2. But you can’t just stick a whole new chromosome into any plant and expect it to work out—unless it reproduces clonally.

RM: We’re very interested, for example, in using artificial chromosome technology where you can literally build your own chromosome. — Another advantage of clonal growth is that it can tolerate additional chromosomes.

BS: It’s not surprising that adding an entire chromosome could cause problems, but why are clones better at dealing with those problems?

AA: It has to do with how sexual reproduction works. Both parents contribute one copy of each their different chromosomes.

BS: Chromosomes are big packages of DNA, basically.

AA: Yeah, and each chromosome from the mother’s egg pairs up with the corresponding chromosome from the father’s sperm to create a combination of both parents’ DNA in the offspring. But, if you toss in an extra chromosome, the whole pairing process gets thrown off.

BS: Ah, so if the plant reproduces clonally instead of sexually, it can just skip that part and make copies of all of its chromosomes, including the extra chromosome.

AA: Right. Rob’s team is still working toward this additional chromosome approach, but in the meantime, they have successfully gotten duckweed to produce oil using a different technique. There’s this gene in corn called WRINKLED1 that’s known to be involved in a biological pathway that produces oil.

RM: Sure enough, if you express WRINKLED1 in duckweed, you do get oil. You don’t get a huge amount of oil and part of the reason for that is that you slow down growth a great deal and this is a predicted consequence of expressing only part of the oil pathway, not the whole thing.

BS: This approach is kind of like taking a shortcut, it seems. Rob wanted to see if duckweed could produce oil, which is a process that involves a number of genes, but this WRINKLED1 gene is the key player. Putting WRINKLED1 into duckweed was enough to get it to make oil, but shortcuts often come with a cost. In this case, the cost was slower growth.

AA: Yeah, this approach was a good kind of proof-of-concept that it is possible to get duckweed to make oil. But as you discussed with Olivier, efficiency is the big problem that third generation biofuel crops like algae and duckweed face.

BS: It’s important to get more energy out of these plants than we put into growing them, and slower growth gets in the way of that.

AA: This is where the extra chromosome approach is useful. Instead of moving just one gene from this oil-producing pathway into duckweed, building a whole chromosome would allow Rob and his team to move all of those supporting genes in the pathway along with it.

RM: We think we can build our own chromosomes in duckweed, which would be very convenient for being able to move entire biosynthetic pathways from one organism to another.

BS: In other words, Rob wants to give duckweed the genetic tools it needs to be better at producing oil.

AA: Right.

AA: There is another angle on this duckweed oil production issue, though.

RM: [at lecture] It turns out that if you grow them under the right conditions, you can overcome much of that growth deficit. One of those conditions, excitingly for us, is growing them in high CO2.

BS: That is very convenient, since we’re living in relatively high CO2 conditions right now.

AA: Relatively…. but to improve duckweed’s growth rate, Rob needs a way to create even higher CO2 conditions. You might have noticed that he sounded a bit different in that clip, and that’s because it’s from a public lecture that he recently gave here with Frank O’Keefe, who’s the CEO of a company called Infinitree that found a way to do just that. Here’s Frank:

FO: What we discovered was remarkable and gave us hope that we could feed greenhouses, vertical farms, with cheap, low-energy CO2.

AA: Frank and his colleagues at Infinitree developed this absorbent material that works as a “humidity swing,” that’s what they call it. When the material is dry, it captures CO2, and when it’s wet, it releases that CO2.

BS: Wow, that seems like it would work well for releasing CO2 into a greenhouse, where it tends to get really humid anyway.

AA: Once Rob and Frank started talking with each other, it became obvious that their projects fit together quite nicely.

RM: We hadn’t really been thinking about a CO2 system like that, but it really makes a huge amount of sense because now that technology allows essentially passive capture of CO2 to make the CO2 concentration much higher and we’ve done some experiments. It makes the duckweed grow much faster, it increases oil in our special strains.

BS: Since this material essentially captures CO2 passively—meaning without putting in more energy—that could really help make duckweed a more sustainable biofuel.

AA: Frank also pointed out the advantages of duckweed’s very small stature. You can grow it in shallow, stackable containers using the system that his team designed.

FO: The reason we would use that plant is that it so voraciously consumes CO2, that for us to grow it in layers—25 layers, per our design, so you’ve got a vertical farm of 25 growth layers—would enable us to put away a lot of CO2.

BS: These are some pretty big plans for the world’s tiniest flowering plant. And I feel good about it! But is it going to be ready for that 2030 goal that I discussed with Olivier at the top of the show?

AA: Even Rob believes that duckweed is not “the one fuel to rule them all” so to speak. It will have to be part of a larger effort that includes other types of biofuels as well.

RM: It’s not like we’re gonna be growing huge amounts of duckweed next week worldwide, but we certainly think of it as a big new potential component. Biofuels, the oil companies are facing a requirement to use a pretty high percentage of biofuels in the next few years, just legislatively they have to do this. So they’re very interested in all sorts of different ways of producing a large amount of biofuels.

BS: That’s great to hear. As Olivier was telling me, the world needs to focus on adopting any kind of biofuel first, before research that improves the efficiency of newer biofuels can start to play its role on a global scale.

OD: Basically, there’s no one size fits all and there’s no “either or” … You can have unsustainable and non-sustainable, and sustainable biofuels in whatever category. But… you need all types of biofuels to really meet that [2030] target. I mean, you will never reach a sufficient level of second generation in 10 years time to really make up for the shortfall if you forget about the first generation. Right? What really matters is… the understanding of the situation for each country level… or even in terms of environment…so that these biofuels are sustainable.

AA: Absolutely. Duckweed is part of this third generation of advanced biofuels, which come with many advantages and are still being improved upon. But if we’re going to have a shot at making that 2030 goal, we’ll need those earlier generations of biofuels in the meantime.

BS: I hear ya. For me, this duckweed project of Rob’s represents that future of “clean” and carbon-neutral fuel we’re looking forward to. But we’re not there yet. We’re going to have to get there in steps, and research makes sure we always have cleaner more energy-efficient steps waiting just ahead of us.

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Episode 15.5: Cellular hide and seek

Following up on Base Pairs 15, we learn how William Coley’s daughter used case notes to start the Cancer Research Institute. Professor Doug Fearon talks about on why the immune system identifies certain types of cancer cells more easily than others and we explore the might of the white blood cell in pop culture.

BS: This is Base Pairs, the podcast about the power of genetic information.

Intro: Great scientific challenges, transcend national frontiers and national prejudices. For the language of science has always been universal.

BS: Hey, everybody. It’s Brian here.

AA: And Andrea.

BS: This is one of our Base Pairs chat episodes. We do these as a follow up to one of our more full storytelling episodes and in this case we’re following up an episode that we did about immunotherapy.

AA: Immunotherapy has kind of become a buzzword in the recent years in stories about say, former president Jimmy Carter who underwent immunotherapy and that seemed to have really helped him beat his cancer.

I had been aware of some new cancer immunotherapies that were in the works like the researcher that we spoke to in that full episode. Doug Fearon is working on a new cancer immuno therapy for pancreatic and colorectal cancer, but what I did not realize is that cancer immunotherapy has a much longer history than the past few years or so.

BS: Right. When we were researching this episode I was fortunate enough to stumble upon this amazing story about the fellow who is now considered the father of immunotherapy. His name was William B Coley. At the time, he didn’t know what he was doing. He didn’t know it was immunotherapy and this is in the, believe it or not, the mid 1800s. They didn’t even know what an immune system was, but he was going around infecting dying cancer patients with bacteria, which-

AA: Seems like the opposite of what you would want to do. Like, aren’t we trying to protect the compromised immune systems of cancer patients?

BS: Right. Not trying to make these people sicker, but that’s exactly what he was trying to do. Is, make these people sicker. So sick in fact, that their immune system flares up and tries to attack all the invaders in the body. It basically goes on high alert and sometimes it was a really successful approach, sometimes it totally wiped out the cancer along with the bacteria in this patient overnight. But, unfortunately the idea behind this became overshadowed by other strategies like chemotherapy and was kind of forgotten until Coley’s daughter, Hellen Coley Nauts discovered all of his noted and what not in the family barn sometime during the Great Depression. I spoke to Pete Coley, who is her nephew about what she was like and what she decided to do about this discovery.

Pete Coley: Helen is an unsung heroine who actually gathered up enough evidence to get more money going down more academic and governmental research. She learned how to write up case histories, not many people do that well. She was trained at the academy of medicine, she trudged up there practically every day from her apartment on 92nd and Madison. She’d go all the way up to 110th and 5th and educated herself. She corresponded with folks all over the world, but … Anyway, I watched her do this. Even when I was in college and after that, I would help her write her fundraising brochures and stuff like that. Finally, she teamed up with Oliver Grace of the Grace Company and they started the Cancer Research Institute in 1953. But, I remember that it all happened in her dining room.

AA: Wow. That is an amazing story. I’m so glad that she made sure that these records got the attention that they deserved.

BS: Right. Helen and the case studies she wrote up really got the ball rolling for immunotherapy, spread the word about it. Obviously, it wasn’t just the Cancer Research Institute that led it to become such a big buzzword, but she was definitely one of the big movers and shakers from that time.

AA: Back in the time of the Coleys, immunotherapy research was really based on trial and error. These observations of, “What happens if I infect this cancer patient with this bacteria? Does it work or does it not?” Trying to glean whatever insights they could off of these kind of just naked eye observations, but now scientists are able to look at cancer at the molecular level. Look into the genome, figure out the nuts and bolts behind what’s going on and why a treatment does or doesn’t work. That is what Professor Doug Fearon, who we spoke to in the full episode is really trying to do. He’s all about learning the rules of the immune system and how cancer plays into those rules. When I talked to Doug he told me something that I hadn’t really considered before, but that really made a lot of sense.

Doug Fearon: Melanoma has a lot of mutations and therefore it is more foreign than tumors that do not have a lot of mutations. It’s easier for the immune system to distinguish melanoma cancer cells from normal cells and therefore it’s easier to promote an immune attack. There’s already and ongoing low grade immune attack and you’re just promoting it. The challenge is treating cancers that have very low mutational burden and don’t have a lot of neoantigens. That’s what the field is focusing on now. It turned out that many colorectal cancer patients and pancreatic cancer patients have low numbers of mutations that do not respond to contemporary immunotherapy and that’s what we’re trying to attack.

AA: Okay. The success of immunotherapy has a lot to do with the kind of load of mutations?

Doug Fearon: The low hanging fruit has been people have already gotten that.

BS: When I heard Doug say this it made me realize that, “Oh. He is taking it a step forward than just saying, ‘Oh. This immunotherapy works and this immunotherapy doesn’t work.’” Et cetera. It’s actually, the same immunotherapy could have a different impact depending on what kind of cancer they’re using it for. Right? Am I interpreting this right?

AA: Yeah. Right. The problem with cancer or part of it at least is that cancer cells look a lot like the body’s own cells, because that’s what they started out as. They’re just the body’s own cells kind of gone rouge. But, different types of cancers can look really different at the genetic level and that means that they look different to the immune system too. When a cancer has more mutations, that tends to make it look more foreign. It’s producing more messed up gene products that the immune system can pick up on, potentially.

BS: Right. That’s what the immune system’s all about, is attacking foreign bodies. Not just cancer, not just heavily mutated cells, but really anything foreign. Like say, a tiny submarine.

AA: Yeah. Brian is not just bringing up tiny submarines out of nowhere, that’s because our resident pop culture aficionado, Sara Roncero-Menendez is here to tell us about how that tiny submarine got there.

SRM: Hey, guys.

AA: Hello, Sara.

BS: Hey. Hey.

SRM: Have you ever watched a TV show and suddenly they have this episode where the character shrink down really, really small and go inside someone else’s body?

AA: Yes. I definitely remember the Rugrats episode where they shrink down to get the watermelon seed out of Chuckie’s little belly.

SRM: Right. It’s a pretty popular formula for kids shows and for adult shows, but it actually mostly stems from this 1966 movie, “Fantastic Voyage” in which a group of scientists shrink down and get inside a tiny submarine in order to save the life of another scientist.

AA: I bet that set of some alarms within the immune system?

SRM: Oh. You betcha. In fact, one of the scientists actually dies, because white blood cells surround and kill him.

BS: Oh. The white blood cell. You mean, the great white of the immune system. Seriously though, it’s a very commonly portrayed immune system cell and I’m assuming it’s the one that you’re gonna be talking about the most?

SRM: Yep. Absolutely. In fact, it’s so infamous in the media landscape there is actually a named trope for it. It’s called, “The seeker white blood cells.” That’s when in one of these episodes the characters involved are confronted by these guardians of the body and have to deal with them in one way or another. One of these examples is from a show that you’ve probably heard something about. It’s everyone’s favorite classic science education show, “The Magic School Bus.”

BS: Yeah. That takes me back.

SRM: In fact, The Magic School Bus has not one, but three different episodes in which Ms. Frizzle and her class go inside the human body.

BS: Three? You’re kidding me. I probably lumped them all together.

SRM: Right. Well, they actually end up talking about different aspects, but the very first episode in which they do so is the one that I want to focus on today. It’s called, “Inside Ralphie.” It takes place when one of Ms. Frizzle’s students, Ralphie gets a bacterial infection and feels really sick. They decide, why not tape the action for their broadcast day by shrinking the magic school bus down really tiny and going inside or Ralphie to see what’s wrong? When they get to Ralphie’s throat they realize that it’s a bacterial infection that’s destroying the cells inside, and then “Dun-da-da.” arrive the white blood cells to fight the bacterial infection.

Speaker 7: Oh, no. Ralphie’s antibodies will mark the bus as bacteria.

Speaker 8: But, we’re not bacteria, we’re Ralphie’s friends.

Ms. Frizzle: But, his white blood cells are doing such a good job they now recognize us as enemies too.

Arnold: Enemies? But, we know what white blood cells do to enemies.

Ms. Frizzle: That’s right Arnold, they’ll try to destroy us.

Group: Destroy us?

Ms. Frizzle: Oh. The wonder of the human body.

AA: I can see why Ms. Frizzle is so psyched about the immune system coming and attacking them, because the immune system is really awesome for protecting us so well. It would be really alarming if it didn’t go after this hunk of metal and foreign humans inside of poor Ralphie’s throat.

BS: Hunk of metal and magic Andrea. It’s magic.

AA: Hunk of metal and magic. Right.

SRM: Yeah. When the white blood cell covers the bus the kids should be very, very afraid, because the white blood cell is very, very good at its job. Speaking of jobs, there is also a much less literal interpretation, but still somewhat accurate to what a white blood cell does in the movie, “Osmosis Jones.” In that movie they treat the body like it’s its own city and that make the white blood cells the police force.

Osmosis Jones: Yo. You see this badge? You see this gun? You see this gooey white sackous membranous around my personhood?

White Blood Cell: Here we go again.

Osmosis Jones: Well, you’re dealing with a white blood cell here. I should be out in the veins fighting disease, not in the mouth on tartar control.

White Blood Cell: You’re lucky you ain’t in a scab.

AA: Okay. Osmosis Jones is showing us the situation from the other side where he’s a frustrated white blood cell just trying to do his job and he feels like he’s not where the action is.

BS: Right. That’s kind of cool, because it makes you realize that the immune system is not just in your blood, it’s everywhere. Even the mouth, taking on gingivitis.

SRM: It certainly gives us a different way of visualizing just how important the white blood cells are to the maintenance of the body, in fact it is actually kind of interesting that these entertainers do understand … If in a broad sense, how the immune system works to keep us healthy.

AA: Yeah. I’m really impressed, to be honest. Especially, after our last chat episode where we saw mad scientists who feel like they’ve got everything all figured out, but don’t.

BS: Just flat don’t.

SRM: They just don’t.

AA: But, yeah. These TV shows and movies, they really used the immune system’s tenacity as part of their narrative as opposed to just ignoring the fact that if you throw a school bus, or a submarine, or a helicopter, or whatever into the body that the immune system is probably going to take note of that.

BS: Cool. That’s it.

SRM: That’s it.

BS: We’re done. If you guys have any questions, comments, please be sure to let us know. You can even leave a review on iTunes. Stay tuned for next month, we’ve got a great episode coming out and it’s gonna touch on the subject of biofuels.

AA: And how the world’s smallest flower is involved.

BS: Spoilers. Stay tuned.

AA: We’re coming to you from Cold Spring Harbor Laboratory, a private, not for profit institution at the forefront of molecular biology and genetics. If you’d like to support the research that goes on here you can find out how to do that at, “CSHL.EDU.” While you’re there, you can check out our newsstand, which showcases our videos, photos, interactive stories, and more.

BS: If that’s still not enough, you can always pay us a visit. Between our undergraduate research program, high school partnerships, graduate school, meetings and courses, and public events there really is something for everyone.

AA: I’m Andrea.

BS: I’m Brian.

SRM: I’m Sara.

AA: This is Base Pairs. More science stories soon.

Episode 15: The immune system unleashed

Cancer immunotherapy has a long and storied history, one that begins with a young woman suffering from a pain in her hand.

BS: Hey everyone, I’m Brian,

AA: And I’m Andrea,

BS: And this is Base Pairs.

AA: The power of genetic information has helped reveal many new treatment approaches to cancer, including a whole class of treatments known as cancer immunotherapies… or, so I thought at least. I was under the impression that cancer immunotherapy—which uses the body’s own immune system to fight cancer—was fairly new. But Brian told me that’s not the case.

BS: Yeah, I know you’ve been talking to a scientist who used genetic information to find a new cancer immunotherapy, which we’ll get to later. But first, I have a story from way before anyone even knew that DNA is the genetic material. It starts back in 1890 with a young woman named Elizabeth Dashiell. Her friends called her Bessie.

BS: Bessie is a young lady, about 17 at the time, and she’s been traveling for summer vacation. She’s excited because she’s befriended a well-off young man who, by all accounts, has taken quite a liking to her. His name is John D Rockefeller Junior,

AA: So if you know a thing or two about U.S. history, you know that things are looking up for Miss Dashiell.

BS: However… as with many memorable stories… this is when disaster rears its ugly head.

PC: “She had injured her hand in a Pullman car jolting.”

BS: That, I should say, is Pete Coley, and we’ll get to where he fits into all this in a second.

AA: Ok, so something bad happened to Bessie, but before you continue… what’s a Pullman car?

BS: Aha yea. Basically, Bessie got her hand stuck between seats in a train car when it violently shook.

AA: Ahhh.

BS: So, months later, the pain from that train car accident is still there. Bessie knows something is wrong and finds herself a surgeon in New York City – a man by the name of William B. Coley.

AA: Oh ok. And how is Pete related?

BS: William was Pete’s grandfather and an up-and-coming surgeon. However, when he examined his young patient, he found something unexpected on that injured hand. What had actually been causing Bessie’s persistent pain was something unrelated to the accident. It was something much-much worse.

AA: What… what was wrong?

BS: Well, Coley knew a bone tumor, called a sarcoma, when he saw one.

PC: “He removed her hand, and tried to save her with surgery, which is was the only thing going in those days.”

BS: But it wasn’t enough. The aggressive cancer spread from Bessie’s limb to the rest of her body, harrying the young girl with painful tumors. All Coley could do was make his patient comfortable, and in 1891, Bessie Dashiell died at the age of 18.

AA: Sheesh. Well, I’ve heard stories like this before, and I can guess where it leads. Coley was frustrated with how powerless he was and… I’m guessing he sets out to improve cancer treatment options?

BS: You nailed it! But uh… this is where the story gets… dark.

AA: I’m pretty sure this was already SUPER SAD, Brian.

BS: Ok but darker. Like… mad scientist dark. Fast forward ten years later, and you’ve got an obsessive William B. Coley walking into hospitals, looking for the sickest, most near-death cancer patients. He’d slice them with a scalpel and then rub a hodgepodge cocktail of bacteria into the wounds.

AA: What?! Why?! You’re right! That does sound mad! Why did no one stop him?!

PC: “He got in trouble almost all of his life but — he had a great reputation for integrity. — Fortunately — he did end up friends to the Rockefellers and a few of his patients. — He, had to be a really live wire guy as well as likable or else none of this would have happened.”

BS: And Coley wasn’t only likable. People trusted in what he was doing, because believe it or not, he was onto something. Coley was chasing after what doctors at the time simply called “spontaneous regression” – rare but documented moments when the tumors of a cancer patient simply disappeared overnight.

PC: “He began to research the case histories in New York, especially, and he got people all around the world to try to find out what was the trigger for this. And, they found that if there was an infection of some kind – it could be, almost any infection… And with a big temperature, and a big response — miraculously — cancer disappeared.”

BS: He first discovered an example of this phenomenon in the case of a German immigrant simply called “Stein.” Years before Colley’s failure to save Bessie, Mr. Stein had been admitted to New York Hospital with a sarcoma very similar to hers. However, unlike the tragedy of Bessie Dashiell, Stein walked out of the hospital disease free only a few days later.

AA: That definitely sounds like spontaneous regression. So, I’m guessing Stein was hit with some kind of fever, like Pete described.

BS: Through some medical record sleuthing, Coley learned that Stein had come down with a severe post-operative skin infection. Remember, this occurred during the late 19th century – when the idea of germs was JUST becoming popular – so many surgeons weren’t even carefully washing their hands just yet.

AA: But fortunately, for Stein, this worked out to his benefit. By getting infected, he somehow was able to beat his cancer.

BS: Crazy, right? Coley even tracked the man down to a neighborhood in New York’s lower east side. Years after developing sarcoma, there Stein was, with no sign of the cancer save for a scar on his neck.

AA: So, Coley surmised that the bacterial infection had somehow caused the tumor to regress… and decided to start purposely inducing infections?

BS: The first cocktail he whipped up mostly contained the streptococcal bacteria –

AA: that’s the bacteria that causes strep throat

BS: – but Coley experimented with other infectious agents as well. He called the mixture “Coley’s Toxins,” and according to his records, it was remarkably effective when it worked.

PC: “It’s like being run over by a locomotive. I mean, wam-o! And you’d have this huge temperature. And the sweats and feel like you’re dying of you know, typhoid fever or something like that. Which was a sign, that you know, that the immune system had activated. I mean it’s a little… it was a pretty crude way of knocking the door down, but it opened up the immune system.”

AA: Ah! So, the infection from Coley’s Toxins was basically jump-starting the immune system – sort of waking it up to go fight off the bacteria and in the process, it also could attack the cancer. That’s super clever! And yet, it doesn’t sound like Coley knew that this was what was happening….

PC: “Yeah. — He had no idea what he was doing. He had NO idea what he was doing — Nobody at the time understood that there was an immune system. All the doctors in the world had never dreamed of it.”

BS: It’s important to point out that a fascination with what would eventually evolve into a study of cancer and the immune system persisted in Coley’s family. In the mid 1900s, his daughter Helen discovered 3,000 of Coley’s case studies in the family barn and soon after became one of the first champions of immunotherapy, founding the Cancer Research Institute. And Pete’s father, Bradley Sr, continued to use a refined version of the Toxins at Memorial Hospital well into the 1950s. Remarkably, some of his patients are still alive today thanks to this treatment!

AA: Immunotherapy got its start through trial and error, because so little was known about the immune system at the time. But in the century since Coley applied the first cancer immunotherapy, scientists have learned a whole lot more about how the immune system works.

DF: If the problem in cancer immunology is turning on the immune system, well, we know the rules for that.

AA: That’s Professor Douglas Fearon, who runs a cancer research lab here at CSHL and has dedicated much of his 50-year career to learning what he likes to call the “rules of the immune system.”

BS: Lack of understanding of those rules is why most of our listeners probably have never heard of Coley’s Toxins until now. The toxins worked in some patients but not others, and since no one knew why, it quickly became overshadowed by another up-and-coming cancer treatment: chemotherapy.

AA: Happily, Doug is closing in on a new cancer immunotherapy—one that doesn’t use unpredictable infections, nor is it like the poisonous chemotherapies that are still used to treat cancer today. It’s being tested in both colorectal cancer and pancreatic cancer patients right now. Doug and his team came up with the idea for this cancer immunotherapy by using genetic information and other tools to figure out how to use the rules of the immune system to their advantage.

DF: If you understand the rules that govern the immune system, then you can imagine these manipulations for immunotherapy.

BS: That’s really different from how Coley developed his immunotherapy. He had a hunch, and while a lot of work went into validating that hunch, its success also involved quite a bit of luck.

AA: Coley had a sense that if you can activate the body’s natural defense, it might be able to fight cancer. But after decades of studying what we now know as the immune system, Doug believes that it is already trying to attack the cancer, in many cases.

DF: I’m predicting that we will find that most patients have an ongoing immune response against their tumors.

BS: Really? Then what’s stopping their immune systems from just killing the cancer?

AA: Something that I found pretty mind-blowing. Cancer is evil, but sometimes I can’t help being impressed by its resourceful tactics. Research from Doug and other scientists suggests that the cancer disguises itself from the immune system—by tricking it into treating the tumor like a wound that needs to heal. attracting what biologists call growth factors, among other things, which in cancer is exactly what you DON’T want to happen!

DF: Maybe the problem is that the body thinks the tumor is a healing wound and it has to have mechanisms to protect the growing cancer cells. The body actually thinks that growing cancer cells is a regenerating tissue.

BS: Ok, I know that cancer is so difficult to defeat partly because it’s an invasion that comes from within. Genetic mutations in our own cells send them down the path to becoming cancerous, but they are still similar to healthy cells in many ways. So, the problem is that the immune system can’t detect the cancer cells because they look too similar to the healthy cells they started out as?

AA: That’s what I thought at first, too. But the disguise is more clever than that. I was amazed when Doug told me about just how sensitive the immune system is. For example, in humans, genes are usually thousands of letters long. If just one of those letters is wrong, like if a C becomes a G, that tiny change in the protein created from that gene is enough to set off an immune response.

DF: One point mutation, right. The immune system can see that as foreign.

BS: Wow, that really shows how good the immune system is at its job. And yet the cancer still outmaneuvers it.

AA: That’s part of why Doug is so confident that many cancer patients do have an immune response to their tumors, and that he just needs to remove whatever is getting in the immune system’s way.

BS: Ahhhh! And this is where learning the rules of the immune system must really help.

AA: Right. When Doug was based at Cambridge, he got interested in these cells called fibroblasts, which make structural materials like collagen—that stuff you often hear about in ads for beauty products. Fibroblasts are also critical in wound healing, and, curiously, are found in tumors.

BS: Many people don’t realize this, but tumors aren’t made up of only cancer cells. They contain lots of healthy cells too.

AA: Doug had his own hunch, though his was guided by much more knowledge of the immune system than Coley could have had. What if fibroblasts, these cells that help in healing wounds, were protecting the cancer cells?

DF: We made a mouse in which we could conditionally kill, at any point in time, the fibroblasts in the tumor. And we found if we did that, the immune system killed the tumor. So, the fibroblasts were immune-suppressive, that was the most unexpected finding. So, then we simply isolated the fibroblasts and said, “What genes are they expressing? How are they doing this?”

BS: Gene expression is kind of like a cellular activity log. It gives a sense of which genes the cell is using at any given moment.

AA: Yeah, and those tests revealed that the fibroblasts inside the tumor were making a particular molecule known to be involved in regenerating tissue, like what happens in wound-healing.

BS: That’s pretty suspicious.

AA: This is the really strange part. It seems that the cancer cells fashion their disguises out of this special molecular material that they get from fibroblast cells.

DF: Another cell in the tumor is making it, but the cancer cells are coating themselves, and this is somehow allowing them to prevent T-cells from coming into the cancer cell regions and attacking the cancer cells.

BS: That is both amazing and distressing.

AA: Fortunately, that new cancer immunotherapy drug we mentioned earlier prevents cancer cells from being able to put on this disguise. Now, Doug’s lab at CSHL is working on figuring out why this molecular cloaking device exists in the first place.

DF: This means by which tumors protect themselves from immune attack did not evolve for the sake of protecting tumors. — Part of my lab is trying to investigate what normal circumstance contributed to the evolution of this tissue protective pathway. That’s going to be relevant in thinking about the biology of the system, but also be very clinically relevant. We’ll need to deal with that in patients.

BS: Doug was a medical doctor before he was a research scientist, and he never loses sight of the fact that he’s doing research to benefit patients. Just like what happened with Coley, when Doug was practicing medicine, he felt like he was hitting a wall because he needed to know more about how the immune system works. Progress in medicine depends on improving our understanding of how the body works—and that comes from basic science.

AA: Yeah, Doug transitioned from being a doctor who treated patients to being a researcher in pursuit of discoveries that would lead to more effective treatments. For much of his career, Doug was actually more interested in turning off the immune system in autoimmune disease patients, instead of turning it on against cancer.

BS: How did he end up studying cancer, then?

AA: Well, treating autoimmune disease more effectively turned out to be an even harder problem than he had thought it would be.

DF: Around 2005, 2006, maybe a little bit earlier, I realized I was getting a bit old and I had not accomplished the deal I had made with myself: I will stop seeing patients so I can make a discovery that can affect the health of patients.

AA: As he was thinking about where his chances of affecting the health of patients were the greatest, something serendipitous happened. He was asked to serve on the Scientific Advisory Board for the Ludwig Institute for Cancer Research, so he read up on cancer to prepare.

DF: I started reading cancer immunology, and it was an eye opener! There were experiments done in the 1970s that allowed one to form hypotheses about why tumors escaped immune control, and I didn’t feel as though it was being followed up by current cancer immunologists. And I had an idea. — Maybe the fibroblasts are creating the immune suppressive microenvironment and instructing all of the immune cells to turn off. — And then, best of all, the idea was right!

BS: Doug is not a boastful guy at all—that is pure excitement about making a discovery that could help patients. But how did he turn that discovery into a treatment? If the fibroblasts are suppressing the immune system… does that mean these immune-boosting supplements we hear about all the time could help fight cancer?

AA: This immune-boosting craze came up when Doug gave a public lecture on immunotherapy here at CSHL with another doctor/researcher named Robert Maki. He’s one of the leaders of a strategic affiliation between CSHL and Northwell Health, New York State’s largest health care provider. Dr. Maki still sees patients regularly, and here’s what he had to say.

RM: The big question I’m always asked—I get this at least twice a clinic, a couple of times today, in fact—is how can I boost my immune system? And pretty clearly, the answer is you just call a cardiac surgeon. You know, Dr. Oz will be happy to tell you all of the good things that you can do to boost your immunity. [audience laughs]

BS: That was a good burn.

AA: It really was. For those who would like to find out which supplements actually have scientific evidence to back them up, Dr. Maki did also recommend something.

RM: Memorial Sloan Kettering have put together a very nice website called About Herbs, and this can tell you a lot about all of these natural products that people are taking.

AA: Anyway, instead of learning immune-boosting strategies from cardiac surgeons like Dr. Oz, Doug was learning from scientists who study viruses.

BS: Wait, what do viruses have to do with any of this?

AA: The cancer immunotherapy drug that Doug’s team developed and is now testing in clinical trials was actually first developed to fight HIV, the virus that causes AIDS. Dr. Maki explained that this really makes so much sense, because both viruses and cancer cells find ways to hide from the immune system.

RM: This is what viruses have been trying to do throughout evolution. So EBV, Epstein-Barr virus, which causes mononucleosis, has engineered itself, has been selected against being seen by the immune system. It’s really very much a stealth virus that has many ways of preventing the immune system from seeing it for example.

BS: HIV must be pretty stealthy too, since it’s so deadly when left untreated.

AA: Yeah, cancer is far from the only swindler out there trying to cheat the immune system. HIV uses a similar tactic to the cancer cells that Doug studies, and so do other viruses. He actually learned about the drug he’s now testing as a cancer immunotherapy when he was reading about West Nile virus.

DF: I said, “Geez, that’s kind of like what we want to do.” So, it was reading that paper that allowed me to choose that candidate — as regulating T-cell infiltration of the tumor.

BS: I would have never guessed that West Nile virus research could spark an idea for treating cancer. But that’s why basic research is so fascinating, and important—it’s how scientists come to make discoveries that they couldn’t have imagined in another context.

AA: Doug is all about that. He came to CSHL in part because the culture around here allows scientists to spend lots of time learning about all kinds of research in biology which helps them make valuable connections.

DF: You can’t design a life so you’re terribly efficient, you gotta have time to be inefficient, to read about things you don’t necessarily know you need to know, but that’s how you discover what you need to know.

BS: Finding out what you don’t know you need to know is quite a task. I’m glad Doug’s hard work looks like it’s paying off.

AA: The clinical trials are still in an early stage, but so far, so good.

DF: The clinical trial is the analysis of the tumors by looking to see how the drug changes the immune reaction of the tumor and the analysis is done by looking at gene changes and gene expression in tumor biopsies before and at the end of treatment, one week of treatment. — Our recent colorectal cancer patient trial suggests that — at least half the patients have T-cells that are coming in and killing cancer cells after our immunotherapy.

BS: That’s fantastic! T-cells are immune cells that are also sometimes called “killer” T-cells, because their job is to attack invaders. If they’re responding, that suggests the drug is getting the immune system to do its thing.

AA: It’s pretty exciting. Doug just recently got the trial with pancreatic cancer patients up and running, and hopes that this very hard-to-treat cancer will respond to the drug as well. But even if that shows success, scientists in his lab are going to keep studying this system, because…

DF: One actually can believe that if we understand how something is happening, we can maybe make it happen even better. So that’s what the work here, funded by the Lustgarten Foundation, is totally focused on.

BS: A scientist’s work is never done!

AA: That we know for sure.

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Episode 14.5: Medicine and mad scientists

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, a follow up on his discussion in Base Pairs 14. Also, in a new pop culture segment, we talk about movie “mad scientists” and how they contribute to misconceptions about how 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.

If you’d like to support the research that goes on here, you can find out how to do that at cshl.edu and while you’re there, you can check out our newsstand, which showcases our videos, photos, interactive stories and more.

Brian: And if that’s still not enough, you can always pay us a visit. Between our undergraduate research program, high school partnerships, graduate school, meetings and courses, and public events, there really is something for everyone.

Andrea: I’m Andrea …

Brian: And I’m Brian …

Sara: And I’m Sara.
Andrea: And this is Base Pairs. More science stories soon.

Episode 14: The cancer answer that wasn’t

Science is a process, something we learn in elementary school as we plan our papier-mâché volcanoes. Make a hypothesis, rigorously test it through observation and experimentation, and then put forth the results. But one step is absolutely crucial—the experiment should be reproducible by others using your methods and materials.

AA: Hey everyone! Andrea Alfano here.

BS: With me, Brian Stallard

AA: And we’re really thrilled to be starting this new season of Base Pairs! But first, I wanted to make a short-but-exciting announcement: Base Pairs and CSHL’s blog, LabDish, have officially moved!

BS: Cue the Music!

[m: Tada!/parade music]

AA: Oh! I uh, wasn’t expecting… [clears throat] well anyway, CSHL.edu has just undergone a huge upgrade [- BS: it’s bigger and better than ever! – ] and with it, you can find every LabDish post and the whole episode list—all two complete seasons—of our Base Pairs podcast.

BS: Right! And as always, we can still be found on SoundCloud, Stitcher, iTunes, and wherever else you get your podcasts.

[parade music fades]

BS: But let’s get straight into today’s episode! And for it, Andrea and I have decided to dive into a subject that many scientists and science enthusiasts…

AA: …which I’d guess is most of you, dear listeners…

BS: …yup, it’s something that you guys may be familiar with already… and might even be a little worried about. [p] That’s because today we’re going to talk about what many are calling science’s “reproducibility crisis.”

[MT]

IO: It’s a little bit like, if you provide enough information, like grandma and her recipe for meatballs, then, the meatballs should more or less come out the same.

AA: That is Doctor Ivan Oransky. He’s a Distinguished Writer In Residence at New York University’s Arthur L. Carter Journalism Institute and the co-founder of the website known as Retraction Watch.

BS: That’s him! I reached out to Ivan because he has written a lot about the so-called “reproducibility crisis,” and I was hoping he could share that knowledge with us. [p] So, of course, the first things we talked about was meatballs.

IO: Now, in terms of grandma’s meatballs, I want a little variation, a little variability, otherwise, life becomes very boring. Biology has that natural tendency—biology has natural variation, natural variability, and so that’s to be expected. It’s not that you would expect to get the exact same results every single time.

BS: But you would still expect to get meatballs… Now, this is a metaphor, obviously, but it really gets at the heart of what we mean when we say “reproducibility” in this episode.

AA: Ok, then let’s say that I, a chef, want to make the next great meatball. I’m reading my cookbook literature and I stumble upon a meatball recipe that I just HAVE to try, and then, maybe build upon. So, I set up my kitchen and get to work.

BS: Now in this metaphor—now follow me here—chef is to scientist, recipe is to paper, cookbook is to journal, kitchen is to lab, etcetera, etcetera, and so on.

AA: Right and at the end of it all, after following the recipe as closely as I can, I have made…

BS: An apple pie.

AA: [laughs] A what?!

BS: An apple pie! Or the most delicious chicken cordon bleu ever, orrrr maybe just a charred square of what was once chop meat. Whatever your result, it’s clear to you and me that that’s not meatballs. Even accounting for the natural variability of biology, like Ivan said, clearly, there was something wrong with the recipe you used.

AA: In other words, the paper’s result—if we step away from the metaphor—was not reproducible. [p] But then what? Say I find out that something is wrong with this paper. What happens then?

[MT: explainer]

BS: Well, one of the celebrated parts of science is that it undergoes peer review and in turn, is self-correcting. If enough folks realize there is something wrong with a recipe, they stop using it. Maybe an edit is made. Or maybe, the recipe itself is removed from the cook book entirely.

AA: That last part is called a retraction—when a paper’s author or the journal where it’s published actually take it down. And being part of Retraction Watch makes Ivan and his colleagues particularly aware of this kind of thing.

IO: So, the rate of retractions has been definitely been on the rise. It’s actually a pretty dramatic increase from year 2000 when there were about 35 retractions in the literature out of about probably about a million papers published. The year 2016, when we had sort of the most up to date information so far, there were more than 1,300 retractions. There were about two million papers published, so, obviously the denominator increased, but, overall, that still represents a pretty significant increase in the number of retractions, and the rate of retractions, more importantly.

BS: Now, Ivan was careful to tell me that knowing the rate of retractions lets you know one thing for certain: The rate of retractions. However, he added that if he had to guess, he’d say the rising rate is –

IO: due to at least two factors. One of them is pretty clear, which is that we’re all better at finding problems in the literature. There are more people looking at papers. It’s also, certainly, at least possible that there’s more misconduct happening.

AA: Oh my. Misconduct. Ivan’s talking about the possibility of fraud. That can happen in highly competitive environments and science, of course, is not immune. However, in the case of our discussion today, Brian, we’re actually going to focus on that other part, right? The fact that we’re getting better at finding problems.

BS: That’s right. This increased scrutiny of scientific literature has led to the discovery of all these papers that, despite being driven by hard work and genuine science, STILL can’t be reproduced. In fact, a stunning analysis in 2015 from the non-profit Global Biological Standards Institute in Washington DC attracted a lot of attention. They estimated that billions of dollars each year are spent on biomedical research that cannot be reproduced successfully. They went as far as to say we might have a “reproducibility crisis” on our hands. But… that might not be the best name for it.

RH: I don’t think this is a crisis, because I think this has actually been a problem in science for a long time.

BS: And that is Richard Harris.

RH: I’m Richard Harris. I have been a science correspondent at NPR for 32 years. I wrote and published a book last year called “Rigor Mortis,” about rigor and reproducibility in biomedical research.

BS: The Financial Times called the book “Rigor Mortis” “a rewarding read for anyone who wants to know the unvarnished truth about how science really gets done.”

AA: Oh! I’ve heard of this book. It describes a lot of the reasons why research may not be reproducible and the problems that this can cause in academia and industry alike, so I was happy to hear Richard had some good news too.

RH: People are now aware about the scope and the seriousness of this issue, and I think that’s good news because I think that means people are thinking about how to make it better.

BS: However, Richard was quick to add that in the case of irreproducibility, it may be that we first want to see even more corrections and retractions.

RH: I think there’s … a little bit of trepidation about admitting errors. If it’s a serious mistake, it’s to say I would like to retract my paper and take it out of the literature because there’s something fundamentally wrong with it. The problem is that that’s very often perceived as a black mark for a scientist. Even if a scientist is really doing the right thing, saying, “Oops, I screwed up a little bit here. I want to tell the community and I want to take this out of the literature,” that’s often seen as a potential sign of fraud or misbehavior or something like that. So, scientists are very reluctant to do that unfortunately and that means a lot of papers in the literature that are problematic aren’t removed.

AA: This is a powerful reminder that scientists—when all is said and done—are people, like you or me! So, it really shouldn’t come as a surprise that mistakes happen and sometimes go undetected, ignored, or unreported.

BS: And to solve this problem, Richard explains that we need to first get rid of the stigma surrounding experimental mistakes. After all, without mistakes to learn from, how else can scientists improve?

RH: I think we have to recognize that error is part and parcel of the scientific process. We can’t pretend or we shouldn’t imagine that everything will be 100% perfect. In fact, I think if scientists strive for that, then they won’t be trying hard enough to push the frontiers … The question is can we shorten the cycle between understanding there’s an error and recognizing that—and getting the word out that actually we have a deeper understanding and that turned out not to be correct and so on.

AA: That’s a wonderful point he’s making, and it reminds me of a recent conversation I had with a biologist right here at CSHL. He told me a story that shows how learning from those kinds of “errors”—the ones that arise from the unknown unknowns at the frontier of discovery—those errors can help drive science forward. Reproducibility, after all, isn’t as black and white as your conversations about retractions may make it seem.

[MT] (chat setup from last year’s interview?)

AA: That scientist’s name is Jason Sheltzer. He’s a CSHL Fellow. And he ended up in the middle of this whole reproducibility issue when he accidentally discovered that the target for a cancer drug that’s in clinical trials… well, that drug target is actually not involved in involved in tumor growth at all.

BS: Uh-oh. And it’s in clinical trials, so that means actual cancer patients are receiving this drug.

AA: Yes.

BS: What went wrong?

AA: Well, ideally scientists would have figured this out earlier of course, so you could say something went wrong in that sense—and we’ll get to that. But when I talked to Jason, this is what he said about the role of contradictory results like these in science.

JS: I think that finding contradictory results, and then understanding why you found you a contradictory result — is a very important scientific endeavor.

BS: Oh Ok. So, we’re talking about contradictory results here. Like when you made apple pie instead of meatballs at the top of the episode. That was quite contradictory.

AA: Right, but I picked this story in particular because it shows how complicated this reproducibility thing actually gets. In fact, up until Jason made his accidental discovery, it was as if everyone thought apple pie WAS meatballs…. But I’m getting ahead of myself.

[MT]

AA: Jason and his team just published their second paper about this, in February, but they first reported results that invalidate the cancer drug target, called MELK (that’s M-E-L-K), about a year ago.

BS: And MELK is a gene?

AA: Yes, MELK is a gene that has the instructions for building the MELK protein. The protein is actually the part that the drug was supposed to be targeting. And when Jason’s team started those experiments, they weren’t even trying to learn about MELK, because they thought what the other scientists thought: that cancer cells are addicted to MELK and therefore getting rid of MELK makes it impossible for them to thrive.

BS: Or in other words, that our apple pie recipe makes meatballs.

AA: That’s a bit of a simplification, but yes. It’s a lot like that.

JS: There are a number of different genes that cancer cells express, which they depend on, which they are addicted to in order to grow and divide and metastasize, and do all the terrible things that they do. Sometimes when you can mutate or block the function of these cancer addictions, you can kill the cancer cells.

BS: And I’m guessing that’s what researchers thought this cancer drug did. They thought it killed cancer cells by blocking MELK.

AA: They thought so. Actually, Jason and his team were so confident that MELK was an addiction for cancer and therefore a good cancer drug target that they used it to kind of standardize their experiment, as a point of comparison.

BS: A control.

AA: Exactly. They were setting up this big screen where they would delete various genes in cancer cells—get rid of those genes entirely—and then see which genes cancer cells could live without and which ones they were totally addicted to. And when you’re designing an experiment like that…

JS: …you want, as controls, to be able to target something that is a known addiction and one of the controls that we chose for our work was this gene called MELK, which had been published to be an addiction of breast cancer. However — it didn’t behave like a cancer cell addiction, and we could mutate this gene in breast cancer cells and they didn’t seem to care at all.

BS: That must have been confusing. Hadn’t the earlier MELK results been reproduced before? They must have if the supposed MELK-targeting drug was already in clinical trials.

AA: Many different groups had independently reproduced the MELK results. Since 2005, more than 30 papers have reported results that implicate MELK as a cancer drug target. Like I mentioned before, there’s more to this reproducibility issue than simply repeating experiments and getting the same results.

JS: In biology people often talk about technical reproducibility and conceptual reproducibility. And technical reproducibility, I think means — doing everything step by step in an exact same manner and then coming out with the same results — and that’s of course very, very important for the biological literature. But one step beyond that is conceptual reproducibility, which is taking a concept or a conclusion demonstrated by an experiment and then showing that you can come to the same conclusion using a different approach.

AA: And getting to conceptual reproducibility by using different approaches to answer the same question is important, because repeating the same experiment over and over again can only get you so far.

JS: With technical reproducibility, if there is some flaw in the technique, if you use a chemical that’s not specific or if there’s some error in the protocol, well if you do the same protocol ten times the exact same way with the exact same error, you’re gonna get the same result each time but that doesn’t mean your conclusion is correct.

AA: In fact, the scientists who did this MELK research did test its effectiveness as a drug target with two different methods, so they did even achieve a level of conceptual reproducibility.

JS: But sometimes in science you can answer a question using two different techniques and get the same answer but you pull a third in and the third gives you a different result, and science has to be internally consistent, and in this case it wasn’t.

BS: Ok, then what did Jason’s team do differently from the scientists who had done all of that earlier research showing that MELK is a promising drug target?

AA: CRISPR.

BS: Ah, that is new—relatively at least. We’ve talked about this tool called CRISPR in a couple of our previous episodes because it has had an enormous impact on biological research in the few years since it’s become widely available. CRISPR—that’s C-R-I-S-P-R—is a gene editing tool that enables scientists to make changes to the genome more precisely than ever before.

AA: Which is great! But that also means the best technology that scientists had at their disposal before CRISPR was not as precise. That doesn’t mean that the older technology was useless—far from it. Jason told me about the pre-CRISPR technology that scientists used in the earlier MELK research.

JS: As a cancer researcher, we try to investigate cancer genomes in different ways and some of the previous ways that have been very popular and in many cases very, very effective have involved a technique called RNA interference.

[MT- explainer]

AA: The whole idea of RNA interference was a really big deal when scientists discovered it in the late 1990s. Earlier on, the thinking was that RNA was little more than a messenger for DNA, the molecule that carries the entire genome. But RNA interference showed that a cell’s RNA often tells the DNA what to do, in a sense. It can “interfere” with the process of making proteins based on particular genes, and it does that by binding to those parts of the DNA.

BS: It basically turns the volume on a gene down, and that’s a really useful way to learn about what a gene does. It’s a way of learning by subtraction, you might say. When one element and only one is altered, is there any difference in the organism or cell? Scientists—including Professor Greg Hannon, who was then at CSHL and now at Cambridge Cancer Research UK—figured out a way to tap into the cells RNA interference system and target specific genes they were interested in. That way, they can see what cells do without that gene.

AA: Super useful. Learned a lot with it. But—

JS: Unfortunately, it also has off-target effects in some cases. And you can try to block the expression of one gene, and you end up blocking the expression of another.

BS: Off-target effects are exactly what they sound like, and they can really throw off an experiment. It can be very hard to draw the right conclusion when you change more than one thing at the same time, especially when you don’t even realize it’s happening.

AA: CRISPR produced such a different result because you can target a gene much more precisely.

JS: With CRISPR, one thing that we were able to do is we were able to generate cancer cells that totally lacked MELK expression. They had a deletion in part of the genome where MELK is encoded, so they have no MELK left whatsoever. So if you have a drug that targets MELK, and then you take a cell line that has no MELK, you would expect that cell to be resistant to that drug. We found exactly the opposite. The cells, which were MELK knockout, which totally lacked MELK expression, still remained totally sensitive to the MELK inhibitor that’s being given to cancer patients.

BS: Oh, that’s a relief! The drug still killed the cancer cells, just not the way that scientists thought it does.

AA: Right. Cancer patients may still benefit from the drug, even if no one knows exactly why. All we know now is that whatever it DOES, it doesn’t do it by targeting MELK! In any case, Jason has reached out the physicians involved in that clinical trial about his team’s MELK findings, and has been in touch with some of them via email.

BS: Well, cells that don’t have MELK at all definitely shouldn’t respond to a drug that targets MELK. That sounds like compelling evidence. But, if Jason and his team already invalidated MELK as a cancer drug target, what is this new paper about?

AA: Even though the first paper was pretty strong evidence that MELK was not a cancer drug target, they were still skeptical.

JS: There were a number of caveats and limitations to the work that we did.

AA: They had still only looked at cancer cells in a dish, not an actual organism.

BS: Experiments done on cells in a dish are really useful, but sometimes cells behave very differently when they’re part of a full, living body.

AA: That was the logical next step to see if their conclusion held up.

JS: We did a number of additional — screens — including what’s called in vivo work, doing experiments in mice instead of just in a Petri dish, where we continued to look at MELK. And our additional experiments largely recapitulated our initial observations, which are that we can delete MELK — and the cancer cells unfortunately, continued to divide.

BS: It seems like a moment that might have at least been bittersweet, not just unfortunate. After all, their results suggested that they were right about MELK! But they didn’t really want to be right about this.

AA: Yeah, Jason was not excited to be right about the conclusions from earlier experiments being wrong because…

JS: …well, because the more drug targets you have in breast cancer, I think the better it is for breast cancer patients.

AA: But being a scientist means you have to go with what the evidence tells you. That’s what the scientific process is all about, and the scientific process is really what science is. Scientists like Jason want to find ways to stop cancer, but they have to make decisions based on evidence, not what they want to happen.

JN: Showing people how evidence-based thinking works with real experiences and real stories I think is important.

BS: That sounds like Jackie Novatt! And… coins clinking? Where was she?

AA: I caught up with her over tea recently here at Blackford Bar on campus, and I had the recorder on while we talked—that’s why you heard coins in the register in the background. She was a researcher here at CSHL until a little over a year ago, and now she’s pursuing teaching at Long Island University’s Pharmacy School. As I’ve been learning about this MELK research story, I keep thinking back to this one part of my conversation with Jackie. She was telling me about her experiences leading tours of the CSHL campus and telling people about the work that scientists do.

JN: I found it important to tell people about the failed experiments too, because that’s not something that you hear a lot about. And I’m sure—I don’t know if you’ve had this taxi driver, but there was one at Rockefeller, there was one at my grad school, and there was one here, where you get the taxi driver that hears you’re going to the Lab and then berates you for sitting on the cure for cancer and then hiding it because we all want money and we want to control the world.

AA [in recording]: I knew this story before you even told it, because I’ve had the same experience.

JN: We’ve all had that experience. And the thing is, people truly believe that because we’ve been fighting the war on cancer for a long time and a lot of money has gone into it, and why the heck don’t we have a cure yet? And the reason is, it’s really hard and it’s really complicated and a lot of experiments fail. And if we only communicate that A leads to B leads to C leads to this beautiful conclusion, then why the heck haven’t we cured cancer yet? So, I think it’s really important to communicate the failures as well so that people see science as a process, not as an endpoint.

BS: It’s heartbreaking to hear this kind of misconception about the power of science.

A: It really is, because the root of it is the belief that science is powerful, which is true. But if you are a busy person who is just catching the headlines, you could get misled about what the power of science is—where it really comes from.

JS: Lots of scientific discoveries get boiled down to, oh this is a cure for Alzheimer’s, oh this is a cure for cancer, oh this a cure for heart disease. But in many instances what’s actually been discovered in the lab is insight into a biological process, is the discovery of a gene that might be important in a particular disease, the finding that a drug in a cell line model or in a mouse line model has a moderately beneficial effect. But often times the translation from what was actually discovered in the laboratory to how it’s reported in say, the newspaper or on a website, you can lose a lot of the detail and you can lose a lot of the subtlety.

BS: Those headlines can make it sound like the science is done, or we’ve reached the “endpoint,” as Jackie put it. But in reality, science reveals answers bit by bit. We always need more because that’s the only way that science can self-correct, like it did with the research on MELK.

AA: Exactly. Now, scientists know that the secret behind that drug’s ability to kill cancer cells is not MELK, but something else. Understanding what is really allowing the drug to kill cancer cells is really valuable knowledge, because it helps researchers design related drugs or fine-tune existing ones. [p] This story shows why scientists have to remain skeptical. Even when science brings us exciting things, like new potential treatments for cancer, there is always more to learn.

IO: when science works, it is absolutely, there’s no question, it’s the best way to understand the world …

AA: That’s Ivan Oransky of Retraction Watch, from the top of the show.

IO: but I will also challenge those aspects of the scientific endeavor—The human endeavor which is science—I will challenge that to be as good as I know that everyone wants it be.

BS: And we wouldn’t have it any other way! … But what does Richard Harris think about all this? After all, his book “Rigor Mortis” dives into many other causes of error and irreproducibility that we didn’t get to explore in this episode.

RH: Science is a matter of trial and error. We learn a little bit and we make an observation. We do our best to interpret those observations but then when we get more information or deeper insights or better tools, we realize, you know, we didn’t quite understand everything as thoroughly as we thought and so we improve our knowledge and our understanding of science.


B: That’s all folks – thanks Rich and Ivan

A: Thanks Jason Jacky…. Musicians in this episode include, Broke For Free, Podington Bear, Lee Rosevere, Ketsa, the united states army old guard fife and drum corps, and—as always—the Blue Dot Sessions.

B: We’ll be back next month with another new episode, but in the meantime, we’d love it if you’d review us on iTunes and tell us what you think of the show!

A: Were coming to you from Cold Spring Harbor Laboratory: a private not-for-profit institution at the forefront of mol biol and genetics. If you’d like to support the research that goes on here, you can find out how to do that at CSHL.edu. And while you’re there, you can check out our news-stand, which showcases our videos, photos, interactive stories, and more.

B: And and if that’s not enough, you can always pay us a visit! Between our Undergraduate Research Program, high school partnership, graduate school, meetings & courses, and public events, there really is something for everyone.

A: I’m Andrea.

B: And I’m Brian.

A: And this is Base Pairs. More science stories soon!

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