Anti-cancer molecule
In the latest episode of Discovery Matters, Dodi and Conor are joined by Dr. Bradley Moore from the Scripps Institution of Oceanography to discuss his research into the medical and synthetic implications of using marine microbes to fight aggressive cancers such as glioblastoma. By leveraging salinosporamide A, Dr. Moore proposes that these deep-sea organisms could potentially be scaled up for human use and repurposed for medicinal and synthetic purposes. Dive into this episode to hear how the ocean has the power to bring forth new discoveries that could save lives!
Show notes
For more information on this 'anti-cancer weapon': Scientists Discover How Molecule Becomes Anticancer Weapon | Scripps Institution of Oceanography (ucsd.edu)
DODI: Conor, for today's episode, we have to go to sunny San Diego. Aside from being a bustling metropolis of biopharma innovation, what comes to mind when you think of San Diego?
CONOR: I think of Top Gun and Maverick, surfing, and waves on the west coast and these marvelous things that are southern sunny California.
DODI: I think it has all the right features to be your dream city if you just didn't live in the sunny United Kingdom, am I right?
CONOR: Yes, it's marvelous here too.
DODI: Today we're concerned with the cancer fighting molecule that was found in the ocean.
CONOR: I knew it! Suffering as a savior. But seriously, marine chemical biology is what matters today on Discovery Matters.
BRAD: I'm Brad Moore. I'm a professor here at Scripps Institution of Oceanography, which is in lovely La Jolla, California.
DODI: Brad is a distinguished Professor of Marine Chemical Biology. He sits in his office at Scripps, which is just a stone's throw from the Pacific Ocean. Predictably, he has an affinity for the ocean and aside from his love of surfing, his love of the ocean is evident in his research. Frankly, he invited me to go surfing when I was out there, but I was too wimpy.
CONOR: Well, you should have gone because there are good brakes.
DODI: I wish I had.
CONOR: I can only agree that you're too wimpy. So, I empathize with Brad's love of the sea.
BRAD: I guess when I look out my window here, and I gaze out at the Pacific Ocean, I see endless possibilities of life that is evolved to our planet and the environment that it lives in. You know, most organisms have evolved their ability to make little molecules to solve big problems that they have to encounter. We as humans can really benefit from this wisdom of nature and evolutionary processes that last millions of years that perfect these little chemical processes. Maybe we can use that inspiration to develop drugs for us.
CONOR: So, in the development of drugs and therapies, taking inspiration from nature is just a favorite topic on our podcast.
DODI: That's right, we had an episode dedicated to biomimicry and how it can be used in space. But if you read the quote, and I think I heard Neil deGrasse Tyson say it (maybe he was quoting someone else) but he says that we know more about space than our oceans.
CONOR: Oceans aren't full of plastic, right? No, they are!
DODI: They are. But space isn’t.
CONOR: It's kind of crazy, though, right? You can look outwards and find new worlds and whatnot. But there’s so much right here under our noses yet to be unlocked in the sea.
BRAD: For millennia, humankind has been taking inspiration from nature to cure our diseases, you can think back to aspirin coming from bark of a willow tree and so on. That isn't new, what is new, is two things. One of those things is the ability to sequence genomes of organisms and do it fast and cheaply. This is now unearthing the ability for us to read the sequence of a genome, a whole bunch of A, T, C and Gs ,these letters mean code for chemistry, and they code for how molecules are born in organisms. t This then gives us a recipe that allows us to take those sequences and then convert them into evolved chemicals that have a purpose. They can connect to a receptor or a protein to turn it on or turn it off. That’s what medicine does. The second thing, it really allows us to look at organisms that do this, which is pretty much every organism on planet Earth, even the gnarliest insects that freak you out. They've got a beauty to their DNA, and allows us to find organisms that are rare, hard to get at. And I just need a smidgen of that organism just to get its DNA that allows me to then read it and to make medicine.
CONOR: This takes me back to the episode on horseshoe crabs and the blood that they have used in medicine and testing and what a great resource they are in nature.
DODI: Exactly. But procuring the blood of those horseshoe crabs is damaging, not sustainable. But Brad's method is. To access these rare organisms, he just needs a smidgen of that organism to get its DNA, read it, and then make the medicine.
CONOR: But this is a fundamentally different way of doing science, but it's going in a good direction.
DODI: Exactly. In past decades, you would have had to get huge amounts of an organism to find its chemical or unlock its biological secrets.
CONOR: So, is Brad editing the DNA to apply this to anti-cancer molecules, how's it working to treat brain tumors, and so on?
BRAD: So, this brain cancer drug that we've been working with, it comes from a little bacterium in the bottom of the ocean, it makes a chemical that just tells things that it likes to eat and to stay away from. This chemical is called salinosporamide. As a drug, it's called Marizomib, but it's in phase three human clinical trials to treat an aggressive cancer called glioblastoma. This cancer takes over 10 000 American lives a year, Senator McCain and Beau Biden passed away with this aggressive cancer. This marine bacterium just happens to make a chemical that passes through the blood brain barrier and targets a very important protein in cancer cells and inhibits it. So, we're really excited about that. But connecting that chemical in that bacterium, we can connect it back to its DNA, and all the genes that encode that little bacterium to make that chemical, we can now take those genes out, and we can edit them. Then we can begin to make new chemicals that that bacterium doesn't make that's based on that anti-cancer drug and be able to then learn exactly how that chemical works against, you know, this cancer target and really understand it at the molecular chemical, atomic detail, and that nerdy kind of stuff that then allows you to make a drug that works in the human body.
CONOR: This is fascinating. I mean, one small molecule at the bottom of the sea could save the lives of so many, and it's going into what, phase three now?
BRAD: Yeah, so we are still pretty much at a stage where we are still learning about how these processes are happening. So, we're less further along. Those examples in the brain cancer one, obviously, this is left the university and now a pharma company is, sponsoring those studies in hospitals around the United States.
DODI: So, this research is the product of the phenomenal hard work of a team of scientists at Scripps Institute of Oceanography. Brad's laboratory is the melting pot for people to come together. This team is working on another cool project.
CONOR: Okay, go on.
DODI: So, you know, plants are all over the place. One reason that plants have done so well on planet Earth, is that they make a certain chemical called a terpenoid. This terpenoid is important in plant biology because it tells a plant how to live. Plants don't have legs, so they can't move. They use these terpenoids to communicate with other things that can move like pollinators, to protect themselves from threats. I don't know if you've read this book yet, but it's gorgeous, it's called 'The Overstory'. It's a Pulitzer Prize winner. It describes the network of trees, and how they're so interconnected. As far as I know, Brad hasn't read the book yet, but he and his team thought about plants. They realized that there are ancient animals at the bottom of the ocean. They don't move, they don't have legs. So, the question is, how do these ancient deep sea-dwelling animals like sponges or corals, how are they communicating with one another?
CONOR: Did they get an answer?
DODI: Well, the discovery of how is fresh off the press. If I may say it's as fresh as the catch of the day.
BRAD: So, it turns out, they use some of the same chemicals as plants use. But it was a big mystery for several decades that we just solved, literally weeks ago. We published a really fun paper on this that corrects an assumption in the scientific literature that thought that perhaps these ancient animals use microbes to make these chemicals because animals were thought not to make these plant-like chemicals. Well, it turns out, when we sequence their genomes, we began to see these little signature sequences in these animals, genomes that said that they make these terpenoids as well. They cluster genes together. They've got these really cool abilities to make these molecules. So, we can now take this coral DNA, and we can put them into bacteria. And we can make these chemicals. It turns out they have exquisite activities against cancer cells, as anti-inflammatory agents. We're really excited about where this can take us. It also has been that to teach us that these coral chemicals don't just cure human disease, but they also might have a really important role in the coral animal itself. Since corals have been around on planet Earth longer than plants, about 150 million years longer, they've been doing this for a much longer. So, it must be important to these soft corals to retain this ability, I guess, not just retained, but evolved this ability to make these really specialized chemicals that must be important for their biology as well as their health. That’s probably how they're communicating with all the other things that are at the bottom of the ocean.
CONOR: So, there's just this rich source of innovation coming out of the sea. It's amazing, it feels a little bit like the fact that we talked about the biodiversity loss in the rainforest being a real loss of opportunities for human health. It's the sea as well.
DODI: Completely. If anybody wants to investigate more detail of that fun study that Brad refers to, that is of course in our show notes.
CONOR: So, in terms of the next step, what does Brad need to do to have this discovery taken further?
DODI: Well, in short, more research.
BRAD: So, we're looking to build a little biofoundry here at Scripps Oceanography. Taking coral DNA and implanting that into bacteria and yeast to make coral chemicals that we can begin to test against as human medicines, and also begin to sort of test materials that could be important to our wellbeing. Our collaborators were just off the California coast. They brought some submersibles down to a couple of kilometers down, so one to three kilometers in depth and collected small samples of these deep-sea corals. We've now sequenced their genomes. We've looked at their chemistry and we're really charging forward with that part. As I said earlier, definitely we just need a few grams of an organism to get that DNA out. Then forever we have that sequence, and we can benefit from that information.
DODI: Speaking of huge benefits, I wondered whether Brad could see this anti-cancer molecule for glioblastoma scaling up and being as easily accessible as aspirin.
BRAD: I guess the industry has already shown its ability to scale up microbial fermentation to make chemicals, we do that all the time. Many of the medicines we take, like antibiotics and penicillin, you can make those with big fermenters that many industries have now that allow us to make small molecules out of microbes. So, that is all setups. I think that's the beauty of this approach right now because there is an existing industry that allows you to do this. Now we're just trying to repurpose these microbes that we have already in fermenters to make products that are important for medicine, like this glioblastoma drug or other products as well, that might be important to our synthetic world that we live in.
CONOR: That's a very pointed way to end. We have an ocean continually being clogged up by human-made poisonous and harmful materials, plastic and all sorts of nasties and it's got all these secrets that could really hold answers to human health.
DODI: Exactly so who knows what other cures and solutions could be lurking in our oceans on a microbial level. Our executive producer is Andrea Kilin. Podcast produced by Bethany Grace Armitt-Brewster. Editing, mixing, music from Tom Henley and Banda Produktions. Thank you as ever. My name is Dodi Axelson.
CONOR: And I'm Conor McKechnie, please rate us on Spotify or whichever platform you're using. If you are listening on Spotify, there's a poll underneath the episode description. Please tell us what you think. We'll see you when we come back with another episode of Discovery Matters.