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Naturally Speaking: Finding Nature's Treasure Trove with the Global Ocean Sampling Expedition; and Natural Products Chemistry

In this episode, the J. Craig Venter Institute's senior computational biologist Douglas Rusch talks about the Global Ocean Sampling Expedition's genomic treasure hunt and the first batch of research results that just came out. We'll also talk about an analysis of pharmaceutical agents in the Journal of Natural Products that showed that the majority of approved agents in the last quarter century are still derived from natural products. Plus we'll test your knowledge about some recent science in the news. Websites mentioned include http://www.plos.org; http://collections.plos.org/plosbiology/gos-2007.php; http://pubs.acs.org/journals/jnprdf

Welcome to Science Talk, the weekly podcast of Scientific American for the seven days starting March 21st. I am Steve Mirsky. This week on the podcast, we will go on an ocean voyage in search of buried treasure, buried in the genomes of all the gazillions of tiny organisms that live in the ocean. We will talk to Douglas Rusch, the first author on the Lee Publications of [about] the first group of papers to come out of the Global Ocean Sampling Expedition, a large genetic treasure hunt. We'll also talk about another research paper that came out last week that kind of dovetails nicely with the expedition material. That's a report about the continued importance of natural products for medicine. Plus we'll test your knowledge about some of the recent science in the news.

First up, Douglas Rusch. He is a senior computational biologist at the J. Craig Venter Institute—the folks behind the Global Ocean Sampling Expedition—and I talked to him at his office in Rockville, Maryland.

Steve: Hi Dr. Rusch. How are you today?

Rusch: I'm doing quite well. How are you Steve?

Steve: I'm fine, thanks. Good to talk to you. Tell us all about the Sorcerer II Global Ocean Sampling Expedition. What is it? What are you looking for? What do you hope to find?

Rusch: This is an expedition to travel around the globe and explore the unseen world of microbial biology that all the microbes in the ocean—they're too small to be seen and they've really never been comprehensively studied before.

Steve: And I read in your publication that this is actually, in a way, inspired by a famous 19th century expedition?

Rusch: Yeah! That would be the Challenger Expedition; they basically traveled around the looking at life under the ocean on the sea floor, and they would collect samples, if they want[ed], about every 200 nautical miles.

Steve: And obviously back then, they were only at macroscopic life, but you are looking at microscopic life.

Rusch: Well back then, everything below the water was a mystery and no one knew the whole extent of life, and so that was really the first grand expedition, one of these, you know, attempts to really catalogue all the life [in the ocean]. And nowadays, well we still don't know lot about what is in the ocean, but technology is solemnly [suddenly] allowing us to look at the smallest inhabitants, the microbes and even the viruses. So that was the goal of this expedition is to really set to catalogue all the genetic and metabolic diversity that's out in the ocean.

Steve: And why should we care about that stuff?

Rusch: Well, microbes play a key role in our world. They were probably the first organisms here on Earth—well they were the first organisms here on earth—and they helped to generate the atmosphere, they modified the water so that it's clean—I mean the oxygen that we breathe, that's a direct result of them being there. They are photosynthetic, so they convert light into chemical energy, so that helps to drive the whole food chain that suffice all the larger organisms, the fish and everything that we rely on. And if you go in other ways they are intimately associated with just about every large organism you see out there. Nothing can live in the absence of these microbes, so this is actually crucial for life.

Steve: Do we even have a reasonable estimate of how many species of microbial life are out there in the oceans?

Rusch: That would be very difficult to answer. I think we're just starting to get an idea of how many microbes are out there. In a single drop of water, there are a million microbes and anywhere from 1,800 to 18,000 different species in a drop of water; but if you took the entire ocean, the extent of that diversity it[s] just enormous. And so we don't know and that's part of the reason for doing this kind of expedition, so to start to get a handle on it.

Steve: Have you personally been involved in the collection or [are] you back home waiting for the samples to come in and then you do the analysis?

Rusch: Most of the time, I am back home sitting at a computer, analyzing the huge amount of data that comes through. I am trying to sit through it to find some of the interesting species, but I did get to go out on the boat on one particular occasion to try and understand how the sampling process takes place. And that helps you work on the paper and to think about the scientific procedures and results that we get.

Steve: Tell us a little bit about the actual boat—how big is it? How many people are on it? Where is it?

Rusch: The boat—right now—it's right out in the Sea of Cortez and collecting samples from a variety of different interesting environment[s], and then it will be moving up to Santiago in the near future. The boat itself is a 95-foot sailing vessel and it's been modified in various places to facilitate the research and to include having the filtering apparatus, and some refrigerators to store the samples; and it has a high-powered microscope so we can look at the organisms in the water.

Steve: And how big of a crew do you need to operate that?

Rusch: It has four sailors on it and then there is at least one staff scientist and sometimes several other people are involved in collecting and analyzing samples in any given time.

Steve: So this is so much better than being stuck in a lab all day, I would imagine.

Rusch: Well you know, most of the time it is a lot better, but when the weather gets rough out there, it's not an easy thing to do. And actual[ly]—quite—being [that] the collection of the samples takes many hours; and so the one time I had to collect it, I basically spent the entire night doing it, and the seas were quite rough and it is definitely hard work.

Steve: The weather started getting rough, the tiny ship was tossed.

Rusch: (laughs) Well, we didn't become stranded on some small deserted island, but... (laughs)

Steve: Right! but it's much longer than a three-hour tour or so.

Rusch: Oh yeah!

Steve: So, the samples come back to you in the lab and what exactly are we looking for? This is a genomic analysis.

Rusch: Yes! So what happens is once the samples are collected, they are collected on several different filters that pull out different size organisms; and so we take—we have been working on the smallest of the microbes, because their genomic content is also simpler to analyze using the currently available sequencing technology—and so then they come back, we build a library of their DNA and then we start sequencing it—and so this, you know, millions or billions of organisms—and we are looking at their DNA just kind of randomly looking through to see what we can find. In the abundant organisms we find a lot of DNA and for the rare ones we find little bits and pieces that tell us something about them.

Steve: Let me just conjecture a little bit. I mean, I would think that the kind of philosophical foundation here is that each one of these species—unique species—has come up with its own kind of chemistry setter—its own solutions to life's problems—and by sifting through all thisose stuff you might find some ingredients that we can co-opt for our own chemistry set?

Rusch: So that's a very astute statement. In fact what we find is that there is tremendous amounts of diversity associated with these microbes—far beyond I think what people would have initially expected—and yes, they are excellent at finding solutions to their environmental problems—needs— and so they are expert chemists; they are better than 10 PhD's on any individual basis. So, and we can sift through their DNA to look for these interesting things, but we are discovering new genes, new variations on existing genes, new combinations of genes that allow them to survive and prosper in the ocean.

Steve: And these papers that have just come out are the first papers that are the result of the expedition, but the expedition still has years to go?

Rusch: Well, yes I mean this is the first quarter of the sample, so there is three-quarters of the global sampling expedition to still analyze and study, and then we are collecting additional samples even now, so this may be going on.

Steve: And where else is the boat going to be traveling to collect samples?

Rusch: So right now we have a plan to go up along the

West Coast of the Americas, stopping in Alaska in the middle of summer and then come back down the coast and repeat-sample in a number of the sites to see how they change over time.

Steve: Can you, if you're comfortable, you know, go out on a limb a little bit? I mean, the thing is a terrific intellectual adventure for its own sake, but would you just muse a little bit about the possible applications of any other findings that may come along?

Rusch: Okay! I thought It is hard to prognosticate two foreign events. I mean—this really is basic research in many ways. In the long run though, we are going to get a better understanding of microbial communities in the ocean and how they interact. And the hope is if we understand these systems well enough, that someday we actually may be able to tweak them or manipulate them or reconstruct them in certain ways, so they can be used to clean out areas that have become uninhabitable because of maybe some toxic chemical spill. We may be able to modify the microbial environment so that the fish will be happier—that will prevent fish infections or other things like that that could happen. I[t’s]n the really [a] kind of pie-in-the-sky idea, but maybe some of the grandiose things that we figure out—how to increase the rate of carbon fixation at the present surface waters so that would be a substantial solution to CO2 buildup in the atmosphere and then global warming. Now there is also the possibility that we'll learn something about how to convert sunlight into chemical energy which may be very valuable as oil supplies dwindle.

Steve: And any biomedical implications?

Rusch: Well in the direct scheme of things it gives us a better understanding of the pathogens that are in the oceans. These have a direct impact on the life of the fish and on the people who eat the fish, so if we can recognize these organisms, we may be able to treat them better or know when or when not to collect fish. There is also the ability to identify bio medically useful proteins— like antibiotics may come out of this; microbes that are constantly at war with each other, so we may be able to pick up a few chicks from that. And in the long run, there [are]is still so many different proteins out there and lots of these proteins are shared in common with humans and other organisms that were much more familiar with birds, plants, animals and so they have come up with new variations on these and that might teach us something about how our bodies function or how these proteins work—so we may be able to find ways to treat cancer or do something else, but those are very long-term research prospects.

Steve: Sure. This might be little bit inside baseball, but what drove your decision to publish in the Public Library of Science?

Rusch: Well there's a number of reasons. Partly it's the idea that [the] path is open to everyone—that we really wanted this information to be freely available to all the researchers. But it's also very practical—there is so much information that we've uncovered that it would take us a hundred years to really start make sense of it. But by bringing in and making this freely available to the entire scientific community—not just in the United States, but around the globe because a lot of countries don't have large scientific budgets. They can't spend a lot of money to get all these journals, so now they can interact with this data freely and work with it and that will increase the pace of discovery and hopefully bring practical results out of this data sooner than later.

Steve: And anything jumped out at you in this first batch of results?

Rusch: Perhaps the most interesting thing—I mean, I am really just bowled over by the diversities that share—any kind of way that you can have variation appears to occur in the ocean. The idea of what a species is, is going to be fundamentally under debate now in the scientific community because these results and other similar results are suggesting that we just have no idea of how to categorize microbial organisms; and just—I mean, so this is diversity in the sense that at the base pair snip [SNP]—which is the same thing that make few people different from each other—are rampant in microbial communities. But then they also have different genes, they have different genomic architectures, so everything that can change is changing. Maybe one of the other things that was really exciting about this was finding how the environment impacts the microbial communities and how they adapt to that, so that's going to give us a—I think in the long run—a much better understanding of how genetic the combination of genes and organisms interact with the environment and what factors in the environment are important to life on Earth.

Steve: And do you get that information because you see the same organisms in slightly different environments and you see how their protein expression differs?

Rusch: So we haven't actually looked at protein expression, but the gene contents vary from spot to spot even though the communities are very similar.

Steve: So you actually will see some genomic evolution taking place in with minor environmental changes in what appear to be the same species?

Rusch: Yeah! You wouldn't be able to tell these organisms apart, other than one group of them is missing this gene and another group has this gene.

Steve: Yeah!

Rusch: I mean that is directly related to the changes in the environment.

Steve: Very interesting. Well it sounds like you've got the rest of your life to work on this?

Rusch: (laughs) Oh yes! This could easily take a lifetime to analyze. We're not done now, so that'll be even more data.

Steve: Right! I've taken enough of your time, since you have so much work to do. So Dr. Rusch thank you very much, I really appreciate talking to you.

Rusch: Al right thank you Steve. It's been a pleasure.

Steve: For a lot more go to the Web site of [the] Public Library of Science—that's www.plos.org—then hit the link for the journal—PLoS biology—you'll find an entire section called a collection of articles from [the] J. Craig Venter Institute's Global Ocean Sampling Expedition, including more research results, editorials, posters, videos, and journalistic features. There is a really interesting piece on the important ethical and legal issues involved in this effort. As the article notes, "What for one person is pure marine scientific research can be another person's bio-prospecting and yet another's bio-piracy"—interesting stuff all at www.plos.org.

Now it's time to play TOTALL.......Y BOGUS. Here are four science stories with a foodie theme this week. Only three are true. See if you know which story is TOTALL.......Y BOGUS.

Story number 1: Americans are eating more fruits and vegetables.

Story number 2: People have been engaged in all kinds of activities—including driving and eating—while under the influence of sleeping pills.

Story number 3: Soy appears both to inhibit and promote prostate cancer.

Story number 4: An April visitor to the space station will be served roast quail and other gourmande extravaganzas.

We'll be back with the answer, but first I want to talk a little about another research report coming out this week. It appears in the March 23rd issue of a publication of the American Chemical Society, the Journal of Natural Products. The lead author is David Newman. He is the chief of the Natural Products Branch of the Developmental Therapeutics Program—that's a combined effort of the National Institutes of Health and the National Cancer Institute. The paper is called "Natural Products as Sources of New Drugs over the Last 25 Years". You know, drugs have always come from nature. The most famous example is probably aspirin, derived from willow tree bark. The anticancer drug, Taxol, famously comes from the Pacific Yew Tree. It wound up being developed when Susan Harvards at the Albert Einstein College of Medicine in the Bronx realized that the molecule interfered with cell division in a unique way by interfering with microtubule assembly. And there are also reports of chimpanzees self-medicating [daily] with natural products and leaves daily. When they have a particular condition, they'll actually search out particular leaves that apparently they know have some kind of a compound of efficacy in them. Anyway, botany and medicine used to be pretty much the same discipline for us humans. And as we got more sophisticated in our abilities to perform chemical analysis, we were able to discover and isolate the particular molecules that other organisms have come up with that coincidentally have effects on our biochemistry. Plants were always a good bet, but we're now paying more attention to microbes and even animals. The paper mentions a glucose control of diabetics that's based on a peptide found in the venom of Gila monster[s] of all things. The report discusses the continued importance in medicine of molecules that nature has come up with, even in the age of combinatorial chemistry that was expected to come up with new and novel compounds with medical potential that are not related necessarily to natural products. The authors note that of drugs that have been approved for use in the last quarter century, about 70 percent are still derived from natural products. The authors play a little fast with their numbers—but only a little—because some of the natural products have been tinkered with during research to enhance their inherent properties when they are being turned into a drug. For example, may be you alter the solubility or make the molecule bind a little tighter by fooling around with the original natural chemical structure just a little bit, but its probably a legitimate approach to credit such compounds in the natural product's column because they wouldn't be in use at all had not the original natural chemical been found to have some kind of property of interest. Newman, the lead author, notes in a news article that appeared on our Web site, that only two big U.S. pharmaceutical companies dedicate substantial efforts to looking at natural products despite all the evidence that it's a fruitful way to do drug development. Here's something from the discussion section of the paper: "The continued and overwhelming contribution of natural products to the expansion of the chemotherapeutic armamentarium is clearly evident, and much of nature's treasure trove of small molecules remains to be explored, particularly from the marine and microbial environments." So you can see why I thought this paper dovetailed with the Global Ocean Sampling Expedition discussion. The author has also wrote: "We wish to draw the attention of readers to the rapidly evolving recognition that the significant number of natural product drugs or leads are actually produced by microbes and/or microbial interactions with the host from whence it was isolated, and therefore we consider that this area of natural product research should be expanded significantly." All the species on Earth—even the microscopic ones—have come up with unique chemical solutions to the challenges of being alive. So rather than reinvent the wheel—or in this case the aromatic hydrocarbon ring—we might as well let these excellent chemists, tiny though they may be, do most of the work for us, as Douglas Rusch just said a few minutes ago of the ocean microbes#133;

Rusch: They are expert chemists. They're better than ten PhD's on any individual basis.

Steve: To find the paper "Natural Products as Sources of New Drugs Over the Last 25 Years", just Google the Journal of Natural Products—that paper comes up March 23rd. Our news story on the Sciam Web site ran on March 19th and that was titled "Mother Nature Still a Rich Source of New Drugs".

Now it's time to see which story was TOTALL.......Y BOGUS. Let's review the four stories.

Story number 1: Americans are eating more fruits and vegetables.

Story number 2: People eating and driving, despite sleeping pills.

Story number 3: Soy inhibits prostate cancer except when it is promoting prostate cancer.

And Story number 4: Space station visitor to be served gourmet meals.

Time is up.

Storynumber 4 is true. Software billionaire Charles Simonyi gets launched to the International Space Station on April 7th, where he'll dine on roast quail, breast of duck, shredded chicken parmentier—whatever that is—and other culinary extravaganzas—that's according to the story on our Web site titled "Space Station Guest's Meal Plan—Roast Quail to Go". The menu was created for Simonyi by Martha Stewart, rumored to be his girlfriend. Whatever he eats up there, it'll probably taste tangy.

Storynumber 3 is true—soy appears to both promote and inhibit prostate cancer. That's according to a big Japanese study [of] over 43,000 men eating a traditional diet rich in soy. The paradox seems to be that soy will inhibit prostate cancer from developing in the first place, but if it does develop, soy's isoflavone compounds may then encourage the cancer to grow and spread. The study appears in the March issue of Cancer Epidemiology Biomarkers & Prevention.

And Storynumber 2 is true. All kinds of reports have surfaced about people engaged in wakeful activities while on sleeping pills. These include driving, Internet shopping, eating, sex, and making phone calls—while the people thought they were asleep. The FDA announced last week that 13 drugs will receive new warning labels alerting people to the slight possibility that they could wind up in a car in their pajamas—or the car got in their pajamas, I'll never know.

All of which means that storynumber 1 about Americans eating more fruits and vegetables is TOTALL.......Y BOGUS. Because a new study found that our consumption of fruits and vegetables is still woefully under the five recommended servings a day and veggie consumption actually dropped slightly lately. For more, check out the Monday March 19th edition of the daily Scientific American podcast 60-Second Science, on which I said, "This is an apple (fruit-crunching sounds)—it's good for you.

Well that's it for this edition of the weekly Scientific American podcast. You can write to us at podcast@sciam.com. Check out news articles at our Web site, www.sciam.com, and the daily Sciam podcast, 60-Second Science, is at the Web site and at iTunes. For Science Talk, the weekly podcast of Scientific American, I am Steve Mirsky. Thanks for clicking on us.

Web sites mentioned include http://www.plos.org; http://collections.plos.org/plosbiology/gos-2007.php; http://pubs.acs.org/journals/jnprdf.

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