When you hear the word "metabolism," what do you think about? Thanks to the groundbreaking work of chemist Gary Patti at Washington University in St. Louis, instead of diet or weight loss, we think: "possible cure for cancer." Patti explains how metabolism is like Google Maps, helps us understand the emerging field of metabolomics, and shares the challenges and promise of metabolism research.
Claire Navarro (host): Thanks for listening to Hold That Thought. I’m Claire Navarro. Here at Washington University in St. Louis, chemist Gary Patti spends a lot of his time thinking about metabolism. If you’re like many people, when you hear the word “metabolism” the first thing that comes to mind might be diet or weight loss. But metabolism is much more than that. As Dr. Patti will explain, metabolism is the complex chemistry that goes on inside our body all the time – and understanding that chemistry may lead to future treatments for cancer. Metabolism research has changed rapidly over the last 10-15 years, but according to Patti, his lab’s work is part of a longer history.
Gary Patti (guest): It was very in fad to do metabolism research in the 50s and the 60s and even the 70s, but around the beginning of the 80s and the 90s, it kind of fell out of fashion to do metabolism research. There was a sense that everything in metabolism had already been discovered. You know the textbooks were written, it was a closed book, and there's just no reason to do research in this area anymore because everything was already known.
CN: That was before the rise of big data, super fast computers, and what are known as the “omic” sciences.
GP: And “omic” really, to take all of the kind of fanciness out of it, just means a lot of something.
CN: Think of genomics, where scientists measure huge numbers of genes. Patti is a leader in the field of metabolomics – the “omic” science of metabolism.
GP: Metabolomics is one of the newest “omic” sciences. It's probably about 10 or 15 years old now. And metabolomics is exactly analogous to genomics. But instead of trying to measure all of the genes, what we try to do is measure all of the metabolites.
CN: That sets up the question, what is a metabolite? As Patti explains it, metabolites are one of the three types of molecules found in biology. First, there are the genome-type molecules.
GP: Genes, DNA, RNA, stuff that encodes what we look like and all of the genetic information.
CN: Then, there are proteins.
GP: Which are things like enzymes that catalyze reactions. Those are really big things.
CN: Big, as far as molecules go, at least. And then finally, there are metabolites.
GP: And metabolites are what the proteins act on. So metabolites that most of us are familiar with are things like glucose, sugars, cholesterol, amino acids - those are all metabolites. They're very small things.
CN: Since metabolites can come from the food you eat, yours may be different from the metabolites in the body of your neighbor or your coworker.
GP: You can imagine that if you're on some really weird funky organic diet that you're putting a lot of things in your body that maybe someone that's just eating McDonald's hamburgers isn't putting in their body. And so there's going to be a lot of molecules that are floating around in that person's body on that diet that may not be present in other people's diet or other people's blood samples.
CN: With metabolomics, Patti measures these itty bitty metabolites using an instrument called a mass spectrometer.
GP: And so what ends up happening when we do metabolomics is that we take a sample and we get thousands and thousands of signals. It's common to get 40,000 signals in a metabolomics experiment.
CN: That’s a lot of signals. But not all of them are actually metabolites – some are false signals, like maybe there was a tiny speck of dust on the test tube. Patti and his team have to sift through all the data and figure out what’s what. But there are a couple of really big challenges. For one, nobody really knows how many metabolites are out there.
GP: This is something that's highly controversial. So some people think there are thousands, hundreds of thousands, and other people think that there's just a small handful - maybe tens or twenties. So it's really a completely wide-open area.
CN: And, perhaps an even bigger challenge is this: nobody knows what most of these metabolites are. Remember all that metabolism research going on in the 50s and 60s, the research that supposedly gave a full picture of metabolism? In reality, that picture wasn’t so complete, after all.
GP: One of the things metabolomics has taught us is that the metabolites that are in the textbooks that we think we knew everything about in the 50s and 60s and 70s represent only a fraction of what is actually present. And for me that's kind of one of the most exciting aspects of metabolomics, that there's all of these new compounds that are floating around in you or me and we just don't know what they are. We don't know what pathways they're in, we don't know what their biology is, what their functions are. And that's one of the things that we're interested in and are doing research on in my lab.
CN: So it’s possible that there are thousands of these mysterious, unknown metabolites in your body right now. And it was only recently that chemists even knew how little they know.
GP: This is really the new frontier. It was like when we thought we had a map of the entire geography and then all of sudden, we've discovered this entirely new space to explore.
CN: So, what does this new frontier have to do with cancer? A moment ago, Patti used the word “pathways” to describe one of the mysteries of metabolism. That idea is important. Because understanding metabolism isn’t just finding and naming all the metabolites, even though that’s a huge job in itself. In your body, these metabolites aren’t just floating around on their own – they change and transform all the time.
GP: If we took a cell and we dropped the molecule of glucose into the cell, it wouldn't stay as glucose. It would get transformed. So there's a lot of chemical reactions in a cell that take that glucose and convert it to something else.
CN: It’s helpful to think about this process of transformation as a pathway. A metabolite starts at point A and ends up at point B.
GP: So I often think of metabolism kind of like Google Maps, and a pathway is really just a road.
CN: Let’s dive into this a bit. Think of opening up Google Maps on your computer or phone. Let’s say you want to get the airport.
GP: We're currently at Washington University and if I asked you how to get to the airport you may have one set of directions, but I may say another set of directions. So there are a lot of different pathways, or a lot of different routes, to go from Washington University to the airport. And similarly, there's a lot of different ways to take glucose carbon and transform it into cholesterol. The pathway describes exactly the process of transformation and how that occurs.
CN: Now just because there are many ways to get from point A to point B, doesn’t mean a route is totally random. Keeping thinking about this trip to the airport.
GP: If I asked you how to get there or if we went out and asked a hundred people how to get there, most people would give us this fairly direct route.
CN: This is also true within our bodies. For most cells, the direct route, the regular way of doing things, leads them to store as much energy as they can. But here’s where things get interesting. Not all cells behave this way.
GP: More recently, a lot of scientists have started thinking about cancer. And one of the things that cancer cells do is they violate that principle - or at least I should say they seem to violate that principle. Cancer cells have a really different metabolism.
CN: So if a cancer cell was hopping into a car to drive to the airport – yes, cancer cells can drive now – it might drive down to South County then over to East St. Louis then up north to the airport. Not the normal way of doing things.
GP: They do this really paradoxical thing where the pathways they employ just don't seem to make sense if our assumption is that cancer cells are trying to get as much energy as possible. And one of the things that I think inspired people to study metabolism again is that basic observation that cancer cells aren't running their metabolism to maximize energy usage out of things like glucose. It's made us think, "how much do we actually understand about metabolism? Why would a cancer cell do this?" It just seems like they would want as much energy as they possibly could get. And so one of the things that my lab is doing, and a lot of other labs are doing, is trying to appreciate why cells run their metabolism this way. And it turns out it's not just cancer cells. It's any cell that's trying to grow rapidly. So any cell that's growing - things like embryos, and other cells that are rapidly growing - also run their metabolism in this way. So there's clearly something beneficial about running your metabolism this way. But we don't yet understand why.
CN: In the future, understanding more about the metabolism of cancer cells could help scientists develop treatments for cancer. But then of course, we come up across yet another challenge. If other kinds of rapidly growing cells behave this way, not just cancer cells, how can you make sure that a medication targets just the cancer cells?
GP: And so one of the things that we're interested in my lab is trying to sort those two things out. What is the difference between a normal healthy cell that's rapidly growing and a cancer cell that's rapidly growing? Because until we understand those differences, we can't shut down, or we can't target, specific pathways. Because we don't want to go after and shut down a pathway like lactate utilization in a cancer cell, if any cell in our body that's rapidly growing also relies upon it.
CN: The possibilities here are really exciting, and Patti’s lab has already made some important discoveries – you can find links to some articles about his lab’s projects on our website. But as we’ve heard, there are so many hurdles along the way. I asked Patti how he deals with all of these challenges when researching something as complex and important as cancer.
GP: My post-doc mentor used to say that the most important quality for successful scientists isn't how smart you are or how good you are with your hands, it's resilience. You just have to be resilient in so many ways. Your experiments often fail, and then when you finally get a successful experiment and you tell somebody about it, like if you tried to publish it in a journal, they will say, "we don't believe it." And then you have to prove that it's right, and you have to go back and repeat it five times, etc. So there's a lot of challenges to overcome in discovery in general. We have success stories where we have found unknowns, we have identified new pathways, we have identified targets and therapeutics for those pathways that are effective in animal models. So there is some enthusiasm that can be got by looking at those success stories, but how much does that help a new student? I think that one of the things that you have to appreciate is that there are a lot of challenges and then when you get a good result, you have to really stop and take it in.
CN: And, even failed experiments teach you something, Patti says. Overall, successful scientists learn to enjoy the whole process and are passionate about they’re trying to accomplish.
GP: It's a big puzzle. We're dedicated, and committed, and obsessed. I think obsessed is a good word. I am obsessed with trying to solve these problems. If you've ever tried to put together a jigsaw puzzle and you get halfway through, you're obsessed with trying to figure out the rest of it - you want to finish it. And I think scientists tend to have that obsession. It's one of the things that really drives us.
CN: Many thanks to Gary Patti for joining Hold that Thought. For many more ideas to explore, please visit us at Holdthatthought.wustl.edu or on Facebook or Twitter. Thanks for listening.