Breathtaking Biology – a metabolome adventure

Dr. Biology:

This is Ask A Biologist. A program about the living world. And I'm Dr. Biology. For some of our listeners, Metabolome is a new word. And if today's episode is going to be an adventure, we should begin with what a metabolome is. So, I want you just to imagine you have a workshop filled with lots of different tools, and each tool represents a molecule in your body. Now think about all the different ways these tools can be used to interact with each other. That's kind of what a metabolome is. 

For a real metabolome, it is a collection of all the different molecules in your body. These molecules called metabolites are important because they help your body do different things. Some metabolites give you energy. Some help your cells grow and others help your body get rid of waste. To name just a few. Just like how different tools can be combined with other tools and used in different ways, the molecules in your body can also be arranged and used in different ways. 

Your body can take in food and break it down into smaller molecules that it needs. It can also change the molecules into different forms to use it in different parts of your body. Some scientists study the metabolome to understand how these molecules work together and how they affect our health. They can look at different metabolites in your body and see if there are any patterns or changes that might be related to certain diseases or conditions. 

Our guide for this episode is Heather Bean. She's a bioanalytical chemist and a faculty member in the School of Life Sciences at Arizona State University. Her research is all about, well, something that takes your breath away and figures out what's in it. Heather, thank you so much for joining me on Ask A Biologist.

Heather:

Thank you so much. Dr. Biology I'm so happy to be here.

Dr. Biology:

Now, I gave my view or my definition of what a metabolome is. Do you agree or would you put a little bit of your own twist on it?

Heather:

I thought that was a really great start. There are different ways that people think about the metabolome often depending on what they are interested in. In the metabolome some people are interested in how the metabolome fits into what we call the central dogma of biology, how our genes encode all the information about how our entire organism is supposed to work, how those genes are transcribed into RNA that are instructions for making proteins. 

The proteins can be structural. They can be enzymatic and perform functions in our body. And then beyond the proteome or the collection of proteins in our body is the metabolome. That is sort of the next link in the chain of going from our genes to our entire phenotype. All the expressions and the ways that our cells function, our organs function, our tissues function, how our entire bodies function, that's our phenotype. 

So, the metabolome is one of the ways I think of it is a link in that chain between our entire being in the genes that lay out the instructions for what we are.

Dr. Biology:

And it's perfect timing because the last episode we had Brandon Ogbunu in here and he's a big fan of RNA, and we actually talked about this central dogma of biology. So, this is the next piece in the story. Well, we talk about metabolomes, and we said animals and plants. So, we're saying all living things.

Heather:

That's true.

Dr. Biology:

So, you have a metabolome and I have metabolome. Yes. Is your metabolism the same as my metabolism?

Heather:

Absolutely not. And my metabolome right now, as I sit at this chair, talking with you is not the same as it was this morning right after I ate breakfast. And it's not the same as it was when I ate the same breakfast yesterday. 

Our metabolome is constantly changing. It's a reflection of everything that we are taking in as far as nutrients. Everything that we are exposed to in our environment, everything that our cells are producing as a process of their day to day living and all of the waste that is being generated. The metabolome is really a very small snapshot in time of how our entire organism is operating. And my metabolism is different than your metabolome is.

Our metabolisms are going to be different from another person's. But part of what I'm interested in is not just the differences, but what are some of the commonalities between metabolomes and what that can tell us about our current physical state at this time?

Dr. Biology:

Could this lead us into some areas such as I mentioned a little bit about disease? Is this one area that would be really important to know about how some metabolisms are very similar?

Heather:

Yes, that's something that I actually specialize in. So, one of my big interests in the metabolome is how we can use metabolic information to diagnose disease or even to just track health. So, one of the things that we routinely do when we go to the doctor's office, particularly once we get a little older, is we give blood samples to monitor our health. And when our blood is taken, there are hormones that are measured checking for the levels of our thyroid or of our insulin. 

There are other markers of inflammation that might be measured or how well our liver is functioning, or our kidney is functioning. Every single one of those measurements that are taken are measuring metabolites. So, these are actually used already in medicine to track our health, to make sure that we are healthy and to look for early indications of signs of problems or of disease. That might tell the doctor that we need some further testing, that our kidneys might be struggling, that our liver might be struggling, and some medications that we might be able to take to help correct that.

Dr. Biology:

When we talk about changes, I'm getting the impression that we have some changes that are really quick, and we have some changes that happen over time.

Heather:

That's a great point.

Dr. Biology:

So, you're focusing on?

Heather:

Both. So, I'll give you a couple of examples of some of the things that we're interested in. One of the aspects of health and disease that is a little bit more long term might be the development of cognitive dysfunctions.

Dr. Biology:

How well we're thinking how well, we’re proecessing...

Heather:

Alzheimer's disease, Parkinson's disease, or even just aging or cognitive functions related to fatigue.

Dr. Biology:

Right. Get enough sleep.

Heather:

Right, absolutely. So, let's just follow that idea of fatigue. If we're not thinking clearly because we didn't sleep well last night, that could be something that could be recovered in just one good night's sleep or a really good nap. But there are also cases of chronic fatigue where we're really accumulating lots of missed nights of sleep or interrupted sleep. And that can really impact your thinking and your cognitive abilities. 

One thing I'm interested in and am working on right now is developing measurements of our metabolites. How does that cognitive fatigue, that chronic fatigue? Does it change the metabolites in our blood and our breath in our urine in a way that we can take a sample and determine how fatigued are you today? 

The reason that that's important is that there are some professions that really require excellent, good, sharp thinking. Think about that doctor in the emergency room or that nurse or that EMT going out to an emergency call. A firefighter responding to a fire. Think about our military personnel in high-stress environments and how they need to be good at thinking on their feet, but also how much chronic fatigue they might be building up over weeks and weeks and months and months of time. 

So, one of the things that we're interested in is whether or not that's altering a person's metabolome in a way that we can take a test to actually measure. How fatigued are you and how likely are you to make mistakes in your job? Have you been on a recovery for a long enough period of time to where now you've gotten rid of all of your fatigue, and you can think clearly again? So, some of these things can be acute. It could be one bad night's sleep, or it can be chronic and build up over time. And we're interested in both those short-term metabolic changes, but also the long ones that take a long time to accumulate and we need some ways to measure how quickly those states are accumulating, how much they're impairing the person and how they're able to function.

Dr. Biology:

What are the instruments you use to do this? Because especially if there’s things that are happening really fast, the long-term ones probably a little easier, but those fast changes. What do you do?

Heather:

Yeah, that's a great question. So, I'll take one step back and mention that so far for the human metabolome, we think that there's over 140,000 compounds that could be measured in our body at any given time. And there's lots of different kinds of compounds. Some of them are very water soluble, and these would be the compounds that are circulating easily in your blood.

When we need to eliminate them, they leave our body in our urine. There are some of these metabolites that are very small molecules, and they don't dissolve well in water. And there are actually what we term volatile organic compounds or VOCs. And these can enter our body through the air we breathe. They are also being made by the cells that are making energy and making waste products. Some of those are the VOCs, the volatile organic compounds, or volatile waste, and our body gets rid of those through breath. 

So, when we want to measure these different types of molecules, 140,000, we need lots of different types of instruments to measure these big different classes of compounds, depending if they are they water-soluble? Are they really solid materials? Are they gaseous materials? And what I specialize in are the compounds that are the VOCs. These are going to be really small molecule metabolites. They exist in the gas phase, meaning they are floating around in the air. And our body primarily gets rid of them through our breath. All of the garbage wastes that are circulatory system picks up as it moves through our body, picking up waste from our liver, from our kidneys, from our tissues, from our brain, from that toe infection that we have. As it's moving around the body, the blood is picking up all the waste from all these sites. It goes to the kidneys to get rid of the water-soluble waste and it goes to the lungs to get rid of the gaseous waste. 

And I specialize in that gaseous waste. So, the instruments that we use, we do a lot of work in analyzing breath as one of the major collections of metabolites from our body. We capture breath on the technical term as a thermal desorption cartridge, but what it is is a very fancy Brita filter. It's a cartridge that's packed with carbon and polymers that can grab all of the organic compounds out of our breath and hold on to them until we are ready to analyze them. We can put breath in the mail. We can collect breath from people all around the world. We put them on these very fancy Brita filters. They go into the mail, they come to the lab here at Arizona State, and then we can heat those cartridges to get those volatile compounds back off of that sample so we can reincarnate a breath sample that came from halfway around the world. 

We can put it back into the gas phase back in our lab here. And then we want to know what are the compounds that we trapped on that cartridge. The way we do that is we use an instrument is called a gas chromatograph. Chromatography is the process of separating molecules. That is what every form of chromatography is for, separating different molecules that have different chemical characters. Gas chromatograph are very specifically designed to separate mixtures of volatile compounds. So, we take this reincarnated breath sample, we revive it, we get it back into the gas phase, and then we separate every single breath, sample using a gas chromatograph so we can see all the hundreds of compounds that a single breath sample.

Dr. Biology:

Wow. Hundreds.

Heather:

Hundreds from just a single exhalation. As I'm giving this answer. Hundreds of VOCs are coming out of my mouth and into this room and if you were to collect my breath over the period of a day, you might see thousands of compounds. Again, my metabolome is changing minute by minute. After I've eaten breakfast, after I've eaten lunch, after I've gone for some exercise, after I've taken a nap the VOCs in my breath are changing because those metabolites are reflecting what my body was doing in those few moments before.

Dr. Biology:

We were talking a bit about how the metabolome changes under different conditions. One of them I think that is really important and I think it's important. It doesn't matter what age you are. I think people run into challenges with sleep and I don't think we realize. I think we're still learning how important sleep is. But what's changing when you're not getting enough sleep and you're not getting sleep for a long period of time? And I say that because, you know, those are the classic, you know, I need to catch up on some sleep. Can you really catch up on some sleep?

Heather:

As far as I understand. So, this is really where working with collaborators is important. I'm not the sleep expert on this project. My collaborator who's at Texas A&M University is the sleep expert and the fatigue expert, and her name is Ranjana Mehta. But I'll tell you some of the things that I've learned from her. So, when it comes to sleep, it does seem possible that you can catch up on sleep to a degree, but it depends on how much sleep deprivation you have. 

So, as far as I understand it, if you missed an entire night, sleep stayed up for 24 hours straight and you take a nap to try to recover some of that sleep, you will recover most of that. If you had a really good, long, high quality nap, but not necessarily the entire full functioning that you would have had if you had had a nice restful night's sleep in the first place. When you build up sleep deprivation by not getting enough sleep night after night after night. For college students, it's a big deal cramming for those finals, staying up too late, doing your homework late at night, waking up, trying to make it to that 9 a.m. class. Chronic fatigue is a big problem in the college student population and just crashing during spring break and sleeping as much as you can won't make up for all of those chronic deficits for many, many missed hours of sleep over long periods of time. And some of the ways that that changes our physiology is it changes our hormones. 

There have been some really good studies that have linked nurses and they work overnight shifts in hospital settings, nurses that are working on long term night shifts so that their sleep is really disrupted compared to how the day and night cycles work for our normal biology, our normal circadian rhythms. It alters their hormones and makes them more susceptible to breast cancer, for instance. So, even for those of us who are not getting enough sleep on a nightly basis, our hormones are being altered and our hormones are some of the key metabolites that regulate so many functions and so many organs and so many tissues and cells in our body that a disruption in hormones can really alter downstream metabolism.

Dr. Biology:

So, the question about metabolomics is how can we use those for disease diagnosis and also treatment? 

Heather:

I will start with treatment first. And there's a couple of ways for us to think about this. So, there are some diseases that are fundamentally metabolic diseases. There are some conditions like diabetes, which are an alteration of our metabolism is largely linked to the hormone insulin, but there are a lot of other downstream effects on our metabolism that are a consequence of insulin, not being produced sufficiently, which alters our ability to metabolize glucose. And glucose is a major energy source for our body, a major nutrient. So, when that is disrupted, your entire metabolism is altered. 

So, some diseases are metabolic diseases and the way their diagnosis to measure metabolites, how well is your insulin level functioning when you eat a meal and then the downstream consequences of that would be do we see your cells metabolize in glucose? If they're not, you'll see certain chemicals showing up in the blood and in the breath that indicate that this person is diabetic. And if they're being treated for diabetes, that is not under control, that the medication isn't working sufficiently. So, that's one way to think about treatment. Sometimes a disease is metabolic, and you can monitor the disease and you can alter the metabolism. The underlying metabolism to make them healthier. There's another way to think about using metabolites for treating disease, and it would be to maybe the disease isn't fundamentally a metabolic disease. Not directly, anyway. We can measure metabolites to see how well a drug is working. 

So, whenever we take a medication, it needs to be active and functioning in our bodies. But our bodies, they are designed to get rid of those things. The reason we have to take an antibiotic twice a day for ten days to treat an infection is because our bodies are altering that drug and getting rid of it. Here's another long word for you. That's called pharmacokinetics, pharmaco, meaning drug kinetics, meaning motion or change. So, our bodies are changing those drugs to get rid of them. And it’s important to know when you're trying to dose someone with the proper dose of a drug, how fast their bodies are getting rid of that drug. Your body will get rid of a drug at a different rate than my body will. And so sometimes metabolites are monitored to see how quickly or how slowly is that individual patient's body getting rid of that drug. That tells the doctor how frequently do they need to take that medicine and at what dose? If my body gets rid of the drug really quickly, I might need to take a higher dose in more frequently in order for that medication to work. 

Dr. Biology:

Right. Right. And it's also why it's so important to take your medications on a regular basis, whatever the amount, the dosage and however often you're supposed to take them.

Heather:

That's right. Yep. Our kidneys are constantly working. Our liver is changing that drug into a form that our kidneys can get rid of. That's their primary function. So, we always have to fight against that whenever we are treating with a medication is our natural biology to get rid of that foreign compounds.

Dr. Biology:

Okay, So, we've talked about the way of treating disease. What about diagnosing?

Heather:

So, that is actually a lot of what I am focused on currently in my research is using the volatile organic compounds or VOCs in our breath, all of those metabolites as hundreds of compounds to identify patterns that help us detect disease. There are some obvious applications of this that I do work on. So, let's say someone has a lung infection. That infection is in their lungs, is going to be creating all sorts of metabolites. The bacteria, the fungus, whatever is causing that infection is creating metabolites. Our immune response is creating metabolites as it's trying to fight that infection in our lungs. 

And all of that metabolism comes out in our breath. We're working on developing breath-based diagnostics to be able to detect whether someone has infectious pneumonia or not. And if they have an infection. One basic question is, is that infection, a bacterial infection, a fungal infection, or a viral infection? Those require three different types of treatment. And a lot of times doctors will prescribe an antibiotic without knowing that that's a bacterial infection and hope that that does the job of making the patient better. 

So, one of our basic goals is can we help the doctor know is an antibiotic needed in this case because this patient has a bacterial infection? Should they be prescribed an antifungal because they might have a fungal pneumonia or do they have a viral pneumonia, something like influenza or COVID that should be either treated with antivirals or just with some good old rest and extra fluids and Tylenol to help them control the fever. So, that's one application of diagnostics based on metabolites.

Dr. Biology:

Do you think that there's the possibility that we'll be doing a lot more diagnostics using just a breath sample. 

Heather:

Yes. 

Dr. Biology:

Where do you think it's going to lead to?

Heather:

Well, here's the crazy thing about breath that a lot of us just don't think about. I mentioned before that urine is one of the major waste streams of our body. It gets rid of all of the water-soluble waste from our body. It could be waste from our brains, waste from our skin tissues, waste from our livers. It all exits through the urine because the blood collects all that waste from all over the body goes through the kidneys and dumps all of that water-soluble waste into the urine. 

The same thing happens with our breath. Our blood is collecting gaseous waste from every single cell in our body. It delivers it to our lungs to get rid of that waste there. So, in every single way that a urine test could test for the function of your kidneys or of your liver, or even whether or not you might have a form of cancer that is developing or whether a blood test is looking for certain metabolic markers of cancer or of diabetes. If those diseases have volatile metabolites associated with them, they will show up in breath. So, I sort of think of potentially any disease or condition that a blood test or a urine test could measure or test for. There could be a breath test developed.

Dr. Biology:

So, your fancy Britta filter.

Heather:

Yes,

Dr. Biology:

Possibly, take it at home.

Heather:

Yes.

Dr. Biology:

Mail it in and get some results. We're not there yet, right?

Heather:

No, but I think we are getting close and possibly quickly.

Dr. Biology:

That sounds exciting.

Heather:

Yeah.

Dr. Biology:

Hey, Heather, I heard rumors about Human Breath Atlas.

Heather:

Yes?

Dr. Biology:

Can you tell me a little bit about it?

Heather:

Yeah, I would love to. So, the breath research community is putting together this grassroots effort. It's a collection of scientists across North America, Europe and Asia so far to build the human breath atlas. And what we want to do is to characterize, detect, identify, quantify every single compound that is in human breath. What can we detect in breath? Define it all. That's what we want to do. Ultimately, we think that we would need to sample a quarter of a million people, collect their breath.

Heather:

Maybe even over a period of time, but at least one time point from a quarter million people and then put all the best instruments on that sample, see how many volatile organic compounds we can detect and see if we can name them all, identify every single one. And we want to just basically make a map of all the chemical information, all the metabolites that are in our breath, so that we can know the foundation from which we are investigating and exploring the breath for many different purposes for diagnosing disease and monitoring health.

Dr. Biology:

That sounds exciting.

 Heather:

Stay tuned. I think you'll see more information coming out about that in the next few months.

Dr. Biology:

So, Heather on Ask A Biologist. I never let a scientist leave without answering three questions. The first one I'm going to ask you will kind of modify it a little bit because it basically says, When did you first know you wanted to be a scientist? I want to know that. But I also want to know, when did you really get excited about the world of metabolomics?

Dr. Biology:

So, when did you first know you wanted to be a scientist and when did you really get excited about metabolomics?

Heather:

First, know I wanted to be a scientist. I really wanted to be an astronaut when I was little. The very first clubs that I joined when I was in elementary school, in middle school were astronomy groups. I did Science Olympiad when I was in middle school and was on the astronomy team, but also when I was a kid, I don't remember if I asked for it or if I just received it as a gift. I got a big chemistry set and I thought it was so cool that you could mix things together and see bubbles and reactions and things change colors and follow a recipe to make an experiment happen. 

So, I don't know that I made a conscious decision when I was a kid that I wanted to be a scientist, but I knew that was the direction I was going. When I went to undergrad, I went to school at Georgia Institute of Technology, Georgia Tech. I thought I was going to be an engineer. So, I had a lot of family members who are engineers, and I was following in their footsteps, and I thought I was going to be a chemical engineer. I love chemistry and I love math. And then I went to a class, and you got to shadow a student who was a chemical engineer. And I went to one of her classes and I went, Oh, that's not what I thought this is about. She was calculating the flow of liquids through pipes because chemical engineers build reactors. I didn't know that. I thought they thought of chemical experiments to do so I decided I would follow chemistry and in fact, I was a biochemistry major. Biochemistry is the study of metabolites. 

[It] turns out I actually didn't like it very much when I was an undergrad. It was my least favorite class and I think it was because it was a lot of memorization, at least the way it was taught to me then. And that was 20 years ago. And I was a little bit lazy about memorizing all that stuff, but it stuck with me. I understood that biochemistry is really describing how cells function, how they get energy, how they transform molecules into energy, how they transform compounds into proteins and proteins into other metabolites that can be used for energy. And that foundation stuck with me. 

When I finished my undergrad, I went and worked for a pharmaceutical company, and it was just really because it was a good job. They needed a chemist. But once I was there and working there for a few years, I was inspired to go back to school. I saw a job at this pharmaceutical company that I wanted, and it was going to require a Ph.D. in chemistry. So, I went back to school, and I actually joined a Ph.D. group that was investigating origins of life chemistry. So, how do bio molecules, how do RNA get formed before there are enzymes in all of the cells that we have that do all this work? How did all this life happen before there were cells? And fundamentally at the root of that, again, it's biochemistry. I kept coming back to it, even though in undergrad I thought it was the worst class that I was taking. 

And when I was done with my Ph.D., I was really interested in seeing if I could figure out a way to sort of move back to human health. So, I'd worked in pharmaceutical industry for a minute. I sort of took this detour into origins of life chemistry, which I loved, and was fascinating, but I wanted to see if I could apply my science and my knowledge more towards a human health angle. And that's when I had the opportunity to join a lab that was doing breath research, that was working on using breath as a source of metabolites to develop new test for detecting infections and for monitoring health. 

So, I turned back to biochemistry again. And also analytical chemistry. How we learn and understand what all the volatile compounds are in breath. I use those skills too, and that's when I really got fascinated with metabolism and metabolomes. So, it's a long, winding road, lots of detours.

Dr. Biology:

And now I'm going to be a little bit mean to you. We're just going to imagine I'm taking all this stuff away from you. My scientists, also, most of them love to teach, so I'm going to take that away. My question is, what would you be or what would you do if you couldn't be the scientist, you are and you're not going to be able to teach?

Dr. Biology:

What would you do?

Heather:

Last week I told someone I think I would be an accountant because I find a lot of satisfaction in spreadsheets and numbers and data and making two columns of information line up and perfectly synchronized. I don't think I would find as much fulfillment in that as being a scientist, but yeah, that was my answer last week.

Dr. Biology:

Right? A bit of order, right?

Heather:

Yeah. Yeah. And just and I love numbers. They have so many secrets and hidden patterns and they tell us so much about the world that we live in. And fundamentally, most of the science that we do gets converted into a number format at some point in time. And so I guess I can find satisfaction in numbers in lots of different ways.

Dr. Biology:

Yeah, I can see that, absolutely. And I can admire a good spreadsheet.

Heather:

It's a thing of beauty.

Dr. Biology:

Yes All right. So, we have the long winding road, so you should be good on this last question.

Heather:

Okay.

Dr. Biology:

What advice would you have for a young scientist or perhaps someone who always wanted to be working as what? What are we going to say as a bio analytical chemist?

Heather:

Well, I think the first thing is that I could never have predicted when I was a kid, that I would end up being a professor or working at a university. I had no idea what professors did. Even when I was earning my bachelor's degree in chemistry, I had no idea that my professors had this entire other research life that they maintained. So, I think one thing is to keep an open mind. 

There are opportunities or interest or ideas that will float your way that you never saw coming. And if it's interesting to you, pursue it. Never, ever feel like you are locked in on a particular path or trajectory because it's simply not true. If you get to high school and you were developing an interest in biology and then suddenly, you're like, I find physics so much more fascinating, pursue that. 

See if there's some opportunity to join a club or to learn some things from YouTube. What a gift. So, much great stuff that you can explore and learn about from information that's online and just learn more. See what it is about that particular topic or idea that was so fascinating to you and see if there's a way for you to pursue it and learn more about it. You might go down that path and be like, Oh, this isn't what I thought this was going to be. I like it as a Nova program, but in practice taking those particular classes. Now that I understand what that particular topics about, not so interesting to me anymore. 

Okay, so pivot, you're never locked in. There's so many ways to exercise your science brain to pursue things that are interesting to you, even if you don't become a professional scientist. Ways that you can engage as a citizen scientist, help to generate those numbers and collect data that if it's interesting to you, there will be ways for you to participate in that in your professional career or in your hobbies in the future.

Dr. Biology:

Right? I say that everyone is a scientist.

Heather:

That's true.

Dr. Biology:

Heather, thank you so much for being on Ask A Biologist.

Heather:

It's been a pleasure. Dr. Biology Thank you so much.

Dr. Biology:

You have been listening to Ask A Biologist, and my guest has been Heather Bean, a bioanalytical chemist and faculty member in the School of Life Sciences. Now don't forget to check out our companion links and images we include for each podcast. It's a great way to dig deeper into some of these topics. The Ask a Biologist podcast is produced on the campus of Arizona State University and is recorded in the Grassroots Studio housed in the School of Life Sciences, which is an academic unit of The College of Liberal Arts and Sciences.

And remember, even though our program is not broadcast live, you can still send us your questions about biology using our companion website. The address is askabiologist.asu.edu or you can use your favorite search engine and enter the words Ask A Biologist. As always, I'm Dr. Biology and I hope you're staying safe and healthy.