Fundamental questions

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{***Pause/Music***}
{***Noah***}

Coming up on Harvard Chan: This Week in Health…

Fundamental questions.

{***Tobias Walther Soundbite***}
(Really a lot of the major advances in human health have been done by measures in public health. And in many areas those are driven by real advances in the basic sciences.)

In this week’s episode: An in-depth conversation with two scientists who are working together to run a unique lab that’s trying to crack the secrets of diseases ranging from diabetes to dementia.

{***Pause/Music***}

{***Noah***}

Hello and welcome to Harvard Chan: This Week in Health. It’s Thursday, January 11, 2018.

I’m Noah Leavitt.

{***Amie***}

And I’m Amie Montemurro.

{***Noah***}

Amie—when you read or hear about a new medical breakthrough—maybe it’s a new drug or treatment for a disease—how often do you think about all the work that went into it: the research, the drug trials, the testing—it can take decades.

{***Amie***}

And at the heart of all that work is basic scientific research.

Before a drug can be developed, scientists must identify a target for that drug, and before that researchers must understand the basic biology of a cell or an organ.

{***Noah***}

It’s this path of discovery that eventually leads to applications that improve health.
But it’s not an easy path—and there’s a fair amount of serendipity along the way.

{***Amie***}

And that’s what we’re focusing on today by talking to two scientists who are asking fundamental questions about how our bodies work.

{***Tobias Walther and Bob Farese Soundbite***}
(Hi, I’m Toby Walther, and I’m professor of genetics and complex diseases and cell biology and also HHMI investigator. Yeah, I’m Bob Farese, and I’m professor of genetics and complex diseases here at the School of Public Health and professor of cell biology at the Medical School.)

{***Amie***}

For the past three-plus years, Tobias Walther and Bob Farese have worked together to run a lab based here at the Harvard Chan School and Harvard Medical School.

Their work largely focuses on understanding how our cells store and then synthesize fat—a process known as lipid metabolism.

And in recognition of the lab’s work in 2015 Walther was named a Howard Hughes Medical Institute Investigator. The prestigious five-year appointment provides each scientist with his or her full salary, benefits, and a research budget.

{***Noah***}

The fact that Walther and Farese are joint leaders of a lab is something that’s almost unheard of—and later on in our interview we’ll be talking about the benefits and challenges of working together to run a lab with nearly two dozen members.

But what’s also unique is their approach to science.

{***Amie***}

As you’ll hear throughout our conversation, Walther and Farese have a passion for asking big questions about our bodies—and really want to dig deep to understand what’s happening inside our cells.

{***Noah***}

Their research specifically focuses on lipids, which are fatty acids and oils that store energy and provide materials needed to build and maintain our cell membranes.

{***Amie***}

And Walther and Farese have a particular interest in something called lipid droplets—the tiny structures in cells that store fat.

These droplets play an important role in the way our bodies function.

{***Noah***}

One way these droplets work is by storing lipids in adipocyte—or fat—cells for later conversion into energy.

This process also protects cells throughout the body from the harmful effects of too much dietary fat.

{***Amie***}

This system is beneficial to our body during periods of hunger—when food and energy isn’t available—but it can break down when people gain and retain excess weight.

Farese and Walther are working to understand what proteins or genes might influence these process.

And so far they’ve identified more than 200 genes that are critical to energy storage and utilization in our bodies.

{***Robert Farese Soundbite***}
(Robert Farese: If we can understand how they work, then we can understand what goes wrong when they don’t work properly and how that gives rise to disease. So I think at the heart of things, we’re just trying to understand fundamental principles about how life works. And then hopefully that gives us insight into mechanisms for multicellular organisms, physiology, human physiology, human disease.)

{***Amie***}

The potential applications of this research are vast—with implications for the treatment of diseases such as obesity, diabetes, and fatty liver disease.

{***Noah***}

And an emerging focus for the lab is understanding the cell-based processes that underly specific neurodegenerative diseases, such as demential, ALS, and Parkinson’s Disease.

{***Amie***}

And this is a key theme of Farese and Walther’s work—if you can understand how our bodies function at the basic cellular level, it can open the door to new ways of thinking about and treating diseases.

They don’t want to just scratch the surface of an issue—they want to dig deep and understand root mechanisms.

{***Noah***}

It’s a partnership that’s been evolving and strengthening for more than a decade.

{***Tobias Walther and Robert Farese Soundbite***}
(Tobias Walther: We met in 2004 or ’05, something in that region.

Tobias Walther: Early January 2005.

Tobias Walther: All right. There you go.

Tobias Walther: God, you don’t remember.

Tobias Walther: No. When we met, I was head of the postdoc almost on my way out in Peter Walter’s Lab at UCSF. And Bob was an investigator at the Gladstone Institute, which is part of UCSF, but it was also across the street. And he had more medical background to this point and done a lot of physiology but had a desire to become better exposed to sort of basic cell biology. That way meant Peter and came to our lab, and we met that way. Started a project together and then been working together ever since essentially.

Robert Farese: I had been running a lab for about 10 plus years at that point and had been involved in identifying some of the enzymes that are in a specific part of the cell called the endoplasmic reticulum that make fats. And I got curious about, okay if they make fats, then how do you store these fats in a cell? How does a cell store these fats? And it was known that they stored them in this part of the cell called oil droplets or lipid droplets. And there was just very little information in any textbook or most of the literature on how these processes occurred.

And so I realized that my training had been in medicine and then physiology and disease mechanisms but not really in fundamental cell biology, and that to follow that I would have to get better trained in that. So I spoke with Peter Walter, who was an eminent cell biologist at UCSF. He welcomed me into the lab for a sabbatical year. And literally, there was an empty desk in the lab, and I sat down next to Toby.

And Toby, as he said, was a senior post-doctoral research fellow at that point. And he said, what are you interested in? What are you working on? And I explained it to him. And he said, that’s pretty cool. I’ll help you with that. And I was like, really? You’ll help me? Because it’s not often that somebody who’s a post-doc is going to take time out to help some dumb sabbatical professor who doesn’t know what he’s doing. But Toby had both the confidence and the genuine interest in the problem to do that.

And we started working together, and it was really fun. And we had a very profitable year where we did a large scale screen and that sort of helped open up the field a bit to the molecules involved in this part of biology. And in addition, Toby eventually crossed paths with someone who worked in my lab, who he’s now married to.)

{***Noah***}

Farese and Walther say one thing that sets their lab apart is the unique combination of skills they bring to the table.

{***Amie***}

And at the time they met, their partnership was really novel: most scientists who were studying fats didn’t spend time diving into the inner-workings of a cell.

{***Noah***}

For Farese and Walther it was an opportunity and a fairly unexplored area.

But for that reason it was also critically important to understand the fundamental biology at play.

{***Amie***}

And in this approach, Walther and Farese are a perfect match: They relish the opportunity to work together to unravel a problem.

But as Walther explains, you can’t do that until you understand basic principles.

{***Tobias Walther and Robert Farese Soundbite***}
(Tobias Walther: There’s only three types of explanations, circular ones, endless regress, or causality. And the only explanation type that has been successful in allowing us to modify outcomes is causality as a type of explanation. And so, we strongly believe that you understand fundamental principles and how things happen, what leads to what, and that type of causality will lay the foundation for all attempts to understand physiology, pathology, and allow us to develop therapeutic avenues. And that has I think not only in our work, but if you look around, I think that generally pans out. Sometimes there is serendipity in discovery. But on the long run, most of the things that work one can understand from a fundamental perspective.

Robert Farese: We’d like to ask fundamental questions like, really how do things work from a fundamental principle standpoint. And try to understand mechanistically in as much detail as we can how something happens. And then I think both of us are very in tune to how does that scale if we understand it at a molecular level. For example, if we understand how a certain protein is involved in storing fat in cells, how does that play out in processes that don’t involve fat in an organism? How is fat absorbed? How is it stored? How is it moved around the body? That kind of thing. And then how does it go wrong in cases where people have way too much fat for example, what goes wrong? So we have an eye towards all of that. But I think our orientation, which again is like how we see the world scientifically and partly why we do this together, is like we’re trying to understand things at a fundamental level as our central mission with us and other people translating these into the larger organismal background and our disease background.)

{***Amie***}

But Walther and Farese admit there are challenges to this approach.

For example, they sometimes have to corral their natural curiosity—because they then risk going off on an unfocused or unproductive tangent.

{***Noah***}

And that challenge, they say, is magnified when managing a lab of 20-plus people—all of whom are smart and bring their own ideas to the table.

{***Tobias Walther Soundbite***}
(Tobias Walther: I find that one of the biggest challenges is to find the right balance between near-sighted focus on detail of an experiment, where you can do an experiment essentially every day, and a vision that means the project– We want to have a project that after five years solves the fundamental problem, which might have tens to hundreds of experiments, and help people navigate on a day-to-day level to build those steps that will eventually get them to that final goal. So that I think is sort of the challenge, to have a long-term vision but focusing on a detail today to make that happen. So I think that everybody struggles with that. That’s certainly not unique to our lab.)

{***Noah***}

When it comes to focus and prioritizing, Walther and Farese says that’s when they really see the value of running a lab together.

{***Amie***}

They can bounce theories off each other, help each other interpret data, and importantly—weed through and filter out the bad ideas.

{***Noah***}

There’s also the day-to-day challenge of dealing with large-scale, projects as Walther alluded to.

In their lab, projects can range from two years on the short-end to up to four to five years on the long-end.

And Farese says he and Walther have an important responsibility to the other scientists in their lab.

{***Robert Farese Soundbite***}
(Robert Farese: The kind of work that we do, a lot of bench science work, it’s incredibly hard work day-to-day. And part of our job is to see where we think the end outcome is going and help to keep things moving in that direction. It’s also to be a cheerleader sometimes. There’s a lot that happens over several years of someone’s life. We have a lot of young people who are literally maturing in front of our eyes as young investigators and young people in general. And so it’s a really interesting environment. It’s fascinating from a mentoring standpoint. And also I think it gives us a lot of satisfaction, too, to see people embark on these big projects, bring them to fruition. Be really proud because generally people are very excited about something they’ve worked quite hard for at the end of the day. And if we put our seal of approval on it and publish it, we’re all very, very proud of these contributions.)

{***Noah***}

And this management and research style has proven fruitful for Walther and Farese.

As we mentioned earlier in the episode, they’ve identified hundreds of genes that affect how cells store lipids.

{***Amie***}

And now that they’ve deepened our understanding of that mechanism, they’re taking a closer a look at what happens when a cell’s capacity to store fat is overwhelmed.

{***Robert Farese Soundbite***}
(Robert Farese: And this in turn triggers a bunch of pathways in the cell to try to deal with those lipids and restore homeostasis. However, if that becomes overwhelmed, then it often can trigger cell death. It can trigger inflammatory pathways, and so forth. So for example, an example that’s very common right now is that accompanying in obesity– many, many people store too much fat in their livers. And in some fraction of those– for some people that goes, okay, they just have fat in their livers– but for another portion of those people, this triggers consequences to the cell that are detrimental, either cell death or inflammatory pathways. The inflammatory pathways in particular stimulate a kind of fat-induced hepatitis. And that can trigger cirrhosis of the liver and liver failure. And this is a big current public health problem, of liver failure due to too much fat in the liver. So we’re trying to understand those processes.)

{***Amie***}

And understanding this process is critical, because in addition to the liver failure that Farese mentioned, excess fat can interfere with the body’s ability to process glucose, resulting in type 2 diabetes and other cellular malfunctions that often lead to heart and blood vessel damage.

{***Noah***}

We’ve actually created a visualization of what this looks like—when cells get overwhelmed by fat—and you can view that video on our website, hsph.me/thisweekinhealth.

{***Amie***}

And as Farese and Walther work to understand these processes they’re filling in critical gaps in our knowledge about how our bodies and cells work.

{***Robert Farese Soundbite***}
(Robert Farese: If you come to one of our lectures on this topic, what you would see is that I think when when we started this, basically we kind of know it starts like there’s two things on the slide. It starts here and ends here, and that’s about all we know. And then we hope that what we’ve helped to do in the past decade or so is begin to put a lot of molecules on these pathways and build an understanding of at the end of the day cells use proteins to carry out, as machinery, to carry out different processes. And so we begin to understand some of the concepts that are involved. And we still have quite a ways to go with what we study. But we think that we’ve made some contributions to that.)

{***Amie***}

This path of discovery for Farese and Walther hasn’t been a linear one—in fact, they say, science rarely is.

{***Noah***}

Walther says that often as a scientist you don’t know exactly where your research will take you.

{***Tobias Walther Soundbite***}
(Tobias Walther: There is serendipity and discovery along the way. And often, there are things that you do not anticipate as being important that turn out to be really important. And then you have to go down that road. And those are some of the most critical decisions we make collectively in the lab, as like is this an important thing to follow or not. And it’s the hardest part because you can go in the wrong direction for a while. Then you have to turn back.)

{***Noah***}

Farese agrees—saying that as a lab they generally try to set out on a linear path, but often find themselves needing to change course.

{***Robert Farese Soundbite***}
(Robert Farese: I basically came up into the field working on cholesterol metabolism and studying enzymes that were involved in cholesterol metabolism. And the way I view it is like we’re captaining a ship. And we set our course towards that lighthouse over there, and we get going. But then we have to kind of keep our eyes open because we never know what we’ll see on the way. And in that way, in that manner in studying cholesterol metabolism, we’re cruising along and banging our head against the wall trying to elucidate the function of one gene that we’d cloned and thought it was involved in cholesterol metabolism. And literally on a lab meeting seeing a band in a completely different part of the gel that told us that this was not cholesterol metabolism at all, but it was involved in fat or triglycerides. And having to keep your eyes open to that possibility because if you don’t, you miss it and you move on.)

{***Amie***}

And an important takeaway from our conversation was that scientists need to have this freedom to discover—to take winding paths, where serendipity may eventually lead to a breakthrough.

{***Noah***}

Farese and Walther told us that most major discoveries don’t start with an application—such as a treatment in mind.

Instead they start with a desire to understand the basic biology. And that opens the door to finding a useful application.

{***Amie***}

But that translation of research—such as a drug target—can’t happen until you understand the basic biology of a disease, or a process in the body.

{***Noah***}

It’s an incredibly important—and difficult part of the research process.

Farese illustrated how by discussing the lab’s recent work on Alzheimer’s.

{***Robert Farese and Tobias Walther Soundbite***}
(Robert Farese: We also work on this frontal lobe dementia project, where there’s a protein called progranulin. And if you’re low on that protein, you can get frontal lobe dementia. But 10 years after the discovery of that, we’re still trying to understand at the cellular level what this protein does. And we don’t yet understand that. If we do, I think we’ll have a much better idea of trying to find treatments for deficiency of that protein. And we may have a much better idea of finding treatments for a whole host of neurodegenerative diseases because we understand the basic principle that’s involved.

Tobias Walther: I also think to some degree if you look at the most common indications and most common diseases, a lot of the obvious simple things have been done. And I think to some degree to really push new frontiers, you do need a better understanding because there are certain limitations of what you can try more or less randomly. And so for that to happen, I think there needs to be more discovery. And you can make a great argument. For instance, in our space one of the more prominent new therapeutic targets is PCSK9. And that’s a protein that is now used for lowering potentially cardiovascular outcomes. That was a long process to come to that. And it started from a number of different observations all made in basic science. All have to do with regulation of lipid metabolism on the one side with mutations in families that were analyzed. So different branches of science had to come together and sort of provide this evidence. And I don’t think you can do that with just saying like, all right this one approach is going to give you all the targets.)

{***Noah***}
A key to understanding basic biology is the access to more powerful tools than ever before—especially when it comes to imaging technology.

{***Amie***}

Farese and Walther say we’re only just beginning to tap the future potential of this technology.

{***Tobias Walther and Robert Farese Soundbite***}
(Tobias Walther: For me, this is the early 20th century in physics is what we are going through right now in some way. For most of the last 20, 30 years, honestly there was no tools to study some of the most important problems. And then people started to study. Use of genetics has come a long way. But how technology has accelerated this is absolutely phenomenal. And I think there’s really at least three or four revolutions. Now, one of them is that you can analyze mammalian genomes that started with mouse knockouts but has now become much more routine. And we can do a lot more things. We have analytics that allows us to really understand the composition of biological systems in every dimension, from the DNA to the proteins to lipids and sugars. And we have imaging technologies that allows us to visualize this at all kinds of levels, essentially anywhere from the subcellular level looking at atomic structures all the way to what happens in an intact organism with intravital microscopy, PET scans, and so forth. So I think this is really unbelievable. And I really feel that only in the last five or so years, this has come together where we can do meaningful things, for instance, in human biology that was really not there before.

Robert Farese: Your example there– the ability to knock out a gene in a mouse, that’s when I started my career basically was that technology, learning that technology and helping to implement it. And now that was a lot of work, years of work, to knock out one gene in a mouse. Now the ability to knock out a gene in a cell is becoming rapidly rather routine in laboratories. It’s accessible. So people can study gene function in a human cell, for example, very, very much easier. And I think science, of course, moves along. And a lot of the questions have been around a long time. But it just depends on the technologies that allows us to investigate, ask questions, analyze the data, see things we haven’t seen before.)

{***Amie***}

And at the heart of that process of investigation is what we’ve talked about a lot in this podcast—asking fundamental questions.

{***Noah***}

But a key for Walther and Farese is also being able to ask those questions, get answers, and then scale their discoveries.

{***Amie***}

The goal is to first focus on universal questions at the core of the issue they’re working on—and from there they can branch out and test.
{***Noah***}

What does this look like in practice?

Farese shares the example of their work on sphingolipids, which are found in cell membranes, particularly nerve cells and brain tissues

{***Robert Farese Soundbite***}
(Robert Farese: And yet very little is known about how these sphingolipid concentrations are regulated and so forth. And Toby, just from a very basic standpoint, recognized that was kind of a fundamental problem we knew very little about and got interested. And so he and folks in his lab at the time did some very basic studies of just like, let’s take genetics in yeast, let’s knock out every gene in yeast and see what affects this. And basically, to make somewhat of a long story short, found some genes in yeast that were important in this sphingolipid metabolism. And it turned out they were related to disease genes that caused ALS-like problems in humans. And now we’re in the process of trying to translate that into mouse and/or human studies. But we’re actually doing a little mini clinical trial in a mouse study with knowledge we got from this new connection between sphingolipids and an ALS-like disease. We’re testing that in a mouse model. And that’s very exciting. And basically shows the principle of just starting with a fundamental observation, making some observations, and then recognizing the potential to understand something that might be useful, for example, in human disease.)

{***Noah***}

And what makes this all possible, says Farese, is the creative synergy that he has with this partner.

{***Robert Farese Soundbite***}

(Robert Farese: I think is hard to find the right person to do that with. You really have to agree on a lot of values. And you have to get to know each other pretty well and really figure out ways that you support each other through these processes. It’s just like anything in life. There’s joys and struggles, and it’s hard. But I think also part of it is it’s really fun. I think that if you can find someone that you enjoy doing a creative process around– For us, we have a lot of fun because basically we have adjoining offices with pocket doors, and we talk about everything. We talk about science. We talk about management issues. We talk about school politics. Whatever it is, we talk about it. And I think we both learn a ton from each other that way. It prompts our thinking. And we end up kind of coming out with pretty similar thoughts on many things based on this. But that’s natural because of that. But it just makes it a lot of fun. And as Toby mentioned, I think we both ran labs individually for quite some time before joining the labs. And everything has its trade-offs. But I think that it really can be a lonely experience running a lab when you don’t have somebody to talk to for all the things that you’re struggling with. And I think it’s been just a wonderful thing to be able to share whatever both your joys and your struggles with someone.)

{***Noah***}

We thought that was actually the end of our interview, but Walther made a really important—and powerful point.

{***Amie***}

We’ve talked a lot in this episode about the importance of basic scientific research—of asking fundamental questions.

And Walther says it’s important to consider that work in the larger context of public health—how the discoveries being made in a lab today, can be used to address some of the world’s major challenges in the future.

{***Tobias Walther Soundbite***}
(Tobias Walther: Really, a lot of advances in human health overall have been done by measures of public health. In many areas, those are driven by real advances in the basic science. What we’re facing now as a planet, one major challenge is non-communicable diseases and chronic diseases. And those are really taking over the planet in every region of the world as major, major problems. And as a consequence, you have a failing health care system. Lots of policy work needs to go into this. But also it really highlights the need to understand better on the level of epidemiology of what are the contributing factors. But then on the level of science, basic science I mean, what are the causal chains that actually lead to all these problems. And really when you think that through, at the end, one crucial component to this is understanding fundamentally how the basic biology works that then has all these implications. And one thing that’s really fabulous here is that we’re sort of the only place in the world where that is brought together under one roof. And where we actually have both people like Bob and myself and the people in our lab who think about the structure of a protein and how this really works all the way to people who think about how, for instance, effects that could be mediated by saturated fatty acids and how that translates to a population. And what should be policy recommendations based on that. And bringing that together is a really powerful thing, I think.)

{***Amie***}

That was our conversation with Tobias Walther and Robert Farese.

{***Noah***}

If you’re interested in learning more about their work and their lab, we’ll have much more information on our website, hpsh.me/thisweekinhealth.

{***Amie***}

Coming up in next week’s episode: New research shows that many large chain restaurants are dropping high calorie items from their menus. We’ll talk with the author of the new study about what the findings mean for America’s fight against diabetes and obesity.

{***Noah***}

In the meantime, you can always listen to this podcast on iTunes, Soundcloud, or Stitcher.

January 11, 2018— Basic science is at the heart of many of our greatest health advances. And in this week’s episode we speak with two scientists who are asking fundamental questions about how our bodies work. The answers could help crack the secrets of diseases ranging from diabetes to dementia.

For the past three-plus years those two scientists,  Robert Farese and Tobias Walther, have done something almost unheard of in public health: run a joint lab. Their work largely focuses on understanding how our cells store and then synthesize fat—a process known as lipid metabolism. It’s work that has wide-ranging implications for a variety of diseases. During an in-depth conversation Farese and Walther shared insight on their work, the joys and challenges of running a lab together, and the importance of basic scientific research.

Learn more

Science by a power of two (Harvard Chan School news)

Bob and Tobi’s Excellent Adventure (Harvard Public Health magazine)

Watch a visualization explaining how our bodies break down dietary fat: