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Research Activities:
The long-term research goal of the McCarty laboratory is to understand the mechanisms of permeation and gating in ion channels and transporters, and how these processes are affected in human disease.
What are you guys up to?
We're interested in studying the primary defect in cystic fibrosis, which is a defect in a protein called CFTR. That protein functions as a chloride ion channel in certain membranes of some tissues that line spaces- those are epithelial tissues. Those tissues that are most important for cystic fibrosis are the lung, pancreas, the intestine, and the sweat glands. Lots of other epithelia express this protein, but they aren't that important for cystic fibrosis.
CFTR is kind of a multi-functional protein. Its main function, as far as we can tell, is to serve as a pathway for the movement of chloride ions across these membranes. That movement of chloride ions is connected to the movement of water, which is important for the proper functioning of these epithelial tissues.
We know a lot about some ion channels, about what their structures look like and what parts of those proteins are important for different functions the protein carries out. But for this channel and for chloride channels in general, we really don't know how their built, and how they work when they are built. So the major research emphasis in my lab is to try and study this protein to determine how it works in the normal case, when the protein is not mutated, in order to try to get some guesstimates on how the disease impacts this protein by making mutations.
There are three basic projects going on in my lab:
One is just trying to understand how this protein works as an ion channel.
Another one centers more on clinical science, where we interact with the CF treatment center on campus. That's a treatment center that provides care for about 550 patients from the southeast. It's one of the largest treatment centers in North America in terms of patient population. A lot of those patients have had their genotype determined, in order to determine what form of mutations they have in their CFTR gene. There are some 850 different mutations of this gene, which is a huge number. And frankly we don't know how each of these mutations impacts this cellular defect. So one thing we're trying to do is to determine how some of those specific genotypes impact the functions of the cells.
Another project is somewhere in-between basic science and clinical science, where we're trying to understand how CFTR works as a regulator of other proteins. So it's been shown that this protein doesn't just function as a chloride-ion channel, but it does other things, one of which is to regulate the activity of a sodium channel that's in those same membranes. It also regulates the activity of another chloride channel that's in those membranes. So this protein is a bit odd- not only is it built in a way that's different from other ion channels, but it has multiple functions. We don't know exactly how that works or how that impacts the cells of patients that have CF.
About that first project- is it not possible to obtain the structure of the ion channel because it's membrane-bound?
Yeah, so, determining crystal structures of proteins has come a long way in the past few years, but so far that's only been successful for soluble proteins- proteins that are in the cytoplasm. And frankly, the soluble parts of this protein, the parts that are not in the membrane, have been determined by structure. But those are not the parts that form the ion pathway. So we have to rely on structure-function experiments where we make specific mutations and determine how those mutations impact the function of the channel.
And from lots of those experiments you can piece together a pretty fair picture of what the channel looks like.
What's up with these CPX drug trials you list on your homepage?
The CPX phase II trial is currently under way. This phase II trial is continuing to look at whether this drug CPX is safe to use and might have some clinical benefit. The idea is that CPX targets specifically the form of the mutation that's found in over 70% of CF patients in North America. I mentioned earlier that there are 800 and some different mutations. In North America one mutation accounts for 70% of patients. This drug targets that specific mutation. In this mutation you wind up having not only very few proteins made, compared to the normal number, but those proteins that are made and are inserted into the correct membranes don't work quite right. So there are two defects with this mutation- and this drug targets both of those defects. It proposes to get more of the protein to the right place, and then ask those proteins to work harder.
So instead of having .1% normal function, you might have 5% normal function. But it's been shown that 5% normal function might be enough to make you look like a normal person. So there are big hopes for that trial. We are one of three centers that are currently seeing patients for this trial.
Tell us about your education to date.
As an undergrad I got very interested in physiological ecology, (**link**) trying to understand how organisms adapt to their environment and what sort of physiological tricks they play in order to adapt. It's really a fascinating field- there's a lot of cool information out there. As I did that I got more interested in how animals regulate their ionic and osmotic content (**link**). That led me to try and understand in marine animals ÐI got my master's in marine biology- are able to do this given the huge stresses of salt content and water flux. Then, when I went to get a Ph.D. I started looking more at the cellular level, but at the same issues- how do ions move across cells and how are those movements regulated.
Finally, when I went off to do my post-doc, I started looking at the molecular level. So now what we do is what I call molecular physiology of ion transport pathways; ion channels.
Phd thesis:
"Control of Cell-Volume Regulation by Calcium in Renal Proximal Tubule Cells"
What's kept you interested in research all these years?
To me there's a lot of fun in physiology, at all those different levels. You're asking questions that involve looking at systems that are functioning in vivo. It's not biochemistry, where you're taking things apart and running them out on gels and seeing what they look like. It's things that are happening in real time. Some of the approaches that we use allow you to look at single protein molecules functioning in real time, which is not something you can do with any other technique that I know of.
I think that the question that you ask when you're doing physiology is that you're trying to understand how things work. Maybe that's a guy thing, I dunno. Maybe more guys like to find out how things work. Working on your car, working on your computer, you know, you take it apart, you like to know how it works. That's what physiology is all about. It's the physics of biology, and physics is also fun.
Every since highschool I've been set on this. I like writing, but I'm not sure I'd call that an intellectual pursuit.
What do you currently teach?
I teach in the Allied Health Sciences program. I teach nine lectures on physiology. The stuff that I teach is the first section of the class, which deals with membrane transport, membrane functions, signal transduction, nervous conduction, things like that; how nerves work. I give a lecture on cystic fibrosis, as well. In the graduate courses, the Ph.D. courses, I teach mostly cell physiology and biophysics. It's very related to my research, which is understanding how these channels work together to make the cell work.
What's your philosophy of teaching?
I think you have to determine before you go in there what the students need to know. I think an overarching strategy is to impress on the students how exciting it is to know this stuff. And not just knowing the facts but knowing how they were determined. Which is the difference between learning science and learning a foreign language, or something like that. A lot of what's important is how these things were figured out.
How do you feel about working in academia?
I like the fact that I'm pretty much my own boss- I have a chairman, I have a deputy chairman- I have people above me, but in terms of my day-to-day business, I'm the boss. I can research on whatever I want to research on, as long as I can get the money for it and get the papers out. I like the flexibility of schedules, which is very important if you have a family. I like the fact that there is always a multitude of things going on around me that I can learn about. You've got to learn something every day. And if you can't do that in an academic environment, you really have your head stuck in the sand.
What are some possible applications of your research?
For instance, here's one obvious idea: CFTR in the normal state doesn't work really well, so that per protein molecule, you don't get a whole lot of ion transport functioning. So one of the possible outcomes of our work is trying to find ways to make this thing work better. Parallel to our work, there are a lot of people doing gene therapy- trying to get the CFTR gene into the cells of CF such that they can get the protein into the cells and get it to work right. If they can put in a copy of the protein or gene that works better, then you would only have to correct one out of ten cells instead of all ten cells.
We also study ways the protein is turned on and off, and if we can figure out how to keep it turned on longer, than we can get more functioning per protein molecule. Our goal is that in order to design better pharmacological therapies, we've got to understand how the wild-type (**link**) protein works. So once we have a really good picture of how the wild-type protein works, then we can design rational strategies of how to make the drugs.
What do you spend your time on?
That varies a lot depending on if you're in a medical school versus an undergrad college, say, GA state university vs. Emory medical school. In the medical school, my appointment is something like 85% research, 15% teaching and other stuff. I spend the vast majority of my time helping my team in the lab get their lab work done, keeping the lab running, reading papers, writing papers, writing grants. And then there are learning opportunities like the journal clubs that we have. There are always two or three seminars per week you want to go to. For me, I identify nine different priorities, nine different people that I am, and you just have to spread your time out amongst the priorities as best as you can.
How's life in Emory's undergraduate biology department?
People in the biology department are sort of in a bad place because they're in the undergrad college, so they have to do more teaching, and yet they're at an institution that includes a medical school, so they have to do more research and get more money, so it's a really bad deal. People in the medical school tend to do less teaching than people in the undergrad college. So if the balance is filled with research time then yes, I have more time for research.
What are your interests outside of work?
My family. Playing soccer. What little bit of pleasure reading that I'm able to do. We do a little bit of community service stuff around here. Once a month we'll pull together some lunches for homeless folk.
What's your advice to students in light of the reported oversupply of Biology Ph.D.s?
I have somewhere copies of occasional reports that come out in Science and say that- I try to do a real good job of making sure that these trainees know that. I fully believe that getting a Ph.D. and being a doctoral scientist isn't for everybody. It's not something to be taken lightly- there's a lot of competition. There's a lot of competition for positions and there's a lot of competition for grant money. So I try to be very up-front about that. There are lots of other opportunities that don't involve going into academics. Emory doesn't have really great industry connections, but that's something that's being developed through some of the graduate programs.
I also don't want to send umpteen-zillion people into medical school, because I think that's probably a bigger mistake. There is more of a glut of M.D.'s then there is of Ph.D.'s
It's funny here at Emory, I think it's three out of five or four out of five students, when they come here, want to go to medical school. And I should say that three out of the four undergrads that have left my lab have gone on to medical school.
What sort of difficulties have you experienced on your path to becoming a successful researcher?
You can't always say it's smooth sailing. There are always periods when you've been working for months and not gotten any data- just a collection of mishaps, perhaps. Certainly there was a time in my Ph.D. program when I was suffering from one of those and felt like I might never get out. I never thought it was due to a lack of intellectual ability- I know that sounds stuffy, but that wasn't the issue. The issue was just bad luck- rabbits dying, people in the lab messing up my reagents, things like that. It takes a lot. Getting a Ph.D. in a science these days and being successful and productive takes a lot of work. You have to have a lot of ducks in a row to make it happen.
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