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Research
The brain systems we were interested in were involved in reward and reinforcement- that then led into studies of drug abuse, because that's where the drugs of abuse act. So I've been doing a lot of work on drug abuse for about ten years. But those targets themselves have all since been cloned and expressed by others, and they now have the particular targets of these drugs available in cell lines, and that lets you have a much cleaner system to study than the entire brain, with all the complexity of that. So now we're just studying those targets we've got expressed in individual cell lines. So the question is 'where does the drug bind on the protein? What's the active site that cocaine binds to?' So the potentials for therapies for treating drug addiction could be developed if the active site were known.
Education
B. S., Rutgers University, 1968; Ph.D., University of North Carolina, 1974; Postdoctoral Research Fellow, University of North Carolina, 1971-1975
I was interested in science even in elementary school. I had a great 7th and 8th grade science teacher. The physics we had in highschool was kind of boring- optics and mechanics. I wasn't that interested in biology either, because of the way it was presented: 'you've got this phylum and that phylum.' So I guess I was just interested in chemistry more than the others.
My graduate training was all artificial intelligence and pattern recognition- computer-oriented things... I worked on interpreting chemical data using advanced methods, like pattern recognition and artificial intelligence... And if I wanted to continue in that I had to go into computer science, and I didn't really want to do that. What I did was get more interested in the biological side of things, and I wanted to study the chemistry of the brain. That's what I started doing when I came here- switched from the computer side of things to the more experimental work. At the time some new methods were being developed to help you monitor the brain chemistry of behaving animals, so I jumped in there because it combined a lot of interests.
Teaching
I really want to get a few major points across. I teach a lot by analogy. I like to go through one system, and a couple other systems that are like that, so that they see that it's all the same.
It's like when you do research: one of the things you learn in investigating something or writing a paper about something, is how to write a paper. And you learn, when you do some investigation in some serious depth, you learn that it's an open-ended process, and you learn how to do research. And so by studying anything you learn how to study other things. I think that's the one thing you really want people to come away with, is how to learn something on their own.
If all you do is give them some closed set of facts, well that's not all that useful for them. I particularly think that they should put stuff together. I like to ask a question at the end of the course that integrates all the parts of the course. If the students can't put that all together- well, then what have they really learned? If they can't use what you've tried to cover, I don't think it's very useful.
The research really helps the teaching, because that's the stuff you can really bring alive in the classroom, so it's not just what happens to be in books. It's much easier to make that interesting and exciting to students just because you've got so much background in it- you're really presenting just some small fraction of that. If all you're doing is repeating what's in the textbook, that's not all that interesting.
This is the first time I've taught a freshmen course in quite a while. The last time I taught a freshmen course it was two sections of 150 each. It was much different.
I'm teaching these kinds of topics at the graduate level with some seniors in it, as well, and I'd thought about making a senior-level seminar. Then this whole curriculum change came along where students had to take freshmen seminars. And most of those are being offered outside the sciences. There are very few freshmen seminars in the sciences. So I said 'well, maybe it would be more interesting to do this course as a freshmen seminar,' and that's what I did, I volunteered.
I wanted to cover a number of topics I didn't know anything about. I have a very narrow focus in the things that I study. I study systems in the brain that deal with drugs of abuse: a very well-defined thing, and the brain is a much bigger place than that. I know a lot of people in this field, and I just called them up and asked them if they'd be willing to do a topic- not a lecture but a topic, to come in and interact w/ the students.
[Dr. Justice's innovative solution was to use interactive teleconferencing in order to enable remote lecturers to conduct entire classes, complete with student interaction, just as if the professor were in the room. Dr. Justice also incorporated web-based readings in the course.]
There is so much stuff on the web- so I didn't have to reinvent things. You can find sites that have all sorts of animations and diagrams and figures and tutorials, and all I had to do was link to it, and then tell students that they should be looking at it.
[Dr. Justice is also involved in CAISER, or the Collaborative Approach in Improving Science Education and Research]
CAISER is something where they're trying to get a group of faculty together to do some modules of stuff that they're interested in, on some topic. All the people that are involved in the project have access to all the modules. And so you amplify your efforts by having someone do something about spectroscopy, someone does something about protein, etc. That way it's not just Emory, it's other institutions around here, and they can all make use of the same material. They can be tutorials, lessons, questions, things, but that's the idea behind them, that they're web-based lessons.
F.Y.I.
Other Interests
I just got back from a hiking/camping trip. I like to hike- I don't do anywhere near as much as I'd like to.
I also do the Science Olympiad. I coach one of those events, last year at Shamrock, next year at Druid Hills. It's a lot more fun than science fairs. What they have is 20-some events, and you go and compete in that event. Science fair, you just show your posterboard. In this thing you go, and you have to build a rubber-band airplane and they time how long it stays aloft, or a device that has to go a particular distance, and the team that comes closest to that distance wins that event. The one I've been involved with is the bottle rocket- take a 2-liter coke bottle, launch it with a parachute, and time how long it stays aloft.
How To Study Brain Receptors for A Given Chemical, A Crash Course
All of these proteins are what are called membrane-bound proteins, in the cell membrane. What that means is that there are almost no structures for these. The only proteins that there are structures for are proteins that you can crystallize, so you do x-ray crystallography on them. Those are only the proteins that you can dissolve in water, that are called water-soluble proteins. All these membrane proteins can't do that. As soon as you take them out of the membrane, they don't have any structure anymore. So, comparatively, there's almost no information about the structures of these proteins. The one we happen to be looking at is the target for cocaine.
So what you have to do is use other methods to study the structure of the protein. The most widely-used method is to simply use mutagenesis- which simply means start replacing all the amino acids in it and ask whether anything happens or not- we don't do that, our lab isn't a mutagenesis lab, but we do things more along the lines of, if someone finds an interesting mutation, we might investigate that fairly thoroughly.
The major effort right now is to take analogues of cocaine- molecules that are like cocaine except that they have a reactive group in them that covalently attaches to the protein- that is, it irreversibly binds to the protein, so you can then go chew up the protein and find out what amino acid that thing got bound to. And that tells you that that region must be in the active site of the cocaine binding site because that's where it stuck. And you can make half a dozen different molecules like that, and that lets you begin to map out the active site of the protein. That tells you where to put all your efforts, or where someone else can put all their efforts in making lots of mutations and asking what happens there. But the protein we're looking at has over 600 amino acids, so you can't just do it willy-nilly.
There's 12 alpha-helixes in this protein we're looking at. And you don't know which of these are really important as the binding site. And you don't know which of these are really important or not. So you find that one these amino acids is the one that one of these inhibitors binds to. That just tells you one real small part of the picture. You've then got to take another inhibitor and see where that binds... once you get 2 or 3 of these domains associated together, you're beginning to get a picture of what parts of the protein are in the active site. That still doesn't tell you which amino acids are making the hydrogen bonds with the cocaine or the substrate- but at least that tells you that those domains are important. That's a long slow process- we're talking several years to work out that picture. As that stuff gets done, other people will play with it too- once you publish others make new compounds to see where they bind. It's a slow step-by-step process. It's not something you do with one experiment or a few experiments and then voila that's the active site.
You gradually build up a picture- once you've got enough of those domains that you knew were involved in some orientation information, then you might think about doing some sort of computer simulation of that- but it's a bit premature now.
It's not like I'm working on drugs to deal with cocaine addiction- that's not what we do- I'm more interested in 'how does this protein work,' 'where does cocaine bind.' Nobody knows how these things work.
All cocaine does is act like a plug in the drain- it doesn't do anything itself to stimulate the brain. What these proteins do is to take other molecule's transmitters in the brain and pump them back in the cells, by some still not clearly understood mechanism. What matters to me is not what cocaine does to the brain so much, but how do these things work in the normal state? How do they function?
This structure thing is open-ended. This will occupy the next ten years.
Once you understood how one of these proteins work, you could use that as a model to try and understand how other proteins work. There are certain ones that are closely related enough that they probably do work the same. If you crack one of these you know a lot about a whole family of them.
All these structures, in terms of how they work, you wonder, in terms of the normal systems, does this have implications in normal function, or in depression or other disorders? It's known that anti-depressants act on these proteins.
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