Small Changes With Big Impacts: Mirror Image ProteinsAug 23, 2014
Announcer: Examining the latest research and telling you about the latest breakthroughs. The Science and Research Show is on The Scope.
Interviewer: When you look in the mirror, your reflection is essentially the same but everything is reversed. My guest, Professor of Biochemistry, Dr. Michael Kay, has figured out how to make mirror images of the proteins in our bodies. These small changes can have big impacts and his discovery has exciting applications in disease therapeutics.
Dr. Kay, your research involves making mirror images of proteins. Can you explain what you mean by that?
Dr. Kay: Proteins come in both left-handed and right-handed versions, and for reasons we don't understand, early in evolution nature picked left-handed. But in theory, they could have been right-handed and these are proteins that would be the mirror images of natural proteins. Just like your hands, they're structurally the same, they look the same, but they have a different handedness to them.
Interviewer: Why would you want to make mirror images of proteins?
Dr. Kay: Proteins and their smaller cousins, peptides, are extremely useful as therapeutics. There are many of them available against all sorts of diverse diseases, but they generally suffer from a problem that they get degraded in the body pretty rapidly by a process called proteolysis, so they're broken down into their component amino acids and then they stop working. This makes these drugs relatively expensive. It means they don't last very long in the body, and you have to give frequent doses of relatively large amounts.
It turns out that these mirror image proteins, because nature has never seen them before, they're not degraded this way. They have the potential to last essentially indefinitely in the body.
Interviewer: How do you go about making a mirror image protein?
Dr. Kay: A normal protein is made just naturally in a cell. A mirror image protein, since nature doesn't know how to make these proteins, we have to make them ourselves chemically from scratch. That process means taking the amino acids that make up a protein and stitching them together, one by one, individually to make up a protein. Once the protein is actually made, there's this second step where you have to fold it into a precise 3D geometry that's the functional state of the protein so that the protein is active.
The way we like to think about it is when a protein is made, both in the cell or in the lab, it basically looks like a limp piece of spaghetti. It's just a long string, and then that has to be folded up into a ball of yarn that's the particular shape that really dictates the function of the protein. In a cell, that process is handled by a set of machines called chaperones, and these take that spaghetti as its being synthesized and assist that to fold to the proper configuration. These are really essential machines in the cell without which life is not possible.
Interviewer: What were you able to figure out with this work that has not been done before?
Dr. Kay: In this work, we synthesized the largest protein that has ever been made by synthetic means. It's a 312 amino acid protein. The specific question we were asking is the chaperones in a cell, could they be used to fold these mirror image proteins even though they've never seen them? Do they have that kind of secret ability to handle this?
Initially that sounds kind of crazy. Things in the cell generally don't perform functions that they're not designed to perform, but we thought this might be possible because chaperones are a very special machine. They're extreme generalists. Basically, the particular chaperone we're working with folds hundreds or maybe even thousands of different proteins of all different shapes and sizes. Because it's such a generalist and it can't grab onto any very specific feature of any one protein, we thought it might be such a generalist that that would even extend to these mirror image proteins. The chemistry just didn't exist to do this previously. Now, with this paper, it's finally gotten to the point where we can make these large proteins that do depend on chaperones and then test whether the natural chaperone has this secret ability to fold mirror image proteins. And in fact, it does.
Interviewer: How do you know when you have a right-handed protein? It's not like you can look at it in a microscope.
Dr. Kay: It's extremely difficult, actually. Just like if you're looking at your image in a mirror or looking at your left and right hands, what's really different about them? The answer is almost nothing. They're the same size. They look the same. They have the same chemistry. Everything is basically identical except this somewhat difficult to describe property of handedness. You can tell your left from your right hand. There's just something that's different about them.
There are a few very specialized techniques, mostly spectroscopy techniques, that can be used that actually can tell the difference, and it just turns out through some very esoteric science that you can have a type of light that interacts differently with a left-handed versus a right-handed sample and then we can detect that using this advanced spectroscopy.
Interviewer: What are the next steps?
Dr. Kay: We need these mirror image proteins to do mirror image drug discovery, to discover these mirror image peptides and proteins that are not degraded by the body. We've been limited to relatively small targets in the past, but now we're really interested in expanding mirror image drug discovery to common cellular targets, things like cancer receptors, proteins involved in inflammation, heart disease, diabetes. These tend to be in that 300 amino acid range. Now that we can make these kinds of proteins and fold them, those types of targets are now available. Now we're excited to start attacking those types of targets with mirror image drug discovery.
Interviewer: One thing that I was really struck by is that you're interested in making a mirror image organism and you give the example of a D. coli, which would be the mirror image of an E. coli. Why would you want to do that?
Dr. Kay: That's right. That is a very good question. We may be a little crazy on this, but the idea is if we can make an organism that was completely synthetic and had all of its components that are mirror image to a natural organism, it would function exactly the same way as the natural organism, except it would eat mirror image food and it would produce mirror image proteins. This would allow us to get around having to manually synthesize individual proteins, so then hundreds or thousands of targets would become readily available using standard cell expression of proteins rather than this tedious individual synthesis by chemistry.
Interviewer: So it would be a little mirror image factory.
Dr. Kay: Exactly.
Dr. Kay: Then there are some kind of spacier applications as well as we get into this deeper. Further ahead, if you have a mirror image organism, it's interesting, just like your hands in the mirror, it would function exactly the same way, but the mirror image organism would not be able to interact with the environment. We're very interested in this idea of coming up with mirror image organisms to allow us to study very dangerous pathogenic organisms or toxins in the lab in a safe way, because they wouldn't be able to attack our body. They'd only be infectious to a mirror image human, which doesn't exist yet.
Bring up Ebola, which has been so important recently. We talk about this idea of Debola. A huge problem with the Ebola virus is it's so dangerous to study that it really slows research down. For instance, our lab, we can't study the virus directly. There are no facilities in Utah that are sufficient for studying Ebola, so we work on individual pieces that are much safer and we collaborate with the US Army, which has a lab that's capable of handling Ebola. But these labs are very specialized, very expensive, and they really slow down the research. So if there was a way to work with something that had all the same properties of Ebola but was completely safe and noninfectious to humans, we could do our research on that kind of mirror image organism and then flip it back to the original left-handed version to test against the real virus at late stages. We could do drug discovery, mechanism, really do some interesting studies that right now are just too difficult from a safety point of view.
Announcer: Interesting, informative, and all in the name of better health. This is The Scope Health Sciences Radio.