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April 17, 2009
NIH Podcast Episode #0082
Balintfy: Welcome to the 82nd episode of NIH Research Radio with news about the ongoing medical research at the National Institutes of Health—the nation’s medical research agency. I’m your host Joe Balintfy. Coming up in this episode, the breakdown of bones, and the history of teeth. Also, we’ll have part three of our series on proteins. But first new insight on the brain activity of bulimics. That’s next on NIH Research Radio.
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Impaired Brain Activity Underlies Impulsive Behaviors in Women with Bulimia
Balintfy: In the first study of its kind, researchers assessed self-regulatory brain processes in women with bulimia nervosa without using disorder-specific cues, such as pictures of food. The study shows that impaired brain activity underlies the impulsive behaviors in women with the eating disorder. It was a controlled study of women with and without bulimia, where researchers saw that those with the eating disorder tended to be more impulsive, and generally did not show as much activity in brain areas involved in self-regulation.
Zehr: What’s not clear is whether or not it’s a cause or a consequence of the disorder.
Balintfy: Dr. Julia Zehr, at the National Institute of Mental Health explains the disorder.
Zehr: Individuals repeatedly eat too much and then engage in purging activities. And those purging activities can be vomiting, or laxatives, and some people also include excessive exercise as one way of compensating for binge eating episodes.
Balintfy: Dr. Zerh adds that binge eating is characterized by feeling a lack of control while eating. She continues that the study shows a biological difference between individuals with bulimia and those without; the difference can lead to research...
Zehr: Where we can look for differences in causation, we can look at different treatment, possibly novel treatments or interventions for the disorder.
Balintfy: The study was conducted by Dr. Rachel Marsh, an NIH-funded scientist from Columbia University. She and her colleagues observed the brain activity of 20 adult women with bulimia, and 20 healthy women of similar age and weight, using functional magnetic resonance imaging.
Marsh: So what we did was we scanned their brains while they were performing a regular cognitive control task or an inhibitory control task.
Balintfy: All of the women viewed a series of arrows presented on a computer screen. Their task was to identify the direction in which the arrows were pointing while the researchers observed their brain activity using the fMRI.
Marsh: So, we’re looking at their brain images and what we saw is that the healthy individuals activated large expanses of frontal striatal circuits, and we know that these areas, this system in the brain, mediates the capacity for self-regulatory control, to respond correctly on these trials in terms of this task. The patients with bulimia activated these circuits much, much less, and this was statistically significant. So they performed less accurately on this task and they did not engage the brain circuits that are necessary to perform accurately on the task.
Balintfy: Dr. Marsh adds that implicating a specific brain circuit that is functioning abnormally will help researchers understand what might be causing the impulsivity associated with bulimia.
Marsh: The other thing that we looked at was what was going on in their brains when they were making errors, and so we also saw that when patients with bulimia were making errors on the task they activated these circuits differently than healthy controls. Balintfy: Researchers are currently conducting further studies on brain functioning in teens with bulimia, which would offer a closer look at the beginnings of their illness. For more information on this study and bulimia nervosa, visit www.nimh.nih.gov.
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Scientists Report Gene Network in Early Tooth Development
Balintfy: Researchers report that they have identified a network of dental genes that likely were involved in building the first tooth half a million years ago. Dorie Hightower brings us this report.
Hightower: New findings introduce a core evolutionary list of molecular pieces needed to make a tooth.
Streelman: This allows us to explore the molecular ancestry of teeth—so basically, how teeth are made in different organisms and how this may have changed over evolutionary history.
Hightower: Dr. Todd Streelman of the Georgia Institute of Technology, explains that he and his colleagues found the network of genes in a very unusual fish—Lake Malawi cichlids.
Streelman: It turns out that these fish are really interesting because they have jaws in their throat around the first, or the most ancestral population of teeth; and then they have teeth associated with the first jaws to evolve, which are very similar to the jaws on the front of your face. So they have teeth in two places and we can ask how these teeth in different populations are made.
Hightower: Teeth are extremely ancient structures that arose in early vertebrates— animals with a backbone—but interestingly predate jaws.
Streelman: We think this provides a developmental context as well as a historical context. It’s well-known that the first teeth probably occurred deep in the pharynx of jawless fishes about half a billion years ago. And what this means is that there’s a really long evolutionary history of teeth in the fossil record and in the organismal record. So by studying a bunch of different organisms and how they actually make their teeth we can try to understand what’s different and what’s common about all teeth.
Hightower: Because humans replace their dentition—or set of teeth only once, Dr. Streelman says that this discovery should provide useful information—to coax diseased teeth back to health with biology rather than the traditional hand-held drill.
Streelman: Many dental defects involve either the misshaping or the misplacement or complete loss of teeth at a certain stage. Some of the groups of organisms we studied replaced their dentition through their entire life. And so if we can understand how sets of genes are used to make replacement teeth or to make teeth of certain sizes and shapes we can better understand how to make biological implants that may function in the place of say, ceramic implants in dentistry.
Hightower: Streelman says that this study also shows the power of evolutionary models like cichlids in biomedical research. Rather than manipulating genes in a laboratory, the cichlids are nature's own experiment.
Streelman: An evolutionary model is a little bit different than maybe a laboratory model. A laboratory model, like the mouse, has been very useful in studying dentitions because you can do all sorts of experimental things. You can rearrange genetic elements, you can turn genes on and off. And an evolutionary model really takes the view that evolution has done these things to the organisms and to their genomes. So evolutionary models express natural variations and we are often interested in studying natural variations because this of course is the type of variation that humans express.
Hightower: Streelman is part of a team of developmental biologists, paleontologists, and computational biologists—all working together to uncover new approaches to dental treatment. For more information about this finding, go to www.nidcr.nih.gov. This is Dorie Hightower, National Institutes of Health, Bethesda, Maryland.
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Scientists Discover Key Factor in Controlling the Breakdown of Bone
Balintfy: We think of teeth and bones as being hard and stable. But bones are actually very dynamic, constantly growing and breaking down.
Germain: People think about them as relatively hard, static structures, but at the micro scale, at the small scale where biologists and, you know, doctors think about it, bone is undergoing remodeling at a fairly high rate.
Balintfy: Dr. Ronald Germain, an immunologist at the National Institute of Allergy and Infectious Diseases, explains the process.
Germain: You have a set of cells that build up bone that are called osteoblasts, and then you have these other cells that we’ve worked on that break down bone called osteoclasts, and it’s the proper balance of the two that give you what appears to be stable bone structure.
Balintfy: In people with bone-destructive disorders such as osteoporosis, however, osteoclast activity outpaces osteoblast activity, leading to a loss of bone density. Dr. Germain says osteoclasts come from a type of white blood cell.
Germain: The way this works is with those white cells that are recruited from the blood after circulating in the bone matrix, because bone is not dead, it’s live, and they get certain signals that cause them to attach to the surface, and if the right set of signals are there besides those attraction signals, then they actually aggregate, fuse together, and make big giant cell, which is the mature osteoclast that can begin to destroy the bone.
Balintfy: While most current therapies for bone-degrading diseases target mature osteoclasts, Dr. Germain explains that a rheumatologist who treats people with bone diseases, Dr. Masaru Ishii from Osaka, Japan, became interested in understanding what signals control immature osteoclasts, precursor cells that might otherwise go back into the bloodstream. Dr. Ishii worked with Dr. Germain’s lab to determine if a specific chemical mediator controlled immature osteoclast migration in live mice.
Germain: And what we discovered is there’s this lipid, this fatty molecule that’s at high concentration in the blood, and when it interacts with a receptor, a receiving apparatus, a sensing apparatus on these precursor cells, it tells them to come back into the blood stream, don’t hang out on the bone’s surface, and don’t make a mature osteoclast, and therefore, more of that signal decreases bone destruction.
Balintfy: According to Drs. Germain and Ishii, these findings, combined with previous data, indicate that it may be possible to use combined therapies that target immature osteoclast migration and mature osteoclast function to treat and prevent certain bone disorders such as osteoporosis and rheumatoid arthritis. For more on this study, and the report published online in Nature, visit www.niaid.nih.gov. To learn more about your bones a skeleton, visit www.niams.nih.gov. And to hear more about the study of proteins, stay tuned. Part three of our series is after this break.
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Proteomics – Part 3 of 3 – Proteomics at the National Cancer Institute
Balintfy: In the past couple episodes of NIH Research Radio, we’ve been learning about proteomics, the study of proteins, and how it might help with personalized medicine, as well as the challenges facing the field of cancer research. Now, we wrap up our discussion with Dr. Henry Rodriguez, the director of the Clinical Proteomic Technologies for Cancer programs at the NCI. We’ll focus on how proteins can be biomarkers.
Dr. Rodriguez: Correct.
Balintfy: And the National Cancer Institute is very involved in that. First, thanks again, and welcome back.
Dr. Rodriguez: Thank you very much.
Balintfy: Let’s talk about how the National Cancer Institute is addressing the promise and some of the challenges we’ve been talking about regards to proteomics for the early detection, diagnosis and treatment of cancer.
Dr. Rodriguez: Absolutely, so one of the things that the National Cancer Institute did is they held a series of workshops, and they absolutely recognize the promise that clinical proteomics can have for cancer. But at the same time, they also recognize that there’s challenges and that the research community has to address and overcome. To that, what they did in late 2006, NCI had then launched the Clinical Proteomic Technologies for Cancer Initiative.
What the program is really doing, which is the reason I just think it’s one of the best things that’s out there and it’s very unique, is that it brings together the best minds in proteomics to greatly improve the protein biomarker pipeline, and at the same time, it’s doing this with a set of various tools, with the platforms, the various necessary reagents and the data for the field so that ultimately, proteomic biomarker discoveries can be translated into a clinic.
Balintfy: Basically, meaning there’s going to be standardization and all this research will focus the standards so that information can be used in the future for potential treatments and—
Dr. Rodriguez: Exactly, and then the part that makes it very unique is that the products that we develop, the data that we generate, all this goes back to the public, so at the same time, they could actually look at what we’re doing. Hopefully, our goal would be is that they would see the value in these metrics and start applying it within their own research laboratory.
Balintfy: And this is being done basically through some different programs?
Dr. Rodriguez: Right, so the program itself actually has three major but well-integrated components to it. One of them they refer to as the Clinical Proteomic Technology Assessment for Cancer commonly referred to as the CPTAC Network. And there’s another one we have where we look at individual investigators, and that’s one we refer to as Advance Platforms and Computational Sciences. The third component is we’re also developing a Proteomic Reagents and Resources Core.
Now, the CPTACS, which is the network, this actually represents one of the most in-depth, multi-disciplinary networks that I’m aware of that’s actually trying to optimize existing platforms, again, to reliably identify, quantify and compare proteins in complex biological mixtures.
The second component becomes, what if it turns out that these analytical tools that the network is looking at might not be the most robust to go from a research environment, ultimately into a clinical setting. So what we did with at NCI is that the second component specifically targets individual investigators.
The third one happens to become what we refer to as the Proteomic Reagents and Resources Core. And what resources we imply there is that every standard operating procedure we develop, every data set that we will develop, that becomes the resource, and the reagents are going to be the antibodies and other things that will go back to the community. So those are the three well-integrated program itself.
Balintfy: What communities are involved in the NCI Clinical Proteomics Technologies for Cancer Initiative.
Dr. Rodriguez: So the initiative itself is referred to as the CPTC, the network of laboratories is what’s referred to as the CPTAC. Now, when it comes to the community, I think this is one that’s quite challenging, but at the same time, it’s one of the most rewarding that I’ve been given the effort now to lead. It currently consists of scientists. Nearly, it looks at 50 federal, academic and private sector organizations.
What makes it quite interesting is that the researchers funded through this program, they represent both seasoned senior investigators who are leading large centers. But at the same time, we also involve junior investigators that’s involved in the individual projects.
At the heart of the program is the one that you just alluded to, which is the CPTAC, and that’s the network of laboratories, and what they do is that they actually help govern the overall initiative along with the other members of the program, and that’s how we ensure that what the individual investigators are doing, they’re informed of what the network is doing. The network is also able to tap into the products and deliverables that’s coming out of the individual investigators but also they take into consideration what would the community at large need to further advance their science.
Balintfy: What do you think that is that the NCI Clinical Proteomic Technologies for Cancer Initiative is going to provide the community?
Dr. Rodriguez: So, kind of an easy way of looking at it is I actually would say that what the program is ultimately going to provide is the foundation for advancing protein science for personalized medicine. So how’s it going to do that? Well, it’s going to provide the necessary optimized tools, the various metrics, methodologies, reagents, data and the standards that’s going to be needed to define the platform performance parameters and sources of variability at every step of the biomarker discovery and the verification pipeline.
In other words, kind of like this proteomics tool kit. You open it up, and here’s all the things you’re going to need to go into your laboratory and have assurance that all this is working correctly; and at the same time, developing collaboration with institutions and by the National Institute of Standards and Technology, which is a sister agent through the Department of Commerce out here in Maryland. We’re also developing various resources and standards through them, because that is the federal arm of developing standards. And our goal is to provide these at very minimal cost to the greater community at large.
The main thing we really see out of it is that all this encompassing is going to dramatically improve the quality of biomarkers candidates that enter the clinic for validation, and we hope that’s going to lay the foundation for the next generation of molecular diagnostic based tools, looking at proteins as the end product that you wish to measure.
Balintfy: I think that kind of wraps up this particular episode and at this moment, we’re kind of wrapping up a series. Is there, you know, maybe some final words or is there something that maybe I’ve missed that we should cover?
Dr. Rodriguez: I think the main thing is that while the genomics community has developed very wonderful science, I think the proteomic community is in its infancy, but the potential and the promise of understanding the proteins, their function, and can you use them for early diagnosis, is what you’re going to see in the next years if the due diligence is done correctly, it will have a tremendous impact when it comes to cancer care at the patient level.
Balintfy: Terrific. Thank you very much.
Dr. Rodriguez: You’re welcome.
Balintfy: This was the third of three features with Dr. Henry Rodriguez at the NCI. To hear the previous segments, visit the NIH Research Radio archive page and check out episodes 80 and 81. For more information about the NCI Clinical Proteomic Technologies for Cancer Initiative, visit the website proteomics.cancer.gov. That’s it for this episode of NIH Research Radio. Please join us again on Friday, May first when our next edition will be available for download. I'm your host, Joe Balintfy. Thanks for listening.
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NIH Research Radio is a presentation of the NIH Radio News Service, part of the News Media Branch, Office of Communications and Public Liaison in the Office of the Director at the National Institutes of Health in Bethesda, Maryland, an agency of the US Department of Health and Human Services.
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