August 12, 2011
NIH Podcast Episode #0140
Balintfy: Welcome to the 140th 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 Director of the NIH discusses global health, translational research and personalized medicine; new research that may lead to a pill that kills a mosquito after it bites you; and looking back, and ahead, to the Women’s Health Initiative. But first, this news update. Here’s Craig Fritz.
Fritz: NIH-funded scientists have developed a strain of mice with a built-in off switch that can selectively shut down the animals’ serotonin-producing cells, which make up a brain network controlling breathing, temperature regulation, and mood. The switch controls only the serotonin-producing cells, and does not affect any other cells in the animal’s brains or bodies. When the researchers powered down the animals’ serotonin producing cells, the mice failed to sufficiently step up their breathing to compensate for an increase of carbon dioxide in the air, and their body temperatures dropped to match the surrounding temperature. The finding has implications for understanding sudden infant death syndrome, or SIDS, which has been linked to low serotonin levels, and is thought to involve breathing abnormalities and problems with temperature control. The finding may also provide insight into depressive disorders, which also involve serotonin metabolism.
At fertilization, a massive release of the metal zinc appears to set the fertilized egg cell on the path to dividing and growing into an embryo, according to the results of an animal study supported by the national institutes of health. The zinc discharge follows the egg cell’s steady accumulation of zinc atoms in the developmental stages before fertilization. The researchers documented the discharge by bathing the eggs in a solution that gives off light when exposed to zinc. They referred to the zinc discharge and accompanying light flash as zinc sparks. Scientists note that the discovery of egg cells’ massive intake and later release of zinc defines a new role for this element in biology. They anticipate the findings will one day lead to information useful for the treatment of infertility as well as the development of new ways to prevent fertilization from occurring.
For this NIH news update – I’m Craig Fritz
Balintfy: News updates are compiled from information at www.nih.gov/news. Coming up: details on mosquito research to fight diseases, the Women’s Health Initiative’s successes and the NIH Director’s insights on global health and rare diseases, that’s next.
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A Conversation with NIH Director Francis S. Collins
Balintfy: Recently, NIH Director Dr. Francis Collins was interviewed by Angie Drakulich [DRA-cue-litch] of BioPharm International in connection with the 2011 BIO Convention where Dr. Collins was a keynote speaker. They discussed NIH's efforts to improve global healthcare, including an update on the human genome project and a focus on infectious and rare diseases in the developing world. Following are some excerpts from Dr. Collins’ comments. The first is about how to best capture innovation, both technology and knowledge, that's used for developing treatments used worldwide.
Collins: Well, I think of innovation very much as a two-way street and we shouldn't think of the ways in which new inventions, new creative ideas come forth in the US or in Europe as only going in one direction, namely, oh well, we'll try to figure out how to distribute those to other parts of the world. We can also learn in what's being called reverse innovation about how to adopt new ideas that are being developed in low-income countries. A particularly good example is the use of cell phone technologies for medical purposes because after all in many countries in Africa or other parts of the world that are very recently getting communication capabilities, it's cell phones that are driving that. They're not limited by the landline ideas that we all sort of grew up with.
So for instance, we have a technology that's being developed and tested in Africa, which is a simple method of assessing whether in fact individuals who are being treated for tuberculosis or HIV/AIDS are compliant with the therapy. So, you have a pillbox, which essentially is hooked up to the cell phone network and every time the pillbox gets opened, it sends a signal to the clinic where that patient is being cared for. So that you can tell was it in fact opened and was it at the appropriate time of day as a pretty good indication that the medicine is actually being taken as directed and there hasn't been some confusion about the importance. Of course, that's crucial for diseases like tuberculosis or HIV/AIDS.
Balintfy: Here Dr. Collins discusses collaboration in particular research regarding rare diseases.
Collins: I certainly do think that collaborative spirit is expanding in a wonderful way and it's driven in part by scientific opportunities where for rare disease, we're discovering the molecular causes at a prodigious rate. There are now some 4000 rare diseases where we know at a pretty detailed level what the actual molecular problem is that leads to that illness, many of these being genetic diseases caused by mutations in the genome. So if you want to see that knowledge applied in terms of developing new therapeutics, that is something that is not trivial, and you certainly don't want to waste the opportunity to bring groups together that might be able to do this faster and you want to duplicate efforts and waste resources.
Balintfy: Dr. Collins also discusses translational research – taking projects from proof of concept in the lab, to clinical trials and patients.
Collins: As you know, the current situation is a little scary when it comes to making such promises because after all the average time it takes from identification of a potential drug target to ultimate approval of that therapy is about 14 years and the failure rate is about 98%. We think the time has come to look at that process the way that an engineer would and see if there are ways that we could optimize some of the steps that currently are slow, expensive, and likely to fail. And that is part of NIH's effort now in putting together a new entity called the National Center for Advancing Translational Sciences.
We certainly will do this in a way that is complementary and not competitive with what the private sector would like to do, but we do expect that this kind of initiative may make projects that previously appeared too risky start to look attractive. So some of this is the idea of de-risking projects, which the private sector might otherwise not feel were economically attractive.
And certainly for NIH itself, we will, when we see opportunities for therapeutic development working through the 27 institutes and centers that have a lot of knowledge about these areas, try to move projects forward to the point where they become commercially viable, and then license them out as quickly as possible in order to get them over the finish line. Again, the goal here is to try to take advantage of remarkable scientific opportunities that might otherwise lie untouched, but also to recognize the economic realities, which means that companies in general are not going to go after projects that they don't think ultimately will become profitable.
Balintfy: He also comments on how close we are to having personalized medicine – specific treatments based on an individual’s genetic code.
Collins: Well, I think we're there in some instances. If you consider for instance a woman who's diagnosed today with breast cancer and has negative lymph nodes at the time of surgery, the question is, is the surgery she just had, the lumpectomy and the radiation that will follow, is that sufficient, is she cured or does she also need adjuvant chemotherapy. Well, personalized medicine is here because about half of the women in the US who are in that situation this year will have their breast cancer cells analyzed to see whether there's a signature there on a very personalized assessment of what's going on at the genetic level that would indicate that they are at a higher likelihood of recurrence and therefore need the chemotherapy. Or whether they're at low risk and can be spared the cost and the side effects of what can be a pretty unpleasant experience. That personalized medicine intervention right now is saving our healthcare system this year about $100M in terms of the women who won't end up needing chemotherapy who otherwise would go through it. So it's a pretty good example.
Pharmacogenomics, another place where increasingly drugs that have different effects in different people based on their genetics. It's possible to assess that from drugs like Abacavir for HIV where it's now on the FDA label essentially require to do a genetic test before you prescribe the drug in order to be sure that this is not an individual that's going to have a hypersensitivity reaction. Or even Plavix, which is after all one of the most highly prescribed drugs and where there's now an FDA label saying physicians should be aware that about a third of the people given that drug will not benefit from it because of their genetics and should be offered some other alternative. So in those instances, I would say personalized medicine ain't the future, it's the present.
Balintfy: For more from this conversation with Dr. Collins see the link in his Video & Sound Gallery at www.nih.gov/about/director/videogallery.htm.
World Mosquito Day
Balintfy: Mosquitoes, not only are they a back-yard pest, but they can cause some serious diseases. The most common mosquito-borne illness in the United States is West Nile virus; that has affected all areas of the continental U.S. But worldwide, mosquitoes are a vector – meaning they are an animal that transmits a pathogen – for several diseases.
Costero: Malaria, dengue, yellow fever, West Nile virus, those are all mosquito-borne disease.
Balintfy: That’s Dr. Andrea Costero, a vector biology program officer at NIH. She explains that NIH is supporting a lot of research on mosquito-borne disease and on mosquitoes because they are the most important vectors of diseases to humans worldwide.
Costero: For malaria, it’s like millions of cases per year. For dengue, it’s millions of cases per year globally. So yeah, they’re pretty prevalent.
Balintfy: And deadly. Malaria alone kills nearly one million people each year; and more than 40 percent of the world’s population lives in areas where there is a risk of contracting malaria. Malaria is caused by a single-celled parasite, but again infection in humans is a result of transmission by mosquitoes.
Costero: We want to find a better way to either control them or avoid them transmitting disease.
Balintfy: That transmission occurs when the mosquito bites a person or animal to get their blood-meal. So why celebrate them on World Mosquito Day August 20th?
Costero: The purpose is to create awareness globally about the importance of mosquitoes as vectors of diseases to humans.
Balintfy: World Mosquito Day commemorates Sir Ronald Ross’s discovery that first showed female mosquitoes transmit malaria.
Miesfeld: Mosquitoes have been around for millions of billions of years and they’re going to be around; and mosquito-borne diseases are something we have to deal with all the time.
Balintfy: That’s Dr. Rodger Miesfeld, an NIH-funded researcher at the University of Arizona. He says mosquitoes become resistant to insecticides so researchers need to stay one step ahead of that resistance.
Miesfeld: That could be in the broad global terms in malaria, dengue fever, yellow fever in developing countries, but also in terms of looking down the road to what might occur if some of these pathogens get into the otherwise pest mosquitoes that we have in our country and in other countries as well.
Balintfy: So Dr. Miesfeld and his team have been looking at stopping a molecular process involved in the mosquitoes’ digestive system. NIH’s Dr. Costero summarizes the science:
Costero: When mosquitoes blood feed, the blood needs to be digested. In order to digest the blood, there are proteins, enzymes that come out of the mosquito gut that degrade the blood and break it down into the proteins that the mosquito needs to generate eggs. So that’s a very complex biochemical process.
So what they’ve found is that the protein that is part of the envelope around the vesicle inside these gut cells that secrete this enzyme, if they mess with that, there’s no secretion of the enzyme; and therefore, the blood cannot be digested to produce eggs.
Miesfeld: Rather than targeting the nervous system or targeting larval development or some of the other lifecycle or biochemical processes in the female mosquito, we’re targeting specifically her ability to digest this gigantic blood meal in a quick enough, short enough time that she can lay eggs.
Balintfy: That gigantic blood meal is the equivalent of a 125-pound human consuming a 12-gallon smoothie made from 25 pounds of hamburger, says Dr. Miesfeld. And if a mosquito can’t lay eggs, the cycle of infection stops.
Another NIH-funded researcher, Dr. Brian Foy at Colorado State University, has done a study following a drug used against worms. He explains that his study looked at mass treatments of whole villages in Senegal.
Foy: The whole point was that we know that the drug has an effect against mosquitoes, and we wanted to measure that effect in terms of the effect meaning that if the drug circulates in people’s body and the mosquito takes your blood, it will ingest a dose of that drug that could be lethal to the mosquito.
Balintfy: And like Dr. Miesfeld’s study, mosquito death was the apparent result. Looking at these two studies together, Dr. Costero says they’re both finding novel approaches to controlling disease transmission and for controlling mosquito populations.
Costero: Both approaches have resulted not only in the pathogen not being able to be transmitted but also in killing the mosquito. So at the same time you’re preventing transmission, you’re also reducing the population of mosquitoes which could have an impact.
Now, just to be clear, I mean this research is at a very early stage, especially Dr. Foy’s research. But he has found evidence of something very interesting, so he is going to pursue that.
Now, Dr. Miesfeld has found something that also is at the early stages because there are always more questions that need to be resolved in order to translate this kind of discoveries into some sort of intervention. That’s going to take a lot of years but the first step obviously is to find something that seems to be useful to prevent transmission or to bring mosquito populations down.
Miesfeld: Basically, what we’ve done is we used a genetic trick to identify proteins in the mosquito that could be good targets, and the next step is to collaborate with chemists to say, “Can you help us find small molecules, chemical compounds that will inhibit that protein and are soluble in many of the solvents that are used in normal insecticides?”
Costero: Somehow the mosquito has to ingest this compound or this thing that’s preventing this protein from doing its work. So that could either be from people taking a pill, as they say, that would not harm people but that would cause the mosquitoes to have this problem, or producing these in sugar-baited traps or nets. I mean the mosquito has to ingest this with the blood meal so that’s going to be the tricky part. But again, this is just the beginning of a long period of work to see if this can be exploited in our favor.
Balintfy: Dr. Foy’s research is also promising says Dr. Costero because it looks at a drug that’s already being used broadly. Dr. Foy adds that it is one of the few drugs in the world that can be given out in mass drug administration to entire villages by non-clinicians. But questions like how frequently and for how long still need to be answered.
Foy: We need to figure out that period of control and we need to do that sustained trial where we’re seeing actually if it correlates to disease and a reduction of disease in people.
Balintfy: And Dr. Foy points out there’s a small catch: they’re not just killing all the mosquitoes that are out there biting people, just the dangerous ones.
Foy: What we’re really doing is kind of killing off the old females and so the only ones that are left, which are still a lot of mosquitoes and are still biting people, are young. And those young ones haven’t had a chance to mature the parasite in their bodies for long enough, and so even though mosquitoes are still biting people after they’ve taken this drug, all those mosquitoes are young so they’re not transmitting malaria, and that’s the key reason why this whole concept works.
Balintfy: Dr. Costero reminds that these are just two examples of research being done on mosquitoes.
Costero: We’re trying to identify either better targets for insecticides or novel controls that are maybe not insecticide-based or could be insecticide-based. We’re supporting work on transgenic mosquitoes for example on traps, on repellents, how do mosquitoes identify humans as humans, as a blood meal, how to prevent them from doing that, etc. So we have a pretty broad portfolio.
Balintfy: For more information on the NIH-funded research being conducted by Drs. Foy and Miesfeld, as well as details on malaria and other mosquito-borne disease studies, visit www.niaid.nih.gov. And coming up next, the Women’s Health Initiative.
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Women’s Health Initiative
Balintfy: The Women's Health Initiative was a major 15-year research program launched in 1991.
Rossouw: As originally conceived, the study was designed to look at the causes and prevention of the major problems of older women, postmenopausal women, and these were cardiovascular diseases, certain cancers, and fractures.
Balintfy: That’s Dr. Jacques Rossouw, chief of the Women’s Health Initiative Branch at the NIH’s National Heart, Lung and Blood Institute.
Rossouw: To get at these questions, the NIH designed three clinical trials, one of hormone therapy mainly to see if it would prevent heart disease, one of a low fat dietary pattern mainly to see if it would reduce breast and colorectal cancer, and one of calcium and vitamin D to see if it would reduce fractures.
You know, these were mega trials because they were designed to get definitive answers.
Balintfy: Altogether the Women’s Health Initiative has involved 161,808 generally healthy postmenopausal women.
Rossouw: The study that has attracted the most attention and has had the most public health impact is the trial of hormone therapy, postmenopausal hormone therapy, which we used to call hormone replacement therapy. But since we now know it's not a true physiological replacement, but simply a drug with risks and benefits, the FDA and ourselves now call it menopausal hormone therapy, or postmenopausal hormone therapy depending on what age you started at.
The trial was designed to run for about eight years. We actually stopped it short of six years because it was clear that there were more risks than benefits and these risks were cardiovascular, coronary heart disease, the thing that we thought we would prevent actually increased, strokes increased, venous thromboembolism increased, breast cancer increased and these far outweighed the benefits of a reduction in fractures and colorectal cancer.
Balintfy: Dr. Rossouw, who talked with Dr. Vivian Pinn, director of the NIH Office of Research on Women’s Health, reviews other major findings.
Rossouw: The trial of dietary, which was a low fat intervention. So women were advised to reduce their fat intake from all sources. And that trial went to its full duration of eight years and what we found is that it did not overall reduce breast cancer risks significantly. There was a 9% reduction, but it fell short of being significant. However, in women who had started off with the highest fat intake at baseline, these are women who start off with about 38% of their energy is fat, and they had the most reduction in their fat intake doing the trial and they did have a significant reduction in their breast cancer risks.
Balintfy: Dr. Rossouw says the major clinical outcomes from the Women’s Health Initiative are opening avenues for even more research.
Rossouw: There's also this huge wealth of data and of specimens, which have led to innumerable ancillary studies and consortium studies where we team up with other groups that have similar data. So we've become very active in the field of genomics and proteomics.
So we've turned from being a public health prevention kind of program to one that is really participating in cutting edge science and I think that is something that's just going to grow in the future.
Balintfy: To hear the entire interview with Dr. Rossouw, listen to the Pinnpoint on Women’s Health podcast. You can find that at the website orwh.od.nih.gov. To learn more about the Women’s Health Initiative, visit www.nhlbi.nih.gov/whi.
Balintfy: And that’s it for this episode of NIH Research Radio. Please join us again on Friday, August 26 when our next edition will be available. If you have any questions or comments about this program, or have story suggestions for a future episode, please let me know. Best to reach me by email—my address is email@example.com. I'm your host, Joe Balintfy. Thanks for listening.
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