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February 11, 2011
NIH Podcast Episode #0127
Balintfy: Welcome to episode 127 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 how young women with a menopause-like condition are at risk for depression, the new discovery of a rare vascular disease, and a listener request to explain aptamers. But first, this news update. Here’s Craig Fritz.
News Update
Fritz: In a study funded by the Eunice Kennedy Shriver National Institute on Child Health and Human Development, researchers have found that surgically treating babies with spina bifida while they’re still in the uterus reduced the rate of disability. Spina bifida is a birth defect in which the brain or spine fails to develop normally in the early embryo. The condition often results in weakness or paralysis below the location of the defect on the spine. The new surgical procedure consists of closing an opening at the back of the spine before birth. This method varies from the traditional approach, which involves repairing the defect in the spinal column after an infant has been born. The technique also increases the chances that a child will be able to walk without crutches and greatly reduces the need to divert fluid away from the brain, a common problem with spina bifida. Scientists note that in spite of an increased risk for preterm birth, children who underwent surgery while in the uterus did much better, than those who had surgery after birth.
Researchers at the National Institutes of Health and the University of Hong Kong have discovered that high levels of a particular protein in cancer cells are a reliable indicator that a cancer will spread. By measuring the protein’s genetic material in tumors that had been surgically removed from patients, along with measuring the genetic material from surrounding tissue, the researchers could predict at least 90 percent of the time whether a cancer would spread within two years. The researchers found that when the level of the specific protein in tumors was more than twice that in the surrounding tissue, the cancer was highly likely to return or to metastasize. At or below this threshold level, the cancer was much less likely to recur. The findings raise the long term possibilities of new tests to gauge the likelihood that a cancer will spread and, ultimately, of a treatment that could prevent cancer from spreading. Scientists suggest that a patient’s specific protein levels could be a key guide in individualizing their cancer care to improve outcomes.
For this NIH News Update – I’m Craig Fritz
Balintfy: Thanks Craig. News updates are compiled from information at www.nih.gov/news. Coming up we’ve talked about nanoparticles in past episodes, now what’s an aptamer? Also, discovering a new disease, and depression risk for young women, that’s next on NIH Research Radio.
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Young women with menopause-like condition at risk for depression
Balintfy: Primary ovarian insufficiency, also called premature ovarian failure is a condition where the ovaries in a woman younger than 40 stop functioning normally. Now a new study is showing these women are much more likely than other women to experience depression at some point during their lives. Wally Akinso reports that the finding suggests that all women diagnosed with the condition should be evaluated for depression.
Akinso: Young women with a menopause-like condition are at risk for depression according to a study conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health.
Nelson: Our research group has been interested in the role of irregular menstrual cycles and the health of girls and young women.
Akinso: Dr. Lawrence Nelson is the head of the Integrative and Reproductive Medicine Group at the NICHD.
Nelson: The problem we’re specifically working on is premature menopause; the more accurate scientific term for it is primary ovarian insufficiency. But this is young women who develop signs and symptoms of menopause maybe even in their teens or early twenties.
Akinso: Women with primary ovarian insufficiency stop producing normal amounts of reproductive hormones, develop hot flashes, and typically become infertile. The study authors evaluated 174 women with primary ovarian insufficiency and found that 67 percent either were currently clinically depressed or had been depressed at least one time in their lives.
Nelson: We found in this specific study with this specific condition that the onset of irregular menstrual cycles can be assigned that proceeds the development of depression. So it seems like a useful approach to educate women and their clinicians if they're having irregular menstrual cycles it could be an early sign that they're leading towards premature menopause or primary ovarian insufficiency. It is also associated in this patient population with an increase incidence of depression and could be an earlier sign of that to allow earlier treatment.
Akinso: In the study, more than 73 percent of women with primary ovarian insufficiency first experienced depressive symptoms after developing the irregular menstrual cycles believed to be an indicator of impending primary ovarian insufficiency. Dr. Nelson says depression plays a role even before diagnosis of this condition.
Nelson: So not only did we find that irregular menstrual cycles can be an early sign to a diagnosis of depression in this group of women; we also found that women with this premature menopause or primary ovarian insufficiency are about twice as likely to develop depression compared to other women. So not only women with this condition more likely to get depressed, the depression shows up in association with the menstrual cycle irregularity even before they get the diagnosis.
Akinso: Dr. Nelson says primary care physicians should evaluate their patients with a diagnostic screening test to determine if treatment or referral to a mental health specialist for further evaluation is needed. For more information on this study, visit www.nichd.nih.gov or visit www.nimh.nih.gov. This is Wally Akinso at the National Institutes of Health Bethesda, Maryland.
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NIH Researchers Identify Genetic Cause of New Vascular Disease - 1
Balintfy: The NIH Undiagnosed Diseases Program is a clinical research initiative with two goals: to provide answers to patients with mysterious conditions that have long eluded diagnosis, and to advance medical knowledge about rare and common diseases. Recently researchers at the Undiagnosed Diseases Program have identified the genetic cause of a rare and debilitating vascular disorder not previously explained in the medical literature. In other words, this is a new one. This adult-onset condition is associated with progressive and painful calcification of arteries in the lower extremities, yet spares patients’ coronary arteries. Wally Akinso reports on the discovery.
Akinso: Clinical researchers at the National Institutes of Health have identified the genetic cause of a rare and debilitating vascular disorder.
Gahl: We studied here a vascular disease that affected the large vessels of the lower extremity and also affected some of the joint capsules of our body.
Akinso: Dr. William Gahl is the National Human Genome Research Institute Clinical Director of the NIH Undiagnosed Disease Program.
Gahl: And the way that it affected those vessels, there was calcification of those vessels and also some enlargement of the vessels and so blood wasn’t actually going through those vessels appropriately.
Akinso: Although symptoms of the disorder include leg and joint discomfort, medical evaluations of the patients ruled out rheumatoid arthritis or other joint-related problems. Genetic analyses performed by NIH researchers suggested a novel disorder and pinpointed the cause of the condition as mutations or variants, in the NT5E gene.
Gahl: The NT5E gene is like many other genes. It encodes a protein and the protein is called CD73 and that is what makes it special. So if you had a defect in that gene you’re not producing the CD73 protein and therefore there’s calcification that occurs and this whole mechanism is something that was found out because of individual patients who had this disorder and who’s gene mutation we found; again that gene was the NT5E gene.
Akinso: NIH clinical researchers examined members of two families with the arterial calcification disorder as part of the NIH Undiagnosed Disease Program. A third case has been identified outside the country. Dr. Gahl says vascular calcification often results from poor diet and lack of exercise, but the calcium buildup in arteries of these patients increases because the systems to inhibit calcium buildup are not working in their cells.
Gahl: We found that the gene was defective and we found that in three different families with this very, very unusual disorder. So the gene is defective and the gene product was not being made or it was being made improperly. Therefore it wasn’t functioning appropriately.
Akinso: Dr. Gahl adds this study shows that genomic tools are a powerful ally in the search to discover and understand rare diseases. The researchers refer to this condition as ACDC, or arterial calcification due to CD73 deficiency. For more information, visit www.nhgri.nih.gov. This is Wally Akinso at the National Institutes of Health Bethesda, Maryland.
NIH Researchers Identify Genetic Cause of New Vascular Disease – 2
Balintfy: Now there’s more to this story. In addition to it not being every day that a new disease is discovered, there are patients – people – that are affected by this discovery. Here’s their perspective:
Benge: I got excited when they said they hoped that they could find something to help take care of it. He said it would be a while, but you know, if they can find it. Wow! It would be a celebration.
Balintfy: That’s Louise Benge from Brodhead, Kentucky. She and her sister Paula Allen were flown to the NIH Clinical Center for appointments with the Undiagnosed Diseases Program team.
Benge: They done a lot of testing, a lot of things to try to figure out what was going on. They done genetic testing, and got blood from all our family members, including our parents. That's how they figure out it was genetic.
Balintfy: Until now, she says, none of her doctors could figure out what caused the calcium to buildup in her arteries. She first experienced unexplained leg pain.
Benge: Mine started when I was about 25 years old. Like when I would walk for long periods of time, not even long periods of time, sometimes, the back of my legs would get hard as rocks. It hurt so bad, the calves of them. And then as the years went, it kind of progressed and got a little worse.
Balintfy: Louise and her four siblings all have arterial calcification due to deficiency of CD73 (ACDC). Paula Allen knew from her older sister’s experience about the symptoms.
Allen: Mine started like hers, the calves of your legs feel like stones or something and they hurt. I didn't wait to go to the doctor as long as she did because I knew what was coming, and they told me the same thing, that he could do surgery, but that it would have to be redone in five years, so I didn't even try it.
Balintfy: Paula and Louis describe what it’s like living with the symptoms.
Allen: I had to go to Lexington last week for some training and a friend of mine went with me and we parked in the garage and had to walk down the sidewalk to the building, which isn't very afar. A block or so. Here I am way in the back, just taking my good sweet time because by the time I got to the building, my legs were hurting.
Benge: And we can go out and play kickball and do things with the grandkids like we used to do when we were younger and that kind of bothers us both but we have to deal with it. It’s there and there’s nothing we can do about it so we just kind of have to do what we can and go on.
Boehm: Certainly, the physical manifestation of this disorder presents significant problems for patients with ACDC including pain and limited range when walking, reduced circulation and blood pressure in lower leg.
Balintfy: Dr. Manfred Boehm is an NIH physician who studies vascular biology in the National Heart, Lung and Blood Institute.
Boehm: We had a key advantage in reaching diagnoses in this case, involvement of many family members who could contribute samples for our testing. We were not only able to look for markers in the DNA of siblings but also from their parents. We analyzed the DNA of Louise and Paula’s parents who did not have the disorder, and their siblings who had the disorder.
Balintfy: Dr. Boehm says this discovery of ACDC has been an exciting step in providing new insights for this patient group as well as a new understanding about vascular biology.
Boehm: In the coming months we are anticipating offering these patients the option of participating in a clinical treatment study at NIH that is currently being reviewed for approval. This will involve treatment and continuous study.
Benge: We're just hoping that they can find a cure and help us. That's what we are looking forward to.
Balintfy: A special thanks to Louis Benge and her sister Paula Allen. For more information on ACDC and the NIH Undiagnosed Diseases Program visit the website: rarediseases.info.nih.gov/undiagnosed. Coming up next, what are aptamers? Some basic science that may have promise for future breakthroughs. That’s next on NIH Research Radio.
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What are aptamers?
Balintfy: Recently, an NIH Research Radio listener sent an email, asking that we do a story about aptamers. So we’re turning to Dr. Peter Preusch, Program Director with the National Institute of General Medical Sciences to find out what exactly they are, what are they made of and how do they work ...
Preusch: Aptamers are oligomers. Now, oligomer means a short polymer, usually in this case of nucleotides forming DNA or RNA molecules that have been selected for their ability to bind to other target molecules with relatively high affinity and specificity.
Balintfy: By high affinity and specificity, that means they’re accurate and good at what they do?
Preusch: That’s right. That is, they bind tightly. And specificity meaning the degree to which they bind to a specific molecule to which they have been selected versus closely related, but non-identical targets.
Balintfy: Are aptamers like antibodies that we know from our immunes system - they latch onto the bad things in our body and take them away?
Preusch: Well, aptamers aspire to be like that. The vision of those working in the field are that aptamers may have advantages over antibodies in certain applications and that they will have that same degree of utility eventually.
Balintfy: How long have aptamers been around, Dr. Pruesch?
Preusch: Well aptamers have been around about 20 years now. The first papers were published in 1990 — one in Nature and one in Science in the same month of August. The one was from the laboratory of Jack Szostack at Harvard Medical School, a work by Andrew Ellington and himself, specifically on a process for selective enrichment and amplification of RNA molecules from a random pool of RNAs, based on their ability to bind to either an oligo-dT target or to one of several organic dyes that had at that time been commonly used for purification of proteins.
Balintfy: This paper also introduces the term “aptamer.” Where did that come from?
Preusch: Well, that’s the first use of the word and they chose it from the Latin “aptus,” to fit, meaning that these are molecules that fit tightly with other molecules.
Balintfy: What else is interesting about the paper?
Preusch: This is a fine example of basic research being pursued for reasons that don’t directly lead to, or are not immediately motivated particularly by the desire to diagnose or cure disease, but answer fundamental questions about biology which, down the road, are paying off in advances and diagnosis and cures.
Balintfy: What about the other paper on aptamers by Craig Turek and Larry Gold at the University of Colorado?
Preusch: Well, so this was the second paper that came out, the one that came out in Science as opposed to Nature. And the important thing here is that it introduced a somewhat different experimental method referred to as SELEX, and that has gone on to be a process that is of considerable interest and value. Their approach to the question was somewhat different from that of Ellington and Szostak in that they started with a known protein RNA recognition pair. Then they went back and randomized the sequence that was recognized in that RNA and asked, “Well, if we set up the appropriate selection conditions, can we recapture that original sequence by a process of in vitro evolution and selection?” And indeed, they were able to recapture the original sequence plus one other sequence that had a few mutations but also bound as tightly as the original complex.
Balintfy: We’ve talked about nanotechnology in past episodes. How are aptamers like nanoparticles in terms of possibly treating a disease, like cancer?
Preusch: The problem is one of delivery. So, the aptamer can be specific for your favorite cancer-related protein target. It might disrupt it wonderfully in a test tube. But getting it into the tissue and having it only interfere with the protein target in the cancerous tissue but not the normal tissue, having the aptamer have a lifetime in the body which is suitable for it to have an effect, those are all major, major issues. So the question about nanotechnology — interestingly enough, if you don’t like the aptamers the size they are, you can always hook them onto a nanoparticle. And so you could have a hybridization of these two technologies to achieve the delivery goal. Now the question is does nano-particle delivery of a drug do a better job than some other mechanism of delivery, in this case, aptamers? And I think that’s still in the research stage, not in the conclusion stage.
Balintfy: So there basically is a lot more research that needs to be done on aptamers?
Preusch: I think a lot of the work that has been done so far would be called proof of principle work. The ability of aptamers to be used for diagnostic tests has certainly been explored. They certainly are capable of specific recognition of things that you would want to measure. The question is really one of economics and adoption in the marketplace and, you know, downstream events like does the insurance company reimburse the tests or not? And whether it becomes preferred by the caretakers over something that exists already.
Balintfy: What can we say about the therapeutic potential of aptamers?
Preusch: There is certainly, again, potential. There have been a lot of experiments done that show you can have an effect on a biological system. There’s one aptamer drug on the market now, but only one. So the question is, is that the beginning of what will be a large pipeline of new drugs coming through or is that a rare exception? The specific entity that is used here is an aptamer that’s used to treat a retinal disease that can be administered intra-ocularly, so a small amount of material delivered in a very specific place where it can have its effect. How many more applications of that kind will be occurring in medicine? I don’t know. But it’s a very different subject than how do you treat metastatic cancer with aptamers, for example.
Balintfy: Thanks to Dr. Peter Preusch, Program Director with the National Institute of General Medical Sciences. Dr. Preusch adds, to find out more about aptamer research, you can use the NIH RePORTER tool to look up NIH grant support in this subject area – find that at the website: report.nih.gov. He also recommends the PubMed.gov website where you can look up publications and articles covering aptamers.
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Balintfy: Again, I talked to Dr. Preusch about aptamers because of a listener request. If you have a story suggestion for a future episode, or any questions or comments about this program, please let me know. Best to reach me by email—my address is jb998w@nih.gov.
And that’s it for this episode of NIH Research Radio. Please join us again on Friday, March 28 when our next edition will be available. I'm your host, Joe Balintfy. Thanks for listening.
Announcer: 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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