June 18, 2010
NIH Podcast Episode #0112
Balintfy: Welcome to the one-hundred-twelfth 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, a better treatment option for diabetes-associated swelling in part of the eye; a recording device that melts into place—in the brain! And the genome of the Neanderthal—what it tells us about history, and ourselves. But first, this news update.
Balintfy: Kidney transplants nearly always fail if patients stop taking their immunosuppressive drugs. To keep the immune system from attacking transplanted organs, patients must take immunosuppressive drugs for the rest of their lives. But these drugs suppress the entire immune system, which can make it hard to fight off infections. But for a tiny percentage of kidney transplant cases, the transplants aren't rejected. Scientists have now identified a distinctive genetic signature in patients who successfully stopped taking their regimen of immunosuppressive drugs after having a kidney transplant. The finding may help to identify other transplant recipients who could safely reduce or end their use of harsh drugs that block transplant rejection.
Researchers have observed two previously unknown steps in the spread of the malaria parasite through the bloodstream. And in laboratory cultures, the researchers interfered with one of these steps, raising the possibility that new drug treatments could be developed to combat the disease. In 2008, malaria is estimated to have caused as many as a million deaths worldwide. Malaria is caused by a single-celled parasite, which is transmitted to humans through the bite of an infected mosquito. The parasite infects red blood cells and reproduces inside them. When the infected cell bursts, the new parasites spread, infecting more red blood cells. In their study, the researchers focused on how the new parasites escape infected cells. They also discovered they could, in effect, seal the membrane of an infected blood cell with a surface-acting compound, halting the release of the parasites.
And finally, scientists have found that the 2009 H1N1 pandemic influenza vaccine protects mice from the 1918 influenza virus. The new vaccine works against the old virus because the 1918 and the 2009 strains of H1N1 influenza share features that allow vaccine-generated antibodies to recognize both viruses. Investigators say more studies are needed, but their current results suggest people who are vaccinated against 2009 H1N1 influenza or were exposed to the virus could have similarly cross-protective antibodies against the 1918 strain of H1N1.
News updates are compiled from information at www.nih.gov/news. Coming up next combining treatments for diabetes-associated swelling of the retina. Plus, a new brain-recording devise, and news on the Neanderthal genome. Stay tuned.
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Comparative-Effectiveness Study Confirms New Treatment for Diabetic Macular Edema
Balintfy: Diabetic retinopathy is the most common cause of vision loss in working-age Americans. This condition damages the small blood vessels in the eye's light-sensitive tissue, called the retina.
Cartwright: I suddenly realized when I was driving that I couldn’t see the road signs nor the highway signs, and my first thought was that I needed driving glasses.
Balintfy: Sallie Cartwright went to her ophthalmologist, and after a very thorough examination, found out she needed to go to a retina specialist as soon as possible.
Cartwright: My right eye was worthless and my left eye was legally blind, and glasses would not help me.
Balintfy: When damaged blood vessels begin to leak fluid near the center of the retina, known as the macula, macular edema occurs. In macular edema the retinal tissue swells, which can lead to vision loss if left untreated. Dr. Neil M. Bressler from the Wilmer Eye Institute, at the Johns Hopkins University explains.
Bressler: People who have macular edema from diabetes actually have developed some damage to the blood vessels that are lining the back part of the eye. This is the light-sensitive portion of the eye that helps us see, and unfortunately in people with diabetes, these blood vessels can be damaged. That damage leads to fluid leaking in the retinal tissue, which then swells and with that swelling, very often you can have vision loss.
Balintfy: Laser treatment has been the standard care for the past 25 years. But new research is showing that eye injections of a medication, often in combination with laser treatment, result in better vision than laser treatment alone.
Bressler: The new treatment option now is to use a new drug, which is called Ranibizumab, or the trade name is Lucentis, and by injecting that as often as every four weeks for at least one to two years, we found that you could get improvement in vision about 50 percent of the time.
Balintfy: A recent study involved 52 clinical sites that are part of the Diabetic Retinopathy Clinical Research Network, which is chaired by Dr. Bressler. He says the results of this study likely will have a major impact on how ophthalmologists treat macular edema in people with diabetes.
Bressler: This is the first time in 25 years that we have definitive proof that a new treatment can likely lead to even better results, and this is very important because diabetes is not only common, but unfortunately it’s growing in its prevalence.
Ferris: We think the results from this large multi-center trial will provide new treatments for our patients with diabetic macular edema beyond laser and will improve their chances of good vision in the future.
Balintfy: That’s Dr. Frederick L. Ferris III, Clinical Director at the National Eye Institute. He adds that these treatments are really just the beginning.
Ferris: We now know we can improve on laser treatment for diabetic retinopathy. There are many studies that we have planned to further refine how we can better help our patients with diabetic macular edema.
Narrator: For patients like Sallie Cartwright who participated in the study, results are already tangible.
Cartwright: So to go from worthless and legally blind to seeing at 20/20, which is perfect vision without glasses is incredible.
Balintfy: For more about Diabetic Macular Edema, this study and eye-health research, visit www.nei.nih.gov.
A Brain-Recording Device that Melts into Place
Balintfy: NIH-funded researchers have developed a brain implant made partly of silk. It almost “melts” onto the brain's surface and is capable of recording brain activity. Wally Akinso reports on how the technology could be used to develop seizure control devices and brain-computer interfaces.
Akinso: Scientists have developed a brain recording device that essentially melts into place according to a NIH study.
Stewart: The point of the study was to design a flexible electrode array so that it would be possible to make the best electrical contact with brain tissue.
Akinso: Dr. Randall Stewart is a program director at the National Institute of Neurological Disorders and Stroke.
Stewart: In this paper the authors placed a 5x6 array of recording electrodes on a thin layer of polyimide—polyimide is a flexible plastic resin. This combination was then placed on a sheet of silk to make it easier to manipulate the electronics. And this component of the silk is it provides strength and it come be dissolved away. Now how did it impact the study? After you put the electrode array in place then you can put a salt solution on, it dissolve the silk away. And then that allows good electrical contact of the electrodes that remain behind. What that does is the thin film adheres to the brain, it conforms to the brain and allows good electrical contact.
Akinso: Researchers approached the design of a brain implant by first optimizing the mechanics of silk films and their ability to hug the brain. They tested electrode arrays of vary thickness on complex objects, brain models and ultimately in the brains of living, anesthetized animals.
Stewart: The idea here was to show that you can make high quality recordings of the brain's electrical activity.
Akinso: Dr. Stewart says this technology could pave the way for better devices to monitor and control seizures and to transmit signals from the brain past damaged parts of the spinal cord.
Stewart: This electrical recording device, you can use it to help patients with spinal cord injuries, as an example. You can place it on the brain, detect the signals that the brain produces and then use those signals to activate muscles or perhaps prosthetic devices.
Akinso: The study was supported by the NINDS, and the National Institute of Biomedical Imaging and Bioengineering. For more information, visit www.ninds.nih.gov. This is Wally Akinso at the National Institutes of Health Bethesda, Maryland.
Balintfy: Coming up, details on the genes of Neanderthals. That’s next.
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Complete Neanderthal Genome Sequenced
Balintfy: Researchers have produced the first whole genome sequence of the 3 billion letters in the Neanderthal genome, and the initial analysis suggests that up to 2 percent of the DNA in the genome of present-day humans outside of Africa originated in Neanderthals or in Neanderthals' ancestors. We turn to Larry Thompson, Communications Director for The National Human Genome Research Institute for this interview.
Thompson: With me is Dr. Jim Mullikin, The Acting Director of NIH Intramural Sequencing Center and a Computational Geneticist. Dr. Mullikin is the co-author of the May 7, 2010 paper in Science Magazine, in which an international team of researchers have sequenced the complete genome of the Neanderthal the closest distinct relative of modern humans. So Dr. Mullikin, let’s start from the beginning and just tell what this study was about and we’ll start to go through what you found.
Mullikin: Well, it has been an amazing journey with the group, led by Svante Pääbo at the Max Planck Institute in Leipzig, Germany. He’s been working on the study of ancient DNA for quite some time and he has analyzed the DNA from the bones of Neanderthals, and earlier on, before this study had found that you could sequence the mitochondrial DNA, which is a small subunit of the cells. But in this study, what he also found was that you could sequence the nuclear part of the DNA and get information from that as well. And that’s what they did. They, through a tour-de-force, they took the small fragments they got out of the bones and sequenced it to enough coverage to cover much of the genetic material of the Neanderthal genome.
Thompson: The bones that were studied how old are they and how did they get DNA from that?
Mullikin: So, the bones that have been found range in age from about 80,000 years old to 40,000, 45,000, 40,000 years old. They are quite old and they have been in these caves, buried under layers and layers of sediment for all those 10s of thousands of years. And, when they unearthed those bones, they used, in clean room environment, they were able to take those bones and take small bits of the bones and make it into a powder. And from that, they could extract the DNA from the powder material, and some of it, not much of it, but some small fraction of it, was actually from that the Neanderthal that died in that position.
Thompson: So that’s really quite remarkable. So would sequence this DNA the same way you would sequence modern DNA from say a patient?
Mullikin: Well not, it’s much harder than that. One of the problems with this particular research is to also understand that you don’t want to contaminate it with modern human DNA. So they had to make extra special care in handling the DNA, prior to sequencing it. But the sequencing part of it, once they were able to turn the molecules of DNA into something that they could sequence, they could look for the pieces that looked like Neanderthal DNA. That they were short fragments of DNA, that had been altered by the eons of time that they had been underground. The change in a distinctive pattern so they can know which ones are real, that are the old pieces from the ones that might be contamination. Contamination was one of the main focuses of understanding what might be contaminate and what was real Neanderthal DNA. We tried to remove as much of the contaminate as possible from the sequence. We got it down to below 1 percent.
Thompson: Of error. That’s really remarkable, just being able to do it all by itself is quite remarkable. But how would you sum up the significance of this study?
Mullikin: After we were able to sequence it and essentially map it back to other closet living relatives, homo sapiens and chimpanzees, we aligned the sequence back to both of those species and were able to find the differences that are unique to the Neanderthal, and more important, what are similar between Neanderthal and modern humans and modern chimpanzees. So, it is a kind of three way analysis of the DNA of Neanderthal. And from that, we can find is an interesting genetic history from the last 400,000 years since our ancestors, our common ancestors with Neanderthal split and went their separate ways. And that is a very interesting time period that we don’t have a lot of information on and now we have highlighted that information through this study.
Thompson: So what does it tell us about Human Evolution?
Mullikin: The other study that we have done without Neanderthal sequence like the international HAP MAP project, that I was also involved in, that can see things that are in a different time scale than what you see in the 400,000 year kind of time point that you see from the Neanderthal study. In particular you will be able to see that since the split, that one or both branches of this tree we’ve differed in our sequences in a way that changes skeletal bone structure, metabolism, cognitive ability, those sort of things we don’t know which way they went from which species, but they were different, and its interesting and those genes were highlighted in this study.
Thompson: So what your saying is that you lined up the Neanderthal genome to the human genome and you see the differences were in the genes in bone formation or for wound healing, it’s the genes that are involved, we don’t know if it were good or bad.
Mullikin: The way we did that is we were able to do that was we were able to look at the variation in modern humans that have a fixed difference relative to chimpanzees in all modern humans. And then when you look at the Neanderthal we see that they are the ancestral form just like the chimpanzee or maybe a variable of those types, but they have been fixed in the human lineage and those must be important to have that particular genetic profile.
Thompson: So are these genetic insights do they provide any explanation on why Neanderthal went extinct?
Mullikin: It does not explain why they went extinct. That’s still a great mystery don’t know if the genetic information would tell us anything about that though.
Thompson: So I understand that from the paper one of the great surprises was that we found some Neanderthal footprints, some fossil genes in our DNA, tell me about that a little.
Mullikin: Neanderthal, the study of the bones and the fact that the Neanderthal overlapped with modern humans in the same geographical locations at the same time between 40—80,000 years ago, was intriguing and everyone always wondered if there was a chance that there have been some interbreeding between species, or modern humans and Neanderthal. So it’s been controversial, both sides have been debated just off the bone evidence. But now, with the genetic information, we see a clear signature that there was a breeding event that happened, probably in the fertile crescent. Probably about 50,000 years ago, 60,000 years ago. From the early ancestors that moved out of Africa into the fertile crescent area. But before they split into the Eurasian continents. So it’s a very interesting time point where this happened, we know something happened, we’ll get more details to if it was just one chance event that happened or whether it was many events over many thousands of years. We don’t know those details yet, but we definitely know that there is Neanderthal DNA as I said, when they split 400,000 years ago, we went our different ways. But modern humans and Neanderthals met back up again about 60-80,000 years ago and exchanged some DNA, there was some breeding that went on and we see that clearly in the signature.
Thompson: So some portion of modern human have some amount of Neanderthal DNA, what’s the percentage?
Mullikin: You see about 2 percent of the out of Africa populations, at least the ones that we studied and those would have been the individuals we studied are Europeans, an individual from France, Asian individual, Guyanese individual, and we also studied two individuals DNA from West Africa and Southern Africa and these comparisons and it showed that the Africa individuals do not have any signatures of this mixing, and all of the limited amount of individuals who we studied outside of Africa do show similar mixing level of about 2 percent. And that’s a significant number. If we have 30,000 genes in our genome, that would mean 600 genes have a signature of Neanderthal. Sounds small, but it’s significant and we can see it in the data.
Thompson: So does that change our current understanding of the origin and migration of modern human is that modern human arose in Africa migrated up through the middle east and then radiated across the planet. But does this information change our understanding of that story of modern origins?
Mullikin: That’s still the way things went, it’s just the extra bit of information that we’ve seen now is that there was introgression. A return of DNA from the Neanderthal into the out of Africa population. Just a sprinkling, it’s not a huge amount we’ll find out more as we sequence more modern humans from both within Africa and outside of Africa to see how wide spread it really is across the out of Africa population. But also if there are any signatures that we’ve missed so far because of limited sampling within Africa, we could get better information about that for the future.
Thompson: So it’s a small sampling right now, and we just have sentinel chunks of DNA that we’ve looked at. But right now it does not look like Neanderthal re-migrated back into Africa or mixed its genes back to Africa, but stayed in the north and populations passing through that area, picked up the DNA.
Mullikin: That’s right, the Neanderthal do not have seem to migrated back, or the DNA that was transferred into the modern humans did not come back into Africa until much later, as now modern day people can move anywhere around the planet. But back 60,000 years ago, it was pretty limited in travel.
Thompson: But this is still a first peek, so there’s much more to be learned as we go forward as we looking at Neanderthal DNA and many populations of Modern humans across the planet. So, what’s next in the Neanderthal Genome research?
Mullikin: Well now that the data will be released, everyone can have a look at it and apply their new methods or any new methods that come along to analyze the data. It will be pretty accessible to everyone and I wouldn’t imagine Svante will stop in these efforts. I think there will be more coming from his group
Thompson: Very interesting stuff, Dr Jim Mullikin, Acting Director NIH Sequencing Center, co-author of this paper on the Neanderthal Genome and thank you very much for joining us and explaining this really fascinating story.
Balintfy: And thanks to Larry Thompson for sharing that interview. To learn more about the Neanderthal Genome and research on the human genome, visit the website, www.genome.gov. And that’s it for this episode of NIH Research Radio. Please join us again on Friday, July 2nd 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 firstname.lastname@example.org. I'm your host, Joe Balintfy. Thanks for listening.
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