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Dr. Mirjana Savatic of Stony Brook who has been able to visualize the marker of stem cells in the brain using magnetic resonance spectroscopy. Dr. Savatic is now collaborating with Dr. Lauren Krupp of Stony Brook to apply these methods.

Linkup for science

Gov. Eliot Spitzer is urging labs at Stony Brook, Cold Spring Harbor and Brookhaven to join in a peerless "research engine." How might this work? A stem cell study published recently in Science came from just such a collaboration. Here, the scientists tell their story.From scientific research, seeking a medical toolI am a child neurologist with basic neuroscience training. In my research I am interested in early brain development; in my practice I treat premature babies with conditions such as autism, mental retardation and cerebral palsy.

After finishing my residency about six years ago, I went to the Cold Spring Harbor Laboratory to study stem cells with Grigori Enikolopov. My goal has been to continue to do science, and transfer the science to clinical practice.While studying basic mechanisms that affect neural stem cells, it became clear to me that a major issue is the ability to visualize the cells in the human brain.I also know that a big barrier in evaluating babies with neurological diseases is that we don't use all the imaging techniques that we use in adults. While we use some forms of MRI (magnetic resonance imaging), we don't use contrast agents (which make parts of the body easiser to see) because neonates have poor clearance through their kidneys. And we can't do PET (positron emission tomography) or SPECT scans (single-photon emission computerized tomography) in kids under 18 because that involves radioactive injections. This limits our abilities to study early brain development.One of the MRI techniques that can be used in babies and young children is MRI spectroscopy, which gives information about the functional status of a chosen part of the brain. On Long Island, this kind of MRI is available at Stony Brook Hospital. At Cold Spring Harbor, we were growing neural stem cells. I had the idea to take these to the Keck Center for Structural Biology at Stony Brook, where they have a super high-power magnet for spectroscopy of cells. We found that the neural stem cells have a specific signature: a unique marker that distinguishes them from any other cell type in the brain.This was thrilling, but we know that cells behave a certain way in a laboratory culture and that things can really change when they are in their natural environment. So we had to test if we could find the marker in live animals. In came Brookhaven, which has an MRI imaging facility with a high-power magnet for viewing mice and rats. We worked with Helene Benveniste to develop the best hardware for imaging the stem cells in the brain. We also had to develop new mathematical methods to isolate the signal coming from stem cells, because it was buried among signals from other cells in the brain.This required help from an engineer at the Department of Computer and Electrical Engineering at Stony Brook, Petar Djuric.I knew Petar because he's from Serbia, as am I, and there aren't many of us around here. He is an expert in signal processing - pulling out a signal from the "noise."He had never worked with spectroscopy data but developed an algorhythm - a mathematical formula - that led to software with which we could see the stem cell marker in the brains of live animals. Now the big question was whether we could see the stem cells in the human brain. In collaboration with radiologist Mark Waghul at Stony Brook Hospital, we imaged five volunteers, analyzed the data using Petar's software and found that indeed the signal was there - tiny but definitely present.- Mirjana Maletic-SavaticAssistant Professor, Department of NeurologyStony Brook UniversityAt Cold Spring Harbor, the investigation beginsMirjana Maletic-Savatic initiated this project; she brought people together. It was through her vision that the project became successful.She had come several years ago to work in my laboratory, where we study adult cell stems in the brain and their relation to mood and psychiatric disorders. We are devising techniques to look for and visualize stem cells and neurogenesis (the generation of new neurons in the adult brain).The stem cells that Mirjana took to Stony Brook to observe with spectroscopy were grown in our lab. The project couldn't have moved forward without the signal processing algorithms developed at Stony Brook, animal data collected at Brookhaven and human data from Stony Brook.Far beyond the initial project, with the same people we are now looking for other things - imaging of tumors, for example, and stem cells connected to antidepressent treatments and disease.Sometimes you do a project and publish a nice paper, and basically that's it. But it's different in this case. It's important that these people are experts. This is not the kind of thing where you say, "Now I've learned it, and I will develop it myself."It's about areas of knowledge that are best used in a collaboration. - Grigori EnikolopovAssociate Professor, Cold Spring Harbor LaboratoryAt Brookhaven, rat brain gets a micro-MRIIn 2004 at Brookhaven Lab, with New York State and federal grant money, we built a laboratory for small-animal magnetic resonance imaging (microMRI). We were able to get a horizontal system, so the animal can be in its natural position during the imaging process. Mirjana Maletic-Savatic contacted me because she had heard about the animal microMRI laboratory. We hadn't met before, and I had not been involved in stem cell research. She came and told me about the experiments she wanted to do, and I thought it was a great idea. It took some time to get the magnet up and running and the right hardware - especially for precise positioning - and adequate and stable animal anethesia to get the data she needed.It's like doing an MRI on a human, except you need a much better signal-to-noise ratio, because there is so much less data coming from the small rat brain compared to the human brain. You need special hardware and software to do this.Mirjana's first step had been to take stem cells from Cold Spring Harbor Lab and put them into a vertical magnet at Stony Brook. She found a marker for these particular stem cells. As a clinician, she wanted to do the same for stem cells known to exist in the human brain. But you can't manipulate the human brain and take the stem cells away or add more for your experiment - you would have to do this on an animal. She needed to know if she could see the same signatures in the stem cells of rat brains that she had seen in the cultured stem cells at Stony Brook.We did many different manipulations. The rat is lying on a little receiver coil, which covers a lot of the brain, not just the part with stem cells. We could get data from both parts. Mirjana also injected stem cells, so we could get an increase in the signal, and see more data from the stem cells. We know from other animal experiments that one of the strongest stem cell responses you can get is when you expose the brain to electric convulsive shock, a technique used sometimes to treat humans who are extremely depressed. This produces more stem cells.We did this to some anesthetized rats (all survived) and then we compared signals before and after five days of shock treatment. You could see that the stem cell signature was increased. The key moment was when we finally had the whole story together: the original stem cell data showing the signature; animal data from my lab, and the human data from Stony Brook Hospital.- Helene Benvenisteprofessor of anesthesiology, Stony Brook University; scientist, Medical Dept.Brookhaven National LaboratoryAt Stony Brook, creating the right softwareI already knew Mirjana Maletic-Savatic, and she described to me the research she was doing on stem cells, which sounded extremely interesting. When we started working on the project, Mirjana had to explain her hypothesis in a relatively simple way, so I could understand it. It took several meetings for me to get a good feel for the problem.My field is signal processing, a branch of applied mathematics in which we extract information from data. It's used not only in biomedicine, but in fields from astronomy (to detect distant stars) to Wall Street (to predict what tomorrow's stock values will be). In this case, the question was: Are there stem cells in the tissue? And if so, how many?Working with people in other disciplines is not unusual in my field. But this was a huge project that required a lot of collaboration. For example, I talked to radiologists who take the tube with the cells and make measurements so I could understand what these measurements meant and be as exact as possible.There are three important ingredients in any experiment: 1) the hypothesis and preparation of samples to be tested; 2) collection of data - this must be done carefully; if data is bad, you won't find information; 3) the data has to be processed properly - you can have the information and miss it. I come at the end of the chain. The good news is that we can give feedback to the people ahead of us. It's like a circle: Sometimes you tell them this is bad data, and they look at the machine and adjust.We adapted methods that we were familiar with. Suppose you want to build a house outside for the dog. You have in mind what it should look like, what it should do (for example, protect the dog). Then you can figure out materials you need to build it. In this case, we knew what certain algorhthyms (mathematical formulas) can do. We modified them to serve the purpose we wanted.When the other scientists gave us data, they would know which part of brain it was from (a stem cell area or not), but they kept us blind. The interesting thing was to see if our results confirmed their hypotheses.- Petar M. DjuricProfessor, Department of Electrical and Computer EngineeringStony Brook UniversityAt last, the finding is tested on live humansI was not involved in this project as it was being developed because I was running a major research institute in Germany at the time.But I had been on Long Island in the '80s and early '90s in the psychiatry department at Stony Brook University, and I was considering a job offer to return here to Brookhaven lab. During a visit to Brookhaven to look into that job, I went to see Helene Benveniste, whose work I had heard about. She told me about this finding: Mirjana Maletic-Savatic's team thought they could measure neurogenic stem cells. This blew me away because my own work is to define neurogenesis in connection with anti-depressant drugs.Anti-depressants appear to increase neuron production. We had tested this in animal models behaviorally and concluded that neurogenesis was not driving the depressive syndrome. But the debate was going round and round, because ultimately you have to test it in people. I said to Helene that they'd never get the study published unless animals could be sacrificed to look at actual tissue. If every cell was counted histologically, it would nail down that the method worked.My only contribution to this study was suggesting that they look at neurogenic cells that are specifically labeled by a staining technique and compare that to the results with the MRI method they were using. They got the same results both ways. Then there was nothing to do but to write the paper. - Fritz Henn, associate director for Life SciencesBrookhaven National LaboratoryMaking collaboration work"We will help bring together the University at Stony Brook and the world-renowned Brookhaven and Cold Spring Harbor laboratories," Gov. Elliot Spitzer announced in his State of the State address. "The result will be a peerless cross-disciplinary research engine in the areas of cancer, neurobiology, plant genetics and bioinformatics. The economic benefit for Long Island will be tremendous. The chance for New York to lead the world will be unparalleled." How this would be carried out is the subject of a study expected to be funded in the budget that Spitzer will propose this week. In the meantime, our scientists made some recommendations:Mirjana Maletic-Savatic: Science collaborations cannot be forced. Therefore, having grants that mandate collaborations of a person from each institution will be hard to achieve, even though our example shows that it is possible. It will be better to foster science-clinical collaborations in general and not necessarily three-institution collaborations. I would also like to see a more substantial link between the institutions. Scientists from Cold Spring Harbor have adjunct appointments at Stony Brook, but really just on paper. Another way to strengthen the connections is through seminars and mini-symposia.Grigori Enikolopov: We should be focused on developing innovative and risky ideas and approaches, something that is supported less and less by the federal agencies. I would allocate part of the funds to revolving scientific councils that would review applications and give grants very fast, and thus support new ideas and directions; time is of the essence. State funding should require that a certain fraction of new hires be directly involved in collaborations among the institutions. Helene Benveniste: It's essential that scientists be hired into new positions with the sole purpose of developing collaborations. My laboratory at BNL would not have had our many collaborations with Stony Brook if I had not been at Brookhaven and jointly working at Stony Brook and insisting on cultivating them. Similarly, Mirjana's working at both Stony Brook and Cold Spring Harbor strengthened the neurogenesis-imaging-neurobiology connection in the stem cell project. Cross-disciplinary and cross-institutional projects require a lot of work, joint positions and frictionless infrastructure. The latter is important so that scientists can work across the institutions with minimal bureaucratic interference.Fritz Henn: In both the stem cell research led by Mirjana and subsequent work on cancer at Cold Spring Harbor published in Science last week, we see the need to integrate diagnostic possibilities and basic science insights with studies on patient populations from Stony Brook. Through recruitment of faculty who relate to one another and development of unique facilities at each institution, building on the exceptional talent already here, a remarkable center for multidisciplinary clinical research and biofuels could emerge and serve as a driver of new industry. What happened at each placeA child neurologist grows and studies neural stem cells in a laboratory specializing in stem-cell research, hoping to apply what she learns to the clinical practice of medicine.Neural stem cells are identified in the brains of living animals by a magnetic resonance imaging (MRI) machine designed for studying rats and mice.Magnetic resonance spectroscopy shows neural stem cells grown at Cold Spring Harbor have a specific marker. Software is created to read data from neural stem cells in living animals. The marker is found in neural stem cells in living human brains.This five-year study was published in the Nov. 9, 2007, issue of Science. Researchers say the breakthrough makes it possible to study development of brain nerve tissue, which could lead to improved diagnosis and treatment of depression, Parkinson's and a wide variety of brain disorders.

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