Breakthrough Reveals Blood Vessel Cells Are Key to Growing Unlimited Amounts of Adult Stem Cells

Breakthrough Reveals Blood Vessel Cells Are Key to Growing Unlimited Amounts of Adult Stem Cells

  2:22:00 AM    Science Lover

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In a leap toward making stem cell therapy widely available, researchers at the Ansary Stem Cell Institute at Weill Cornell Medical College have discovered that endothelial cells, the most basic building blocks of the vascular system, produce growth factors that can grow copious amounts of adult stem cells and their progeny over the course of weeks. Until now, adult stem cell cultures would die within four or five days despite best efforts to grow them.

Diagram showing the location of endothelial cells. (Credit: Courtesy of Wikimedia Commons / Stijn A.I. Ghesquiere)

"This is groundbreaking research with potential application for regeneration of organs and inhibition of cancer cell growth," said Dr. Antonio M. Gotto Jr., the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College and Provost for Medical Affairs of Cornell University.

This new finding sets forth the innovative concept that blood vessels are not just passive conduits for delivery of oxygen and nutrients, but are also programmed to maintain and proliferate stem cells and their mature forms in adult organs. Using a novel approach to harness the potential of endothelial cells by "co-culturing" them with stem cells, the researchers discovered the means to manufacture an unlimited supply of blood-related stem cells that may eventually ensure that anyone who needs a bone marrow transplant can get one.

The vascular-cell model established in this study could also be used to grow abundant functional stem cells from other organs such as the brain, heart, skin and lungs. An article detailing these findings appears in the March 5 issue of the journal Cell Stem Cell.

In adult organs, there are few naturally occurring stem cells, so using them for organ regeneration is impractical. Until now, strategies to expand cultures of adult stem cells, which invariably used animal-based growth factors, serum, and genetically manipulated feeder cells, have only been marginally successful. This study, which employs endothelial cells to propagate stem cells without added growth factors and serum, will likely revolutionize the use of adult stem cells for organ regeneration, as well as decipher the complex physiology of the adult stem cells.

"This study will have a major impact on the treatment of any blood-related disorder that requires a stem cell transplant," says the study's senior author, Dr. Shahin Rafii, the Arthur B. Belfer Professor in Genetic Medicine, co-director of the Ansary Stem Cell Institute and a Howard Hughes Medical Institute Investigator, at Weill Cornell Medical College. Currently, stem cells derived from bone marrow or umbilical cord blood are used to treat patients who require bone marrow transplants. Most stem cell transplants are successful, but because of the shortage of genetically matched bone marrow and umbilical cord blood cells, many patients cannot benefit from the procedure.

"Over the last few decades, substantial funding has been spent to develop platforms to expand adult stem cell cultures, but these efforts have never been able to coax an authentic adult stem cell to self-renew beyond a few days," continues Dr. Rafii. "Most stem cells, even in the presence of multiple growth factors, serum, and support from generic non-endothelial stromal cells, die after a few days. Now, employing our endothelial stem cell co-cultures, we can propagate bona fide adult stem cells in the absence of external factors and serum beyond 21 days with an expansion index of more than 400-fold."

If this vascular-based stem cell expansion strategy continues to be validated, physicians could use any source of hematopoietic (blood-producing) stem cells, propagate them exponentially, and bank the cells for transplantation into patients.

In a true first, the study demonstrates how this novel vascular cell platform or "vascular niche" can self-renew adult hematopoietic stem cells for weeks, both in vitro and in vivo, by co-culturing them on a bed of endothelial cells. The researchers chose endothelial cells because they are in close contact with blood stem cells, and previous work from Dr. Rafii's lab had demonstrated that endothelial cells produce novel stem-cell-active growth factors. However, maintenance of the endothelial cells is cumbersome and if they are not "fed" specific substances, such as growth factors known as "angiogenic factors," they immediately die. To get around this problem, the researchers genetically engineered the endothelial cells to stay in a long-term survival state by inserting a recently discovered gene cloned from adenoviruses, which does not promote oncogenic transformation of the human cells. This earlier discovery, using a single gene to put endothelial cells into a long-lasting "suspended animation" state without harming their ability to produce blood vessels, was also discovered in Dr. Rafii's lab and published in the journal Proceedings of National Academy Sciences in 2008.

Endothelial Cells Could Generate Stem Cells and Their Differentiated Progeny

In this study, the researchers also discovered that endothelial cells not only could expand stem cells, but also instruct stem cells to generate mature differentiated progeny that could form immune cells, platelets, and red and white blood cells, all of which constitute functioning blood.

"We are the first group to demonstrate that endothelial cells elaborate a repertoire of stem-cell-active growth factors that not only stimulate stem cell expansion but also orchestrate differentiation of these stem cells into their mature progeny," says Dr. Jason Butler, a senior investigator at Weill Cornell Medical College and first author of the study. "For example, we have found that expression of specific stem-cell-active factors, namely Notch-ligands, by the endothelial cells lining the wall of working blood vessels promote proliferation of the blood-forming stem cells. Inhibition of these specific factors on the endothelial cells resulted in the failure of the regeneration of the blood-forming stem cells. These findings suggest that endothelial cells directly, through expression of stem-cell-active cytokines, promote stem cell reconstitution."

Further describing this innovative concept, in a high-impact article published in the January 2010 issue of Nature Reviews Cancer, Drs. Rafii and Butler, and Dr. Hideki Kobayashi, who is also a co-author of the current study, have elaborated on specific endothelial cell-produced growth factors that promote the growth of tumor cells besides stem cells.

Development of the vascular-cell technology that supports long-lasting growth of stem cells will also allow scientists to generate abundant sources of functional and malignant stem cells for genetic and basic studies. This study has also resolved a long-standing controversy in which several groups had claimed that bone-forming cells (osteoblasts) exclusively support the expansion of blood-forming stem cells. "However, using a highly sophisticated molecular imaging approach, we show that regenerating blood-forming stem cells in the bone marrow are in intimate contact with the blood vessels, indicating that endothelial cells are the predominant regulator of stem cell repopulation in the adult bone marrow," states Dr. Daniel Nolan, a senior scientist in Dr. Rafii's lab and a co-author of the new study.

One other important concern addressed in this study was whether forced expansion of the stem cells over a long period of time would induce cancerous mutations in the stem cells. However, the authors of this study show that, even after one year, there was no indication of tumor formation, such as leukemias, when the expanded stem cells were transplanted back into mice. This suggests that the endothelial cells provide a milieu that proliferates stem cells without creating cancer risk.

The current breakthrough represents the culmination of many years of work by Dr. Rafii and his lab, including their research in converting adult mouse spermatogonial stem cells to endothelial cells (Nature, September 2007) and in deriving stable, copious endothelial cells from human embryonic stem cells (Nature Biotechnology, Jan. 17, 2010).

The ability to generate many stable endothelial cells from human embryonic stem cells leads to new research opportunities, according to Dr. Zev Rosenwaks, who is a co-author in this study and director and physician-in-chief of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, as well as the director of the Tri-Institutional Stem Cell Initiative Derivation Unit at Weill Cornell Medical College.

Dr. Rosenwaks says, "Generation of endothelial cells derived from diseased embryonic stem cells that are being propagated in our Derivation Unit will open up new avenues of research to molecularly eavesdrop on the communication between vascular cells and stem cells. This innovative line of investigation -- to determine how normal and abnormal human vascular cells induce the formation of organs during development of embryos and how dysfunction of endothelial cells results in developmental defects -- will lay the foundation for novel platforms for therapeutic organ regeneration."

Dr. Rafii sees even more opportunities. "Identification of as yet unrecognized growth factors produced by human embryonic cell-derived endothelium and adult endothelial cells that support stem cell expansion and differentiation will establish a new arena in stem cell biology. We will be able to selectively activate endothelial cells not only to induce organ regeneration, but also to inhibit specifically the production of endothelial cell-derived factors in order to block the growth of tumors. Our findings are the first steps toward such goals and they highlight the potential of vascular cells for generating sufficient stem cells for therapeutic organ regeneration, tumor targeting, and gene therapy applications," concludes Dr. Rafii.

Co-authors include Daniel J. Nolan, Eva L. Vertes, Hideki Kobayashi, Andrea T. Hooper, Koji Shido, Ian A. White, Mariko Kobayashi, Yuki Kimura and Marco Seandel of the Howard Hughes Medical Institute and the Department of Genetic Medicine and Ansary Stem Cell Institute at NewYork-Presbyterian Hospital/Weill Cornell Medical Center; Zev Rosenwaks, Chad May and Larry Witte of NewYork-Presbyterian Hospital/Weill Cornell Medical Center; Carrie Shawber and Jan Kitajewski at NewYork-Presbyterian Hospital/Columbia University Medical Center; Barbara Varnum-Finney of ImClone Systems Incorporated; and Irwin D. Bernstein at Fred Hutchinson Cancer Research Center, Seattle. The study received funding from the Howard Hughes Medical Institute.

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A Search Engine for the Human Body

A Search Engine for the Human Body

  2:12:00 AM    Science Lover

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Microsoft software recognizes organs and other structures in medical images.

A new search tool developed by researchers at Microsoft indexes medical images of the human body, rather than the Web. On CT scans, it automatically finds organs and other structures, to help doctors navigate in and work with 3-D medical imagery.

Inside out: A close up of a CT processed by new software from Microsoft.
Credit: Microsoft Research

CT scans use X-rays to capture many slices through the body that can be combined to create a 3-D representation. This is a powerful tool for diagnosis, but it's far from easy to navigate, says Antonio Criminisi, who leads a group at Microsoft Research Cambridge, U.K., that is attempting to change that. "It is very difficult even for someone very trained to get to the place they need to be to examine the source of a problem," he says.

When a scan is loaded into Criminisi's software, the program indexes the data and lists the organs it finds at the side of the screen, creating a table of hyperlinks for the body. A user can click on, say, the word "heart" and be presented with a clear view of the organ without having to navigate through the imagery manually.

Once an organ of interest has been found, a 2-D and an enhanced 3-D view of structures in the area are shown to the user, who can navigate by touching the screen on which the images are shown. A new scan can also be automatically and precisely matched up alongside a past one from the same patient, making it easy to see how a condition has progressed or regressed.

Criminisi's software uses the pattern of light and dark in the scan to identify particular structures; it was developed by training machine-learning algorithms to recognize features in hundreds of scans in which experts had marked the major organs. Indexing a new scan takes only a couple of seconds, says Criminisi. The system was developed in collaboration with doctors at Addenbrookes Hospital in Cambridge, U.K.

The Microsoft research group is exploring the use of gestures and voice to control the system. They can plug in the Kinect controller, ordinarily used by gamers to control an Xbox with body movements, so that surgeons can refer to imagery in mid-surgery without compromising their sterile gloves by touching a keyboard, mouse, or screen.

Body search: This CT image shows organs and other features identified by the Microsoft software. A list of these features appears at left.
Credit: Microsoft Research

Kenji Suzuki an assistant professor at the University of Chicago, whose research group works on similar tools, says the Microsoft software has the potential to improve patient care, providing it really does make scans easier to navigate. "As medical imaging has advanced, so many images are produced that there is a kind of information overload," he explains. "The workload has grown a lot."

Suzuki says Microsoft's approach is a good one, but that medical professionals might be more receptive to the design if it indexed signs of disease, not just organs. His own research group has developed software capable of recognizing potentially cancerous lung nodules; in trials, it made half as many mistakes as a human expert.

Criminisi sticks by the notion of using organs as a kind of navigation system but says that disease-spotting capability is also under development. He says, "We are working to train it to detect differences between different grades of glioma tumor"—a type of brain tumor.

The Microsoft group also intends the tool to be used at large scales. It could automatically index a collection of 3-D scans or other images, making possible new ways of tracking medical records, says Criminisi. Today, records are kept as text that describes scans and other information. A search tool that finds the word "heart", for example, would not know if that meant it appeared in a scan or was mentioned in another context. If a hospital's computer system indexed new scans, the Microsoft software could automatically record what was imaged in a person's records and when.

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New Energy Source for Future Medical Implants: Sugar

New Energy Source for Future Medical Implants: Sugar

  7:50:00 PM    Science Lover

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MIT engineers have developed a fuel cell that runs on the same sugar that powers human cells: glucose. This glucose fuel cell could be used to drive highly efficient brain implants of the future, which could help paralyzed patients move their arms and legs again.

This silicon wafer consists of glucose fuel cells of varying sizes; 
the largest is 64 by 64 mm. Image: (Credit: Sarpeshkar Lab)

The fuel cell, described in the June 12 edition of the journal PLoS ONE, strips electrons from glucose molecules to create a small electric current. The researchers, led by Rahul Sarpeshkar, an associate professor of electrical engineering and computer science at MIT, fabricated the fuel cell on a silicon chip, allowing it to be integrated with other circuits that would be needed for a brain implant.

The idea of a glucose fuel cell is not new: In the 1970s, scientists showed they could power a pacemaker with a glucose fuel cell, but the idea was abandoned in favor of lithium-ion batteries, which could provide significantly more power per unit area than glucose fuel cells. These glucose fuel cells also utilized enzymes that proved to be impractical for long-term implantation in the body, since they eventually ceased to function efficiently.

The new twist to the MIT fuel cell described in PLoS ONE is that it is fabricated from silicon, using the same technology used to make semiconductor electronic chips. The fuel cell has no biological components: It consists of a platinum catalyst that strips electrons from glucose, mimicking the activity of cellular enzymes that break down glucose to generate ATP, the cell's energy currency. (Platinum has a proven record of long-term biocompatibility within the body.) So far, the fuel cell can generate up to hundreds of microwatts -- enough to power an ultra-low-power and clinically useful neural implant.

"It will be a few more years into the future before you see people with spinal-cord injuries receive such implantable systems in the context of standard medical care, but those are the sorts of devices you could envision powering from a glucose-based fuel cell," says Benjamin Rapoport, a former graduate student in the Sarpeshkar lab and the first author on the new MIT study.

Rapoport calculated that in theory, the glucose fuel cell could get all the sugar it needs from the cerebrospinal fluid (CSF) that bathes the brain and protects it from banging into the skull. There are very few cells in the CSF, so it's highly unlikely that an implant located there would provoke an immune response. There is also significant glucose in the CSF, which does not generally get used by the body. Since only a small fraction of the available power is utilized by the glucose fuel cell, the impact on the brain's function would likely be small.

Karim Oweiss, an associate professor of electrical engineering, computer science and neuroscience at Michigan State University, says the work is a good step toward developing implantable medical devices that don't require external power sources.

"It's a proof of concept that they can generate enough power to meet the requirements," says Oweiss, adding that the next step will be to demonstrate that it can work in a living animal.

A team of researchers at Brown University, Massachusetts General Hospital and other institutions recently demonstrated that paralyzed patients could use a brain-machine interface to move a robotic arm; those implants have to be plugged into a wall outlet.

Mimicking biology with microelectronics

Sarpeshkar's group is a leader in the field of ultra-low-power electronics, having pioneered such designs for cochlear implants and brain implants. "The glucose fuel cell, when combined with such ultra-low-power electronics, can enable brain implants or other implants to be completely self-powered," says Sarpeshkar, author of the book "Ultra Low Power Bioelectronics." This book discusses how the combination of ultra-low-power and energy-harvesting design can enable self-powered devices for medical, bio-inspired and portable applications.

Sarpeshkar's group has worked on all aspects of implantable brain-machine interfaces and neural prosthetics, including recording from nerves, stimulating nerves, decoding nerve signals and communicating wirelessly with implants. One such neural prosthetic is designed to record electrical activity from hundreds of neurons in the brain's motor cortex, which is responsible for controlling movement. That data is amplified and converted into a digital signal so that computers -- or in the Sarpeshkar team's work, brain-implanted microchips -- can analyze it and determine which patterns of brain activity produce movement.

The fabrication of the glucose fuel cell was done in collaboration with Jakub Kedzierski at MIT's Lincoln Laboratory. "This collaboration with Lincoln Lab helped make a long-term goal of mine -- to create glucose-powered bioelectronics -- a reality," Sarpeshkar says. Although he has just begun working on bringing ultra-low-power and medical technology to market, he cautions that glucose-powered implantable medical devices are still many years away.

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Single Gene Regulates Motor Neurons in Spinal Cord

Single Gene Regulates Motor Neurons in Spinal Cord

  10:49:00 AM    Science Lover

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In a surprising and unexpected discovery, scientists at NYU Langone Medical Center have found that a single type of gene acts as a master organizer of motor neurons in the spinal cord. The finding, published in the September 9, 2010 issue of Neuron, could help scientists develop new treatments for diseases such as Lou Gehrig's disease or spinal cord injury.

This image shows the pattern of motor neuron 
innervation in the body of a mouse embryo. 
(Credit: Image courtesy of Heekyung Jung)

The "master organizer" is a member of the Hox family of genes, best known for controlling the overall pattern of body development. By orchestrating a cascade of gene expression in the early embryo, Hox genes allow for the creation of an animal's overall structure and body part orientation. Scientists first discovered the genes in fruit flies but they have since detected Hox activity in mammals. Humans harbor 39 such genes and 21 have been identified as coordinating motor neurons in the spinal cord.

"We knew that there were 21 Hox genes that determine how connections are made between motor neurons in the spinal cord and muscles in the limbs," says Jeremy S. Dasen, PhD, an associate professor in the Departments of Physiology and Neuroscience at NYU Langone Medical Center and a Howard Hughes Medical Institute Early Career Scientist. "But what was surprising to us in this study was that a single Hox gene acts as a global organizer of motor neurons and their connections. The next step will be to see how Hoxc9 in motor neurons affect motor behaviors such as walking and breathing."

In mammals, many hundreds of motor neurons are needed to control the variety of muscle cells used to coordinate movement. Proper function depends on each of these neurons in the embryo finding its way from the spinal cord to the group of muscles that it is equipped to control. Dr. Dasen and his colleagues have been working to discover the blueprint for this motor neuron diversity.

For this study, scientists studied mice with a mutation in Hoxc9 gene. They analyzed the molecular markers that distinguished between motor neurons in the limb and thoracic area and discovered mutation of Hoxc9 transformed the thoracic motor neurons into limb motor neurons. In a series of biochemical experiments they further showed that Hoxc9 orchestrates gene expression in motor neurons by repressing the Hox genes dedicated to limb coordination.

"What we are trying to understand is how the nervous system is wired to control movements such as breathing and walking and see how genetic programs can further control these circuits in terms of exploring this paradigm as a way at looking at the vital circuits of the body," adds Dr. Dasen.

Co-authors of the study include Heekyung Jung, Julie Lacombe, and Jonathan Grinstein of NYU Langone Medical Center. The research was done in collaboration with researchers at Columbia University Medical Center, Massachusetts Institute of Technology and Memorial Sloan Kettering Cancer Center.

The study was supported by a grant from the National Institutes of Health in Bethesda, Maryland.

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Salt Grain-Sized Cameras Can Travel Inside Body

Salt Grain-Sized Cameras Can Travel Inside Body

  11:57:00 PM    Science Lover

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Cameras have shrunk over time, but they've never been this small. 
* German engineers have created the smallest microcameras of their kind.
* The new inexpensive disposable cameras can be produced 25,000 at a time.
* The microcamera's applications include medical and automotive imaging.

A new microcamera developed by German 
researchers measures a mere 1 millimeter on each side.

A new camera is as small as a coarse grain of salt -- the tiniest of its kind. This microcamera could go far: traveling deep into the human body to reveal hidden nooks and crannies. And it could be used in cars to keep drivers safe.


"I have it here on the desk," said Michael Töpper, project manager at the Fraunhofer Institute for Reliability and Microintegration in Berlin, the large German R&D facility that worked on the device. "If you look at the camera, it's hard to believe that this is working."


Fraunhofer developed the camera with the specialized image sensor company Awaiba, which sought to improve miniaturized cameras for medical applications. Current microcameras require individual, manual manufacturing techniques that have kept costs high. Töpper and his colleagues developed a method to assemble the cameras on a single wafer using specialized polymers to bond the parts.


"The last step is then dicing the image sensor into individual camera chips," he said.


Each of the three sides of the camera measures a mere 1 millimeter. One wafer can be used to assemble 25,000 lenses on 25,000 cameras. The resulting resolution for each of the miniature cameras is in the range of 25,000 pixels. While that's not high enough for a professional photographer, it is high for medical applications, Töpper said.


More efficient manufacturing means lower costs, and the microcameras themselves are disposable. Töpper points to a process for sterilizing reusable endoscopic cameras, saying that usually involves lots of chemicals. Although the new microcameras are not recyclable, he says that they are primarily made from silicon and glass. "There are no hazardous materials."


In medicine, gastroenterologists regularly use small cameras to check patients. Colon cancer is the second leading cause of cancer death, resulting in 150,000 cases every year, according to Dr. Gregory Cooper, a Case Western Reserve University professor of medicine and oncology, and gastroenterologist at University Hospitals Case Medical Center.


"Most colon cancers are thought to be preventable if the patient has a colonoscopy," he said.


Screening for polyps and colorectal cancer can involve a fairly invasive double-balloon endoscope requiring sedation, or a large swallowable "pill cam" that sometimes moves through a 25-foot small bowel too fast to capture all the information.


Dr. Cooper said he thinks the Fraunhofer microcamera technology looks interesting, although he notes that a scope used with the disposable camera would still need sterilization.


"If it can get around some of the current limitations of endoscopy, i.e. the sedation and the need to sterilize things, the limited visualization of the small bowel -- I think it has promise," he said.


At the moment Awaiba is testing the devices, and plans to put the microcameras into production within the next two years, Töpper said. Beyond medicine, the cameras could serve a useful purpose in the automotive industry. Installing them in cars might make camera-assisted parking more ubiquitous, and they could also help monitor drivers who risk falling asleep at the wheel.


"If you think about very, very small cameras, you will find dozens of applications," Töpper said. "Just think about the camera in the phone: 10 years ago everybody was laughing. 'Who needs a camera in a phone?'"

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Resurrecting the So-Called 'Depression Gene'::Genes May Play Role in Response to Adversity

Resurrecting the So-Called 'Depression Gene'::Genes May Play Role in Response to Adversity

  8:01:00 PM    Science Lover

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University of Michigan Health System researchers have found new evidence that our genes help determine our susceptibility to depression.

Our genes help determine our susceptibility to depression, 
new research suggests. (Credit: iStockphoto/
Nicholas Belton)

Their findings, published online in the Archives of General Psychiatry, challenge a 2009 study that called the genetic link into question and add new support to earlier research hailed as a medical breakthrough.

In the summer of 2003, scientists announced they had discovered a connection between a gene that regulates the neurotransmitter serotonin and an individual's ability to rebound from serious emotional trauma, such as childhood physical or sexual abuse.

The journal Science ranked the findings among the top discoveries of the year and the director of the National Institute of Mental Health proclaimed, "It is a very important discovery and a real advance for the field."

That excitement was dampened in 2009, however, after the research was called into question by a study published in the Journal of the American Medical Association. The New York Times reported that analysis, which examined results from 14 different studies, showed the initial findings had "not held up to scientific scrutiny."

Srijan Sen, M.D., Ph.D, an assistant professor of psychiatry at the University of Michigan Medical School, and his colleagues are presenting a new, broader analysis of the follow-up studies to date. The U-M team examined 54 studies dating from 2001 to 2010 and encompassing nearly 41,000 participants -- making it the largest analysis of the serotonin gene's relationship to depression.

"When we included all the relevant studies, we found that an individual's genetic make-up does make a difference in how he or she responds to stress," says Sen.

The U-M analysis supports previous findings that individuals who had a short allele on a particular area the serotonin gene had a harder time bouncing back from trauma than those with long alleles.

Rudolf Uher, Ph.D., a clinical lecturer at the Institute of Psychiatry in London, says the U-M research will help cut through the debate about the genetic connection and refocus the field on making new advances to help those affected by mental illness.

"The major strength of the analysis is that it is the first such work that included all studies that were available on the topic," Uher says. "And it gives a very clear answer: the 'short' variant of the serotonin transporter does make people more sensitive to the effects of adversity."

The authors of the initial study from 2003 were also excited by the U-M team's results.

"Their careful and systematic approach reveals why the JAMA meta-analysis got it wrong," says Terrie Moffitt, Ph.D., a professor at Duke University and one of the authors of the 2003 study. "We hope that the same journalists who were so hasty to publish a simplistic claim in 2009 will cover this more thoughtful new analysis."

When the U-M team restricted their analysis to the 14 studies included in the 2009 JAMA paper, they also failed to find a genetic link, suggesting to Sen that the scope of the analysis, not the methodology, was responsible for the new findings.

The U-M analysis found robust support for the link between sensitivity to stress and a short allele in those who had been mistreated as children and in people suffering with specific, severe medical conditions. Only a marginal relationship was found in those who had undergone stressful life events.

But that's also common sense. Different stressful life events may have very different effects, Sen says. For instance, there is no reason to think that the effects of divorce, at a biological level, would be similar to the effects of losing your home or being physically assaulted.

Still, the study results don't mean that everyone should run out and get a genetic test; additional susceptibility from having a short allele is only one factor among many that determine how an individual responds to stress, Sen says.

Additional research will help to map an individual's genetic profile for depression.

"This brings us one step closer to being able to identify individuals who might benefit from early interventions or to tailor treatments to specific individuals," Sen says.

Funding: The research was supported by grants from the National Institutes of Health, University of Michigan Depression Center and Studienstiftung des Deutschen Volkes.

Additional U-M Authors: Margit Burmeister, Ph.D., Kerby Shedden, Ph.D., former graduate student Katja Karg

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Ancestral Populations Of India And Relationships To Modern Groups Revealed

Ancestral Populations Of India And Relationships To Modern Groups Revealed

  10:55:00 AM    Science Lover

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In a study published in the September 24th issue of Nature, an international team describes how they harnessed modern genomic technology to explore the ancient history of India, the world's second most populous nation.

A map showing the groups across India included in the Nature study. 

(Credit: Photo courtesy of D. Reich, K. Thangaraj, N. Patterson, A. Price and L. Singh)

The new research reveals that nearly all Indians carry genomic contributions from two distinct ancestral populations. Following this ancient mixture, many groups experienced periods of genetic isolation from each other for thousands of years. The study, which has medical implications for people of Indian descent, was led by scientists at the Centre for Cellular and Molecular Biology (CCMB) in Hyderabad, India together with US researchers at Harvard Medical School, the Harvard School of Public Health and the Broad Institute of Harvard and MIT.

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Brain Disease 'Resistance Gene' Evolves in Papua New Guinea Community; Could Offer Insights Into CJD

Brain Disease 'Resistance Gene' Evolves in Papua New Guinea Community; Could Offer Insights Into CJD

  2:40:00 AM    Science Lover

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A community in Papua New Guinea that suffered a major epidemic of a CJD-like fatal brain disease called kuru has developed strong genetic resistance to the disease, according to new research by Medical Research Council (MRC) scientists.

Variant Creutzfeldt-Jakob disease (vCJD) is a prion disease that was first described in 1996 in the United Kingdom. There is now strong scientific evidence that the agent responsible for the outbreak of prion disease in cows, bovine spongiform encephalopathy (BSE or 'mad cow' disease), is the same agent responsible for the outbreak of vCJD in humans. 

(Credit: Sherif Zaki, Wun-Ju Shieh / Courtesy of CDC)

 

Kuru is a fatal prion disease, similar to CJD in humans and BSE in animals, and is geographically unique to an area in Papua New Guinea. In the mid 20th Century, an epidemic of kuru devastated a population in the Eastern Highlands of Papua New Guinea. The infection was passed on at mortuary feasts, where mainly women and children consumed their deceased relatives as a mark of respect and mourning. This practice was banned and ceased in the late 1950s.

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‘Glue’ produced by shellfish may replace surgical stitches

‘Glue’ produced by shellfish may replace surgical stitches

  9:31:00 AM    Science Lover

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The new technology that will eliminate stitches could lead
to increased precision for exacting operations such as eye surgeries

Using the natural glue that marine mussels use to stick to rocks, and a slightly modified inkjet printer, a team of researchers from North Carolina State University in the US has devised a new way of making medical adhesives that could replace traditional sutures and result in faster healing, less scarring and increased precision for exacting operations such as eye surgery.

Sutures and synthetic adhesives have been in use for joining tissue together in the wake of a surgery.

Though sutures work well, they require enormous skill and longer operating times. Synthetic adhesives, though widely used, are the source of increasing concerns over their toxicological and environmental effects.

Since non-biodegradable synthetic medical adhesives do not break down in the body, they may lead to medical problems.

The new study shows that adhesive proteins found in the “glue” produced by marine mussels may be used in place of the synthetic adhesives without such concerns, as they are non-toxic and biodegradable.

Dr Roger Narayan, one of the authors of the study, says that the mussel proteins can be placed in solution and applied using inkjet technology to create customised medical adhesives, which may have a host of applications.

He thinks this approach may “significantly improve wound repair in eye surgery, wound closure and fracture fixation”.

“This is an improved way of joining tissues because the use of the inkjet technology gives you greater control over the placement of the adhesive. This helps ensure that the tissues are joined together in just the right spot, forming a better bond that leads to improved healing and less scarring,” Narayan says.

The researcher adds that this increased control would be a boon for surgery that relies on extreme precision, such as eye repair.

A research article on this study will appear in the Journal of Biomedical Materials Research B.

If you like this post, buy me a beer at $1!

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Generating Power from a Heart

Generating Power from a Heart

  9:07:00 PM    Science Lover

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Nanowire generators could one day lead to medical devices powered by the patient's own heart.

Live wire: A single zinc oxide nanowire can be attached to a rat’s heart, where it produces electric current as it bends with every beat.
Credit: Guang Zhu, Georgia Tech

A tiny, nearly invisible nanowire can convert the energy of pulsing, flexing muscles inside a rat's body into electric current, researchers at Georgia Institute of Technology have shown. Their nano generator could someday lead to medical implants and sensors powered by heartbeats or breathing.

Zinc oxide nanowires show the piezoelectric effect, producing electricity when they are under mechanical stress. Georgia Tech professor of materials science and engineering Zhong Lin Wang and his group first demonstrated these nanowire generators in 2005. Since then they have made devices that can harness the energy of a running hamster and tapping fingers, and have also combined their piezoelectric nanowires with solar cells.

In their latest work, published in the journal Advanced Materials, Wang's team shows that the nanogenerator works inside a live animal. The researchers deposited a zinc oxide nanowire on a flexible polymer substrate and encapsulated the device in a polymer casing to shield it from body fluids. It was then attached to a rat's diaphragm. The rodent's breathing stretched the nanowire, and the device generated four picoamperes of current at two millivolts. When attached to a rat's heart, the device gave 30 picoamperes at three millivolts.

Zinc oxide nanogenerators would be an ideal power source for nano-scale sensors that monitor blood pressure or glucose levels and detect cancer biomarkers. These can run on low power levels of about one microwatt, but they need a long-lasting nano-sized power source instead of a battery to be truly nano scale. "Our ultimate goal is to make self-powered nano devices for medical applications," says Wang.

The femtowatt scale of power generated by the devices is far too low to be practical right now (power = current x voltage). But that should change soon, Zhang says. While the researchers have only tested a single nanowire device inside a rat, they have also built a device that integrates hundreds of nanowires in an array. This device, which the researchers recently reported in the journal Nature Nanotechnology, gives an output current of about 100 nanoamperes at 1.2 volts, producing 0.12 microwatts of power. Wang says the next step is to connect this higher-output nanogenerator to a nano sensor inside an animal.

Better piezoelectric materials than zinc oxide nanowires exist and are also being considered for biomedical applications. The most efficient piezoelectric material known is PZT, a compound of lead, zirconium, and titanium. It is 10 times more efficient than zinc oxide at converting mechanical stress into electric current, says Michael McAlpine, a mechanical engineering professor at Princeton University. By sandwiching PZT between silicone pieces, he has made a material that can harvest 80 percent of the energy applied when flexed. Like Wang, he is focusing on using the material to power medical implants.

McAlpine says the material gives 10 nanowatts of power from human finger tapping. Larger sheets could generate enough power to charge a pacemaker, but the material has not been tested in animals yet. Here, zinc oxide might have an advantage over PZT because it is biocompatible. The lead in PZT would require the device to be robustly encased in silicone or another biocompatible polymer.

The biggest challenge for both materials, however, will be getting higher power outputs, McAlpine says. "It's amazing that they could implant these devices in these animals and get power out," he says. "But we still have to go far with our devices to get a meaningful power output."

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Nobel Prize in Physiology or Medicine 2010 Was Awarded to Robert G. Edwards for IVF Fertilization

Nobel Prize in Physiology or Medicine 2010 Was Awarded to Robert G. Edwards for IVF Fertilization

  12:10:00 AM    Science Lover

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Robert Edwards has been awarded the 2010 Nobel Prize for the development of human in vitro fertilization (IVF) therapy. His achievements have made it possible to treat infertility, a medical condition afflicting a large proportion of humanity including more than 10% of all couples worldwide.

In vitro fertilization. (Credit: iStockphoto)

As early as the 1950s, Edwards had the vision that IVF could be useful as a treatment for infertility. He worked systematically to realize his goal, discovered important principles for human fertilization, and succeeded in accomplishing fertilization of human egg cells in test tubes (or more precisely, cell culture dishes). His efforts were finally crowned by success on 25 July, 1978, when the world's first "test tube baby" was born. During the following years, Edwards and his co-workers refined IVF technology and shared it with colleagues around the world.

Approximately four million individuals have so far been born following IVF. Many of them are now adult and some have already become parents. A new field of medicine has emerged, with Robert Edwards leading the process all the way from the fundamental discoveries to the current, successful IVF therapy. His contributions represent a milestone in the development of modern medicine.

Infertility -- a medical and psychological problem

More than 10% of all couples worldwide are infertile. For many of them, this is a great disappointment and for some causes lifelong psychological trauma. Medicine has had limited opportunities to help these individuals in the past. Today, the situation is entirely different. In vitro fertilization (IVF) is an established therapy when sperm and egg cannot meet inside the body.

Basic research bears fruit

The British scientist Robert Edwards began his fundamental research on the biology of fertilization in the 1950s. He soon realized that fertilization outside the body could represent a possible treatment of infertility. Other scientists had shown that egg cells from rabbits could be fertilized in test tubes when sperm was added, giving rise to offspring. Edwards decided to investigate if similar methods could be used to fertilize human egg cells.

It turned out that human eggs have an entirely different life cycle than those of rabbits. In a series of experimental studies conducted together with several different co-workers, Edwards made a number of fundamental discoveries. He clarified how human eggs mature, how different hormones regulate their maturation, and at which time point the eggs are susceptible to the fertilizing sperm. He also determined the conditions under which sperm is activated and has the capacity to fertilize the egg. In 1969, his efforts met with success when, for the first time, a human egg was fertilized in a test tube.

In spite of this success, a major problem remained. The fertilized egg did not develop beyond a single cell division. Edwards suspected that eggs that had matured in the ovaries before they were removed for IVF would function better, and looked for possible ways to obtain such eggs in a safe way.

From experiment to clinical medicine

Edwards contacted the gynecologist Patrick Steptoe. He became the clinician who, together with Edwards, developed IVF from experiment to practical medicine. Steptoe was one of the pioneers in laparoscopy, a technique that was new and controversial at the time. It allows inspection of the ovaries through an optical instrument. Steptoe used the laparoscope to remove eggs from the ovaries and Edwards put the eggs in cell culture and added sperm. The fertilized egg cells now divided several times and formed early embryos, 8 cells in size.

These early studies were promising but the Medical Research Council decided not to fund a continuation of the project. However, a private donation allowed the work to continue. The research also became the topic of a lively ethical debate that was initiated by Edwards himself. Several religious leaders, ethicists, and scientists demanded that the project be stopped, while others gave it their support.

The birth of Louise Brown -- an historic event

Edwards and Steptoe could continue their research thanks to the new donation. By analyzing the patients' hormone levels, they could determine the best time point for fertilization and maximize the chances for success. In 1978, Lesley and John Brown came to the clinic after nine years of failed attempts to have a child. IVF treatment was carried out, and when the fertilized egg had developed into an embryo with 8 cells, it was returned to Mrs. Brown. A healthy baby, Louise Brown, was born through Caesarian section after a full-term pregnancy, on 25 July, 1978. IVF had moved from vision to reality and a new era in medicine had begun.

IVF is refined and spreads around the world

Edwards and Steptoe established the Bourn Hall Clinic in Cambridge, the world's first centre for IVF therapy. Steptoe was its medical director until his death in 1988, and Edwards was its head of research until his retirement. Gynecologists and cell biologists from all around the world trained at Bourn Hall, where the methods of IVF were continuously refined. By 1986, 1,000 children had already been born following IVF at Bourn Hall, representing approximately half of all children born after IVF in the world at that time.

Today, IVF is an established therapy throughout the world. It has undergone several important improvements. For example, single sperm can be microinjected directly into the egg cell in the culture dish. This method has improved the treatment of male infertility by IVF. Furthermore, mature eggs suitable for IVF can be identified by ultrasound and removed with a fine syringe rather than through the laparoscope.

IVF is a safe and effective therapy. 20-30% of fertilized eggs lead to the birth of a child. Complications include premature births but are very rare, particularly when one egg only is inserted into the mother. Long-term follow-up studies have shown that IVF children are as healthy as other children.

Approximately four million individuals have been born thanks to IVF. Louise Brown and several other IVF children have given birth to children themselves; this is probably the best evidence for the safety and success of IVF therapy. Today, Robert Edwards' vision is a reality and brings joy to infertile people all over the world.

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Scientists Override Errant Form of Genetic Signaling for First Time: Changing Genetic 'Red Light' to Green Holds Promise for Treating Disease

Scientists Override Errant Form of Genetic Signaling for First Time: Changing Genetic 'Red Light' to Green Holds Promise for Treating Disease

  3:24:00 PM    Science Lover

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In a new study published June 15 in the journal Nature, scientists discovered an entirely new way to change the genetic code. The findings, though early, are significant because they may ultimately help researchers alter the course of devastating genetic disorders, such as cystic fibrosis, muscular dystrophy and many forms of cancer.

Scientists discovered an entirely new way to change 
the genetic code. (Credit: © Rodolfo Clix / Fotolia)

The genetic code is the set of instructions in a gene that tell a cell how to make a specific protein. Central to the body's protein production process is messenger RNA, or mRNA, which takes these instructions from DNA and directs the steps necessary to build a protein. For the first time, researchers artificially modified messenger RNA, and in doing so changed the original instructions for creating the protein. The end result: A different protein than originally called for.

"The ability to manipulate the production of a protein from a particular gene is the new miracle of modern medicine," said Robert Bambara, Ph.D., chair of the Department of Biochemistry and Biophysics at the University of Rochester Medical Center. "This is a really powerful concept that can be used to try to suppress the tendency of individuals to get certain debilitating, and sometimes fatal genetic diseases that will forever change their lives."

Protein production is not a perfect process -- far from it. Frequent mutations or mistakes in DNA and messenger RNA can lead to flawed proteins that have the potential to cause serious harm. In the study, researchers focused on a common type of mutation that occurs when an mRNA molecule contains a pre-mature "stop" signal, known as a pre-mature stop codon. A premature stop codon orders a cell to stop reading the genetic instructions partway through the process, resulting in the creation of an incomplete, shortened protein.



Researchers were able to alter mRNA in a way that turned a stop signal into a "go" signal. As a result, the cell could read the genetic instructions all the way through and create a normal, full-length protein. The team produced these results both in vitro and in live yeast cells.

"This is a very exciting finding," said Yi-Tao Yu, Ph.D., lead study author and associate professor of Biochemistry and Biophysics at the Medical Center. "No one ever imagined that you could alter a stop codon the way we have and allow translation to continue uninterrupted like it was never there in the first place."

The findings are important because current estimates suggest that approximately one third of genetic diseases are caused by the presence of pre-mature stop codons that result in shortened proteins. The results could aid the development of treatment strategies designed to help the body override stop codons and produce adequate amounts of full-length proteins, whose absence causes diseases like cystic fibrosis and contributes to different types of cancer.

Yu, along with first author John Karijolich, Ph.D., used another type of RNA -- guide RNA -- to modify messenger RNA. Guide RNAs are short RNAs that bind to specific sequences in RNA and allow just one particular site to be modified. "Guide RNAs give us tremendous power to zero in on one spot in the genome and make very targeted changes," noted Bambara.

The team developed an artificial guide RNA and programmed it to target and change a specific stop codon in an mRNA.

"The fact that this strategy worked -- that the guide RNA we created found its way to its target, the stop codon, and directed the desired structure change -- is pretty remarkable. Guide RNAs weren't thought to have access to messenger RNA, so no one believed they could target messenger RNA for modification," said Karijolich, who conducted the research as a graduate student at Rochester, but is now a postdoctoral fellow in the Department of Biochemistry at the Robert Wood Johnson Medical School. "Our results bring up the question of whether a similar process may be happening naturally."

"Previous research has presented other ways to modify the genetic code, but what is really unique about our method is that it is at the RNA level and it is site specific. We can express the artificial guide RNA in a cell and direct it to make a modification at a single site and only that site," said Yu.

Altering messenger RNA in this way may be another mechanism human cells use to create many different types of proteins. Given our complexity, humans have surprisingly few genes. While it is well established that the majority of human genes code for more than one protein, mRNA modification may be an unrealized way that humans are able to do this.

Yu plans to pursue this research further, studying whether and how targeted mRNA modification is happening naturally.

The study was funded by the National Institute of General Medical Sciences at the National Institutes of Health.

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Genetic Secrets of Human Longevity

Genetic Secrets of Human Longevity

  9:18:00 PM    Science Lover

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While environment and family history are factors in healthy aging, genetic variants play a critical and complex role in conferring exceptional longevity, according to a new study by a team of researchers from the Boston University Schools of Public Health and Medicine and the Boston Medical Center.

While environment and family history are factors in 
healthy aging, genetic variants play a critical 
and complex role in conferring exceptional 
longevity. (Credit: iStockphoto/Catherine Yeulet)

In a study released July 1 online by the journal Science, the research team identified a group of genetic variants that can predict exceptional longevity in humans with 77 percent accuracy -- a breakthrough in understanding the role of genes in determining human lifespan.

Based upon the hypothesis that exceptionally old individuals are carriers of multiple genetic variants that influence their remarkable survival, the team conducted a genome-wide association study of centenarians. Centenarians are a model of healthy aging, as the onset of disability in these individuals is generally delayed until they are well into their mid-nineties.

Researchers led by Paola Sebastiani, PhD, a professor of biostatistics at the BU School of Public Health and Thomas Perls, MD, MPH, associate professor of medicine at the BU School of Medicine and a geriatrician at Boston Medical Center, built a unique genetic model that includes 150 genetic variants, known as single nucleotide polymorphisms (SNPs). They found that these 150 variants could be used to predict if a person survived to very old ages (late 90s and older) with a high rate of accuracy.

In addition, the team's analysis identified 19 genetic clusters or "genetic signatures" of exceptional longevity that characterized 90 percent of the centenarians studied. The different signatures correlated with differences in the prevalence and age-of-onset of diseases such as dementia and hypertension, and may help identify key subgroups of healthy aging, the authors said.

Notably, the team found that 45 percent of the oldest centenarians -- those 110 years and older -- had a genetic signature with the highest proportion of longevity-associated genetic variants.

"These genetic signatures are a new advance towards personalized genomics and predictive medicine, where this analytic method may prove to be generally useful in prevention and screening of numerous diseases, as well as the tailored uses of medications," said Dr. Perls, founder and director of the New England Centenarian Study.

The researchers developed a novel Bayesian statistical approach to analyze genotype data from more than 1,000 centenarians and several control groups, and to identify those SNPs that were most predictive of being centenarians or controls. The team began by using the SNPs that were most likely associated with exceptional longevity, and once the researchers identified 150 SNPs, they found that adding more variants did not further improve the ability to predict whether a person was a centenarian or a control subject.

Dr. Sebastiani noted: "The methodology that we developed can be applied to other complex genetic traits, including Alzheimer's disease, Parkinson's, cardiovascular disease and diabetes. It reinvigorates the potential high utility of collecting and analyzing such data."

Besides looking at which genetic variants were associated with longevity, the authors looked into whether the absence of disease-associated variants also played an important role. They did this by analyzing how many disease-associated variants each centenarian had, compared to each of the controls. Their analysis found little difference between the two groups, suggesting that the presence of genetic variants associated with longevity is of more importance than the absence of disease-associated variants.

If these findings are confirmed, they would suggest that "predicting disease risk using disease-associated variants may be inaccurate and potentially misleading, without more information about other genetic variants that could attenuate such risk" the authors commented.

Overall, the authors said, their preliminary data "suggest that exceptional longevity may be the result of an enrichment of longevity-associated variants that counter the effect of disease-associated variants and contribute to the compression of morbidity and/or disability towards the end of these very long lives." They added that "further investigation is needed to understand how and why these variants collectively predispose for exceptional longevity."

The researchers noted that the 77-percent accuracy rate of predictions "shows that genetic data can indeed predict exceptional longevity without knowledge of any other risk factor."

But they added: "This prediction is not perfect, however, and although it may improve with better knowledge of the variations in the human genome, its limitations confirm that environmental factors (e.g., lifestyle) also contribute in important ways to the ability of humans to survive to very old ages."

Drs. Sebastiani and Perls also cautioned that they developed this genetic risk model as a way to dissect the complex genetic bases of exceptional longevity and to discover the different genetic paths to age 100 and older. An understanding of the implications of this model's use in the general population would be necessary before this test is marketed, they said.

The study was funded by grants from the National Institute of Aging (NIA) and the National Heart Lung and Blood Institute (NHLBI) of the National Institutes of Health (NIH).

"This is a novel approach to studying genetic contributions to exceptional longevity," said Winifred K. Rossi, deputy director of the NIA's Division of Geriatrics and Clinical Gerontology. "It adds to a growing set of analytical tools that aim to identify and understand the complex genetic and environmental factors that lead to healthy long life."

In addition to Perls and Sebastiani, other authors include: Nadia Solovieff and Stephen W. Hartley of the BU School of Public Health Biostatistics Department; Daniel A. Dworkis, Efthymia Melista and Monty Montano of the BU School of Medicine Department of Medicine; Jemma B. Wilk and Richard H. Myers of the BU School of Medicine Department of Neurology; Martin H. Steinberg and Clinton T. Baldwin of the BU School of Medicine Departments of Medicine and Pediatrics and Boston Medical Center; Stacy Anderson of the BU School of Medicine Department of Medicine, Section of Geriatrics, and Boston Medical Center; and Annibale Puca of IRCCS Multimedica, Milano, Italy.

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