Health,Stem Cells, and Technology

Monday, November 28, 2011

Stem-Cell-Seeded Bioartificial Tracheal Transplant In Human Patient

A stem-cell-seeded bioartificial nanocomposite tracheobronchial scaffold can be used successfully to replace a complex airway defect, according to a proof-of-concept study published online Nov. 24 in The Lancet.

Tracheal tumours can be surgically resected but most are an inoperable size at the time of diagnosis, and are therefore not amenable to surgery. New therapeutic options are needed. A Swedish surgical group at the Karolinska Institute report the clinical transplantation of a tracheobronchial airway with a stem-cell-seeded bioartificial nanocomposite.

Prof Paolo Macchiarini and colleagues reported the outcome of a clinical transplantation of the tracheobronchial airway, made from a stem-cell-seeded bioartificial nanocomposite, in a 36-year-old male patient. The patient, who had previously been treated with debulking surgery and radiation, presented with recurrent primary cancer of the distal trachea and main bronchi. Following tumor resection, a tailored bioartificial nanocomposite, previously seeded with autologous bone-marrow mononuclear cells processed in a bioreactor for 36 hours, was used to replace the airway. Over a period of 14 days, postoperative granulocyte colony-stimulating (GCSF) factor filgrastim (enhances white blood cell production) and epoetin beta (hormone that increases red blood cell production), were given to enhance the regenerative process. Analyses performed included flow cytometry, scanning electron microscopy, confocal microscopy epigenetics, microRNA (miR), and gene expression.

The investigators found that, after the reseeding and bioreactor process, an extracellular matrix-like coating and proliferating cells, including a CD105+ subpopulation, were noted in the scaffold. The patient was tumor-free and asymptomatic five months following transplantation, and there were no major complications. Peripheral cells displaying elevated mesenchymal stromal cell phenotype were mobilized, and epoetin receptors, antiapoptotic genes, and miR-34 and miR-449 biomarkers were upregulated postoperatively.
The successful overall clinical outcome of this first-in-man bioengineered artificial tracheobronchial transplantation provides ongoing proof of the viability of this approach, in which a cell-seeded synthetic graft is fabricated to patient-specific anatomical requirements and incubated to maturity within the environment of a bioreactor.

Sunday, November 27, 2011

New Start-Up Provides Health Care Shopping Network

People can easily compare prices on automobiles, cameras, vacations, and homes, but in the United States, patients are left in the dark when paying for health care. Patients typically don't find out how much any given medical procedure costs until well after they receive treatment, be it a diagnostic test, blood draw, or major surgery.

Now a new start-up based in San Francisco, called Castlight Health, allows employers and health plans to lower the cost of providing health care benefits, while offering employees and plan members a consumer-friendly way to get the most for their out-of-pocket costs.

According to Castlight Health, the company offers companies the following opportunities:

Reduce health care costs—guaranteed—so savings can be applied to other programs or to the bottom line

Successfully implement innovative benefit designs, including Consumer-Directed Health Plans, Reference-Based Pricing, and shared savings models

Make smart health care shoppers out of employees and plan members—empowering them to get the most for each dollar spent

Castlight collects data on medical costs primarily from statements of benefits that insurers provide to large employers after workers' claims have been paid. The firm also provides information about quality that it gathers from a variety of sources, including the federal Health Data Initiative, a nonprofit coalition of employers called the Leapfrog Group. Along with quantitative data, the company aggregates patient reviews from consumer websites.

Growth of Castlight depends in part on cooperation from insurers. While some insurers, including Cigna and Aetna, have been willing to share data about the prices they pay health-care providers such as physicians and hospitals, other insurers insist that such information is a trade secret.

Sunday, November 20, 2011

Stanford Develops Speed Of Light, Efficient Computer Device

Dr. Jelena Vuckovic, professor at Stanford's School of Engineering has demonstrated an ultrafast nanoscale light-emitting diode (LED) that is orders of magnitude lower in power consumption than today's laser-based systems and is able to transmit data at the very rapid rate of 10 billion bits per second. The inventors say the device is a major step forward in providing a practical ultrafast, low-power light source for on-chip data transmission. Consider the drift speed of electrons through a copper wire of cross-sectional area 3.00 x 10-6 m2, with a current of 10 A will be approximately 2.5 x 10-4 m/s or about a quarter of a milimeter per second, while the waves propagates at some fraction of the speed of light (0.5 depending on the cable). Compare that figure to the speed of light, which is 186,000 miles per second.

Nanophotonics is key to the technology. In the heart of their device, the engineers have inserted little islands of the light-emitting material indium arsenide that, when pulsed with electricity, produce light. These "quantum dots" are surrounded by photonic crystal, an array of tiny holes etched in a semiconductor. The photonic crystal serves as a mirror that bounces the light toward the center of the device, confining the light inside the LED and forcing the light to resonate at a single frequency. In other words, the light becomes single-mode, similar to that in a LASER.

Without these nanophotonic ingredients, i.e. the quantum dots and the photonic crystal,  no one has been able to produce an LED efficient, single-mode, and fast all at the same time. Further, the new device includes another invention. Existing devices are actually two devices, a laser coupled with an external modulator. Both devices require electricity. Vuckovic's diode combines light transmission and modulation functions into one device, drastically reducing energy consumption.

The new LED device transmits data, on average, at 0.25 femto-joules per bit of data. By comparison, today's typical "low" power laser device requires about 500 femto-joules to transmit the same bit. The new device is about 2,000 times more energy efficient than best devices in use today.

I blogged earlier about Intel's new 3D chip being invented at UC Berkeley back in the 1990s, and now expect to see Stanford's new chip realized in future computers. For anyone doubting the importance of strong US government involved in the "Triad," that is government funding academia's research and teaching, and the government's support of translating the technology to our high tech corporations, see this as yet one more example of what we must continue to do as nation to maintain our technical superiority and revitalize our national economy.


Friday, November 18, 2011

Multiple Sclerosis May Originate In The Gut

Multiple sclerosis and other diseases may originate in the gut according to a growing body of evidence. Epigenetic changes originating in dietary influences on the immune system of the gut may be a critical factor in controlling the expression of gene function related to a number of disease states including MS and cancer. For example, insufficiencies in dietary intake of methyl donors and cofactors, such as folate, vitamins B6 and B12, and methionine, have been associated with cancer risk. And Vitamin D deficiency, EBV infection, and smoking are major epigenetic determinants of MS.

Research is beginning to demonstrate that chronic inflammation within our gut, coupled with low vitamin D levels, and poor vitamin D receptor function induce the activation of auto-reactive T cells that destroy cells serving to produce the covering (myelin) of nerve cells. MS is a debilitating neuroinflammatory disease that occurs when auto-reactive T cells gain entry into the CNS and destroy myelin producing oligodendrocytes. Studies suggest that the T cells enter the CNS via a leaky blood brain barrier that results from a leaky gut or other types of chronic inflammation.

An early finding in MS patients and other autoimmune disease is the constant finding of low levels of DHEA. Interestingly, when DHEA is replaced studies show the severity of disease progression is limited. In some cases, the disease exhibited remission when DHEA levels are normalized. The DHEA level has been suggested to be down regulated because of the constant stress on the adrenal to make cortisol due to the non stop nature of the inflammatory cascade in autoimmune diseases.  

The likelihood of developing multiple sclerosis, a disease in which proteins on the surface of the myelin layer in the brain activate the immune system, is influenced by genes. However, environmental factors have an even greater impact on the disease’s development. Scientists have long suspected that MS is caused by infectious agents. Max Planck researchers in Germany have now shown that multiple sclerosis is triggered by natural intestinal flora.
This finding was made possible by newly developed genetically modified mice. In the absence of exposure to any external influences, inflammatory reactions arise in the brains of these animals which are similar to those associated with multiple sclerosis in humans. However, this only occurs when the mice have intact intestinal flora. Mice without microorganisms in their intestines and held in a sterile environment remained healthy. When the scientists “vaccinated” the animals raised in sterile conditions with normal intestinal microorganisms, they also became ill.
According to Dr. Wekerle, professor of neurobiology at Max Planck, the intestinal flora influence immune systems in the digestive tract, where mice without intestinal flora have fewer T cells. Moreover, these animals’ spleen produces fewer inflammatory substances, like cytokines. In addition, their B cells produce few or no antibodies against myelin. When the researchers restored the intestinal flora to the mice, their T cells and B cells increased their cytokine and antibody production.
Work on the influences of the gut and immune system on MS are just beginning, but the take home point is that, like many other diseases, lifestyle changes can greatly influence the initiation and progression of diseases through epigenetic mechanisms.

Autoaggressive B-Cell (shown in green) in lymph node near the brain

Tuesday, November 15, 2011

Autologous Stem Cells Show Promise in Healing Damaged Hearts

Efforts to use stem cells to help revitalize hearts damaged by heart attack were propelled by three studies presented Monday at the annual meeting of the American Heart Association.
Dr. David Leistner presented at the conference how infusing bone marrow stem cells into the heart soon after a heart attack might improve survival, and how cardiac stem cells might also come to the aid of patients battling heart failure.
Physicians have recently been using bone marrow-sourced stem cells to repair the damage done to cardiac tissue by heart attack. And two new studies presented at the meeting may help define the "window of opportunity" during which this therapy is likely to save lives.
Infusing these cells into the heart several days after a heart attack is safe and provides benefits that last up to five years, one study found. However, waiting 10 to 20 days after a heart attack to inject the cells back into the heart is too long, the second trial concluded.
In the first study, German researchers led by Dr. David Leistner of the University Hospital of Frankfurt found fewer deaths, fewer subsequent heart attacks and fewer procedures needed to open blocked arteries in people who received bone marrow stem cells within a few days of a heart attack. Earlier studies had shown that this experimental treatment improved heart muscle function for up to four months after a heart attack, but the new study, involving 62 patients, showed that these benefits last for up to 5 years.
However, another study presented at the meeting found that waiting 10 to 20 days after a heart attack to infuse bone marrow stem cells may be too long. A third study was presented showing the results of a phase 1 (early) clinical trial presented at the AHA meeting, published simultaneously in The Lancet, demonstrating significant benefit from cardiac stem cell infusions for heart failure patients who had suffered a heart attack. This is the first time this approach has been tested in humans, the team said.
In the Stem Cell Infusion in Patients with Ischemic Cardiomyopathy (SCIPIO) study, researchers retrieved cardiac cells from individuals who were undergoing bypass surgery to re-open blocked arteries. The cells were taken from undamaged areas of the heart, purified, harvested and then injected back into the patients' hearts four months later.
Dr. Roberto Bolli of the University of Louisville and colleagues report that the therapy improved heart function for 16 people with heart failure who received an infusion of their own cardiac stem cells. What's more, the scars on their hearts are healing.

Proof Found For Unifying Quantum Principle

When Dr. John Cardy, then professor of physics at UC Santa Barbara, proposed in 1988 a far-reaching principle to constrain all possible theories of quantum particles and fields, he expected his proposal to be quickly rebutted. But now after 25 years his theorem may have been quietly proved earlier this year.

If the solution holds, Cardy's principle is likely to guide future attempts to explain physics beyond the current standard model, and will certainly have implications for any previously unknown particles that may be discovered at the Large Hadron Collider (LHC) at CERN, Europe's particle physics lab near Geneva, Switzerland.

Roughly speaking, a quantum field theory in our everyday world, with three spatial dimensions and one time dimension, has a calculable quantity, called “a” for historical reasons, that helps characterize it. The conjecture is that if you take any quantum field theory, and study the phenomena that it exhibits at longer and longer distance (for instance, if you compare how a quark and an antiquark behave when they are very close together to how they behave when they are further apart) you will find that “a” always decreases. Very roughly: at short distances quarks and antiquarks can bounce off each other easily, through the strong nuclear force, but at long distances the strong nuclear force traps them tightly inside hadrons, such as a proton. In this transition, the quantity ``a'' decreases. There’s been lots of evidence in favor of this conjecture for many years, but now a proof seems to have been found . Dr Cardy’s theorem requires a tricky and interesting new technical idea, after which the proof becomes elegant and simple.

Many quantum field theories have yet to be solved and thus cannot be used to produce comprehensive predictions of what particles will do. One example is quantum chromodynamics--the theory of the strong nuclear force that describes the interactions between quarks and gluons. Without a unifying principle physicists strugle to relate physics at the high-energy, short-distance scale of quarks to the physics at longer-distance, lower-energy scales, such as that of protons and neutrons.

Although lots of work has gone into relating short- and long-distance scales for particular quantum field theories, there are relatively few general principles that do this for all theories that can exist. Cardy's a-theorem could be one such principle. A version of it had already been proven in two dimensions, but Cardy proposed that the theorem may hold in four dimensions, such as the three dimensions of space and one of time that exist in the space in which we live. However, the theorem seemed to be have been killed off in 2008, when two physicists found a counter-example: a quantum field theory that didn't obey the rule.

Then, in 2010, Seiberg and his colleagues revisited the counter-example and found that it was flawed. That set the stage for others to check Cardy's conjecture, and for Schwimmer and Komargodski to put forward their proof.

Now that the conjecture has some firm backing, it is likely to be applied more widely than before. The most fruitful territory will be the many quantum field theories that have been proposed to unify physics beyond the standard model, including supersymmetry, in which known particles are paired with extra-heavy counterparts that have yet to be found. The a-theorem would help because given predictions from a theory at low energy, it would constrain what the predictions at high energy should look like, and vice versa.

Physicists hope that the LHC will find evidence for supersymmetry or other particles beyond the standard model, and when that happens theorists will need all the help they can get to explain them. The a-theorem will be a guiding tool for theorists trying to understand many aspects of physics

Another application may be in condensed matter physics, in which quantum field theories are used to describe novel phases of materials. One limitation is that the a-theorem has so far been proved only for two and four dimensions, whereas some applications in condensed matter physics involve surfaces with only three dimensions, two in space and one in time. Such work should now proceed to prove a version of the theorem in odd numbers of dimensions.

Saturday, November 5, 2011

Eradicating Aging Cells May Prevent Disease

Scientist have long believed that aging cells damage the surrounding tissue, and that this damage underlies a number of age-related disorders. A new study in mice appears to confirm the hypothesis. The study shows that selectively eliminating those aging, or "senescent," cells, could help prevent the onset of everything from muscle loss to cataracts.
Senescent cells no longer divide, and therefore fail to replenish aging tissue. More recently, researchers have suggested that these cells may be secreting chemicals that poison the cells around them. To determine the role of senescent cells in the diseases of aging, scientists at the Mayo Clinic in Rochester, Minnesota, identified senescent cells in mice that had been genetically engineered to age rapidly using a biomarker, called p16Ink4a. The biomarker is specific to these cells, only labeling the senescent cells. For the length of the animals' lives, they were injected with a drug that induced only those biomarker-containing senescent cells to commit suicide, while leaving non-senescent cells untouched.
The results were significant because in tissues that contained the labeled cells, including everything from fat to muscle to eyes, selective removal of senescent cells appeared to postpone age-related damage. Treated mice had no cataracts, and showed increased muscle mass, strength, and subcutaneous fat when compared to mice that hadn't received the drug.
Dr. Jan van Deursen, Ph.D., professor of biochemistry at the Mayo Clinic led the study showing there is a causal link between these senescent cells and age-related decline in tissue function. The study provides  proof of principle that if you remove this particular cell type from an organism, performed in a mouse but it will probably hold true for humans, tissues and organs would function better and would be more resistant to aging if we can remove senescent cells.

Prior to this study, the data were unclear how senescent cells contributed to aging. The cells make up a very small proportion of all tissue, estimated to be between 1 and 4 percent in even the oldest animals, and many scientist doubted that such a small number of cells could have such a toxic effect. Rather, they thought, when the cells lost their ability to divide, the inability to replace lost tissue might be what caused symptoms of aging.
Not only does the study propose a biomarker for aging, levels of p16Ink4a, but also validates the idea that drugs can be made to target senescent cells without causing harm to healthy cells. As I always point out, biology is a system, a very complex system, and the present work will require much additional work before we realize any significant advance is using this mechanism to treat human disease and conditions.

The current study used a mouse strain that had been genetically tweaked for rapid aging to speed up the experiment—because these mice tend to die early from other causes, the researchers were unable to determine whether increasing the animals' "health span" would also increase their life span. Van Deursen and his colleagues are now beginning a more extensive study in normally aging mice in order to further investigate the effects of senescent-cell removal. Then, one of many challenges, will be to translate these findings into a way of eliminating senescent cells in humans. One will need continual removal of senescent cells, doing so in a very specific way without inducing harm to normal cells.

We know that the body’s immune system clears away senescent cells all the time but does so less efficiently with age. Perhaps the immune system could be trained to attack senescent cells more aggressively. I've previously described how the immune system clears the debris from the neurogenic niche, where stem cells reside to form new brain cells, and now we have evidence that, perhaps, this process of "cleansing" the neurogenic niche may be enhanced so that mental activity and brain repair can be aided.

Tuesday, November 1, 2011

Genomic Plasticity: Retrotransposons May Alter Brain Stucture And Function

Dr Geoff Faulkner at the Roslyn Institute in Scotland has shown that mobile DNA molecules  jump from one location in the genome to another, and may contribute to neurological diseases, explain differences in "identical twins," and could have subtle influences on normal brain function and behavior.

Retrotransposons are mobile genetic elements that use a "copy-and-paste" mechanism to insert extra copies of themselves throughout the genome. First discovered in plants about 60 years ago by Dr. Barbara McKlintock at Cold Sping Harbor Labs in New York, they are now known to make up more than 40 percent of the entire human genome and may play an important role in genome evolution.

Dr. Faulkner and his group used state-of-the-art DNA sequencing technology to screen for retrotransposons in tissue samples taken postmortem from three individuals who were healthy when alive and had no neurological disease or signs of abnormality in their brain tissue. Focusing on two brain regions, the hippocampus and caudate nucleus, they identified nearly 25,000 different sites for the three main retrotransposon families.
Their analyses identified more than 7,700 insertion sites for L1, the best-characterized retrotransposon family that was already known to be active in brain cells. They also found nearly 14,000 insertion sites for the Alu family, which has not been reported in the brain until now.

Each sample had its own set of unique retrotransposition events. The retrotransposons preferentially integrated in genes that were expressed in the brain. Dr. Faulkner thinks these genes are more susceptible because their DNA is packaged in an accessible way.

Many of the insertion sites were located within genes that play key roles in normal brain function. These include genes encoding receptors for the neurotransmitter dopamine and membrane transporters that mop up neurotransmitter molecules from the spaces between neurons after their signaling is complete. Some were located in tumor-suppressor genes, which are known to be deleted in several different types of brain cancer. Others were found in genes encoding regulatory proteins that are linked to psychiatric illnesses such as schizophrenia and the developmental disorder Smith–Magenis syndrome.

The scientists also found that there was far more jumping-gene activity in the hippocampus than in the caudate nucleus. This is interesting, because the hippocampus is known to be critical for learning and memory, and is widely thought to be one of the few parts of the brain that continues to produce new cells throughout life. 

Retrotransposons are normally silenced to prevent harmful mutations from occurring in egg and sperm cells, but are mobilized during certain stages of brain development, when neurons are being produced from dividing stem cells. Retrotransposons then take the opportunity to jump at random into parts of the chromosome that have been opened up for DNA replication.

As well as generating mutations by inserting themselves into and disrupting genes, retrotransposons can alter gene activity if inserted into adjacent regulatory regions of DNA. But Faulkner says that their effects are not necessarily harmful. Retrotransposition is thought, in general, to be beneficial, but sometimes may contributes to disease.

Once thought to be rare, these events actually take place surprisingly often. According to one recent estimate, they occur in many or most brain cells, perhaps several hundred times within each cell. Each neuron is likely subjected to a unique combination of insertions, leading to a genetic variability within populations of cells.

The full significance of this "genomic plasticity" is still not clear, but the authors suggest that it could influence brain development and behavior. It may, for example, partly account for the differences in brain structure and behavior between identical twins, and could even affect thought processes by subtly influencing the changes in nerve cell connections that occur with experience.

Dr. Faulkner and his colleagues are now planning another study with a larger sample size. They want to determine how much variability there is in this phenomenon in the healthy human population, to evaluate if there is a correlation between retrotransposition frequency and brain tumor formation, and to see whether variability is increased or reduced in Alzheimer's disease.