Health,Stem Cells, and Technology

Saturday, March 24, 2012

Rod-Like Photoreceptors Derived From Adult Stem Cells

The quest to regenerate photoreceptors in certain retinal diseases such as retinitis pigmentosa and macualar degeneration has taken a step forward with the recent evidence that functional rod-like photoreceptors can be obtained in vitro from adult stem cells (retinal neurospheres) derived from the adult ciliary epithelium (CE). The study was led by Dr. Valeria Marigo, Ph.D. at the University of Modena and the University of Pisa, confutes previous studies that suggested retinal photoreceptors could not be differentiated from retinal neurospheres.

The Pisa group's conclusion that stem cells derived from the CE are able to generate rod-like cells, was based on both molecular and functional evidence, a novel approach compared to those previous studies  often relying on only genetic and proteomic data.  Prof. Marigo's work analyzed the co-expression of Rho with several proteins involved in phototransduction and, using the AAV2/8-pRho-EGFP construct to compare at the single-cell level the maturation of rod-fated cells with those that had not activated the rod differentiation program, they measured function correlates including macroscopic currents through rod-specific ion channels. This elegant study also demonstrated that only EGFP+ cells responded to cGMP by activating a current whose biophysical properties of low noise (i.e. small unitary conductance), reversal close to −10 mV, and a sensitivity to the calcium electrochemical gradient (i.e. mixed cationic permeability) and lack of voltage-dependence, were consistent with cations permeation through cGMP-gated channels. Calcium imaging corroborated the electrophysiological studies, and the data are congruent with previous studies characterizing the biophysical properties of rod photoreceptors.

Once again, careful studies that include functional data and not just genetic data demonstrate the need to perform multidimensional studies instead of relying on simple genetic analysis.

Thursday, March 22, 2012

Low Doses of Hormonelike Chemicals Have Big Consequences

Many studies have established that natural hormones act at extremely low serum concentrations, typically in the picomolar to nanomolar range, and additional studies published in the peer-reviewed literature document that endocrine disrupting chemicals (EDCs) can act in the nanomolar to micromolar range, and some show activity at picomolar levels.

In 2001, the Environmental Protection Agency (EPA)and the National Toxicology Program (NTP) assembled a group of scientists to perform a review of the low-dose EDC literature. At that time, the NTP panel defined low-dose effects as any biological changes 1) occurring in the range of typical human exposures or 2) occurring at doses lower than those typically used in standard testing protocols, i.e. doses below those tested intraditional toxicology assessments. Other definitions of low dose include 3) a dose below the lowest dose at which a biological change (or damage) for a specific chemical has been measured in the past, i.e. any dose below the lowest observed effect level or lowest observed adverse effect level (LOAEL) , or 4) a dose administered to an animal that produces blood concentrations of that chemical in the range of what has been measured in the general human population (i.e. not exposed occupationally, and often referred to as an environmentally relevant dose because it creates an internal dose relevant to concentrations of the chemical measured in humans). This last definition takes into account differences in chemical metabolism and pharmacokinetics (i.e. absorption, distribution, and excretion of the chemical) across species and reduces the importance of route of exposure by directly comparing similar blood or other tissue concentrations across model systems and experimental paradigms. Although these different definitions may seem quite similar, using just a single well-studied chemical like bisphenol A (BPA) shows how these definitions produce different cutoffs for exposure concentrations that are considered low dose. For many chemicals, including EDCs, a large number of studies meet the criteria for low-dose studies regardless of whether the cutoff point for a low dose was based on the range of typical human exposures, doses used in traditional toxicology, or doses that use an internal measure of body burden.

Dozens of substances that can mimic or block estrogen, testosterone, and other hormones are found in the environment, the food supply, and consumer products, including plastics, pesticides and cosmetics. One of the biggest controversies about these chemicals is whether the small, constant doses that most people are exposed to are harmful.

In the new report, researchers led by Tufts University's Dr. Laura Vandenberg, Ph.D. and Dr. John Myers, Ph.D. of Environmental Health Sciences, concluded after examining hundreds of studies that health effects "are remarkably common" when people or animals are exposed to low doses of endocrine-disrupting compounds. As examples, they provide evidence for several controversial chemicals, including bisphenol A, found in polycarbonate plastic, canned foods and paper receipts, and the pesticide atrazine, used in large volumes mainly on corn.

The scientists concluded that scientific evidence clearly indicates that low doses cannot be ignored. They cited evidence of a wide range of health effects in people – from fetuses to aging adults – including links to infertility, cardiovascular disease,obesity, cancer and other disorders.

Whether low doses of endocrine-disrupting compounds influence human disorders is no longer conjecture, given the many epidemiological studies showing that environmental exposures are associated with human diseases and disabilities.

In addition, the scientists investigated whether a decades-old strategy for testing most chemicals – exposing lab rodents to high doses then extrapolating down for real-life human exposures – is adequate to protect people. They concluded that it is not, and so they urged reforms. Many hormone-like chemicals have health effects at low doses that do not occur at high doses, so that our current testing procedures need to be changed.

Tuesday, March 13, 2012

Quantum Mechanics In Biology: The Quantum Zeno Effect

Beginning in 1996 Dr. Luca Turin of MIT has been the leading proponent of the vibration theory of olfaction, which proposes that the vibrational spectroscopic properties of molecules can be an important determinant of their associated smells, rather than just the specific "lock and key" ligand binding proposed by the orthodox shape theory of olfaction. Turin suggested that a plausible mechanism for such a molecular spectroscope could be inelastic electron tunneling. Dr. Luca's vibration theory received possible support from a 2004 paper published in the journal Organic Biomolecular Chemistry by Takane and Mitchell, showing that odor descriptions in the olfaction literature correlate more strongly with vibrational frequency than with molecular shape. Although biophysical simulations published in Physical Review Letters in 2006 suggest that Turin's proposal is viable from a physics standpoint, Turin's theory has remained highly controversial.

Now, in  a recent paper, Gabor Vattay and Stuart Kauffman at the University of Vermont in the U.S. and Samuli Niiranen at the Tampere Institute of Technology in Finland lend support to Turin's theory, and to the role that quantum effects seem to play in many living systems.

Vattay, Kauffman, and Niiranen have shown that in certain special circumstances, quantum systems can remain coherent over much greater timescales and distances than previously thought, and that biology exploits this coherence in a way that explains the recent observations of quantum events in biology. Their model focuses on  quantum chaos, in which small changes to a quantum system can have a huge influence on the system's behavior, just as in classical chaotic systems. Thus, when a system changes from a state described by quantum mechanics to a state of quantum chaos, the system passes through a kind of phase transition. The transition is key.

When a system is finely balanced between two phases, all kinds of strange behavior can occur. For example, water changes from a gas to a liquid to a solid at certain temperatures and pressures. These states all have well-defined properties. However, there is a certain temperature and pressure at which all three states of water can coexist where the distinction between gas, liquid, and solid essentially disappears. This is the transition.

The new model suggests a similar kind of critical transition occurs as quantum systems switch to a chaotic system. At the transition, the distinction between chaotic behavior and ordinary quantum behavior disappears. Further, at the transition, quantum coherence changes from the rapidly decaying to a much more sustained phenomenon. In this transition state, according to the theory, the observed processes of quantum biology must take place. Their model demonstrates this by simulating the improved coherence of the light harvesting complexes involved in photosynthesis. According to the authors, "The results may open up new possibilities to design low loss energy and information transport systems." 

Friday, March 9, 2012

NIH Develops Method To Label And Track Stem Cells In Human Body

Researchers with the National Institutes of Health (NIH) have developed a method to label transplanted cells, including stem cells, so they can be tracked by MRI, potentially offering a way to measure how many transplanted immune or stem cells reach their target during cell therapy.

Scientists at the NIH formed a complex that, when incubated in transplant cells, labeled nearly 100 percent of those cells for magnetic resonance imaging in animal models.

Research has shown that fewer than 3 percent of intravenous transplanted cells arrive to their target, and the condition of the transplanted cells is hard to evaluate. This brings up questions of cell dose, multiple doses, dose timing, how to make cell therapy approaches more effective, and whether alternative means of stem cell  therapy are needed. One alternative means of stem cell therapy is the use of of SRM and S2RM Technology, where the molecules from stem cells can be dosed in patients at known concentrations, precise timing schedules, and administered using convenient and effective strategies.

In current clinical practice, cell tracking is done with radioisotopes or implantation of an easily located reporter gene, but the short half-life of isotopes, modification to the cell genome, and the possibility of toxicity limit these methods.

The complex created by the researchers is a combination of three FDA-approved drugs. Ferumoxytol is a drug with iron oxide and magnetic properties that allow for MRI tracking. The other two drugs, negatively-charged heparin and positively-charge protamine, allow for successful and smooth incorporation into the transplant cell. Since these three drugs are already used clinically, extensive safety testing should not be necessary and the investigative new drug application evaluation should be shortened.

The tracking method, pending regulatory agency review, will be first tested in humans in an ongoing trial at the City of Hope Medical Center in Duarte, Calif, near Los Angeles. Supported by the California Institute of Regenerative Medicine in San Francisco, the study is testing the transplant of genetically engineered neural stem cells on patients with a specific type of brain tumor.

Thursday, March 8, 2012

Cancer Gene Mutation More Complex Than Previously Thought

Professor Charles Swanton, of University College London's Cancer Institute and his research team have shown that taking a sample or biopsy from just one part of a tumour might not give a full picture of its genetic diversity and may explain why physicians, despite using genetically targeted drugs, are often unable to save patients whose cancer has spread.

These data may help explain why, despite recent development of a wave of highly targeted drugs designed to tackle cancers of specific genetic types, the prognosis remains poor for many patients with solid-tumour disease like breast, lung, or kidney cancer that has spread to others parts of the body.

Further, the molecular changes that drive the growth of the cancer once it has spread may be different from those that drive the growth of the primary tumour. The next step will be to understand what's driving this diversity in different cancers and identify key driver mutations that are common throughout all parts of a tumour. Once again, the simple use of genetic analysis, without other types of testing, for example epigenetic and metabolic analysis, fails to correctly identify a simple pathway to understand and control disease.

Tuesday, March 6, 2012

Should I Use Statins?

Decisions in life usually require one to weigh the risk to benefit ratio. Such is the case with the statins. The benefits of statins in preventing heart disease has been clearly established, but there are minor risks too.

Some patients taking statins may have a small increased risk of higher blood sugar levels and of being diagnosed with type 2 diabetes. Elevated diabetes was shown in a 2008 study of Crestor using nearly 18,000 patients. A separate study published in Lancet ( 2010) found that statins can raise the risk of diabetes by 9 percent. Animal studies have shown impaired muscle function. And memory loss was reported from anecdotal adverse event analysis, and not from experimental studies.

Bottom line, every drug has side effects, despite the benefits. At this point, the benefits of the statins far outweigh the risks for many patients with cardiovascular disease.

Sunday, March 4, 2012

"Older" Endogenous Adult Stem Cells Improve Cardiac Function After Heart Attack

A University of California San Francisco team of scientists conducted a stem cell study in mice suggesting a novel strategy for treating damaged cardiac tissue in patients following a heart attack. The approach potentially could improve cardiac function, minimize scar size, lead to the development of new blood vessels -- and avoid the risk of tissue rejection.

In their study, Ye et al (2012) have shown that: 1) there is a significant increase in the proliferative capacity of stem cells isolated from the “middle aged” heart following acute MI resulting in a significant rise in the number of stem cells in vitro; 2) this increase is time-dependent and is most pronounced within the first week after heart attack in the animal model studied; 3) transplanted stem cells from infarcted myocardium engraft in ischemic myocardium, improve cardiac function, and promote endogenous angiogenesis; 4) adult heart contains Isl1+ cells and Isl1 expression in stem cells is 17-fold higher than in total adult cardiac tissue; 5) Isl1 expression in the Sca-1+CD45− subpopulation within stem cells is 3-fold higher than in total stem cells; 6) Sca-1+CD45− cells in stem cells can be cloned, expanded, and have the characteristics of multipotent cardiac progenitor cells in vitro; and 7) after injection into ischemic myocardium, cloned Sca-1+CD45−cells not only survive long-term, but also differentiate into endothelial and smooth muscle cells, promote endogenous angiogenesis, reduce cardiomyocyte apoptosis, reduce infarct size, and improve cardiac function. Of special note, these experiments were performed in middle-aged mice, rather than in young adults, to simulate a more clinically relevant disease model of older adults.

Under the experimental conditions used in their study, they did not find evidence for differentiation of cloned Sca-1+CD45− cells into cardiomyocytes in vivo. I would suggest looking at the SRM mediated effects, and not just assuming that differentiation is the key to successful results. As BRS' scientists have pointed out, many of the positive effects associated with adult stem cells can be attributed to SRM (stem cell released molecules).

Friday, March 2, 2012

Stem Cells Capable Of Producing New Eggs

For decades, scientists have believed women were born with all the eggs they’ll ever have. Now Dr. Jonathon Tilly, Ph.D. professor at Harvard, is challenging that dogma, saying his team at Massachussetts General Hospital has discovered that the ovaries of young women harbor very rare stem cells capable of producing new eggs. Dr Tilly's data, published in Nature Medicine, suggests that our current view of ovarian aging is incomplete. There may be much more to the story than simply the trickling away of a fixed pool of eggs in the woman's body.
Like any new work that changes our current concepts in biology, Professor Tilly's work will not be immediately accepted by the scientific community. Tilly’s previous work drew fierce skepticism, and independent experts are urging caution about his latest findings. A key next step is to see whether other laboratories can verify Dr. Tilly's work. If the findings are confirmed, years of additional research will be required to learn how to use the newly discovered stem cells.
Dr. Tilly argues that using stem cells to grow eggs in lab dishes might one day help preserve cancer patients’ fertility, and has co-founded a company, OvaScience Inc., to develop the findings into fertility treatments.