Genes Have Help in Determining Our Traits

Yale scientists find that a type of RNA together with a common protein to protect organisms from harmful genetic variations
Monday, 27 December 2010

For decades, biology textbooks have been clear – our traits are the product of our genes. But a new study by Yale University researchers published Dec. 26 in Nature Genetics suggests another mechanism can regulate variations of traits even in genetically identical individuals.

A particular type of RNA works in concert with a common protein to protect organisms from harmful genetic variations without the help of genes, reports Haifan Lin, director of the Yale Stem Cell Center, professor of cell biology and genetics and senior author of the paper.

“This mechanism may help explain how ordinary cells such as fibroblasts can be converted to stem cells and why some cancers develop at random,” Lin said.

The theory that factors other than genes are responsible for an organism’s traits, or phenotype, has been around for almost 70 years but has only gained steam in the past decade. For instance, cloned animals are often born with different colours than the animals that are the source of their DNA. But what causes these changes remained unclear.

About a decade ago, scientists found that a noticeable percentage of flies lacking a protein called Hsp-90 ended up with bizarre and random abnormalities such as legs growing where eyes should be. It seemed clear that Hsp-90 protected an organism against harmful genetic variations in its genome. Yet, since Hsp-90’s role is to mobilize other molecules to respond to stress, researchers suspected other factors were involved.

One school of thought suspected that Hsp-90 prevents the display of random abnormalities by suppressing the activities of “jumping genes” that can relocate to other areas of the genome and cause mutations. However, the Yale researchers report that their work with flies shows that a type of small RNA called Piwi-interacting RNA, or piRNA, acts in concert with Hsp-90 and another molecule to prevent both the creation of variants and the activation of existing genetic variants. Genes do play a role in protecting against harmful variations but probably work through actions of the molecules piRNA and Hsp-90.

Lin, who studies piRNAs in reproductive cells and stem cells, says that the variations in levels of Hsp-90 and piRNAs among individual cells of the same type might explain why a small number of ordinary cells can be reprogrammed into stem cells and also why harmful mutations are created in some cancers.

“This study shows that we still have a lot to learn about the most basic principles of gene regulation,” Lin commented.

“Studies of this kind may provide missing puzzles in our understanding of normal development and malignancies.”

Source: Yale University
Contact: Bill Hathaway

Reference:
Drosophila Piwi functions in Hsp90-mediated suppression of phenotypic variation
Vamsi K Gangaraju, Hang Yin, Molly M Weiner, Jianquan Wang, Xiao A Huang & Haifan Lin
Nature Genetics, 26 December 2010, doi:10.1038/ng.743
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Human Spermatogonial Stem Cells Can Become Insulin-secreting Pancreatic Cells

Human Spermatogonial Stem Cells Can Become Insulin-secreting Pancreatic Cells
Sunday, 12 December 2010

Insulin-secreting pancreatic islet cells have been generated from human spermatogonial stem cells (SSCs) directly isolated from human testicular tissue, researchers reported today at the American Association of Cell Biology 50th Annual Meeting in Philadelphia.

When grafted into diabetic mice that lacked a transplant-rejecting immune system, the bioengineered cells functioned much like somatic β-islet cells, the Georgetown University (GU) Medical Center researchers said.

By decreasing the animals' blood glucose levels, the human-derived islet cells demonstrated their potential to counter diabetic hyperglycaemia in humans, added G. Ian Gallicano, Ph.D., who heads the GU research team.

Gallicano said that these results represent the first step of a transplant strategy to deliver β-islet cells that would not be rejected by the patient with type 1 diabetes because the stem cells would be obtained from the patient's own SSCs, the earliest precursors of male gamete sperm cells.

This transplant strategy would avoid the host-versus-graft issues that have plagued other transplant treatments for type 1 diabetes, Gallicano explained, because the SSCs would be obtained from male patients, modified in the laboratory to secrete insulin, and transplanted back to the donors.

Although surgeons currently transplant islet tissue from deceased donors into female and male patients with type 1 diabetes, this therapy is hampered by a woeful shortage of suitable donations and by complications resulting from host-versus-graft disease.

Gallicano said that obtaining beta-islet-like cells from the male patient's SSCs could solve the problem of immune rejection in males with type 1 diabetes, since the "treatment based on this research would be 'autologous,' that is, the cells come from the patient and would be recognized as 'self.'"

The fundamental approach of transforming male gametes into pluripotent stem cells might also be applicable to the female counterpart, oocytes, he added.

The β-islet-like cells were engineered from germ-derived pluripotent stem (gPS) cells produced from the SSCs. The engineered β-islet cells secreted insulin and exhibited many of the markers characteristic of normal islet cells including C-peptide (pro-insulin) production and the expression of PDX1, a transcription factor involved in pancreatic development.

Source: American Society for Cell Biology
Contact: Cathy Yarbrough
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Advance in Isolation of Neuronal Stem Cells

A Step Forward for Treatment of Brain Diseases
Wednesday, 08 December 2010

Scientists have created a way to isolate neural stem cells – cells that give rise to all the cell types of the brain – from human brain tissue with unprecedented precision, an important step toward developing new treatments for conditions of the nervous system, like Parkinson's and Huntington's diseases and spinal cord injury.

These neurons, oligodendrocytes and

astrocytes were derived from a single

human neural stem cell. Credit: Univ.

of Rochester Medical Center.

The work by a team of neuroscientists at the University of Rochester Medical Center was published in the Nov. 3 issue of the Journal of Neuroscience. Neurologist Steven Goldman, M.D., Ph.D., chair of the Department of Neurology, led the team.

The latest paper marks a six-year effort by Goldman's team to develop a better way to isolate pure preparations of neural stem cells directly from the human brain. These stem cells can renew themselves and have the potential to become a number of brain cell types – for instance, oligodendrocytes that might help people with multiple sclerosis, or neurons to help people with Parkinson's disease. But after the first few months of human embryonic development, they become rare in the brain, and it's challenging for scientists to find, isolate and manipulate them. Yet those challenges must be met if stem cells are to live up to their promise as treatments for a host of human diseases of the nervous system.

So far, most efforts aimed at isolating human foetal stem cells have entailed cultivating brain tissue in tissue culture in the laboratory for months, then separating out the stem cells for study. In addition, today's techniques don't separate out just stem cells; typically, similar cells known as progenitor cells, which have already committed to becoming a certain type of cell, are also captured. The difference is crucial for scientists who often prefer to capture only uncommitted neural stem cells, whether to treat brain diseases requiring the replacement of multiple cell types or to better understand their function.

The Goldman lab's new technique snags only neural stem cells and does so directly from brain tissue. The technology saves months of time and labour in the laboratory and also gives scientists a clearer look than ever before at exactly how stem cells operate in the brain.

In its studies, Goldman's team found some surprises. As expected, certain classes of genes encoding for proteins active in mouse neural stem cells – such as members of the Notch and WNT families – were highly active. But when the scientists looked more closely, they found that the freshly isolated neural stem cells expressed some genes from these families that were previously virtually unknown in humans, and which had never before been implicated in human brain function. At the same time, some of the genes that are important and active in mouse neural stem cells proved not to be so in the human cells.

"While research in mice and other animals serves as a guide, ultimately you have to study human tissue and humans to really understand disease in people," said Goldman, who is also co-director of Rochester's Center for Translational Neuromedicine.

"While the general signalling pathways active in mice and people are very similar, the individual genes are quite different. This is not something we would have predicted. It's a good demonstration that you can't use mouse studies to fully dictate what kinds of therapeutics should be used in people."

The ability to gather human cells more efficiently should aid potential treatments built around transplanting stem cells. In the last few years, a couple studies using human neural stem cells in the nervous system have begun in children with incurable brain diseases known as paediatric leukodystrophies. But the field is in its infancy, and Goldman believes that the cell types currently being used will soon be replaced by more effective types of transplantable stem and progenitor cells.

The new technology is built around a piece of DNA that codes for a protein known as Sox2, which has long been recognized as a key stem cell gene. Since the gene is active only in stem cells, finding a way to see and isolate cells with an active Sox2 gene is the key.

To track it down, the team identified the DNA sequence, known as an enhancer, which determines whether Sox2 is active in neural stem cells. The scientists took that piece of DNA, coupled it to a gene that makes cells emit light of a particular wavelength, and then packaged the resulting synthetic DNA into a virus. They used the virus to deliver the synthetic DNA to neural stem cells in the brain tissue. The technique compelled neural stem cells – and only the stem cells – to emit light of a certain colour, which in turn allowed a laser-based system to tag and capture just those cells. The result was a pure population of human neural stem cells, the first such population ever purified so specifically or directly.

Source: University of Rochester Medical Center
Contact: Tom Rickey

Reference:
Prospective Identification, Isolation, and Profiling of a Telomerase-Expressing Subpopulation of Human Neural Stem Cells, using sox2 Enhancer-Directed Fluorescence-Activated Cell Sorting
Su Wang, Devin Chandler-Militello, Gang Lu, Neeta S. Roy, Alex Zielke, Romane Auvergne, Nancy Stanwood, Daniel Geschwind, Giovanni Coppola, Silvia K. Nicolis, Fraser J. Sim, and Steven A. Goldman
J. Neurosci. 2010 30: 14635-14648; doi:10.1523/JNEUROSCI.1729-10.2010
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Swiss Agency Approves Clinical Trial of UCI-created Neural Stem Cell Therapy

StemCells Inc. study will be first of its kind for chronic spinal cord injury
Tuesday, 07 December 2010

Aileen Anderson and Brian Cummings led

the pre-clinical studies for the neural stem

cell treatment.

Credit: Hoang Xuan Pham / UCI.

A therapy developed by Aileen Anderson and Brian Cummings of UC Irvine's Sue and Bill Gross Stem Cell Research Center in collaboration with researchers at StemCells Inc. will be the basis of the world's first clinical trial using human neural stem cells to treat spinal cord injury.

Swissmedic, the Swiss regulatory agency for therapeutic products, has authorized a Phase I/II clinical trial for chronic spinal cord injury, cases in which inflammation has stabilized and recovery has reached a plateau.

The trial will utilize StemCells Inc.'s proprietary purified human neural stem cells and will be conducted at the University of Zurich's University Hospital Balgrist, one of the world's leading medical centres for spinal cord injury and rehabilitation.

It's designed to assess both safety and preliminary efficacy in patients with varying degrees of paralysis who are between three and 12 months post-injury at the time of transplantation. Enrolment is expected to begin in early 2011.

"This is tremendously exciting news," said Anderson, UCI associate professor of physical medicine & rehabilitation and anatomy & neurobiology.

"Human neural stem cells may hold great promise for helping people with spinal cord injuries regain lost function."

In their collaboration with StemCells Inc., Anderson and Cummings conducted eight years of preclinical studies in rodents that demonstrated the significant therapeutic potential of human neural stem cells.

Their efforts have shown how these cells, when transplanted into damaged spinal columns, can differentiate into neural tissue cells – such as oligodendrocytes and early neurons – and migrate to injury sites. In recent studies, the researchers found that the treatment restored hind-limb function in mice when transplanted in the early chronic period after spinal cord injury.

Other stem cell studies have focused on the acute, or early, phase of spinal cord injury, a period of up to a few weeks after the initial trauma when drug therapies can lead to some functional recovery. The Swiss trial is significant because it will test treatment safety and restoration of mobility during the chronic, or later, phase. There are currently no drug therapies to help restore function during this phase.

"About 1.3 million individuals in the U.S. are living with chronic spinal cord injury," said Cummings, UCI associate professor of physical medicine & rehabilitation and anatomy & neurobiology.

"This trial will be the first opportunity to demonstrate that human neural stem cells may be a viable treatment approach for them."

The Swiss spinal cord injury trial is the second involving UCI stem cell researchers. Earlier this year, the U.S. Food & Drug Administration approved a Phase I safety trial of an embryonic stem cell treatment created by Hans Keirstead. Conducted by Geron Corp., the multisite acute spinal cord injury trial enrolled its first patient in October.

About the Sue and Bill Gross Stem Cell Research Center:
Promoting basic and clinical research and training in the field of stem cell biology at UC Irvine, the centre is a leading international institution in stem cell research and clinical applications. It consolidates existing research strengths and clinical initiatives at UCI and serves as a nucleus for growth via collaboration and new recruits. The centre provides an organizational structure for all areas of stem cell research, supports premier graduate training, maintains a core stem cell facility and equipment, hosts guest researchers and annual meetings, and contributes to research and dialogue on policy and ethical issues related to stem cells.


Source: University of California - Irvine
Contact: Tom Vasich
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Questions Raised about Genetic Testing of Newborns

New extended genetic screening of newborns for rare diseases is creating confusion
Tuesday, 07 December 2010

Mandatory genetic screening of newborns for rare diseases is creating unexpected upheaval for families whose infants test positive for risk factors but show no immediate signs of the diseases, a new UCLA study warns.

"Although newborn screening undoubtedly saves lives, some families are thrown on a journey of great uncertainty," said UCLA sociology professor Stefan Timmermans, the study's lead author.

"Rather than providing clear-cut diagnoses, screening of an entire population has created ambiguity about whether infants truly have a disease — and even what the disease is."

The study, which appears the December issue of the Journal of Health and Social Behavior, describes these families as "the collateral damage of newborn screening," an unanticipated consequence of the expansion of mandatory screening for a wide range of conditions in 2005.

"Basically you're telling families of a newborn, 'Congratulations, but your child may have a rare genetic condition. We just don't know, and we don't know when we'll know,'" Timmermans said.

Conducted with Mara Buchbinder, who earned a doctorate in anthropology at UCLA and is now an assistant professor of social medicine at the University of North Carolina–Chapel Hill, the study paints a picture of families caught in limbo. They have to wait months for conclusive evidence that their children are out of the woods for conditions that have been associated with schizophrenia, mental retardation, heart and lung disease, coma, and sudden death.

In many cases, the medical results never come; the children slowly age out of having risk factors for up to 29 metabolic, endocrine or haemoglobin conditions. But by that time, some families are so traumatized that they follow unwarranted and complicated regimens for years afterward, including waking their children up in the middle of the night, enforcing restrictive diets and limiting contact with other people.

"Years after everything appears to be fine, parents are still very worried," Timmermans said.

For three years, Timmermans and Buchbinder followed 75 California families whose newborns received screenings that sent up red flags for diseases characterized by an inability to digest food containing fat, proteins or sugars. Of the total, 40 of the infants became what the researchers describe as "patients-in-waiting" — children who have not developed symptoms but whose genetic tests raise flags.

"The parents don't know whether their child is a false positive or they're a true positive," Timmermans said.

In one particularly poignant case of a patient-in-waiting, a father refused to allow anyone but the infant's mother to care in any way for the boy, fearing contamination that might aggravate his potential condition. More than a year after the baby's birth, the mother had not been apart from the baby. Her dream, she confessed to the researchers, was to be able one day to go on a date with her husband.

Parents of another patient-in-waiting were afraid to pursue an out-of-state job opportunity because they were uncertain about the quality of medical care that would be available for their child with potential medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD), a condition that prevents babies from being able to turn fat into energy. Without treatment, MCADD babies can experience seizures, extreme sleepiness or comas, and even die. In addition, several parents decided to either give up a job or not return to a job in the hopes of keeping a closer eye on their children in case symptoms of the rare diseases did eventually surface.

"When the test results ultimately suggest the risk is nothing or not as significant as with patients who are symptomatic, the physicians are ready to let go of preventative measures," Timmermans said.

"But the parents are reluctant to give them up because they come to believe that they're keeping their child disease-free. Over and over again, we saw parents and doctors at odds."

The genetic testing of newborns dates back four decades, when the approach showed promise in identifying phenylketonuria (PKU), a genetic disorder characterized by the body's inability to utilize an essential amino acid, phenylalanine. The disorder causes a build-up of phenylalanine in the blood, which can result in mental retardation, brain damage, seizures and other problems. But if PKU sufferers are identified early enough, they can avoid these problems through diet and medication.

The advent of new screening technologies in the late 1990s vastly increased the number of potential diseases that could be detected with a blood sample easily obtained by pricking the heel of a newborn. Genetic testing of newborns got another shot in the arm in 2005 when the American College of Medical Genetics called for mandatory screening of 29 conditions and 24 sub-conditions. By 2009, all 50 U.S. states and the District of Columbia screened for at least 21 of the 29 recommended conditions, and the full recommendations had been adopted by 44 states, including California.

Other countries have since adopted genetic screening, but they test for fewer conditions and add new conditions more slowly than the U.S. The study findings cast doubt on the medical efficacy of the battery of screenings administered widely in America, the researchers said.

"Expanded newborn screening has called into question whether screening targets correspond to actual diseases or just benign forms of human variation," Buchbinder said.

"There are many more positive screenings than were anticipated based on the incidence of the diseases in the general population," Timmermans added.

Nobody knows the number of families who fall into the ‘patient-in-waiting’ category, but it is assumed to be a relatively small number. Still, the number is much larger than was anticipated when screening for a wide range of conditions began in 2005, the study argues.

The researchers also suggest the need for increasing the speed with which follow-up tests are administered so that parents of patients-in-waiting spend less time wringing their hands.

"When the American College of Medical Genetics advocated for the expansion of newborn screening, they argued that the societal benefit of newborn screening would be the avoidance of diagnostic odysseys in which parents of kids with rare diseases travel from doctor to doctor in an attempt to find out what is wrong with them," Timmermans said.

"Our study shows that, in fact, the expansion of newborn screening has created a new population on diagnostic odysseys — the parents of these patients-in-waiting. Now we need to figure out how to dramatically shorten or eliminate this unexpected and stressful journey."

Source: University of California - Los Angeles
Contact: Meg Sullivan
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New Possibility of Reversing Damage Caused by MS

New Possibility of Reversing Damage Caused by MS
6 December 2010

Damage caused by multiple sclerosis could be reversed by activating stem cells that can repair injury in the central nervous system, a study has shown.


Nerve fibres in rodents showing

remyelination. Credit: Dr Andrew

Jarjour.

Researchers from the Universities of Cambridge and Edinburgh have identified a mechanism essential for regenerating insulating layers - known as myelin sheaths - that protect nerve fibres in the brain. In additional studies in rodents, they showed how this mechanism can be exploited to make the brain's own stem cells better able to regenerate new myelin.
In multiple sclerosis, loss of myelin leads to the nerve fibres in the brain becoming damaged. These nerve fibres are important as they send messages to other parts of the body.

The scientists believe that this research will help in identifying drugs to encourage myelin repair in multiple sclerosis patients.

Professor Robin Franklin, Director of the MS Society's Cambridge Centre for Myelin Repair at the University of Cambridge, said:

"Therapies that repair damage are the missing link in treating multiple sclerosis. In this study we have identified a means by which the brain's own stem cells can be encouraged to undertake this repair, opening up the possibility of a new regenerative medicine for this devastating disease."

The study, funded by the MS Society in the UK and the National Multiple Sclerosis Society in America, is published in Nature Neuroscience.

Professor Charles ffrench-Constant, of the University of Edinburgh's MS Society Centre for Multiple Sclerosis Research, said:

"The aim of our research is to slow the progression of multiple sclerosis with the eventual aim of stopping and reversing it. This discovery is very exciting as it could potentially pave the way to find drugs that could help repair damage caused to the important layers that protect nerve cells in the brain."

Multiple sclerosis affects almost 100,000 people in the UK and several million worldwide. It often targets young adults between the ages of 20 and 40.

Source: University of Cambridge
Contact: Genevieve Maul

Reference:
Retinoid X receptor gamma signaling accelerates CNS remyelination
Jeffrey K Huang, Andrew A Jarjour, Brahim Nait Oumesmar, Christophe Kerninon, Anna Williams, Wojciech Krezel, Hiroyuki Kagechika, Julien Bauer, Chao Zhao, Anne Baron-Van Evercooren, Pierre Chambon, Charles ffrench-Constant & Robin J M Franklin
Nature Neuroscience, 05 December 2010, doi:10.1038/nn.2702
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The Gene-environment Enigma

Understanding gene-environment interactions at the most basic level
Saturday, 04 December 2010

Personalized medicine centres on being able to predict the risk of disease or response to a drug based on a person's genetic makeup. But a study by scientists at Washington University School of Medicine in St. Louis suggests that, for most common diseases, genes alone only tell part of the story.

That's because the environment interacts with DNA in ways that are difficult to predict, even in simple organisms like single-celled yeast, their research shows.

"The effects of a person's genes – and, therefore, their risk of disease – are greatly influenced by their environment," says senior author Barak Cohen, PhD, a geneticist at Washington University School of Medicine.

"So, if personalized medicine is going to work, we need to find a way to measure a human's environment."

The research is available online in PLoS Genetics.

To understand gene-environment interactions at the most basic level – at the individual DNA letters that make up the genetic code – the researchers turned to a model organism, the yeast Saccharomyces cerevisiae, culled from North American oak trees and vineyards, where it grows naturally. They asked whether growing the yeast in different environments would influence the rate at which the yeast produce spores, a form of sexual reproduction.

This complex trait is heavily influenced by genetics, Cohen's earlier research has shown. In a study published in 2009 in Science, he determined that just four DNA variants, called single nucleotide polymorphisms (SNPs), account for 90 percent of the efficiency with which yeast produce spores.

In that study, the researchers noted that yeast from oak trees produced spores with 99 percent efficiency; the vineyard strains were far less efficient, at 7 percent. Then, they put each combination of the four SNPs in both the oak and vineyard strains, to determine how the genetic variants interacted with one another.

The researchers showed that the four variants "interacted like crazy such that the combined effects of any four variants were always larger than the sum of their individual effects," Cohen says.

By developing a statistical model to account for the genetic interactions, they could genotype any combination of the four SNPs in either strain of yeast and predict with a high level of confidence their effect on sporulation.

But in that study, the yeast were grown in the same environment – glucose.

In the current study, the scientists grew the two yeast strains with all 16 combinations of four SNPs in different simple sugars: glucose, fructose, sucrose, maltose, raffinose, grape juice, galactose and a combination of sucrose, glucose and fructose.

"These were all mono- or di-saccharides, so the environments are not radically different from one another," Cohen explains.

"It's not like we heated up the yeast or froze them, added acids or put them in a centrifuge. We simply changed the carbon source and measured the effects of those four SNPs in the different environments."

Surprisingly, the researchers found that the effects of the four SNPs on spore production were dramatically different in the different environments. The effects of different combinations of SNPs in one environment were not an accurate predictor of the effects of those same SNPs in other environments.

For example, one combination of the four SNPs increased sporulation efficiency by 40 percent in glucose, but that same SNP combination increased efficiency by 80 percent when the yeast were grown in raffinose.

Indeed, the relative importance of particular SNPs and their interactions were not constant but varied with the genetic background of the yeast strain and the environment.

"Having a particular combination of SNPs was never a great predictor," Cohen says.

"If we didn't know the environment in which the yeast were grown, we could not accurately predict the effect of the SNPs on producing spores. And if we can't make accurate predictions about the way environment influences complex traits in yeast, then it will be exceedingly difficult to do so in people."

The new research raises many questions: what is a human's environment and how can it be measured? Is the environment a person lived in during childhood important or the environment he lives in now?

Cohen suspects that any environment that matters is likely to leave a measurable molecular signature. For example, eating a lot of fatty foods raises triglycerides; smoking raises nicotine levels; and eating high-fat, high-sugar foods raises blood sugar levels, which increases the risk of diabetes. The key, he says, is to figure out what are good metabolic readouts of the environment and factor those into statistical models that assess genetic susceptibility to disease or response to medication.

"Measuring the environment becomes crucial when we try to understand how it interacts with genetics," Cohen says.

"Having a particular genetic variant may not have much of an effect but combined with a person's environment, it may have a huge effect."

Cohen says he is not hopeless when it comes to personalized medicine. As scientists conduct ever-larger studies to identify rare and common variants underlying diseases such as cancer, diabetes and schizophrenia, they will be more likely to uncover variants that have larger effects on disease. Even then, however, a person's environment will be important, he adds.

Source: Washington University School of Medicine
Contact: Caroline Arbanas

Reference:
Gene-environment interactions at nucleotide resolution
Gerke J, Lorenz K, Ramnarine S, Cohen B.
PLoS Genetics, published 30 Sep 2010, 10.1371/journal.pgen.1001144
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Scientists Home in on Chemicals Needed to Reprogram Cells

Groundbreaking discovery moves field closer to therapeutic applications
Friday, 03 December 2010

Scripps Research Institute scientists have made a significant leap forward in the drive to find a way to safely reprogram mature human cells and turn them into stem cells, which can then change into other cell types, such as nerve, heart, and liver cells. The ability to transform fully mature adult cells such as skin cells into stem cells has potentially profound implications for treating many diseases.

Scripps Research Associate Professor

Sheng Ding.

In research published in the December 3, 2010 issue of Cell Stem Cell, Scripps Research Associate Professor Sheng Ding, PhD, reports a novel cocktail of drug-like small molecules that, with the assistance of a gene called Oct4, enables reprogramming of human skin cells into stem cells.

"Our ultimate goal is to generate induced pluripotent stem cells with defined small molecules," Ding said.

"This would offer a fundamentally new method and significant advantages over previous methods, such as genetic manipulation or more difficult-to-manufacture biologics."

Using small-molecule compounds to reprogram adult human cells back to their pluripotent state — able to change into all other cell types — avoid the ethical controversy around embryonic stem cell research, and pave the way for the large-scale production of stem cells that could be used inexpensively and consistently in drug development. Cures for Alzheimer's, Parkinson's, and many other diseases might be possible if new cells could be created from a patient's own cells to replace those that have succumbed to disease or injury.

Substituting Chemicals for Genes
Scientists discovered in 2007 that fully differentiated mature cells, such as skin cells, could be "reprogrammed" to become pluripotent by using four transcription genes. One problem with this technique is that these genes, once inserted into a cell, permanently alter the host cell's DNA.

"There are many concerns when the host cell's genome is manipulated," Ding says.

"One major worry is that since the four genes are [cancer-causing] oncogenes, they could induce tumours or interrupt functions of other normal genes."

Because of this danger, scientists have been searching for methods that could induce reprogramming without the use of these cancer-causing genes. The method the Ding lab has been pioneering — using small, synthetic molecules — represents a fundamentally different approach from the previous methods.

"We are working toward creating drugs that are totally chemically defined, where we know every single component and precisely what it does, without causing genetic damage," Ding says.

Breaking New Ground
Scientists have known for at least 50 years that a cell's identity is reversible if given the right signal — cells go forward to become mature, functional cells or they can go backward to become primitive cells. In order for cellular reprogramming to be safe and practical enough to use in cell therapy, researchers have sought an efficient, reliable way to trigger the reprogramming process.

In 2008, the Ding lab reported finding small molecules that could replace two of the required four genes. Now, two years later, through extraordinary effort and unique screening strategy, the lab made a major leap forward by finding a way to replace three out of the four genes.

"We are only one step away from the ultimate goal, which would represent a revolutionary technology," Ding says.

The new study also revealed that the novel compound facilitates a novel mechanism in reprogramming: the metabolic switch from mitochondrial respiration to glycolysis, an important mechanism for tissue regeneration. The small molecules Ding and his colleagues found promote reprogramming by facilitating such metabolic switching — an entirely new understanding of reprogramming.

A future goal is to replace Oct4, a master regulator of pluripotency, in the chemical cocktail.

"That would be the last step toward achieving the Holy Grail," Ding says.

"Our latest discovery brings us one step closer to this dream."

Source: Scripps Research Institute
Contact: Mika Ono

Reference:
Reprogramming of Human Primary Somatic Cells by OCT4 and Chemical Compounds
Saiyong Zhu, Wenlin Li, Hongyan Zhou, Wanguo Wei, Rajesh Ambasudhan, Tongxiang Lin, Janghwan Kim, Kang Zhang, Sheng Ding
Cell Stem Cell, Volume 7, Issue 6, 651-655, 3 December 2010, doi:10.1016/j.stem.2010.11.015
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Bone Marrow Stromal Stem Cells May Aid in Stroke Recovery

Bone Marrow Stromal Stem Cells May Aid in Stroke Recovery
Thursday, 02 December 2010

A research study from the Farber Institute for Neurosciences and the Department of Neuroscience at Thomas Jefferson University determines bone marrow stromal stem cells may aid in stroke recovery. The results is published in Cell Transplantation – The Regenerative Medicine Journal, issue 19(9).

The study examining the effects of a systematic administration of either rat (allogenic) or human (xenogenic) bone marrow stem cells (MSC) administered to laboratory rats one day after their simulated strokes found "significant recovery" of motor behaviour on the first day. Early administration was found to be more effective than administration seven days after the simulated strokes.

"The timing of stem cell treatment was critical to the magnitude of the positive effects," said the study's lead author, Lorraine Iacovitti, Ph.D., professor, Department of Neuroscience at Jefferson Medical College of Thomas Jefferson University.

"In the host animals we found profound changes and preserved brain structure along with long-lasting motor function improvement."

According to Dr. Iacovitti, there has been little research into just how stem cell transplantation modifies inflammatory and immune effects as well as promotes regenerative effects, such as blood vessel growth. They observed increased activation of microglia as well as modification of the circulating levels of cytokines and growth factors, including elevated VEGF and new blood vessel formation (angiogenesis) following transplantation.

"The mechanism through which MSCs achieve these remarkable effects remains elusive," said Dr. Iacovitti.

"It is possible that activated glia cells (non-neuronal cells that perform a number of tasks in the brain) may play some role in the response, perhaps by partitioning off the infarcted region and limiting the spread of ischemic brain damage without inducing scar formation."

The research team concluded that there was "little doubt" that the administration of stem cells can modify the cellular and molecular landscape of the brain and blood, limiting damage and protecting the stroke-injured brain.

Source: Thomas Jefferson University
Contact: Ed Federico

Reference:
Changes in Host Blood Factors and Brain Glia Accompanying the Functional Recovery after Systemic Administration of Bone Marrow Stem Cells in Ischemic Stroke Rats
Yang, M., Wei, X., Li, J.. Heinel, L. A., Rosenwasser, R., Iacovitti, L.
Cell Transplant. 19(9):1073-1084; 2010
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Genomic Fault Zones Come and Go

The fragile regions in mammalian genomes thought to play a key role in evolution go through a 'birth and death' process
Wednesday, 01 December 2010

The fragile regions in mammalian genomes that are thought to play a key role in evolution go through a "birth and death" process, according to new bioinformatics research performed at the University of California, San Diego. The new work, published in the journal Genome Biology on November 30, could help researchers identify the current fragile regions in the human genome – information that may reveal how the human genome will evolve in the future.

"The genomic architecture of every species on Earth changes on the evolutionary time scale and humans are not an exception. What will be the next big change in the human genome remains unknown, but our approach could be useful in determining where in the human genome those changes may occur," said Pavel Pevzner, a UC San Diego computer science professor and an author on the new study. Pevzner studies genomes and genome evolution from a computational perspective in the Department of Computer Science and Engineering at the UC San Diego Jacobs School of Engineering.


According to research performed at UC

San Diego, the fragile regions in mammalian

genomes that are thought to play a key role

in evolution go through a "birth and death"

process. The graphic above is from the new

Genome Biology paper in which the findings

are outlined. Credit: Pavel Pevzner/

Max Alekseyev.

The fragile regions of genomes are prone to "genomic earthquakes" that can trigger chromosome rearrangements, disrupt genes, alter gene regulation and otherwise play an important role in genome evolution and the emergence of new species. For example, humans have 23 chromosomes while some other apes have 24 chromosomes, a consequence of a genome rearrangement that fused two chromosomes in our ape ancestor into human chromosome 2.
This work was performed by Pevzner and Max Alekseyev – a computer scientist who recently finished his Ph.D. in the Department of Computer Science and Engineering at the UC San Diego Jacobs School of Engineering. Alekseyev is now a computer science professor at the University of South Carolina.

Turnover Fragile Breakage Model
"The main conclusion of the new paper is that these fragile regions are moving," said Pevzner.

In 2003, Pevzner and UC San Diego mathematics professor Glen Tesler published results claiming that genomes have "fault zones" or genomic regions that are more prone to rearrangements than other regions. Their "Fragile Breakage Model" countered the then largely accepted "Random Breakage Model" – which implies that there are no rearrangement hotspots in mammalian genomes. While the Fragile Breakage Model has been supported by many studies in the last seven years, the precise locations of fragile regions in the human genome remain elusive.

The new work published in Genome Biology offers an update to the Fragile Breakage Model called the "Turnover Fragile Breakage Model." The findings demonstrate that the fragile regions undergo a birth and death process over evolutionary timescales and provide a clue to where the fragile regions in the human genome are located.

Do the Math: Find Fragile Regions
Finding the fragile regions within genomes is akin to looking at a mixed up deck of cards and trying to determine how many times it has been shuffled.


In this graphic, the coloured marks represent

positions of the putative fragile regions in the

human genome. The Turnover Fragile Breakage

Model suggests that these regions likely form

(still active) fragile regions in the human genome.

The graphic above is from the new Genome

Biology paper in which the Turnover Fragile

Breakage Model (TFBM) is presented. According

to the TFBM, the fragile regions in mammalian

genomes that are thought to play a key role in

evolution go through a "birth and death" process.

Credit: Max Alekseyev/Pavel Pevzner.

 Looking at a genome, you may identify breaks, but to say it is a fragile region, you have to know that breaks occurred more than once at the same genomic position.

"We are figuring out which regions underwent multiple genome earthquakes by analyzing the present-day genomes that survived these earthquakes that happened millions of years ago. The notion of rearrangements cannot be applied to a single genome at a single point in time. It's relevant when looking at more than one genome," said Pevzner, explaining the comparative genomics approach they took.

"It was noticed that while fragile regions may be shared across different genomes, most often such shared fragile regions are found in evolutionarily close genomes. This observation led us to a conclusion that fragility of any particular genomic position may appear only for a limited amount of time. The newly proposed Turnover Fragile Breakage Model postulates that fragile regions are subject to a 'birth and death' process and thus have limited lifespan," explained Alekseyev.

The Turnover Fragile Breakage Model suggests that genome rearrangements are more likely to occur at the sites where rearrangements have recently occurred – and that these rearrangement sites change over tens of millions of years. Thus, the best clue to the current locations of fragile regions in the human genome is offered by rearrangements that happened in our closest ancestors – chimpanzee and other primates.

Pevzner is eagerly awaiting sequenced primate genomes from the Genome 10K Project. Sequencing the genomes of 10,000 vertebrate species – including 100s of primates – is bound to provide new insights on human evolutionary history and possibly even the future rearrangements in the human genome.

"The most likely future rearrangements in human genome will happen at the sites that were recently disrupted in primates," said Pevzner.

Work tied to the new Turnover Fragile Breakage Model may also be useful for understanding genome rearrangements at the level of individuals, rather than entire species. In the future, the computer scientists hope to use similar tools to look at the chromosomal rearrangements that occur within the cells of individual cancer patients over and over again in order to develop new cancer diagnostics and drugs.

Source: University of California at San Diego
Contact: Daniel Kane

Reference:
Comparative genomics reveals birth and death of fragile regions in mammalian evolution
Max A Alekseyev, Pavel A Pevzner
Genome Biology 2010, 11:R117 (30 November 2010), doi:10.1186/gb-2010-11-11-r117
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Blood Stem Cells are Influenced by Their Offspring

Blood Stem Cells are Influenced by Their Offspring
Tuesday, 30 November 2010

Dr. Carolyn de Graaf, from the Walter

and Eliza Hall Institute in Melbourne,

Australia, has shown that mature blood

cells can communicate with, and

influence the behaviour of, their stem

cell "parents." Credit: Cameron Wells,

Walter and Eliza Hall Institute.

A new study by researchers at the Walter and Eliza Hall Institute in Melbourne, Australia, has shown that mature blood cells can communicate with, and influence the behaviour of, their stem cell 'parents'.

The discovery of a blood cell 'feedback loop' in the body opens up new avenues of research into diseases caused by stem cell disorders, and the potential for new disease treatments.

Dr Carolyn de Graaf and Professor Doug Hilton from the Molecular Medicine division and Professor Warren Alexander from the Cancer and Haematology division led the research.

Professor Hilton said the findings, published today in the Proceedings of the National Academy of Sciences, revealed a relationship between the blood cells that wasn't known to exist until now.

"We know that blood stem cells give rise to all the mature blood cells, but the standard assumption was that external factors control blood cell production and the two populations exist in isolation," Professor Hilton said.

"This study shows that the mature cells actually communicate back to the stem cells, changing their gene expression and influencing their behaviour."

The researchers found that blood cell disorders can cause disturbances in the feedback loop, with profound effects on the blood stem cells.

The discovery was made while studying the effect of the loss of Myb, a transcription factor that represses platelet production, in animal models.

Dr de Graaf said the loss of the Myb gene meant the animals had very high numbers of platelets in their blood, which caused changes in the signalling pathways that control stem cell maintenance.

"The stem cells, rather than being maintained in a 'resting state' until needed, were being told to continually cycle and produce mature blood cells," Dr de Graaf said.

"The stem cells were eventually exhausted and blood disorders developed because there were not enough stem cells to produce new red and white blood cells."

The team used new generation genomic technologies to identify gene signatures in the blood stem cells that were caused by the defective signalling, these gene signatures could be used in the future to diagnose and help treat disease.

"If we can understand the genes important for stem cell maintenance and blood cell production, then we can start to look at ways of improving transplantation techniques and therapies for blood disorders," Dr de Graaf said.

Professor Hilton said that patients with stem cell failures could also potentially benefit.

"What we would like to do is to determine whether some of these stem cell failures are due to miscommunication between mature blood cells and stem cells, with the possibility of finding new ways to treat these disorders down the track," he said.

Source: Walter and Eliza Hall Institute
Contact: Penny Fannin

Reference:
Regulation of hematopoietic stem cells by their mature progeny
Carolyn A. de Graaf, Maria Kauppi, Tracey Baldwin, Craig D. Hyland, Donald Metcalf, Tracy A. Willson, Marina R. Carpinelli, Gordon K. Smyth, Warren S. Alexander, and Douglas J. Hilton
PNAS November 29, 2010, doi:10.1073/pnas.1016166108
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iPS Cells Undergo Abnormal Chromosomal Changes in Culture

Hebrew University research carries cautionary warning for future stem cell applications
Monday, 22 November 2010

Research work carried out at the Hebrew University of Jerusalem arouses a cautionary warning in the growing field of the development of stem cells as a means for future treatment of patients through replacement of diseased or damaged tissues by using the patient's own stem cells. The research indicates a possible danger of cancerous tissue development in the use of such cells.

Hebrew University stem cell researchers

(from left): Uri Ben-David, professor Nissim

Benvenisty and Dr. Yoav Mayshar. Credit:

The Hebrew University of Jerusalem.

Embryonic stem cells, which are undifferentiated cells, have the potential to develop into all cell types of the adult body, and thousands of researchers all over the world are working to develop the techniques which will make possible their eventual application.

Research in the field has been carried out initially using embryonic stem cells taken from human embryos. However, a breakthrough occurred when, a number of years ago, Japanese scientists succeeded in creating embryonic-like stem cells from mature human cells through an induced "reprogramming" process. This made it possible to obtain stem cells from a patient which can be used in his or her own treatment, thus avoiding the possibility of cell rejection. These cells are called induced pluripotent stem (iPS) cells.

In order for stem cells to be used in the clinic, however, they must be raised in cultures for an extended period. During this period, it has been observed that embryonic stems cells underwent chromosomal changes, which included changes that characterize cancerous tumour growth.

Research that has been carried out in the laboratory headed by Nissim Benvenisty, the Herbert Cohn Professor of Cancer Research at the Silberman Institute of Life Sciences at the Hebrew University of Jerusalem, has now shown that the iPS cells also undergo abnormal chromosomal changes in culture.

Prof. Benvenisty, together with his post-doctoral fellow Yoav Mayshar and his doctoral student Uri Ben-David, developed a new analytical method for determining the genetic structure of the chromosomes in the iPS cells through determining the cellular patterns of gene expression.

Each cell generally bears two copies of each chromosome in the genome. The Hebrew University researchers discovered that, in time, three copies of chromosomes (trisomy) began to appear in the culture, and that the cells with the extra chromosome were able to rapidly overpower the other, normal cells in the culture. Such trisomies are present in abnormal tissue development, including cancerous growths.

The researchers examined over 100 cell lines, which were published by 18 different laboratories around the world, in addition to the iPS cultures raised in their own laboratory, and in this way were able to solidly verify a great number of chromosomal changes in cell lines that until now were considered normal.

In an article published in Cell Stem Cell journal, the Hebrew University researchers have reported their discovery. They noted that the chromosomal changes were not incidental, but rather appeared systematically on chromosome 12 and involved up-regulation of specific genes, which reside on that chromosome. This discovery is liable to hinder progress on the development of the use of human iPS cells in future therapy because of the tumourigenic danger involved.

"Our findings show that human iPS cells are not stable in culture, as was previously thought, and require reassessment of the chromosomal structure of these cells," said Prof. Benvenisty.

"Also, our work shows for the first time the gene expression changes that accompany these chromosomal aberrations found in the culture, paving the way for our beginning to understand the mechanism by which these changes occur.”

"The chromosomal changes in these iPS cells require everyone to exercise great care in continuing to work with them, since these changes apparently will influence the differentiation potential and the tumourigenic risk of these cells."

According to Prof. Benvenisty:

"The method we have developed for identifying chromosomal changes through gene expression is likely to serve also in other work involving analysis of different kinds of cells, including cancer cells. It is relatively simple to use and enables one to observe the changes without having to directly analyze the DNA of the cells."

The discovery is patented by Yissum, the Technology Transfer Company of the Hebrew University of Jerusalem, which is currently searching for commercial partners for further research and development.

Source: The Hebrew University of Jerusalem
Contact: Jerry Barach

Reference:
Identification and Classification of Chromosomal Aberrations in Human Induced Pluripotent Stem Cells
Yoav Mayshar, Uri Ben-David, Neta Lavon, Juan-Carlos Biancotti, Benjamin Yakir, Amander T. Clark, Kathrin Plath, William E. Lowry, Nissim Benvenisty
Cell Stem Cell, Volume 7, Issue 4, 521-531, 8 October 2010, 10.1016/j.stem.2010.07.017
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Fibrodysplasia Ossificans Progressiva: A Rare Disease Reveals New Path for Creating Stem Cells

As debilitating as disease can be, sometimes it acts as a teacher
Sunday, 21 November 2010

Researchers at Harvard Medical School and the Harvard School of Dental Medicine have found that by mimicking a rare genetic disorder in a dish, they can rewind the internal clock of a mature cell and drive it back into an adult stem-cell stage. This new "stem cell" can then branch out into a variety of differentiated cell types, both in culture and in animal models.

"This certainly has implications for personalized medicine, especially in the area of tissue engineering," says Bjorn Olsen, the Hersey Professor of Cell Biology at Harvard Medical School and Dean of Research at the Harvard School of Dental Medicine.

These findings appear November 21, online in Nature Medicine.

Fibrodysplasia Ossificans Progressiva (FOP), which affect fewer than 1,000 people worldwide, is a horrific genetic disease in which acute inflammation causes soft tissue to morph into cartilage and bone. Over the course of a few decades, patients gradually become thoroughly ossified, as though parts of their body have turned to stone. There is no cure or treatment.

Damian Medici, an instructor of medicine at Harvard Medical School and Beth Israel Deaconess Medical Center, found that, unlike normal skeletal tissue, the pathological cartilage and bone cells from these patients contained biomarkers specific for endothelial cells — cells that line the interior of blood vessels. This led him to question whether or not the cartilage and bone growing in soft tissues of FOP patients had an endothelial origin.

Medici and his colleagues transferred the mutated gene that causes FOP into normal endothelial cells. Unexpectedly, the endothelial cells converted into a cell type nearly identical to what are called mesenchymal stem cells, or adult stem cells that can differentiate into bone, cartilage, muscle, fat, and even nerve cells. (Embryonic stem cells have the potential to become any type of cell, whereas adult stem cells are limited.)

What's more, through further experiments the researchers found that instead of using the mutated gene to induce the transformation, they could incubate endothelial cells with either one of two specific proteins (growth factors TGF-beta2 and BMP4) whose cellular interactions mimicked the effects of the mutated gene, providing a more efficient way to reprogram the cells.

Afterwards, Medici was able to take these reprogrammed cells and, in both culture dishes and animal models, coax them into developing into a group of related tissue types.

"It's important to clarify that these new cells are not exactly the same as mesenchymal stem cells from bone marrow," says Medici.

"There are some important differences. However, they appear to have all the potential and plasticity of mesenchymal stem cells."

"The power of this system is that we are simply repeating and honing a process that occurs in nature," says Olsen.

"In that sense, it's less artificial than other current methods for reprogramming cells."

According to study collaborator Frederick Kaplan, Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine at the University of Pennsylvania School of Medicine and a world expert on FOP:

"While we want to use this knowledge to stop the renegade bone formation of FOP, these new findings provide the first glimpse of how to recruit and harness the process to build extra bone for those who desperately need it."

Medici and Olsen echo this, stating that the most direct application for these findings is the field of tissue engineering and personalized medicine. It is conceivable that transplant patients may one day have some of their own endothelial cells extracted, reprogrammed, and then grown into the desired tissue type for implantation. Host rejection would not be an issue.

Source: Harvard Medical School
Contact: David Cameron

Reference:
Conversion of vascular endothelial cells into multipotent stem-like cells
Damian Medici, Eileen M Shore, Vitali Y Lounev, Frederick S Kaplan, Raghu Kalluri & Bjorn R Olsen
Nature Medicine, early online publication, Nov 21, 2010, doi:10.1038/nm.2252
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Origin of Cells Associated with Nerve Repair Discovered

Findings could one day lead to improved treatment of spinal cord injuries
Tuesday, 16 November 2010

Scientists have discovered the origin of a unique type of cell known for its ability to support regeneration in the central nervous system. Their findings, published this week in the journal Proceedings of the National Academy of Sciences USA (PNAS), raise the possibility of obtaining a more reliable source of these cells for use in cell transplantation therapy for spinal cord injuries.

Olfactory Nerve. The origin of cells

associated with nerve repair has been

discovered. The findings could one

day lead to improved treatment of

spinal cord injuries.

Credit: Dr. Perrine Barraud.

Olfactory ensheathing cells (OECs), as the name suggests, ensheath and protect the nerve fibres in the olfactory nerve, which transmit olfactory (smell) information to the brain from receptor cells sitting in the lining of the nose. Excitingly, OECs can promote nerve repair when transplanted into the damaged spinal cord. They can also be grown in dishes from pieces of nasal lining but, unfortunately, in such small quantities that this may not be a viable option for use in treatments.

Dr Clare Baker, from the Department of Physiology, Development and Neuroscience at the University of Cambridge, lead author of the study, said: "In theory, one should be able to purify OECs from a patient's nose and transplant them into the damaged spinal cord to promote nerve repair, without any fear of graft rejection.”

"Unfortunately, there aren't very many OECs in the nasal lining, and this tissue also contains other peripheral nerve fibres, ensheathed by cells that look very similar to OECs but which are less effective at promoting spinal cord repair. As a result, it has thus far proven difficult to purify sufficiently large numbers of OECs from the nasal lining for effective use in cell transplantation therapy."

For the last 25 years, OECs have been thought to be formed by the nasal lining itself. The new research, however, reveals a different origin for OECs that may enable scientists in the future to produce them in large quantities from adult stem cells.

The researchers, funded by the Wellcome Trust and the Isaac Newton Trust, have discovered that, like all other cells ensheathing peripheral nerve fibres, OECs are actually derived from a group of embryonic stem cells called "neural crest cells". Neural crest stem cells persist in adult skin and hair follicles, and other researchers have already shown that it is possible to isolate these stem cells and grow them in the lab.

"The next step is to work out how to turn these stem cells into OECs. To do this, we need to investigate how this process happens normally in the developing embryo," Dr Baker said.


Cross-section of the embryonic chicken

olfactory bulb showing neural

crest-derived olfactory ensheathing

cells (green). (Blue, axons; red,

low-affinity neurotrophin receptor.)

Credit: Dr. Perrine Barraud.

 "It is important to note that it will take many years for our research to have any impact on therapy for people with damaged spinal cords. However, we are hopeful that our discovery provides a fresh starting point for new research into ways of purifying large numbers of these cells for use in treatments," Dr Baker continued.

In order to determine the origin of OECs, the scientists tagged embryonic neural crest cells with 'green fluorescent protein' (GFP), so that only neural crest cells and their descendants glowed green under ultraviolet light. They did this in chicken embryos by transplanting GFP-labelled neural crest cells into unlabelled host embryos; they also looked at mouse embryos in which, through a genetic trick, the only cells that expressed GFP were neural crest cells.

They were then able to follow what happened to neural crest cells and their descendants as the olfactory nerve developed. By analysing thin sections of these embryos under the microscope, they were able to see that lots of green neural crest-derived cells were associated with the developing olfactory nerve fibres. These green cells expressed molecular markers characteristic of OECs, and crucially, they ensheathed bundles of the olfactory nerve fibres, i.e., they were indeed olfactory ensheathing cells.

Source: University of Cambridge
Contact: Contact: Genevieve Maul

Reference:
Neural crest origin of olfactory ensheathing glia
Perrine Barraud, Anastasia A. Seferiadis, Luke D. Tyson, Maarten F. Zwart, Heather L. Szabo-Rogers, Christiana Ruhrberg, Karen J. Liu, and Clare V. H. Baker
PNAS, 15 November 2010, doi:10.1073/pnas.1012248107
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The Next Generation of Bioethics

Pharmaceutical company bioethics? Public health bioethics? Regenerative medicine bioethics?
Tuesday, 16 November 2010

To celebrate 40 years of pioneering bioethics publication, the Hastings Center Report, the world's first bioethics journal, looked to the future, asking young scholars to write about what the next generation of bioethicists should take up. Out of 195 compelling submissions, four of the best essays were selected for publication in the November-December issue.

Three of the essays envision bioethics forging into new areas, such as the ethical obligations of pharmaceutical industry, questions around the emerging field of regenerative medicine, and public health. Another proposes broadening the approach to dying, a foundational issue of bioethics. An undergraduate, a graduate student, an early career professor who is also a practicing physician, and a Belgian researcher are the authors.

A second set of essays, focusing on bioethics methodology, will be published in 2011.

"Picking the essays we wanted to publish turned out to be surprisingly difficult," said Gregory E. Kaebnick, editor of the Report.

"We not only wanted good essays; we also wanted to represent the range of topics that people had written about and the range of people writing them up. But it's a good problem to have, of course, and it gives us great confidence about the future of bioethics."

• "Establishing a 'Duty of Care' for Pharmaceutical Companies" calls upon bioethics to focus on the ethical responsibilities that drug companies have to the people they supply. Just as doctors, nurses, and other clinicians have a duty to give competent care to patients, drug companies should "place the good of the populace over the good of the stockholders," writes Remy Miller, a junior at Transylvania University who plans to pursue degrees in medicine and bioethics. She suggests that companies start by adhering to the bioethics principles of justice, beneficence, and autonomy.

• "A Role for Moral Vision in Public Health" recommends that bioethics join forces with public health to develop a moral vision to inform policy and practice. While public health interventions were once accomplished through improvements in infrastructure, such as better sanitation, "today's public health goals often require changing individual behaviour, often through state action," writes Daniel B. Rubin, a doctoral student in public health and a law student at the University of Michigan Rubin.
  
  "Such interventions raise substantive questions about the extent to which government . . . should intrude on individual bodies to improve the health of the body politic."

• "The Art of Dying Well" argues that one of the most pressing bioethical concerns is to create a framework for teaching an aging population to prepare for death and support one another through the dying process. Even though bioethics has always debated end-of-life issues, Lydia Dugdale, MD, an assistant professor at Yale School of Medicine, says, "American society remains ill equipped for the experience of dying." Among the reasons are advances in medical technology that have "obscured the distinction between death and life," physicians' difficulty in discussing end-of-life issues with their patients, and the secularization of Western culture, which has marginalized the role of religion in preparing people for death. Bioethics can help, Dugdale says, by working to create "a modern version of the Ars moriendi, or Art of Dying, which expressed the societal and ecclesiastical response in the Middle Ages to the widespread death caused by the plague."

• "The Challenge of Regenerative Medicine" outlines the ethical questions raised by the effort under way in all medical fields to regenerate human tissue as a means of treating degenerative diseases.
  "In the future, regenerative medicine may therefore touch most of our lives," writes Leen Trommelmans, PhD, who teaches ethics and philosophy to nursing, midwifery, and facility management students at KaHO Sint-Lieven in Belgium and does research at the Centre for Biomedical Ethics and Law at Catholic University in Leuven. So far, bioethics has focused on the use of stem cells in regenerative medicine, but other questions remain unexamined, including the rights of donors whose cells are used, the availability of costly regenerative treatments to those who cannot afford them, and the prospects of using regenerative medicine for enhancement, such as the prevention of aging.

Source: The Hastings Center
Contact: Michael Turton
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A New Read on DNA Sequencing

A New Read on DNA Sequencing
Tuesday, 16 November 2010

The twisting, ladder-like form of the DNA molecule — the architectural floor plan of life — contains a universe of information critical to human health. Enormous effort has been invested in deciphering the genetic code, including, most famously, the Human Genome Project. Nevertheless, the process of reading some three-billion nucleotide "letters" to reveal an individual's full genome remains a costly and complex undertaking.

Stuart Lindsay is a biohysicist at the Biodesign

Institute at Arizona State University. Credit: The

Biodesign Institute at Arizona State University.

Now biophysicist Stuart Lindsay, of the Biodesign Institute at Arizona State University, has demonstrated a technique that may lead to rapid, low cost reading of whole genomes, through recognition of the basic chemical units — the nucleotide bases that make up the DNA double helix. An affordable technique for DNA sequencing would be a tremendous advance for medicine, allowing routine clinical genomic screening for diagnostic purposes; the design of a new generation of custom-fit pharmaceuticals; and even genomic tinkering to enhance cellular resistance to viral or bacterial infection.

Lindsay is an ASU Regents' Professor and Carson Presidential Chair of Physics and Chemistry as well as director of the Biodesign Institute's Center for Single Molecule Biophysics. His group's research appears in the current issue of the journal Nature Nanotechnology.

Lindsay's technique for reading the DNA code relies on a fundamental property of matter known as quantum tunnelling, which operates at the subatomic scale. According to quantum theory, elementary particles like electrons can do some very strange and counter-intuitive things, in defiance of classical laws of physics. Such sub-atomic, quantum entities possess both a particle and a wave-like nature. Part of the consequence of this is that an electron has some probability of moving from one side of a barrier to the other, regardless of the height or width of such a barrier.

Remarkably, an electron can accomplish this feat, even when the potential energy of the barrier exceeds the kinetic energy of the particle. Such behaviour is known as quantum tunnelling, and the flow of electrons is a tunnelling current. Tunnelling is confined to small distances — so small that a tunnel junction should be able to read one DNA base (there are four of them in the genetic code, A, T, C and G) at a time without interference from flanking bases. But the same sensitivity to distance means that vibrations of the DNA, or intervening water molecules, ruin the tunnelling signal. So the Lindsay group has developed "recognition molecules" that "grab hold" of each base in turn, clutching the base against the electrodes that read out the signal. They call this new method "recognition tunnelling."

The current paper in Nature Nanotechnology shows that single bases inside a DNA chain can indeed be read with tunnelling, without interference from neighbouring bases. Each base generates a distinct electronic signal, current spikes of a particular size and frequency that serve to identify each base. Surprisingly, the technique even recognizes a small chemical change that nature sometimes uses to fine-tune the expression of genes, the so called "epigenetic" code. While an individual's genetic code is the same in every cell, the epigenetic code is tissue and cell specific and unlike the genome itself, the epigenome can respond to environmental changes during an individual's life.

To read longer lengths of DNA, Lindsay's group is working to couple the tunnelling readout to a nanopore — a tiny hole through which DNA is dragged, one base at a time, by an electric field. The paper in Nature Nanotechnology has something to say about this problem too.

"It has always been believed that the problem with passing DNA through a nanopore is that it flies through so quickly that there is no time to read the sequence" Lindsay says. Surprisingly, the tunnelling signals reported in the Nature Nanotechnology paper last for a long time — nearly a second per base read.

To test this result, Lindsay teamed with a colleague, Robert Ros, to measure how hard one has to pull to break the complex of a DNA base plus the recognition molecules. They did this with an atomic force microscope.

"These measurements confirmed the long lifetime of the complex, and also showed that the reading time could be speeded up at will by the application of a small additional pulling force" says Ros.

"Thus the stage is set for combining tunnelling reads with a device that passes DNA through a nanopore," says Lindsay.

Sequencing through recognition tunnelling, if proven successful for whole genome reading, could represent a substantial savings in cost and hopefully, in time as well. Existing methods of DNA sequencing typically rely on cutting the full molecule into thousands of component bits, snipping apart the ladder of complementary bases and reading these fragments. Later, the pieces must be meticulously re-assembled, with the aid of massive computing power.

"Direct readout of the epigenetic code holds the key to understanding why cells in different tissues are different, despite having the same genome" Lindsay adds, a reference to the new ability to read epigenetic modifications with tunnelling.

Lindsay stresses much work remains to be done before the application of sequencing by recognition can become a clinical reality.

"Right now, we can only read two or three bases as the tunnelling probe drifts over them, and some bases are more accurately identified than others," he says. However, the group expects this to improve as future generations of recognition molecules are synthesized.

"The basic physics is now demonstrated" Lindsay says, adding "perhaps it will soon be possible to incorporate these principles into mass produced computer chips."

The day of the "genome on a lap-top" might be coming sooner than previously thought possible.

Source: Arizona State University
Contact: Joseph Caspermeyer
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ZenMaster

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For more on stem cells and cloning, go to CellNEWS at
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