Diabetes Reversed in Mice Using stem Cells

Canadian scientists were able to reverse diabetes in mice with a human stem cell transplant, igniting hopes for a cure for the widespread disease, caused by the failure of the pancreas to produce enough insulin to stabilize blood sugar levels in humans.

A paper outlining the work, led by Timothy Kieffer of the University of British Columbia and conducted in partnership with New Jersey-based company BetaLogics, appeared in the journal Diabetes on Tuesday.

Diabetic mice were weaned off of insulin after receiving the pancreatic stem cell transplant, which restarted the cycle in which insulin production rises or falls based on blood sugar levels.  Three to four months later, the mice could maintain healthy blood sugar levels even after being fed a lot of sugar.

"We are very excited by these findings, but additional research is needed before this approach can be tested clinically in humans," Kieffer said in a statement on Tuesday.

The researchers cautioned that their study used mice that had a suppressed immune system, the better to prevent rejection of the transplanted cells.

"We now need to identify a suitable way of protecting the cells from immune attack so that the transplant can ultimately be performed in the absence of any immunosuppression," Kieffer said.

In 2009, a different team of researchers led by scientists from the University of Sao Paulo in Brazil and Northwestern University reported in the Journal of the American Medical Association that they were able to successfully reverse type 1 diabetes by injecting 8 patients with some of their own stem cells.

Some studies have shown that this kind of stem cell transplantation is only a temporary fix - after anywhere between six months to three years, the insulin-producing cells are again attacked by the patient's immune system.

SOURCE: Rezania et al. "Maturation of Human Embryonic Stem Cell-Derived Pancreatic Progenitors into Functional Islets Capable of Treating Pre-existing Diabetes in Mice." Diabetes 27 June 2012.

Gene Therapy Researchers develop correction for blindness

A new gene therapy method developed by University of Florida researchers has the potential to treat a common form of blindness that strikes both youngsters and adults. 

The technique works by replacing a malfunctioning gene in the eye with a normal working copy that supplies a protein necessary for light-sensitive cells in the eye to function. The findings are published today (Monday, Jan. 23) in the Proceedings of the National Academy of Sciences online.

Several complex and costly steps remain before the gene therapy technique can be used in humans, but once at that stage, it has great potential to change lives.

"Imagine that you can't see or can just barely see, and that could be changed to function at some levels so that you could read, navigate, maybe even drive — it would change your life considerably," said study co-author William W. Hauswirth, Ph.D., the Rybaczki-Bullard professor of ophthalmology in the UF College of Medicine and a professor and eminent scholar in department of molecular genetics and microbiology and the UF Genetics Institute.

"Providing the gene that's missing is one of the ultimate ways of treating disease and restoring significant visual function."

The researchers tackled a condition called X-linked retinitis pigmentosa, a genetic defect that is passed from mothers to sons. Girls carry the trait, but do not have the kind of vision loss seen among boys.

About 100,000 people in the U.S. have a form of retinitis pigmentosa, which is characterized by initial loss of peripheral vision and night vision, which eventually progresses to tunnel vision, then blindness.

In some cases, loss of sight coincides with the appearance of dark-colored areas on the usually orange-coloured retina.

The UF researchers previously had success pioneering the use of gene therapy in clinical trials to reverse a form of blindness known as Leber's congenital amaurosis. About 5 percent of people who have retinitis pigmentosa have this form, which affects the eye's inner lining.

"That was a great advance, which showed that gene therapy is safe and lasts for years in humans, but this new study has the potential for a bigger impact, because it is treating a form of the disease that affects many more people," said John G. Flannery, Ph.D., a professor of neurobiology at the University of California, Berkeley who is an expert in the design of viruses for delivering replacement genes. Flannery was not involved in the current study.

Scientists Nearer to Finding Solution for Age-Related Problems

A team of scientists from the Salk Institute, Ecole Polytechnique Federale De Lausanne (EPFL) and the University of Lausanne have created super strong mice by controlling its natural muscle growth.

This invention will help solve genetic muscular degeneration and other age-related problems.

The scientists changed the activity of certain genes by tweaking a genome regulator called NCOR1.

They suppressed a thyroid hormone which regulates growth in most mammals and created mice that were twice as strong as normal.

According to Johan Auwerx, the lead author from Ecole Polytechnique Fédérale de Lausanne (EPFL), "This could be used to combat muscle weakness in the elderly, which leads to falls and contributes to hospitalizations."

"In addition, we think that this could be used as a basis for developing a treatment for genetic muscular dystrophy."

"There are now ways to develop drugs for people who are unable to exercise due to obesity or other health complications, such as diabetes, immobility and frailty," said Ronald M Evans, a professor at the Salk Institute.

"We can now engineer specific gene networks in muscle to give the benefits of exercise to sedentary mice."

It may be recalled that cell biology expert Norman S Wolf dealt with muscular degeneration in his book 'Comparative Biology on Aging.' Wolf had argued that by restricting calories and doing regular exercise, humans could slow aging process and reduce muscular degeneration.

In the present case, the mice, which underwent genetic mutation, became true marathoners, running faster and longer before showing any signs of fatigue. They were able to cover almost twice the distance compared to the normal mice. They also exhibited better tolerance to cold.

Unlike "genetic accelerators," the new work shows that suppressing an inhibitor is a new way to build muscle, which in this experiment confirmed that the muscle fibers of the modified mice are denser, more massive, and the cells in the tissue contain higher numbers of mitochondria-cellular organelles that deliver energy to the muscles.

Auwerx said that if these results were confirmed in humans, the experiment would attract attention especially from the athletes and medical experts.

The Salk Institute conducts biological research on molecular biology, genetics, neuroscience and plant biology. Five scientists from here have won Nobel Prizes.

Recently, the institute discovered a safer way to cure asthma, allergies and arthritis. It has also done research on a drug that reduces baldness.

The EPFL (Switzerland) focuses on education, research, technology and has conducted several researches on subjects like microbiology and robotics.

$1,000 dollar genome by 2012

By 2012, sequencing the human genome will be done in two hours and will cost $1,000, Ion Torrent’s Jonathan Rothberg said at a recent conference.

As companies race to crack the $1,000 genome, contending DNA machines in the marketplace suggest an end is near.

Ion Torrent’s DNA machine reads sequences based on chemicals and electronic technology.

The technology is called the Personal Genome Machine and it has been used to determine the source of E. coli or mutations present in the genomes of patients’ cancers.

The Ion Personal Genome Machine, which is about the size of a desktop computer, uses chemistry and semiconductor technology to produce readouts of genetic information in a couple of hours.

Christopher Mims wrote in Technology Review:

“Right now don’t have very many correlations between those 3 billion base pairs [of the human genome] and outcomes or medicines,” says Rothberg.

He predicts it will take at least 10 years of clinical experiments with full genome sequencing to get us to the point where we can begin to unlock its value.

“And it will be 20 years before we understand cancer at same level as HIV and can come up with combinations of medicine [tailored] for each individual,” says Rothberg.

Illuminating the 'Dark Matter' of the Genome: Vast hidden network regulates gene expression in cancer

Researchers have uncovered a vast new gene regulatory network in mammalian cells that could explain genetic variability in cancer and other diseases.

(Credit: Image courtesy of Columbia University Medical Center)

Researchers at Columbia University Medical Center (CUMC) and two other institutions have uncovered a vast new gene regulatory network in mammalian cells that could explain genetic variability in cancer and other diseases.

The studies appear in the online edition of Cell.

"The discovery of this regulatory network fills in a missing piece in the puzzle of cell regulation and allows us to identify genes never before associated with a particular type of tumour or disease," said Andrea Califano, PhD, professor of systems biology, director of the Columbia Initiative in Systems Biology, and senior author of the CUMC research team.

For decades, scientists have thought that the primary role of messenger RNA (mRNA) is to shuttle information from the DNA to the ribosomes, the sites of protein synthesis.

However, these new studies suggest that the mRNA of one gene can control, and be controlled by, the mRNA of other genes via a large pool of microRNA molecules, with dozens to hundreds of genes working together in complex self-regulating sub-networks.

The findings have the potential to broaden investigations into how tumors develop and grow, who is at risk for cancer, and how to identify and inactivate key molecules that encourage the growth and spread of cancer.

For example, in the case of the phosphatase and tensin homolog gene (PTEN), a major tumour suppressor, deletions of its mRNA network regulators in patients appear to be as damaging as mutations of the gene itself in several types of cancer, the studies show.

The newly identified regulatory network (called the mPR network by the CUMC investigators) allows mRNAs to communicate through small bits of RNA called microRNAs.

Researchers first realized about a decade ago that microRNAs, by binding to complementary genetic sequences on mRNAs, can prevent those mRNAs from making proteins.

Turning this concept on end, the new studies reveal that mRNAs actually use microRNAs to influence the expression of other genes.

When two genes share a set of microRNA regulators, changes in expression of one gene affects the other. If, for instance, one of those genes is highly expressed, the increase in its mRNA molecules will "sponge up" more of the available microRNAs.

As a result, fewer microRNA molecules will be available to bind and repress the other gene's mRNAs, leading to a corresponding increase in expression. Although such an effect had been previously elucidated, the range and relevance of this kind of interaction had not been characterised.

"It turns out that this type of microRNA-mediated regulation is commonplace in the cell, and thousands of genes are regulating one another through hundreds of thousands of microRNA-mediated interactions," says Pavel Sumazin, PhD, research scientist in systems biology and a first author of the CUMC paper.

"This is similar in size and effect to other regulatory networks, such as transcriptional regulatory networks, where target genes are regulated by transcription factors."

In the CUMC study, Dr. Sumazin and his colleagues analyzed glioblastoma mRNA and microRNA expression data from the Cancer Genome Atlas, a public database, uncovering a regulatory layer comprising more than 248,000 microRNA-mediated interactions.

Looking specifically at the tumour suppressor gene PTEN, the researchers found that it is part of a sub-network of more than 500 genes.

Of these genes, 13 are frequently deleted in glioblastoma and seem to work together through microRNAs to stop PTEN activity -- achieving the same result as if the tumors had inactivating mutations or deletions of PTEN itself.

Read More on this article at Science Daily

Gene therapy clears HIV from human body

A person with HIV who didn't take antiretroviral drugs for three months remained free of the virus, thanks to a groundbreaking gene therapy. The success raises the prospect of keeping HIV in check permanently without antiretrovirals.

The gene therapy works by locking the virus out of the CD4 white blood cells it normally infects. Of six people with HIV given the treatment, one cleared the virus completely and another two saw 10-fold drops in circulating virus.

"We're over the moon to have seen that in this small phase I study," says Jeff Nichol, executive vice president for research at Sangamo BioSciences, the company in Richmond, California, that is developing the treatment. "Having one virus-free patient and 10-fold reductions in another two is amazing."

Most importantly, analysis of data from the six patients, and from four others in a separate trial, revealed the secret of the more successful outcomes, paving the way for the therapy to work better in future.

Zinc fingers

To deliver the treatment, doctors remove blood from the patient and isolate CD4 and other white blood cells. Specialised molecular "scissors" called zinc finger proteins enter the cells and sabotage a gene called CCR5, which makes a protein that helps HIV to enter cells. It is unclear what role CCR5 plays normally, although researchers know that cells can survive without it – and will remain uninfected by HIV.

These cells are then returned to the patient in the hope that they will multiply and provide a permanent source of cells immune to HIV, potentially locking out HIV completely. The link between CCR5 and HIV was first suggested in 1996. 

The concept was first tested inadvertently in Germany in 2006, when a person with leukaemia who was also HIV positive received a bone marrow transplant that happened to come from someone whose blood cells couldn't make CCR5 proteins. The patient was HIV-free by 2008.

Most people have two working copies of CCR5, one from each parent. The patient who did best in the Sangamo trial already had one defective copy, which is thought to explain why the therapy worked better in him than in the others. 

Further analysis showed that after the treatment he had twice as many cells in which both copies of the CCR5 gene had been sabotaged than any other trial participant.

The two patients who saw 10-fold reductions in circulating virus also had more doubly sabotaged cells than the three who didn't respond as well.

Double sabotage

The secret to making the treatment work best, Sangamo says, is therefore to eliminate both genes in as many cells as possible. If only one is sabotaged, cells can still make enough CCR5 protein to allow the virus to invade. In doubly sabotaged, or "bi-allelic" cells, there is no way in.

"The way forward is to get as many bi-allelic cells as possible back into the patient," says Nichol.

In the light of the findings, Sangamo has plans to try depleting the patient's native blood system with drugs before returning the altered cells. 

Depletion causes blood cells to multiply faster than normal to compensate for the shortage, resulting in a more rapid expansion of the numbers of HIV-resistant bi-allelic cells.

Nichol's colleagues presented the results on Sunday at the Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago.

Researchers develop mouse genetic blueprint

An overview of variants called from 17 mouse genomes relative to the reference. 

Four wild strains (CAST/EiJ, WSB/EiJ, PWK/PhJ and SPRET/EiJ) are shown in a circle with tracks indicating the relative density of single nucleotide polymophisms (SNPs), structural variants (SVs) and uncallable regions.

Transposable element insertions (TEs), a subset of the SV calls, are shown as a separate track. Corresponding tracks are shown for each of the 13 classical laboratory strains to the right of the circle.

Links crossing the circle indicate regions on the reference where the wild strain is closest to the reference. (Credit: From Keane et al. Mouse genomic variation and its effect on phenotypes and gene regulation.

Nature, 2011; 477 (7364): 289 DOI: 10.1038/nature10413)

Researchers have developed a valuable mouse genetic blueprint that will accelerate future research and understanding of human genetics.

The international team, led by researchers at the Wellcome Trust Sanger Institute and the University of Oxford, explains in two papers published in Nature on Sept. 14, 2011 how they decoded and compared the genome sequence of 17 mouse strains.

In creating this unique resource, the biggest catalogue for any vertebrate model organism, the team found an astonishing 56.7 million unique sites of variation (known as SNPs) between the strains, in addition to other more complex differences.

Among these they identified sequence differences associated with over 700 biological differences, including markers for diseases such as diabetes and heart disease, so linking genes with medically important individual differences.

The catalogue, which was funded principally by the Medical Research Council and the Wellcome Trust, can be used by researchers to understand the genetic basis of individual variation, and to ask fundamental questions about how genes function and make us more or less likely to have particular diseases.

Inbred strains of mice are invaluable sources of genetic information. Every animal within each inbred strain is essentially genetically identical, but each strain is different from the others both in their genes and across a huge range of medically and biologically important characteristics.

"We are living in an era where we have thousands of human genomes at our finger tips," says Dr Adams, from the Wellcome Trust Sanger Institute, who led the project.

"The mouse, and the genome sequences we have generated, will play a critical role in understanding of how genetic variation contributes to disease and will lead us towards new therapies."

As a direct result of the project, researchers will place less reliance on breeding mice to find mutations; using this resource they will be able to find mutations much more quickly by the click of a digital mouse to search for the data on their computer.

These strains of mice are used in every corner of biology to further our understanding of human disease, and there is much more to discover. With the variants to hand, the challenge moves to understanding the biological consequences.

Brocolli's Cancer fighting properties

Researchers already knew that a chemical found in broccoli, cauliflower, and related vegetables, called isothiocyanate, appeared to stop the growth of cancer by causing apoptosis, or cell death, in cancer cells. But researchers didn't know why.

Recent research at Georgetown University found that isothiocyanate sticks to a defective protein found in cancerous cells.

The broccoli-born chemical only binds to the protein when it is defective. The normal version is left alone.

Production of the protein in question is controlled by the gene p53. It normally helps stop a cell from replicating uncontrollably. But when gene p53 is mutated, the protein comes out defective.

Not only that, cells with mutated p53 genes are also more resistant to chemical cancer treatments.
P53 mutations occur in half of all human cancers, including lung, breast and colon.

Eating your broccoli may help reduce cancer risks because the presence of isothiocyanate was observed to increase the death rate of cancer cells with the p53 mutation.

Researchers found that after the cauliflower chemical, isothiocyanate, bound to the defective p53 protein, breast cancer cells died. One reason for this may be that the mutated gene also makes the cancerous cells vulnerable to toxic effects from isothiocyanate that normal cells are resistant to.

Gene responsible for severe Osteoporosis disorder discovered

Scientists have identified a single mutated gene that causes Hajdu-Cheney syndrome, a disorder of the bones causing progressive bone loss and osteoporosis (fragile bones).

The study, published in Nature Genetics today, gives vital insight into possible causes of osteoporosis and highlights the gene as a potential target for treating the condition.

There are only 50 reported cases of Hajdu-Cheney syndrome (HCS), of which severe osteoporosis is a main feature. Osteoporosis is a condition leading to reduction in bone strength and susceptibility to fractures.

It is the most common bone disease, with one in two women and one in five men over 50 in the UK fracturing a bone because of the condition. This represents a major public health problem yet, until this study, possible genetic causes of osteoporosis were poorly understood.

The team of scientists, led by the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre (BRC) at King’s College London and Guy’s and St Thomas’, set out to investigate the genetic cause of HCS in order to detect clues to the role genes might play in triggering osteoporosis.

Using a cutting edge technique for identifying disease-causing genes, known as exome sequencing, the team were able to identify NOTCH2 as the causative gene using DNA from just three unrelated HCS patients.

The team then confirmed their findings in an additional 12 affected families, 11 of whom had an alteration in the identical portion of the same gene.

Professor Richard Trembath, Head of King’s College London’s Division of Genetics and Molecular Medicine and Medicine Director of the NIHR BRC, said: “Up until now, we knew very little about the genetic mechanisms of severe bone disease but these findings add to our understanding of the uncommon condition of HCS and provide an important basis to develop future studies in more common forms of osteoporosis, including the development of potential new therapies.”

UK Boy has world's rarest Genetic Disorder

Every little boy is unique to their parents but six year old Mackenzie Fox-Byrne is also special to the scientific world. He is thought to have the world's rarest genetic disorder because he is the only person on earth known to suffer from it.

Mackenzie, whose condition has given him learning difficulties and left him unable to speak, is the result of a gene mutation doctors have never seen before.

his development appeared to be behind that of her other children, Kamara, 14, and Katie, 12.

At three months old, he was still not lifting his head from his cot, he found it difficult to hold down food and had trouble sleeping.

Doctors initially feared he might have the muscle-wasting disease Muscular Dystrophy, but instead tests results showed a much more bewildering picture.

Mrs Fox-Byrne, 40, of Market Drayton, Shropshire, said: "They knew it was unique and told me excitedly that they had found something rare that no one else has.

"Unfortunately, that was all they could tell me. They couldn't tell me how he is going to progress or whether he might fall ill in the future.

"No one else on earth has ever had this condition."

Mackenzie's test results showed he had a triplication of a small region on the long arm of his X-chromosome.

At the moment the little boy cannot speak, has low muscle tone, is still in nappies and has no sense of danger.

He also has learning difficulties which mean he has the mental age of a two-year-old and goes to a special school in Shrewsbury.

Mrs Fox-Byrne, who lives with her partner Andy, 47, said: "It's quite terrifying to be told he is the only person in the world to have this condition.

"Although we worry about what might happen to him in the future, I just try to put it out of my mind. You could go crazy thinking about it."

Karen Temple, professor of medical genetics at Wessex Clinical Genetics Service confirmed Mackenzie was a totally unique case.

She said: "We have to learn what we can from the little boy as he grows up.

"The problem with Mackenzie isn't that he has got genes missing – as is the case sometimes – it's that he has got extra parts.

"This little boy has had this chromosome problem since he was conceived, we can learn from how he is now and that helps us to predict his future."

Study details machinery of immune protection against colitis and inflammatory diseases

Study details machinery of immune protection against colitis and inflammatory diseases ScienceBlog.com

Scientists report a protein made by a gene already associated with a handful of human inflammatory immune diseases plays a pivotal role in protecting the intestinal tract from colitis.

St. Jude Children's Research Hospital investigators led the research, which points to possible new strategies for combating colitis. Colitis is a chronic inflammatory disease associated with colon damage, resulting in abdominal pain, bleeding and other symptoms.

The work also expands the link between the Nlrp3 protein and Crohn's disease, said Thirumala-Devi Kanneganti, Ph.D., assistant member of the St. Jude Department of Immunology and the paper's senior author.

Md. Hasan Zaki, Ph.D., a St. Jude postdoctoral fellow, is first author of the study, which appears in the March 18 online edition of the journal Immunity.

Researchers demonstrated that in a mouse model of colitis, Nlrp3 plays a pivotal role in keeping the intestinal tract intact, thus preventing further damage that occurs if intestinal bacteria leak into the body.

Nlrp3 works by anchoring a large, multi-protein complex known as the Nlrp3 inflammasome where the messenger protein interleukin 18 (IL-18) is made. IL-18 belongs to a family of molecules known as cytokines, which shape the body's immune response.

In this study, researchers showed IL-18 produced by the Nlrp3 inflammasome helped mice maintain healthy colon by triggering production of more epithelial cells to compensate for those damaged or destroyed by colitis.

"This paper provides the basis for more effective, potentially disease-modifying approaches to treatment," Kanneganti said. She added that in this study, scientists showed the specific pathway activated in the epithelial cells lining the colon for IL-18 production.

Previous studies linked changes in the NLRP3 gene to several auto-inflammatory problems in which a person's immune system mistakenly attacks healthy tissue. The gene is part of the body's innate immune response. That is the branch of the immune system programmed to act immediately against infectious diseases and other threats.

"I believe if we target molecules that are part of the innate immune response we can find cures for many diseases, including cancer," Kanneganti said. She and her colleagues focused on Nlrp3 in colitis after reports that patients with Crohn's disease, another disorder characterised by chronic intestinal inflammation, had low levels of the protein.

In a series of experiments, scientists demonstrated that the Nlrp3 inflammasome not only helps protect against chemically induced colitis in mice, but also showed how and where in the body the protection occurred.

The researchers demonstrated that in response to colitis, the Nlrp3 inflammasome is activated in the epithelial cells lining the colon, where IL-18 can be produced.

Investigators also established that IL-18 is crucial for protecting the colon from colitis. In fact, researchers reported that injecting IL-18 into mice that lacked the molecule eased colitis symptoms.

The other authors of this study are Kelli Boyd, Peter Vogel and Michael Kastan (all St. Jude) and Mohamed Lamkanfi (Ghent University, Ghent, Belgium).

This research was supported in part by the National Institutes of Health, the National Cancer Institute and ALSAC.

To read the full article click here

Gene therapy cures colour-blind monkeys - health - New Scientist

Gene therapy cures colour-blind monkeys - health - 16 September 2009 - New Scientist

Two colour-blind monkeys nicknamed Dalton and Sam have been "cured" through gene therapy.

The breakthrough could be a prelude to new gene treatments for human vision disorders that currently result in blindness. And because the treated monkeys were "middle aged", it challenges the assumption that gene therapies cannot work in adults because their brain connections are too set in their ways to change beneficially.

A human gene injected into the monkeys' eyes enabled them for the first time to produce Clong-wavelength opsin" the pigment sensitive to red and green light. "That gave them a retina like that of a normal person with full colour vision," says Jay Neitz at the University of Washington in Seattle.

The team used squirrel monkeys because the males are known to be colour-blind, whereas females have full colour vision. Males do have a full set of colour-sensing "cone" cells in their eyes, but they only make pigments for detecting blue and yellow light, making them blind to red and green.

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