Guardian of the Cell


Scientists unravel the structure, key features of a human immune-surveillance protein, setting the stage for more-precise immune therapies

protein structure
Scientists have identified the key structural and functional features of a critical immune protein in humans that guards against cancer, viral and bacterial infections.

 

The human body is built for survival. Each one of its cells is closely guarded by a set of immune proteins armed with nearly foolproof radars that detect foreign or damaged DNA.

One of the cells’ most critical sentinels is a “first responder” protein known as cGAS, which senses the presence of foreign and cancerous DNA and initiates a signaling cascade that triggers the body’s defenses.

The 2012 discovery of cGAS ignited a firestorm of scientific inquiry, resulting in more than 500 research publications, but the structure and key features of the human form of the protein continued to elude scientists.

Now, scientists at Harvard Medical School and Dana-Farber Cancer Institute have, for the first time, identified the structural and functional differences in human cGAS that set it apart from cGAS in other mammals and underlie its unique function in people.

A report on the team’s work, published July 12 in Cell, outlines the protein’s structural features that explain why and how human cGAS senses certain types of DNA, while ignoring others.

“The structure and mechanism of action of human cGAS have been critical missing pieces in immunology and cancer biology,” said senior investigator Philip Kranzusch, assistant professor of microbiology and immunobiology at Harvard Medical School and Dana-Farber Cancer Institute. “Our findings detailing the molecular makeup and function of human cGAS close this critical gap in our knowledge.” Importantly, the findings can inform the design of small-molecule drugs tailored to the unique structural features of the human protein—an advance that promises to boost the precision of cGAS-modulating drugs that are currently in development as cancer therapies. “Several promising experimental immune therapies currently in development are derived from the structure of mouse cGAS, which harbors key structural differences with human cGAS,” Kranzusch said. “Our discovery should help refine these experimental therapies and spark the design of new ones. It will pave the way toward structure-guided design of drugs that modulate the activity of this fundamental protein.”

The team’s findings explain a unique feature of the human protein—its capacity to be highly selective in detecting certain types of DNA and its propensity to get activated far more sparingly, compared with the cGAS protein in other animals.

Specifically, the research shows that human cGAS harbors mutations that make it exquisitely sensitive to long lengths of DNA but render it “blind” or “insensitive” to short DNA fragments.

“Human cGAS is a highly discriminating protein that has evolved enhanced specificity toward DNA,” said co-first author Aaron Whiteley, a postdoctoral researcher in the Department of Microbiology and Immunobiology at Harvard Medical School. “Our experiments reveal what underlies this capability.”

Location, location, location

In all mammals, cGAS works by detecting DNA that’s in the wrong place. Under normal conditions, DNA is tightly packed and protected in the cell’s nucleus—the cellular “safe”—where genetic information is stored. DNA has no business roaming freely around the cell. When DNA fragments do end up outside the nucleus and in the cell’s cytosol, the liquid that encases the cell’s organelles, it’s usually a sign that something ominous is afoot, such as damage coming from within the cell or foreign DNA from viruses or bacteria that has made its way into the cell.

The cGAS protein works by recognizing such misplaced DNA. Normally, it lies dormant in cells. But as soon as it senses the presence of DNA outside the nucleus, cGAS springs into action. It makes another chemical—a second messenger—called cGAMP, thus setting in motion a molecular chain reaction that alerts the cell to the abnormal presence of DNA. At the end of this signaling reaction, the cell either gets repaired or, if damaged beyond repair, it self-destructs.

But the health and integrity of the cell are predicated on cGAS’ ability to distinguish harmless DNA from foreign DNA or self-DNA released during cell damage and stress. “It’s a fine balancing act that keeps the immune system in equilibrium. An overactive cGAS can spark autoimmunity, or self-attack, while cGAS that fails to detect foreign DNA can lead to tumor growth and cancer development,” said co-first author Wen Zhou, a postdoctoral researcher at Harvard Medical School and Dana-Farber Cancer Institute.

The current study reveals the evolutionary changes to the protein’s structure that allow human cGAS to ignore some DNA encounters while responding to others.

A foe, an accomplice

For their work, the team turned to an unlikely collaborator—Vibrio cholerae, the bacterium that causes cholera, one of humankind’s oldest scourges.

Taking advantage of a cholera enzyme that shares similarities with cGAS, the scientists were able to recreate the function of both human and mouse cGAS in the bacterium.

Teaming up with colleagues from the lab of Harvard Medical School bacteriologist John Mekalanos, the scientists designed a chimeric, or hybrid, form of cGAS that included genetic material from both the human and mouse forms of the protein. Then they compared the ability of the hybrid cGAS to recognize DNA against both the intact mouse and intact human versions of the protein.

In a series of experiments, the scientists observed activation patterns between the different types of cGAS, progressively narrowing down the key differences that accounted for differential DNA activation among the three.

The experiments revealed that out of the 116 amino acids that differ in human and mouse cGAS, only two accounted for the altered function of human cGAS. Indeed, human cGAS was capable of recognizing long DNA with great precision but it ignored short DNA fragments. The mouse version of the protein, by contrast, did not differentiate between long and short DNA fragments

“These two tiny amino acids make a world of difference,” Whiteley said. “They allow the human protein to be highly selective and respond only to long DNA, while ignoring short DNA, essentially rendering the human protein more tolerant of DNA presence in the cytosol of the cell.”

Plotting the genetic divergence on an evolutionary timescale, the scientists determined that the human and mouse cGAS genes parted ways sometime between 10 million and 15 million years ago.

The two amino acids responsible for sensing long DNA and tolerating short DNA are found solely in humans and nonhuman primates, such as gorillas, chimps and bonobos. The scientists hypothesize that the ability to ignore short DNA but recognize long DNA must have conferred some evolutionary benefits. “It could be a way to guard against an overactive immune system and chronic inflammation,” Kranzusch said. “Or it could be that the risk of certain human diseases is lowered by not recognizing short DNA.”

In a final set of experiments, the team determined the atomic structure of the human cGAS in its active form as it binds to DNA. To do so, they used a visualization technique known as X-ray crystallography, which reveals the molecular architecture of protein crystals based on a pattern of scattered X-ray beams.

Profiling the structure of cGAS “in action” revealed the precise molecular variations that allowed it to selectively bind to long DNA, while ignoring short DNA.

“Understanding what makes the structure and function of human cGAS different from those in other species was the missing piece,” Kranzusch said. “Now that we have it, we can really start designing drugs that work in humans, rather than mice.”

Other investigators included Carina de Oliveira Mann, Benjamin Morehouse, Radosław Nowak, Eric Fischer, and Nathanael Gray. The work was supported by the Claudia Adams Barr Program for Innovative Cancer Research, by the Richard and Susan Smith Family Foundation, by the Charles H. Hood Foundation, by a Cancer Research Institute CLIP Grant, by the National Institute of Allergy and Infectious Diseases grant AI-01845, by National Cancer Institute grant R01CA214608, by the Jane Coffin Childs Memorial Fund for Medical Research, by a Cancer Research Institute Eugene V. Weissman Fellow award, and by a National Institutes of Health T32 grant 5T32CA207021-02.

Relevant Disclosures: The Dana-Farber Cancer Institute and Harvard Medical School have patents pending for human cGAS technologies, on which the authors are inventors.

Harvard Medical School Harvard Medical School (http://hms.harvard.edu) has more than 11,000 faculty working in 10 academic departments located at the School’s Boston campus or in hospital-based clinical departments at 15 Harvard-affiliated teaching hospitals and research institutes: Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Brigham and Women’s Hospital, Cambridge Health Alliance, Dana-Farber Cancer Institute, Harvard Pilgrim Health Care Institute, Hebrew SeniorLife, Joslin Diabetes Center, Judge Baker Children’s Center, Massachusetts Eye and Ear/Schepens Eye Research Institute, Massachusetts General Hospital, McLean Hospital, Mount Auburn Hospital, Spaulding Rehabilitation Network and VA Boston Healthcare System.

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Gene Used In Embryogenesis Can Repair Adult Tissue.


There are some amazing genes and cellular processes active during embryonic development that are never seen again later in life. Though some insects and amphibians are able to carry those traits into adulthood, mammals have a dramatic decrease in the ability to regenerate tissue after birth. A new study has shown that one embryonic protein can be used to help regenerate adult tissue in a living organism, not just in a dish.

The protein Lin28a typically only contributes to processes during embryogenesis, affecting things like metabolism and the pluripotency of stem cells. A study published Nov. 7 in Cell has shown that these proteins can actually be used in adult tissue and help in the regeneration of cartilage, hair follicles, bone, and mesenchyme, a type of undifferentiated connective tissue. It works by binding microRNA in the cell’s nucleus to inhibit let7. Let7 encourages cells to mature and lose the regenerative abilities.

Mice that had been genetically altered to produce Lin28a throughout life had outstanding regenerative power. Though regular mice typically stop producing new hair at around 10 weeks, those with a continued presence of Lin28a kept growing fur throughout their lives. Lin28a also boosted regeneration of limbs. During development, Lin28a is commonly found in the limb buds, but is hardly expressed in those regions after birth. For the mice over expressing Lin28a, some digits that were amputated early in life grew back nearly completely. This ability was diminished as the mouse approached adulthood. Because cardiac tissue also wasn’t regenerated by the presence of Lin28a, there could be other unknown proteins that regulate body aging.

Lin28a was also shown to promote prompt healing of damaged ears, increase metabolism, and contribute to cell proliferation and migration, which are necessary for tissue repair. Unfortunately, some of these attributes can also lead to tumorigenesis, which has been the focus of a great deal of recent cancer research.

This discovery is a long way off from having clinical significance as a miracle “fountain of youth” treatment. Because Lin28a binds to RNA, not the surface of the cell, current drug delivery systems would be very ineffective. Also, because the protein affects so many different tissues in the body, it would be incredibly difficult to target only the desired area. In the future, however, this could be used as a treatment for diseases like alopecia and for tissues that have been injured or are degenerating.

Home Test for Pharyngitis May Reduce Unneeded Strep Cultures.


A patient-driven approach to streptococcal pharyngitis diagnosis using a new home test score might save on unnecessary physician visits, cultures, and treatment, according to a retrospective cohort study published online November 4 in the Annals of Internal Medicine. However, some experts are skeptical of the home score algorithm and of its potential cost-savings.

“Globally, group A streptococcal (GAS) pharyngitis affects hundreds of millions of persons each year,” write Andrew M. Fine, MD, MPH, from the Division of Emergency Medicine-Main 1, Boston Children’s Hospital in Massachusetts, and colleagues. “In the United States, more than 12 million persons make outpatient visits for pharyngitis; however, clinicians cannot differentiate GAS pharyngitis from other causes of acute pharyngitis (for example, viral) on the basis of a physical examination of the oropharynx.”

Most cases of sore throat are viral, rather than bacterial, and therefore are self-limiting and transient even without antibiotic treatment. To classify risk for GAS pharyngitis and guide management of adults with acute pharyngitis, the American College of Physicians and Centers for Disease Control and Prevention recommend use of clinical scores to identify low-risk patients. According to consensus guidelines, such patients should not be tested or treated for GAS pharyngitis.

The goal of this study was to help patients decide when to visit a clinician for evaluation of sore throat. The study sample consisted of 71,776 patients at least 15 years of age who were evaluated for pharyngitis from September 2006 to December 2008 at one of a national chain of retail health clinics.

Using information from patient-reported clinical variables, as well as local incidence of GAS pharyngitis, the investigators created a score and compared it with the Centor score and other traditional scores, using information from clinicians’ assessments. Clinical variables in the new score were fever, absence of cough, and age.

The investigators estimated outcomes if patients who were at least 15 years of age with sore throat did not visit a clinician when the new score indicated less than 10% likelihood of GAS pharyngitis, compared with being managed by clinicians following guidelines using the Centor score. The researchers suggest that following this strategy would avoid 230,000 clinician visits in the United States each year, and that 8500 patients with GAS pharyngitis who would have received antibiotics under clinician management would not receive antibiotics.

A limitation of this approach is current lack of availability of real-time information about the local incidence of GAS pharyngitis, which is needed to calculate the new score. Study limitations include retrospective design and reliance on self-report of symptoms.

“A patient-driven approach to pharyngitis diagnosis that uses this new score could save hundreds of thousands of visits annually by identifying patients at home who are unlikely to require testing or treatment,” the authors write.

Experts Question Limitations and Cost-Savings of the New Score

In an accompanying editorial, Edward L. Kaplan, MD, MMC, from the Department of Pediatrics, University of Minnesota Medical School in Minneapolis, warns of limitations of the new home score. These include overly broad age range, as GAS pharyngitis is rare in persons older than 50 years, and the assumption that GAS pharyngitis has even prevalence across communities.

Dr. Kaplan recommends stratification by age categories and notes that uncomplicated GAS pharyngitis has not been reportable to health departments for several decades in most states, making incidence difficult to determine. Other limitations include failure to account for potential effects of the decisions made by the multiple clinicians from more than 70 clinics attended by patients in this sample, and lack of differentiation of true GAS infection from upper respiratory tract “carriers” among adults.

“Until we have a proven cost-effective vaccine to protect against Streptococcus pyogenes, we cannot expect the magnitude of this medical and public health issue to decrease,” Dr. Kaplan writes. “Even if a cost-effective vaccine is developed, how it may affect true infections and the carrier state in children may be entirely different in adults. Fine and colleagues have proposed an interim approach, but there are surely others.”

In a second editorial, Robert M. Centor, MD, from the University of Alabama at Birmingham in Huntsville, questions the potential cost-savings if the new score were widely used. Alternative strategies to improve treatment and reduce costs include clinical assessment that eliminates testing for patients at low risk, as well as the use of generic antibiotics for those with GAS pharyngitis. He also warns that all guidelines and recommendations for GAS pharyngitis apply only to patients who have had symptoms for fewer than 3 days.

“If symptoms persist or worsen, then the patient no longer has acute pharyngitis; therefore, we should use a different diagnostic and therapeutic approach,” he writes.

Other questions posed by Dr. Centor include whether patients would actually download and use such a test before deciding whether to seek medical care for sore throat and why many physicians, clinics, and emergency departments do not follow published guidelines recommending against antibiotic use for patients with low probability of GAS pharyngitis.

“Although the goals [of this study] are admirable, the approach does not seem practical or cost-saving,” Dr. Centor concludes. “We have more practical strategies for decreasing costs for patients with sore throat.

Fountain of youth? Scientists discover why wounds heal quicker for young people


Fountain of youth? Scientists discover why wounds heal quicker for young people .

The mystery of why wounds heal more quickly in the young compared to the elderly may soon be solved following the discovery of two of the genes involved in tissue regeneration.

Scientists believe that the findings will help to develop new drugs and treatments for faster wound-healing as well as shedding light on the ageing process itself, and what could amount to a genetic “fountain of youth”.

Two teams of researchers found separate genes that accelerate tissue regeneration in laboratory mice. Both genes, which are also present in the human genome, are more active in young mice compared to older mice.

The scientists believe that the genes, called Lin28a and IMP1, are designed to be especially active during the foetal stages of development and are gradually turned off as an animal ages – which could explain why wounds take longer to heal in the elderly and how ageing occurs.

One of the teams, led by George Daley of the Boston Children’s Hospital and Harvard Medical School, activated the Lin28a gene in adult mice and found that shaved fur on their backs grew back much faster than in ordinary adult mice where the gene had not be artificially boosted.

“It sounds like science fiction, but Lin28a could be part of a healing cocktail that gives adults the superior tissue repair seen in juvenile animals,” said Dr Daley, whose study is published in the journal Cell.

Asked what the implications are for human health, Dr Daley said: “My strongest conclusion is that Lin28a, or drug manipulations that mimic the metabolic effects of Lin28a, enhances wound healing and tissue repair, and thus in the future might translate into improved healing of wounds after surgery or trauma in patients.”

The study revealed that the Lin28a gene is responsible for a protein that binds to the key molecules of RNA involved in the metabolism of energy within the mitochondria, the “power packs” of the cells. The result is that when the gene is active, the cells are better and more efficient at repairing themselves – the activated genes also accelerated the repair of injuries.

Tissue regeneration is important in early foetal development and when damaged tissues need to be healed. A gradual loss of tissue regeneration and repair is one of the hallmarks of ageing so anything that could improve it could lead to anti-ageing treatments

“We were surprised that what was previously believed to be a mundane cellular ‘housekeeping’ function would be so important for tissue repair,” said Shyh-Chang Ng of Harvard Medical School, the lead author of the Cell study.

“One of our experiments showed that bypassing Lin28a and directly activating mitochondrial metabolism with a small-molecule compound also had the effect of enhancing wound healing, suggesting that it could be possible to use drugs to promote tissue repair in humans.”

The second gene, IMP1, also produces a protein that binds to the RNA molecules, but this time it promotes the self-renewal of key stem cells during foetal development, and also during tissue repair in later life, said Hao Zhu of the University of Texas in Dallas.

“This finding opens up an exciting possibility that metabolism could be modulated to improve tissue repair, whereby metabolic drugs could be employed to promote regeneration,” Dr Zhu said.

Scientists believe that the findings will help to develop new drugs and treatments for faster wound-healing as well as shedding light on the ageing process itself, and what could amount to a genetic “fountain of youth”.

Two teams of researchers found separate genes that accelerate tissue regeneration in laboratory mice. Both genes, which are also present in the human genome, are more active in young mice compared to older mice.

The scientists believe that the genes, called Lin28a and IMP1, are designed to be especially active during the foetal stages of development and are gradually turned off as an animal ages – which could explain why wounds take longer to heal in the elderly and how ageing occurs.

One of the teams, led by George Daley of the Boston Children’s Hospital and Harvard Medical School, activated the Lin28a gene in adult mice and found that shaved fur on their backs grew back much faster than in ordinary adult mice where the gene had not be artificially boosted.

“It sounds like science fiction, but Lin28a could be part of a healing cocktail that gives adults the superior tissue repair seen in juvenile animals,” said Dr Daley, whose study is published in the journal Cell.

Asked what the implications are for human health, Dr Daley said: “My strongest conclusion is that Lin28a, or drug manipulations that mimic the metabolic effects of Lin28a, enhances wound healing and tissue repair, and thus in the future might translate into improved healing of wounds after surgery or trauma in patients.”

The study revealed that the Lin28a gene is responsible for a protein that binds to the key molecules of RNA involved in the metabolism of energy within the mitochondria, the “power packs” of the cells. The result is that when the gene is active, the cells are better and more efficient at repairing themselves – the activated genes also accelerated the repair of injuries.

Tissue regeneration is important in early foetal development and when damaged tissues need to be healed. A gradual loss of tissue regeneration and repair is one of the hallmarks of ageing so anything that could improve it could lead to anti-ageing treatments

“We were surprised that what was previously believed to be a mundane cellular ‘housekeeping’ function would be so important for tissue repair,” said Shyh-Chang Ng of Harvard Medical School, the lead author of the Cell study.

“One of our experiments showed that bypassing Lin28a and directly activating mitochondrial metabolism with a small-molecule compound also had the effect of enhancing wound healing, suggesting that it could be possible to use drugs to promote tissue repair in humans.”

The second gene, IMP1, also produces a protein that binds to the RNA molecules, but this time it promotes the self-renewal of key stem cells during foetal development, and also during tissue repair in later life, said Hao Zhu of the University of Texas in Dallas.

“This finding opens up an exciting possibility that metabolism could be modulated to improve tissue repair, whereby metabolic drugs could be employed to promote regeneration,” Dr Zhu said.

Scientists believe that the findings will help to develop new drugs and treatments for faster wound-healing as well as shedding light on the ageing process itself, and what could amount to a genetic “fountain of youth”.

Two teams of researchers found separate genes that accelerate tissue regeneration in laboratory mice. Both genes, which are also present in the human genome, are more active in young mice compared to older mice.

The scientists believe that the genes, called Lin28a and IMP1, are designed to be especially active during the foetal stages of development and are gradually turned off as an animal ages – which could explain why wounds take longer to heal in the elderly and how ageing occurs.

One of the teams, led by George Daley of the Boston Children’s Hospital and Harvard Medical School, activated the Lin28a gene in adult mice and found that shaved fur on their backs grew back much faster than in ordinary adult mice where the gene had not be artificially boosted.

“It sounds like science fiction, but Lin28a could be part of a healing cocktail that gives adults the superior tissue repair seen in juvenile animals,” said Dr Daley, whose study is published in the journal Cell.

Asked what the implications are for human health, Dr Daley said: “My strongest conclusion is that Lin28a, or drug manipulations that mimic the metabolic effects of Lin28a, enhances wound healing and tissue repair, and thus in the future might translate into improved healing of wounds after surgery or trauma in patients.”

The study revealed that the Lin28a gene is responsible for a protein that binds to the key molecules of RNA involved in the metabolism of energy within the mitochondria, the “power packs” of the cells. The result is that when the gene is active, the cells are better and more efficient at repairing themselves – the activated genes also accelerated the repair of injuries.

Tissue regeneration is important in early foetal development and when damaged tissues need to be healed. A gradual loss of tissue regeneration and repair is one of the hallmarks of ageing so anything that could improve it could lead to anti-ageing treatments

“We were surprised that what was previously believed to be a mundane cellular ‘housekeeping’ function would be so important for tissue repair,” said Shyh-Chang Ng of Harvard Medical School, the lead author of the Cell study.

“One of our experiments showed that bypassing Lin28a and directly activating mitochondrial metabolism with a small-molecule compound also had the effect of enhancing wound healing, suggesting that it could be possible to use drugs to promote tissue repair in humans.”

The second gene, IMP1, also produces a protein that binds to the RNA molecules, but this time it promotes the self-renewal of key stem cells during foetal development, and also during tissue repair in later life, said Hao Zhu of the University of Texas in Dallas.

“This finding opens up an exciting possibility that metabolism could be modulated to improve tissue repair, whereby metabolic drugs could be employed to promote regeneration,” Dr Zhu said.

Childhood Poverty Linked to Poor Brain Development.


Exposure to poverty in early childhood negatively affects brain development, but good-quality caregiving may help offset this effect, new research suggests.

A longitudinal imaging study shows that young children exposed to poverty have smaller white and cortical gray matter as well as hippocampal and amygdala volumes, as measured during school age and early adolescence.

“These findings extend the substantial body of behavioral data demonstrating the deleterious effects of poverty on child developmental outcomes into the neurodevelopmental domain and are consistent with prior results,” the investigators, with lead author Joan Luby, MD, Washington University School of Medicine in St. Louis, Missouri, write.

However, the investigators also found that the effects of poverty on hippocampal volume were influenced by caregiving and stressful life events.

The study was published online October 28 in JAMA Pediatrics.

Powerful Risk Factor

Poverty is one of the most powerful risk factors for poor developmental outcomes; a large body of research shows that children exposed to poverty have poorer cognitive outcomes and school performance and are at greater risk for antisocial behaviors and mental disorders.

However, the researchers note, there are few neurobiological data in humans to inform the mechanism of these relationships.

“This represents a critical gap in the literature and an urgent national and global public health problem based on statistics that more than 1 in 5 children are now living below the poverty line in the United States alone,” the authors write.

To examine the effects of poverty on childhood brain development and to understand what factors might mediate its negative impact, the researchers used magnetic resonance imaging (MRI) to examine total white and cortical gray matter as well as hippocampal and amygdala volumes in 145 children aged 6 to 12 years who had been followed since preschool.

The researchers looked at caregiver support/hostility, measured observationally during the preschool period, and stressful life events, measured prospectively.

The children underwent annual behavioral assessments for 3 to 6 years prior to MRI scanning and were annually assessed for 5 to 10 years following brain imaging.

Household poverty was measured using the federal income-to-needs ratio.

“Toxic” Effect

The researchers found that poverty was associated with lower hippocampal volumes, but they also found that caregiving behaviors and stressful life events could fully mediate this negative effect.

“The finding that the effects of poverty on hippocampal development are mediated through caregiving and stressful life events further underscores the importance of high-quality early childhood caregiving, a task that can be achieved through parenting education and support, as well as through preschool programs that provide high-quality supplementary caregiving and safe haven to vulnerable young children,” the investigators write.

In an accompanying editorial, Charles A. Nelson, PhD, Boston Children’s Hospital and Harvard Medical School, in Massachusetts, notes that the findings show that early experience “weaves its way into the neural and biological infrastructure of the child in such a way as to impact development trajectories and outcomes.”

“Exposure to early life adversity should be considered no less toxic than exposure to lead, alcohol or cocaine, and, as such it merits similar attention from health authorities,” Dr. Nelson writes.

Discovery of new gene regulator could precisely target sickle cell disease.


A research team from Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and other institutions has discovered a new genetic target for potential therapy of sickle cell disease (SCD). The target, called an enhancer, controls a molecular switch in red blood cells called BCL11A that, in turn, regulates hemoglobin production.

The researchers — led by Daniel Bauer, MD, PhD, and Stuart Orkin, MD, of Dana-Farber/Boston Children’s — reported their findings today in Science.

Prior work by Orkin and others has shown that when flipped off, BCL11A causes red blood cells to produce fetal hemoglobin that, in SCD patients, is unaffected by the sickle cell mutation and counteracts the deleterious effects of sickle hemoglobin. BCL11A is thus an attractive target for treating SCD.

The disease affects roughly 90,000 to 100,000 people in the United States and millions worldwide.

However, BCL11A plays important roles in other cell types, including the immune system’s antibody-producing B cells, which raises concerns that targeting it directly in sickle cell patients could have unwanted consequences.

The discovery of this enhancer — which regulates BCL11A only in red blood cells — opens the door to targeting BCL11A in a more precise manner. Approaches that disable the enhancer would have the same end result of turning on fetal hemoglobin in red blood cells due to loss of BCL11A, but without off-target effects in other cell types.

The findings were spurred by the observation that some patients with SCD spontaneously produce higher levels of fetal hemoglobin and enjoy an improved prognosis. The researchers found that these individuals possess naturally occurring beneficial mutations that function to weaken the enhancer, turning BCL11A’s activity down and allowing red blood cells to manufacture some fetal hemoglobin.

“This finding gives us a very specific target for sickle cell disease therapies,” said Orkin, a leader of Dana-Farber/Boston Children’s who serves as chairman of pediatric oncology at Dana-Farber Cancer Institute and associate chief of hematology/oncology at Boston Children’s Hospital. “Coupled with recent advances in technologies for gene engineering in intact cells, it could lead to powerful ways of manipulating hemoglobin production and new treatment options for hemoglobin diseases.”

“This is a very exciting study,” said Feng Zhang, PhD, a molecular biologist and specialist in genome engineering at the McGovern Institute for Brain Research at the Massachusetts Institute of Technology (MIT) and the Broad Institute of MIT and Harvard, who was not involved in the study. “The findings suggest a potential new approach to treating sickle cell disease and related diseases, one that relies on nucleases to remove this regulatory region, rather than adding an exogenous gene as in classic gene therapy.”

Source:DFCI

 

 

 

Gastric bypass makes gut burn sugar faster.


Diabetic rats control blood glucose better after weight-loss surgery.

A procedure increasingly used to treat obesity by reducing the size of the stomach also reprogrammes the intestines, making them burn sugar faster, a study in diabetic and obese rats has shown.

If the results, published today in Science1, hold true in humans, they could explain how gastric bypass surgery improves sugar control in people with diabetes. They could also lead to less invasive ways to produce the same effects.

“This opens up the idea that we could take the most effective therapy we have for obesity and diabetes and come up with ways to do it without a scalpel,” says Randy Seeley, an obesity researcher at the University of Cincinnati in Ohio, who was not involved in the work.

As rates of obesity and diabetes skyrocket in many countries, physicians and patients are turning to operations that reconfigure the digestive tract so that only a small part of the stomach is used. Such procedures are intended to allow people to feel full after smaller meals, reducing the drive to consume extra calories. But clinical trials in recent years have shown that they can also reduce blood sugar levels in diabetics, even before weight is lost23.

“We have to think about this surgery differently,” says Seeley. “It’s not just changing the plumbing, it’s altering how the gut handles glucose.”

Nicholas Stylopoulos, an obesity researcher at the Boston Children’s Hospital in Massachusetts, and his colleagues decided to learn more about this mechanism by studying one of the most popular weight-loss procedures, the Roux-en-Y bypass. The surgery reduces the stomach to about the size of a hen’s egg, and rearranges the intestines into the shape of a Y. The arm of the Y that is connected to the reduced stomach pouch is called the Roux limb.

Stylopoulos and his team performed the surgery on obese and non-obese diabetic rats, and then watched for changes in the Roux limb. They found that blood levels of compounds and proteins indicative of sugar use were higher in these rats than in controls that underwent a sham operation. The researchers then injected the Roux-en-Y-treated rats labelled glucose and imaged the animals’ digestive tracts. They found that the Roux limb was taking up and using the sugar, perhaps to compensate for receiving fewer digested nutrients from the shrunken stomach.

The team now hopes to study this process in biopsies from humans who have undergone the procedure, says Stylopoulos. In particular, he and his colleagues want to focus on the role of a protein called GLUT1, which transports glucose into cells. Rats that had been given a Roux-en-Y bypass had higher levels of GLUT1 in the Roux limb than controls, and chemically inhibiting the protein halted the uptake of labelled glucose by the Roux limb.

That, says Stylopoulos, suggests that GLUT1 may be a useful target in the hunt for drugs that could reproduce the effects of a gastric bypass.

The hunt may heat up as surgeons weigh the risks of performing bypasses on obese children, and on adults with diabetes who are only slightly overweight, notes Stylopoulos. “It’s all still very controversial,” he says. “The hope is that one day we can bypass the bypass.”

Source Nature

 

Gene mutation may contribute to body weight regulation, obesity.


Through mice and human studies, researchers at Boston Children’s Hospital suggest that a rare genetic mutation which can contribute to severe obesity could lead to further questions about weight gain and energy expenditure among obese patients.

“We found other mutations that weren’t as clearly damaging to the gene,” researcherJoseph Majzoub, MD, chief of endocrinology at Boston Children’s Hospital, said in a press release. “It’s possible that some of these more common mutations actually are pathogenic, especially in combination with other genes in the same pathway.”

According to researchers, the loss of either melanocortin-2 receptor (MC2R) or melanocortin receptor accessory protein (MRAP) in humans can cause severe resistance to adrenocorticotropic hormone, resulting in glucocorticoid deficiency. To study whether changes to melanocortin receptor accessory protein-2 (MRAP2) are associated with human obesity, Majzoub and colleagues conducted coding sequences in obese and control patients from the Genetics of Obesity Study cohort and the Swedish Obese Children’s Cohort.

Four rare heterozygous variants were absent from cohort-specific controls and 1,000 genomes were found in “unrelated, nonsyndromic, severely obese individuals, with all but one variant in the C-terminal region of the protein,” researchers wrote.

Although the rare mutations directly cause obesity in less than 1% of the obese population, other suspected mutations could be more likely to causeobesity, researchers wrote. These findings suggest that MRAP2 disruption could contribute to body weight regulation, prompting a need for further research to confirm these data.

Source: Endocrine Today

 

Brain Imaging Study Confirms Addictive Nature of Processed Carbs.


Story at-a-glance

  • Using brain imaging, researchers confirm that highly processed carbohydrates stimulate brain regions involved in reward and cravings, promoting excess hunger
  • Previous research has demonstrated that refined sugar is more addictive than cocaine, giving you pleasure by triggering an innate process in your brain via dopamine and opioid signals
  • Food manufacturers have gotten savvy to the addictive nature of certain foods and tastes, including saltiness and sweetness, and have turned addictive taste into a science in and of itself
  • Refined carbohydrates like breakfast cereals, bagels, waffles, pretzels, and most other processed foods quickly break down to sugar, increasing your insulin levels, which eventually leads to insulin resistance.
  • pretzel
  • A staggering two-thirds of Americans are now overweight, and one in four are either diabetic or pre-diabetic.
  • Carb-rich processed foods are a primary driver of these statistics, and while many blame Americans’ overindulgence of processed junk foods on lack of self-control, scientists are now starting to reveal the truly addictive nature of such foods.
  • Most recently, researchers at the Boston Children’s Hospital concluded that highly processed carbohydrates stimulate brain regions involved in reward and cravings, promoting excess hunger.1 As reported by Science Daily:2
  • “These findings suggest that limiting these ‘high-glycemic index’ foods could help obese individuals avoid overeating.”
  • While I don’t agree with the concept of high glycemic foods, it is important that they are at least thinking in the right direction. Also, the timing is ironic, considering the fact that the American Medical Association (AMA) recently declared obesity adisease, treatable with a variety of conventional methods, from drugs to novel anti-obesity vaccines…
  • The featured research is on the mark, and shows just how foolhardy the AMA’s financially-driven decision really is. Drugs and vaccines are clearly not going to doanything to address the underlying problem of addictive junk food.
  • The study, published in the American Journal of Clinical Nutrition3 examined the effects of high-glycemic foods on brain activity, using functional magnetic resonance imaging (fMRI). One dozen overweight or obese men between the ages of 18 and 35 each consumed one high-glycemic and one low-glycemic meal. The fMRI was done four hours after each test meal. According to the researchers:
  • “Compared with an isocaloric low-GI meal, a high-glycemic index meal decreased plasma glucose, increased hunger, and selectively stimulated brain regions associated with reward and craving in the late postprandial period, which is a time with special significance to eating behavior at the next meal.”
  • The study demonstrates what many people experience: After eating a high-glycemic meal, i.e. rapidly digesting carbohydrates, their blood sugar initially spiked, followed by a sharp crash a few hours later. The fMRI confirmed that this crash in blood glucose intensely activated a brain region involved in addictive behaviors, known as the nucleus accumbens.
  • Dr. Robert Lustig, Professor of Pediatrics in the Division of Endocrinology at the University of California, a pioneer in decoding sugar metabolism, weighed in on the featured research in an article by NPR:4
  • “As Dr. Robert Lustig… points out, this research can’t tell us if there’s a cause and effect relationship between eating certain foods and triggering brain responses, or if those responses lead to overeating and obesity.
  • ‘[The study] doesn’t tell you if this is the reason they got obese,’ says Lustig, ‘or if this is what happens once you’re already obese.’ Nonetheless… he thinks this study offers another bit of evidence that ‘this phenomenon is real.’”
  • Previously, Dr. Lustig has explained the addictive nature of sugar as follows:
  • “The brain’s pleasure center, called the nucleus accumbens, is essential for our survival as a species… Turn off pleasure, and you turn off the will to live… But long-term stimulation of the pleasure center drives the process of addiction… When you consume any substance of abuse, including sugar, the nucleus accumbens receives a dopamine signal, from which you experience pleasure. And so you consume more.
  • The problem is that with prolonged exposure, the signal attenuates, gets weaker. So you have to consume more to get the same effect — tolerance. And if you pull back on the substance, you go into withdrawal. Tolerance and withdrawal constitute addiction. And make no mistake, sugar is addictive.”
  • Previous research has demonstrated that refined sugar is more addictive than cocaine, giving you pleasure by triggering an innate process in your brain via dopamine and opioid signals. Your brain essentially becomes addicted to stimulating the release of its own opioids.
  • Researchers have speculated that the sweet receptors located on your tongue, which evolved in ancestral times when the diet was very low in sugar, have not adapted to the seemingly unlimited access to a cheap and omnipresent sugar supply in the modern diet.

    Therefore, the abnormally high stimulation of these receptors by our sugar-rich diets generates excessive reward signals in your brain, which have the potential to override normal self-control mechanisms, thus leading to addiction.

  • But it doesn’t end there. Food manufacturers have gotten savvy to the addictive nature of certain foods and tastes, including saltiness and sweetness, and have turned addictive taste into a science in and of itself.
  • In a recent New York Times article,5 Michael Moss, author of Salt Sugar Fat, dished the dirt on the processed food industry, revealing that there’s a conscious effort on behalf of food manufacturers to get you hooked on foods that are convenient and inexpensive to make.

    I recommend reading his article in its entirety, as it offers a series of case studies that shed light on the extraordinary science and marketing tactics that make junk food so hard to resist.

  • Sugar, salt and fat are the top three substances making processed foods so addictive. In a Time Magazine interview6discussing his book, Moss says:
  • “One of the things that really surprised me was how concerted and targeted the effort is by food companies to hit the magical formulation. Take sugar for example. The optimum amount of sugar in a product became known as the ‘bliss point.’ Food inventors and scientists spend a huge amount of time formulating the perfect amount of sugar that will send us over the moon, and send products flying off the shelves. It is the process they’ve engineered that struck me as really stunning.”
  • It’s important to realize that added sugar (typically in the form of high fructose corn syrup) is not confined to junky snack foods. For example, most of Prego’s spaghetti sauces have one common feature, and that is sugar—it’s the second largest ingredient, right after tomatoes. A half-cup of Prego Traditional contains the equivalent of more than two teaspoons of sugar.
  • Another guiding principle for the processed food industry is known as “sensory-specific satiety.” Moss describes this as “the tendency for big, distinct flavors to overwhelm your brain, which responds by depressing your desire to have more.” The greatest successes, whether beverages or foods, owe their “craveability” to complex formulas that pique your taste buds just enough, without overwhelming them, thereby overriding your brain’s inclination to say “enough.”
  • Novel biotech flavor companies like Senomyx also play an important role.
  • Senomyx specializes in helping companies find new flavors that allow them to use less salt and sugar in their foods. But does that really make the food healthier? This is a questionable assertion at best, seeing how these “flavor enhancers” are created using secret, patented processes. They also do not need to be listed on the food label, which leaves you completely in the dark. As of now, they simply fall under the generic category of artificial and/or natural flavors, and they don’t even need to be tested for safety, as they’re used in minute amounts.

·         Brain Imaging Shows Food Addiction Is Real

·         The Extraordinary Science of Addictive Junk Food

·         Novel Flavor-Enhancers May Also Contribute to Food Addiction

How to Combat Food Addiction and Regain Your Health

To protect your health, I advise spending 90 percent of your food budget on whole foods, and only 10 percent on processed foods. It’s important to realize that refined carbohydrates like breakfast cereals, bagels, waffles, pretzels, and most other processed foods quickly break down to sugar, increase your insulin levels, and cause insulin resistance, which is the number one underlying factor of nearly every chronic disease and condition known to man, including weight gain.

By taking the advice offered in the featured study and cutting out these high-glycemic foods you can retrain your body to burn fat instead of sugar. However, it’s important to replace these foods with healthy fats, not protein—a fact not addressed in this research. I believe most people may need between 50-70 percent of their daily calories in the form of healthful fats, which include:

Olives and olive oil Coconuts and coconut oil Butter made from raw, organic grass-fed milk
Organic raw nuts, especially macadamia nuts, which are low in protein and omega-6 fat Organic pastured eggs and pastured meats Avocados

 

I’ve detailed a step-by-step guide to this type of healthy eating program in my comprehensive nutrition plan, and I urge you to consult this guide if you are trying to lose weight. A growing body of evidence also suggests that intermittent fasting is particularly effective if you’re struggling with excess weight as it provokes the natural secretion of human growth hormone (HGH), a fat-burning hormone. It also increases resting energy expenditure while decreasing insulin levels, which allows stored fat to be burned for fuel. Together, these and other factors will turn you into an effective fat-burning machine.

Best of all, once you transition to fat burning mode your cravings for sugar and carbs will virtually disappear, as if by magic… While you’re making the adjustment, you could try an energy psychology technique called Turbo Tapping, which has helped many sugar addicts kick their sweet habit. Other tricks to help you overcome your sugar cravings include:

  • Exercise: Anyone who exercises intensely on a regular basis will know that significant amounts of cardiovascular exercise is one of the best “cures” for food cravings. It always amazes me how my appetite, especially for sweets, dramatically decreases after a good workout. I believe the mechanism is related to the dramatic reduction in insulin levels that occurs after exercise.
  • Organic black coffee: Coffee is a potent opioid receptor antagonist, and contains compounds such as cafestrol — found plentifully in both caffeinated and decaffeinated coffee — which can bind to your opioid receptors, occupy them and essentially block your addiction to other opioid-releasing foods.7 This may profoundly reduce the addictive power of other substances, such as sugar.

Source: mercola.com

 

Rare Gene Mutations Suggest One More Path to Obesity.


New research suggests that people with rare mutations of a gene linked with regulating metabolism may be highly susceptible to becoming obese.

The gene involved is known as Mrap2 in mice and as MRAP2in humans. It’s expressed predominantly in the brain, in some of the regions that regulate energy balance. The gene encodes a protein that apparently is linked with increasing metabolism and decreasing appetite.

7-18-13-mice-obesity

To examine the gene’s effect on weight gain, researchers at Boston Children’s Hospital first inactivated Mrap2 in mice. The mice appeared normal until they were about a month old. Then they started to gain more weight, became excessively hungry, and ate more than their siblings with Mrap2 intact.

Even when their food was restricted to the same amount as their normal siblings, mice with the inactivated gene still gained more weight. They didn’t gain weight at the same rate as their siblings until they ate 10% to 15% less food. Mice with both copies of Mrap2 inactivated gained the most weight, but even mice with 1 working copy of the gene gained more weight and had bigger appetites than the normal mice.

When allowed to eat freely, mice with the inactivated gene ate almost twice as much as their siblings. They had more visceral fat, which surrounds organs deep in the abdomen and is linked with cardiovascular disease, diabetes, and colorectal cancer. They also had more fat in their liver, according to the results published online today in the journal Science

“These mice aren’t burning the fat; they’re somehow holding on to it,” the study’s lead investigator, Joseph Majzoub, MD, said in a statement.

Majzoub, chief of endocrinology at Boston Children’s, noted that he and his collaborators found similar mutations in obese participants in the Genetics of Obesity Study, an international effort to determine why some people become severely obese at a young age. They found 4 rare MRAP2 mutations in 500 obese study participants, all who had 1 working copy of the gene.

Rare MRAP2 mutations lead to obesity in fewer than 1% of people with such severe weight problems, the researchers said. But they suspect that other, more common mutations occur in the gene and may interact with various genetic and environmental factors to cause more widespread forms of obesity. They plan to expand the scope of their research to examine that possibility.

Source: http://newsatjama.jama.com