Frontiers of Medicine

"We're removing the doorway that HIV uses to get into cells"

Natural immunity is the most reliable way to protect yourself from viruses, bacteria and parasites. And the best way to acquire such immunity, in most cases, is to expose your immune system to the bug in question—either by getting infected or getting immunized.

Until now, such protection was only possible with diseases like chicken pox or polio. But now, scientists at Harvard University say that people might soon arm themselves against HIV in a similar way, but through a different method.

Chad Cowan and Derrick Rossi, both in the department of stem cell and regenerative biology at Harvard University, and their colleagues report in the journal Cell Stem Cell that they have successfully edited the genomes of blood cells to make them impervious to HIV. In order survive, HIV needs to insert its genome into that of a healthy cell, and to infect these cells, HIV latches onto a protein on their surface called CCR5. If CCR5 is mutated, however, it’s as if the locks have been changed and HIV no longer has the right key; it can’t attach itself and the cells are protected from infection. So the scientists tried a new gene editing technique called CRISPR that allows them to precisely snip out parts of a cell’s genome, and they spliced out the CCR5 gene. To their surprise, the technique was relatively efficient, transforming about half of the cells they treated with CRISPR into CCR5-free, or HIV-resistant, cells.

“It was stunning to us how efficient CRISPR was in doing the genome editing,” says Cowan.

Scientists have previously used CRISPR to make another change in how HIV infects cells; they snipped out the HIV genes that the virus inserted into healthy cells. That process essentially returned HIV infected cells back to healthy ones.

The latest results, however, suggest that the technique may be useful even before HIV gets inside cells. CRISPR could be useful in treating HIV patients if it can replace patients’ own immune cells with the blockaded versions. The cells Cowan and Rossi used were blood stem cells, which give rise to the body’s entire blood and immune system. In order to work as a potential treatment for HIV, patients would provide a sample of blood stem cells from their bone marrow, which would be treated with CRISPR to remove the CCR5 gene, and these cells would be transplanted back to the patient. Since the bone marrow stem cells populate the entire blood and immune system, the patient would eventually have blood cells that were protected, or “immunized,” against HIV. “We’re removing the doorway that HIV uses to get into cells,” says Cowan.

To test this idea, they are already working with another research group to see if the HIV-impervious cells can treat mice infected with HIV.

Because healthy cells would be barricaded from HIV, the process might also lead to a cure for the disease. While the results are currently being tested to treat animals already infected with HIV, it may also be possible to one day transform a person’s immune cell genomes to be protected against the virus. Some people are already fortunate enough to be protected this way—a small percentage of people of European ancestry have natural immunity against HIV because they have two copies of mutated CCR5. They have been well studied and so far, their CCR5 aberrations don’t seem to be linked to any known health issues. “They are totally normal except for the fact that they are resistant to HIV,” says Cowan. “That’s a heartening thing: to have a group of people who are alive today who have been studied and looked at and seem totally fine.”

That’s why clinicians who research the virus and treat HIV patients are excited by the possibilities of CRISPR-aided strategies. If it’s possible to close the door on HIV, then it may be realistic to start thinking about closing the door on the AIDS epidemic in the near future.

New medicine effective against superbugs

Scientists have created the first antibiotic-free drug to treat bacterial infections in a major development in combatting drug-resistance, according to The Times.

A small patient trial showed that the new treatment was effective at eradicating the MRSA superbug which is resistant to most antibiotics. The drug is already available as a cream for skin infections and researchers hope to create a pill or an injectable version of it in the next five years.

Antibiotics have been one of the most important drugs since the invention of penicillin almost 90 years ago. But the World Health Organization has repeatedly warned of the threat of antimicrobial resistance, saying “a post-antibiotic era – in which common infections and minor injuries can kill” is a very real possibility in the 21st century.

But scientists say this new technology is less prone to resistance than antibiotics because the treatment attacks infections in a completely different way. The treatment uses enzymes called endolysins — naturally occurring viruses that attack certain bacterial species but leave beneficial microbes alone.

Mark Offerhaus, the Chief Executive of the Dutch biotech firm Micreos which is leading the research, said the development of the new drug marks “a new era in the fight against antibiotic-resistant bacteria”, adding that millions of people stand to benefit from this.

[The Times]

Why there might be an HCV vaccine on the horizon

The first human clinical trial of a new hepatitis C vaccine shows that it’s safe in humans, says a study published in the journal Science Translational Medicine. Researchers at the University of Oxford have shown that their first-of-its-kind vaccine for the transmissible liver disease is both effective and safe in an initial safety trial.

An estimated 3.2 million people in the U.S. have chronic hepatitis C, and most do not know they are infected because they don’t have visible or bothersome symptoms. Despite the emergence of effective (but pricey) drugs to treat hepatitis C in the last couple years, there’s still no vaccine. Other types of vaccines spur individuals’ bodies to create antibodies that fight a disease, but that hasn’t worked for hepatitis C. The new potential vaccine induces T cells that target several parts of the virus.

“Our lab spent many years looking at what happens with people who are naturally infected with hepatitis C, because about 20% of people naturally clear the infection using their immune system,” says study author Eleanor Barnes. “That really gives us hope that a vaccination strategy is really possible. We know from looking at these people who naturally clear the infection that the T cell appears to be an important part of that immune response.”

The vaccine is currently undergoing testing in a Phase IIB study in both Baltimore and San Francisco among people who are intravenous drug users, one important mode of transmission for the disease. Results are expected in 2016.

“We have all these different types of new drugs [for hepatitis C], and they really are fantastic. But they are really expensive and you have to give them for 12 weeks or more,” says Barnes. “Most of Hep C is not in developed countries. A lot of it is in resource-poor countries, and I think ultimately we should be looking towards global eradication of Hep C, which will really require a combination of drugs and vaccines.”

A one-two punch is more effective than using two cancer-fighting drugs that boost the immune system against tumors

Cancer researchers are pumping out study after study trying to figure out how best to use the body’s own immune system to fight cancer tumors.

Reporting in the Journal of the American Medical Association, scientists led by Dr. F. Stephen Hodi at Dana Farber Cancer Institute show for the first time that combining two drugs that target the immune system in different ways could help melanoma patients survive longer.

From 2010 to 2011, 245 patients with advanced skin cancer who had not responded to at least one previous treatment were randomly assigned to get a newly approved drug, ipilimumab, designed to help the immune system better target tumors, either alone or in combination with another drug. Ipilimumab (marketed as Yervoy), was among the first anti-cancer medications that allows immune cells to “see” tumors better; since tumors grow from originally normal cells, the immune system often gives them a pass and doesn’t attack them as foreign. But drugs like ipilimumab, called checkpoint blockade inhibitors, help immune cells to look past cancer’s disguise and target abnormally growing tumors.

MORE: A Shot at Cancer

In the study, those who received the combination of ipilimumab and sargramostim, another drug that gives the immune system a laser-like focus on the proteins found on tumors, survived an average of 17.5 months after the study began, compared to 12.7 months for those who took ipilimumab alone. At the end of a year, nearly 70% of those receiving the combination were alive, while 53% of those in the ipilimumab alone group were.

“We show that the combination improves survival, and at the same time decreases side effects,” says Hodi. The patients receiving the two drugs reported fewer gut and respiratory complications, two of the organ systems most affected by checkpoint inhibitor drugs like ipilimumab.

MORE: Why Cancer Drugs May Work Better While You Sleep

The combination, he says, may be more effective since one drug works to suss out tumor cells, like shining a molecular spotlight on them, while the other builds up the body’s defenses against them, allowing immune cells to better target and eliminate cancers.

The time that both groups of patients enjoyed before their melanoma recurred, however, was similar. But Hodi and his team note that the inflammation caused as a side effect of the drugs could be interpreted as early tumor sites, leading researchers to record the presence of tumors that may not be there.

Teasing apart that issue and determining the safe and optimal doses of the combination will require more studies, says Hodi. The dose of ipilimumab he used, for example, was higher than the one approved by the FDA in 2011, since this study was begun before the agency approved the drug. But the idea that a combination of powerful immune-based drugs could help cancer patients fight their disease and survive longer is encouraging. “This world of [new cancer treatments] is moving fast, and there are a slew of possible combinations that others are studying now,” he says. “It’s where the future of cancer therapy will be.”

Obesity is known to be a major risk factor for the condition

Undergoing bariatric surgery significantly lowers an obese person’s risk of develop Type 2 diabetes, a new study suggests.

Adding to prior research that has indicated weight loss surgery could help get rid of Type 2 diabetes, as obesity is known to be a major risk factor for the condition, the new study published in The Lancet Diabetes & Endocrinology shows surgery can lower an individual’s risk before its onset.

Researchers looked at 2,100 obese adults who did not have diabetes and who had all underwent some form of weight loss surgery. They then matched the participants to the same number of obese adults who did not undergo surgery. After following up with the participants for seven years, they learned that the participants who underwent surgery had an 80% lower risk of developing Type 2 diabetes.

The findings are notable, but in a corresponding editorial, Dr. Jacques M Himpens of St. Pierre University Hospital in Brussels says there are holes in the research: “Unfortunately, despite best matching efforts,” he wrote, the patients and controls that were analyzed “differed widely in terms of medical monitoring.” For one, the participants who did not undergo weight loss surgery also did not go through other treatments for their diabetes. And, as Himpens suggests, it’s likely that weight loss in general—without surgery—could reduce risk for Type 2 diabetes risk.

The new findings add to the growing evidence that weight loss can greatly reduce Type 2 diabetes risk and symptoms, but the best ways to achieve that benefit still need further investigation.

Most Americans know that diet and heart health are connected, but a new study in the Journal of the American College of Cardiology looks at a surprising reason as to why.

When your food gets to your stomach, your gut bacteria get to work. And when those bacteria digest carnitine, which is almost exclusively found in red meat, and choline, found in high-fat dairy products and egg yolks, they produce a metabolite called trimethylamine N-oxide, or TMAO. That’s bad news for your heart, because earlier animal research found that TMAO helps transport cholesterol to the arteries, where it forms dangerous plaques that can lead to heart disease.

Stanley Hazen, MD, PhD, department chair of Cellular and Molecular Medicine at Cleveland Clinic’s Lerner Research Institute, and his team measured the blood levels of TMAO in 720 stable patients with heart failure and followed them over five years, wondering if TMAO would help predict who would be in better shape—and who would be still alive.

It did. TMAO levels predicted mortality rates “very strikingly” over the five-year period: More TMAO in the blood meant a 3.4-fold increased risk of mortality—even after adjusting for all the traditional risk factors, Hazen says.

“It suggests that we’ve now learned a new link in the cause [of heart failure],” Hazen says. “It suggests that the impact of dietary manipulation and changes in gut microbe composition may be a way to impact the development and the adverse prognosis in heart failure.”

TMAO research is still fairly new. Just last year in a study of 2,595 people, Hazen’s team found that meat eaters had higher levels of carnitine and greater risk of heart disease, stroke and heart attack than their vegan and vegetarian peers.

Still, Hazen doesn’t think it’s necessary for everyone to stop eating meat altogether. “What we are now trying to do is come up with a therapy that will prevent formation of TMAO, and hopefully prevent the development of cardiac disease…and the development of heart failure in its adverse prognosis,” Hazen says.

“I like kind of joking around, I’m hoping to come up with the pill that allows me to keep eating steak.”

Researchers say genetic sequencing can predict breast cancer risk better than previously thought

Your genes have a lot to say about who you are and how healthy you are. But for certain diseases, including cancer, so many genes are likely involved that it’s hard for doctors to come up with a useful, reliable way to turn your DNA information into a precise risk score.

But in a paper published in the journal Cancer Epidemiology, Biomarkers & Prevention, researchers say that combining the known genetic players in breast cancer can predict with much higher accuracy a newborn girl’s theoretical risk of developing the disease.

MORE: Angelina Jolie’s Surgery May Have Doubled Genetic Testing Rates at One Clinic

Alice Whittemore, a professor of epidemiology and biostatistics at Stanford University School and Medicine, and her colleagues included 86 known genetic variants that have been associated with breast cancer—including BRCA1 and BRCA2, which are relatively rare but confer a very high risk of disease compared to those that have a smaller contribution—and created a computer model that took into account the rates of breast cancer among women who had these genetic variants.

This model served as a predictor for breast cancer based on womens’ genetic makeup. When researchers looked at the top 25% of risk scores, they found that these would account for about half of breast cancer cases in the future. Using previous models, genetic variants could account for only 35% of future cancer cases.

“Our results are more optimistic than those that have been previously published,” says Whittemore, “because we took 86 known genetic variants associated with breast cancer, and took what was in the world’s literature about how common those variants are, and by how much a factor they increase risk. And the more genetic variants that are identified, the better we will get at this.”

MORE: BRCA Gene Can Be A Cancer Triple Whammy, Study Finds

Since the paper was submitted, several new genetic variants have been linked to breast cancer, and adding those to the model, says Whittemore, could make it more effective.

But just because a woman may have been born with a high genetic risk for breast cancer doesn’t mean that she can’t change that risk. The model found that lifestyle factors, which are in a woman’s control, can generally lower that genetic risk as well. And the higher a woman’s genetic risk, the more she can reduce it with healthy behaviors.

“The news is that even if you are at high genetic risk of developing breast cancer, it’s all the more reason to do what you can to modify your lifestyle to lower your risk by changeable factors even if your genes aren’t changeable,” says Whittemore.

Polish doctors used cells from patient's nose to heal spinal injury

A man who was completely paralyzed from the waist down has learned to walk again after Polish doctors transplanted cells from the patient’s nose into the damaged part of his spine. This pioneering research offers hope for treatment to millions of people around the world with spinal cord injuries.

The patient, 38-year-old firefighter Darek Fidyka from Poland, was left with a completely severed spinal cord after being stabbed four years ago. His doctors had given him a less than 1% chance of recovery but thanks to revolutionary surgery carried out in 2012 Fidyka is now able to walk again with a frame. “It’s an incredible feeling, difficult to describe,” he recounts in a BBC documentary to be aired Tuesday “When it starts coming back, you feel as if you start living your life again, as if you are reborn.” Fidyka has been able to resume an independent life and is even able to drive a car.

The procedure was carried out by Polish surgeons in collaboration with British researchers at University College London. Professor Geoffrey Raisman, who led the U.K. research team, called the breakthrough “historic” and said what had been achieved was “more impressive than man walking on the moon.”

[BBC]