New angles for blocking Shiga and ricin toxins, and new light on an iconic biological process

Shiga toxin producing E. coli
Shiga-toxin-producing E. coli (IMAGE: JANICE HANEY CARR / USCDC)

Min Dong, PhD, and his lab are world experts in toxins and how to combat them. They’ve figured out how Clostridium difficile’s most potent toxin gets into cells and zeroed in on the first new botulinum toxin identified since 1969. Now, they’ve set their sights on Shiga and ricin toxins, and not only identified new potential lines of defense, but also shed new light on a fundamental part of cell biology: glycosylation.

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Restoring ‘youthful’ hemoglobin in sickle cell disease: First patient is symptom-free

Manny Johnson of Boston, 21, previously required monthly blood transfusions to keep his severe sickle cell disease under control. After receiving a new gene therapy treatment, he’s been symptom-free for six months.

Researchers at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center reported Manny’s case Saturday at the American Society of Hematology meeting in San Diego. Manny is their first patient, and an ongoing clinical trial will treat additional patients between ages 3 and 40.

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Microglia in the brain: Which are good and which are bad?

Timothy Hammond studying brain microglia in the Stevens Lab at Boston Children's Hospital
If we see microglia in brain disease, are they part of the problem, or part of the solution? asks Timothy Hammond. (PHOTOS: MICHAEL GODERRE / BOSTON CHILDREN’S HOSPITAL)

Microglia are known to be important to brain function. The immune cells have been found to protect the brain from injury and infection and are critical during brain development, helping circuits wire properly. They also seem to play a role in disease — showing up, for example, around brain plaques in people with Alzheimer’s.

It turns out microglia aren’t monolithic. They come in different flavors, and unlike the brain’s neurons, they’re always changing. Tim Hammond, PhD, a neuroscientist in the Stevens lab at Boston Children’s Hospital, showed this in an ambitious study, perhaps the most comprehensive survey of microglia ever conducted. Published last week in Immunity, the findings open a new chapter in brain exploration.

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ctDNA: Bringing ‘liquid biopsies’ to pediatric solid tumors

Brian Crompton studies the use of ctDNA as an alternative way to biopsy pediatric solid tumors
Brian Crompton with Stephanie Meyer (left) and Kellsey Wuerthele (PHOTO: JOHN DEPUTY)

Our blood carries tiny amounts of DNA from broken-up cells. If we have cancer, some of that DNA comes from tumor cells. Studies performed with adult cancers have shown that this circulating tumor DNA (ctDNA) may offer crucial clues about tumor genetic mutations and how tumors respond to treatment.

Brian Crompton, MD, with colleagues at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and elsewhere, is now working to bring ctDNA “liquid biopsies” to pediatric solid tumors as well. The researchers hope that these blood tests will eventually improve early detection, choice of treatment and monitoring of young patients with these diseases without having to sample the tumor itself.

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3D human tissue construct could de-risk vaccine development

Ofer Levy (L) with Guzman Sanchez-Schmitz (PHOTO: MICHAEL GODERRE)

Immunization is one of modern medicine’s greatest success stories. Yet we still lack vaccines for common diseases such as HIV and respiratory syncytial virus. Other vaccines are only moderately effective, like those against tuberculosis or pertussis. The average vaccine can take a decade or more to develop, at a cost of hundreds of millions of dollars, and vaccines that worked flawlessly in mice regularly fail in clinical trials. As a result, many companies are reluctant to enter into vaccine development.

“We need a way to rapidly assess vaccine candidates earlier in the process,” says Ofer Levy, MD, PhD, a physician-scientist in the Division of Infectious Diseases at Boston Children’s Hospital and director of the Precision Vaccines Program. “It’s simply not possible to conduct large-scale, phase 3, double-blind, placebo-controlled studies of every potential vaccine for every pathogen we want to protect against.”

In a paper published today in Frontiers in ImmunologyLevy’s team describes the first modeling laboratory system for testing human immune responses to vaccines — outside the body.

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Proposed cancer treatment may boost lung cancer stem cells, study warns

Epigenetic enzymes and lung cancer: Treating adenocarcinoma with G9a histone methyltransferase inhibitors leads to an increase in tumor cells with stem-like properties. In contrast, inhibiting histone demethylase prevents tumor growth. (SAMUEL ROWBOTHAM/BOSTON CHILDREN’S HOSPITAL)

Epigenetic therapies — targeting enzymes that alter what genes are turned on or off in a cell — are of growing interest in oncology as a way to make cancers less aggressive or less malignant. But now, at least one epigenetic therapy that had looked promising for lung cancer appears to boost the cancer stem cells that are believed to drive tumors. A study published today in Nature Communications also identifies a strategy that reduces these stem cells, curbing lung cancer in mice.

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Only a third of Federally mandated ‘post-marketing’ pediatric drug trials are complete

too few mandated pediatric drug trials are getting done
Despite new requirements, pediatric drug trials largely aren’t getting done. (ADOBE STOCK)

The FDA requires clinical studies of new drugs in pediatric populations, since many drugs developed for use in adults are also used in children. These studies are often “post-marketing” trials after the drug is approved in adults. But an audit by researchers at Boston Children’s Hospital found that only about a third of these mandatory trials were completed within an average of seven years. As a result, most new drug labels continue to lack child-specific information, and most FDA-approved drugs remain untested in children.

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‘Druggable’ cancer target found in pathway regulating organ size

Inactivating NUAK2 curbs cell proliferation in liver cancer
Reducing cancer proliferation: A small molecule that inactivates NUAK2, part of the Hippo/YAP pathway, reduces the number of cancerous cells in the mouse liver. (WEI-CHIEN YUAN/BOSTON CHILDREN’S HOSPITAL)

It’s known that cancer involves unchecked cell growth and that a pathway that regulates the size of organs, known as Hippo, is also involved in cancer. It’s further known that a major player in this pathway, YAP, drives many types of tumors. What’s been lacking is how to turn this knowledge into a practical cancer treatment. In a study published today in Nature Communications, researchers at Boston Children’s Hospital identify a target downstream of YAP, called NUAK2, and show that it can readily be inactivated with a small molecule.

“The Hippo pathway, and especially YAP, has been hard to target with drugs,” says senior study author Fernando Camargo, PhD, of Boston Children’s Stem Cell Research program. “This is the first demonstration of a ‘druggable’ molecule that could be targeted in any type of tumor driven by YAP.”

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Low-carb diets make us burn more calories, finds largest, longest feeding trial to date

Low carb diet helps us burn calories faster, supporting the Carbohydrate-Insulin Model of obesity
Supporting the Carbohydrate-Insulin Model of obesity, a new study finds that low-carb diets increase our energy expenditure.

Most people who diet to lose weight regain the pounds within a year or two, in part because the body adapts by slowing down metabolism and burning fewer calories. A new study known as the Framingham State Food Study, or (FS)2, suggests that low-carb diets can help people keep the weight off, showing that eating fewer carbohydrates increases the number of calories burned. The findings, published today in the BMJ, could help make obesity treatment more effective.

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From the ashes of a failed pain drug, potential treatments for autoimmunity and cancer

BH4 pathway - orchestra concept
ORCHESTRATING T-CELL RESPONSES: The BH4 pathway can be quieted with a small-molecule inhibitor to calm T-cell responses in autoimmune disease, or tuned up to activate T cells in cancer. (ILLUSTRATION: TIBOR KULCSAR/IMBA)

In 2013, renowned Boston Children’s Hospital pain researcher Clifford Woolf, MD, PhD, and Kai Johnsson, PhD, his fellow co-founder at Quartet Medicine, believed they held the key to non-narcotic pain relief. Woolf had shown that tetrahydrobioptrin — a protein also known as BH4 — is a primary natural modulator of neuropathic and inflammatory pain sensitivity. Quartet was founded on the premise that inhibiting BH4 production could prevent the progression of acute pain to chronic pain in millions of patients, without threat of addiction or tolerance.

With solid human genetic data and chemical biology, plus $17 million in series A funding, Quartet looked primed for success. But in the summer of 2017, toxicology studies of the company’s lead candidate revealed neurologic side effects. Hope for the promising pain drug cratered, taking Quartet with it.

Now, however, a surprising discovery about BH4 will likely rekindle interest in the once-promising pathway and could have profound implications for treating autoimmunity and cancer. In yesterday’s Nature, Woolf and his team at Boston Children’s Hospital, together with immunologists from the Institute of Molecular Biotechnology (IMBA) in Vienna report that BH4 also functions as a kind of immunological thermostat in the body, raising and lowering the activity levels of T cells.

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