Stories about: Science

News note: GIANT study homes in on obesity genes

obesity genes
Illustration: Elena Hartley

Yes, some obesity is due to genetics. The largest and most powerful study to date has pinned down 14 variants in 13 genes that carry variations associated with body mass index. They provide new clues as to why some people tend to gain weight and have more trouble losing it. Eight of the variants were in genes not previously tied to human obesity.

The study, published last month, was conducted by the Genetic Investigation of Anthropometric Traits (GIANT) consortium, an international collaboration involving more than 250 research institutions — the same group that brought us height-related genes last year. It combined genetic data from more than 700,000 people and 125 different studies to find rare or low-frequency genetic variants that tracked with obesity.

The study focused on rarer variants in the coding portions of genes, which helped pinpoint causal genes and also helped discover variants with larger effects that those previously discovered by the GIANT consortium. For example, carriers of a variant in the gene MC4R (which produces a protein that tells the brain to stop eating and to burn more energy) weigh 15 pounds more, on average, than people without the variant.

Computational analysis provided some interesting insights into what the 13 genes do. Some, for example, play a role in brain pathways that affect food intake, hunger and satiety. Other variants affect fat-cell biology and how cells expend energy.

This study provided an important confirmation of the role of the nervous system in body weight regulation,” says Joel Hirschhorn MD, PhD, a pediatric endocrinologist and researcher at Boston Children’s Hospital and the Broad Institute of MIT and Harvard, who co-led the study with Ruth Loos, PhD, of the Icahn School of Medicine at Mount Sinai. “Many of the genes from this study were not known to be associated with obesity, but our computational analysis independently implicates these new genes in strikingly similar neuronal pathways as the genes that emerged from our previous work. In addition, our approach newly highlighted a role for genes known to be important in ‘brown fat,’ a type of fat that burns energy and may help keep people lean.”

The researchers think the new findings could help focus the search for new therapeutic targets in obesity.  Read more in Nature Genetics and this press release from Mount Sinai.

Read Full Story | Leave a Comment

Dulling cancer therapy’s double-edged sword: A new way to block tumor recurrence

An immune cell engulfs cancer cells
An immune cell engulfs tumor cells.

Researchers have discovered that killing cancer cells can actually have the unintended effect of fueling the proliferation of residual, living cancer cells, ultimately leading to aggressive tumor progression.

The findings of the multi-institutional research team — including scientists from the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Beth Israel Deaconness Medical Center and the Institute for Systems Biology — contradict the conventional approach to treating cancer.

In their study, published in the January issue of the Journal of Experimental Medicine, the researchers describe how chemotherapy or other targeted therapies create a build-up of tumor cell debris, comprised of dead, fragmented cancer cells. In animal models, the team observed that this cell debris sets off an inflammatory cascade in the body and also encourages lingering, living cancer cells to develop into new tumors.

“Our findings reveal that conventional cancer therapy is essentially a double-edged sword,” says co-senior author on the study Mark Kieran, MD, PhD, who directs the Pediatric Brain Tumor Program at Dana-Farber/Boston Children’s and is an associate professor of pediatrics at Harvard Medical School. “But more importantly, we also found a pathway to block the tumor-stimulating effects of cancer cell debris — using a class of mediators called resolvins.”

Read Full Story | Leave a Comment

Six technologies we backed in 2017

Boston Children's Hospital technology

Boston Children’s Hospital’s Technology Development Fund (TDF) to designed to transform early-stage academic technologies into validated, high-impact opportunities for licensees and investors. Since 2009, the hospital has committed $7.6 million to support 76 promising technologies, from therapeutics, diagnostics, medical devices and vaccines to regenerative medicine and healthcare IT projects. The TDF also assists with strategic planning, intellectual property protection, regulatory requirements and business models. Investigators can access mentors, product development experts and technical support through a network of contract research organizations, development partners and industry advisors.

Eight startup companies have spun out since TDF’s creation, receiving $82.4 million in seed funding. They include Affinivax, a vaccine company started with $4 million from the Gates Foundation, and Epidemico, a population health-tracking company acquired by Booz Allen Hamilton. TDF has also launched more than 20 partnerships, received $26 million in follow-on government and foundation funding and generated $4.45 million in licensing revenue.

Here are the projects TDF awarded in 2017, with grants totaling $650,000:

Read Full Story | Leave a Comment

News Note: Cell ‘barcodes’ trace the natural development of blood

in situ blood development
(Credit: Stem Cell Program, Boston Children’s Hospital)

Genetic labels, or “barcodes,” are shedding new light on the natural process of blood development and immune-cell production, finds a study published in Nature this week. It was led by Fernando Camargo, PhD, and first author Alejo Rodriguez Fraticelli, PhD, at Boston Children’s Hospital’s Stem Cell Research Program, the Harvard Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute.

Most of what we know about blood production is through observing what happens when blood stem and progenitor cells are transplanted into an animal. To observe what happens “in the wild,” researchers went in and tagged the blood stem and progenitor cells of mice, using genetic elements called transposons. This allowed them to track how the cells differentiated into five kinds of blood cells (above: megakaryocytes, erythroid cells, granulocytes, monocytes and B-cell progenitors).

Read Full Story | Leave a Comment

News Note: More evidence that high-glycemic diets cause obesity

a high-glycemic diet

A large genetic analysis lends credence to the idea that insulin spikes after eating high-glycemic foods promote weight gain. People genetically predisposed to produce higher than normal levels of insulin after eating processed carbohydrates — “bad carbs” like white bread, potatoes and refined sugar — were more likely to be obese, the study found.

The researchers, led by David Ludwig, MD, PhD, of Boston Children’s Hospital, Joel Hirschhorn, MD, PhD, of Boston Children’s and the Broad Institute, and Jose Florez, MD, PhD, of the Broad Institute and Massachusetts General Hospital, tapped a collection of large-scale genome-wide association studies. Analyzing data from more than 26,000 people who had glucose challenges, they identified genetic variants linked with high insulin levels 30 minutes after the challenge.

Read Full Story | Leave a Comment

Sensing light without sight: The visual system’s ‘third eye’

ipRGCs provide non-image vision, responding to light independently of rods and cones
Intrinsically photosensitive retinal ganglion cells, rich in melanopsin, respond to light independently of rods and cones. (Courtesy Elliott Milner, PhD)

Michael Tri H. Do, PhD, is an investigator in the F.M. Kirby Neurobiology Center at Boston Children’s Hospital and an assistant professor of neurology at Harvard Medical School.

Light affects us even without impinging on our awareness. In 1995, Charles Czeisler and colleagues at Harvard Medical School described people who lacked visual perception due to retinal degeneration, but nevertheless responded to light subconsciously — despite being blind, their melatonin level was suppressed, and they appeared to synchronize their circadian clock with the solar day. Across the pond at Oxford, Russell Foster and colleagues were finding the same in mice, and learned that these responses began in the eye.

These discoveries spurred an intense research effort that continues to this day. What system confers subconscious sight, and how does it differ from the system that generates visual experience?

Read Full Story | Leave a Comment

2017 pediatric biomedical advances at Boston Children’s Hospital: Our top 10 picks

New tools and technologies fueled biomedicine to great heights in 2017. Here are just a few of our top picks. All are great examples of research informing better care for children (and adults).

1. Gene therapy arrives

(Katherine C. Cohen)

In 2017, gene therapy solidly shed the stigma of Jesse Gelsinger’s 1999 death with the development of safer protocols and delivery vectors. Though each disease must navigate its own technical and regulatory path to gene therapy, the number of clinical trials is mounting worldwide, with seven gene therapy trials now recruiting at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. In August, the first gene therapy won FDA approval: CAR T-cell therapy for pediatric acute lymphoblastic leukemia.

Read Full Story | Leave a Comment

Taking a sideswipe at high-risk neuroblastoma

Microscopy image of human neuroblastoma cells.
Human neuroblastoma cells.

Cancer and other diseases are now understood to spring from a complex interplay of biological factors rather than any one isolated origin. New research reveals that an equally-nuanced approach to treating high-risk neuroblastoma may be the most effective way to curb tumor growth.

One challenge in treating pediatric cancers like neuroblastoma is that they are not initiated from the same kinds of genetic mutations as adult cancers, which usually arise from mutations related to an accumulation of DNA replication errors or environmental factors. In contrast, childhood cancers more often stem from genetic duplications, deletions or translocations, the latter of which occurs when a gene sequence switches its location from one chromosome to another.

Read Full Story | Leave a Comment

Patients’ individual genomes may affect efficacy, safety of gene editing

gene editing - truck delivering code
Subtle genetic variants in or near the gene editing target site could cause reagents to miss an address or arrive at the wrong one, researchers say.

Gene editing has begun to be tested in clinical trials, using CRISPR-Cas9, zinc finger nucleases (ZFN) and other technologies to directly edit DNA inside people’s cells. Multiple trials are in the recruiting or planning stages. But a study in PNAS this week raises a note of caution, finding that person-to-person genetic differences may undercut the efficacy of the gene editing process or, in more rare cases, cause a potentially dangerous “off target” effect.

The study adds to evidence that gene editing may need to be adapted to each patient’s genome, to ensure there aren’t variants in DNA sequence in or near the target gene that would throw off the technology.

Read Full Story | Leave a Comment

Which bacteria in the gut microbiome are really influencing disease?

investigating the 'influencers' in the gut microbiome

Over the last decade, multiple studies have examined possible links between groups of microbes and the presence or absence of multiple diseases, including diabetes, multiple sclerosis, autism and inflammatory bowel disease. But on an individual basis, it’s been unclear which microbes are innocent bystanders, mere markers of disease, and which are active agents, causing harm or providing protection.

Scientists from Harvard Medical School and Boston Children’s Hospital have now designed and successfully used a method to tease out cause-and-effect relationships within the microbiome. Their work, conducted in mice, was described Dec. 6 in Nature.

Read Full Story | Leave a Comment