Stories about: genetics

Getting a grip on genetic loops

Chromatin is housed inside the nucleus. A new discovery about its physical arrangement could pave the way for new therapeutics.
Artist’s rendering of chromatin, which is housed inside the nuclei of mammalian cells. A new discovery about its physical arrangement could pave the way for new therapeutics.

A new discovery about the spatial orientation and physical interactions of our genes provides a promising step forward in our ability to design custom antibodies. This, in turn, could revolutionize the fields of vaccine development and infection control.

“We are beginning to understand the full biological impact that the physical structure and movement of our genes play in regulating health and development,” says Frederick Alt, PhD, director of the Boston Children’s Hospital Program in Cellular and Molecular Medicine (PCMM) and the senior author of the new study, published in the latest issue of Cell.

Recent years of research by Alt and others in the field of molecular biology have revealed that it’s not just our genes themselves that determine health and disease states. It’s also the three-dimensional arrangement of our genes that plays a role in keeping genetic harmony. Failure of these structures may trigger genetic mutations or genome rearrangements leading to catastrophe.

The importance of genetic loops

Crammed inside the nucleus, chromatin, the chains of DNA and proteins that make up our chromosomes, is arranged in extensive loop arrangements. These loop configurations physically confine segments of genes that ought to work together in a close proximity to one another, increasingly their ability to work in tandem.

“All the genes contained inside one loop have a greater than random chance of coming together,” says Suvi Jain, PhD, a postdoctoral researcher in Alt’s lab and a co-first author on the study.

Meanwhile, genes that ought to stay apart remain blocked from reaching each other, held physically apart inside our chromosomes by the loop structures of our chromatin.

But while many chromatin loops are hardwired into certain formations throughout all our cells, it turns out that some types of cells, such as certain immune cells, are more prone to re-arrangement of these loops.

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Phenylketonuria without the ‘phe’: Enzyme therapy offers chance at a better life

Kaylee Goodwin credits pegvaliase for changing her life — including her engagement.
Kaylee Goodwin credits pegvaliase for changing her life — including her engagement. “It’s to the point where I don’t even think I have PKU anymore,” she says.

Kaylee Goodwin, 29, has struggled her whole life to control her blood levels of “phe” — the amino acid known as phenylalanine. “I was told that if my levels were controlled, I would be able to think more clearly and feel better overall,” she says.

Goodwin was born with phenylketonuria (PKU), a genetic metabolic disorder affecting roughly 1 in 16,000 newborns. Her body can’t break down phe because of a genetic mutation disabling the necessary enzyme, phenylalanine hydroxylase (PAH).

If left untreated, phe accumulates in the brain, causing intellectual disability and seizures. But starting in the early 1960s, newborn screening programs have been able to test for PKU. Goodwin tested positive and was prescribed a special phe-free diet by Harvey Levy, MD, at Boston Children’s Hospital.

Through the diet, Goodwin has dodged serious brain damage and was able to attend college and start a career as a dancer and actress. But because phe is in nearly all naturally occurring proteins, she couldn’t eat meat, eggs, dairy products, legumes, most grains and many fruits and vegetables. Instead, she had to consume a foul-tasting amino acid formula.

“I spent my entire life carrying special foods and medical formula around with me, and weighing and measuring foods,” she says.

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Mothers’ life experiences may affect their newborns’ telomeres — especially boys’

mother and newborn with telomeres

A new study adds to a growing body of evidence that mothers’ experiences affect their babies’ chromosomes. For the first time, it also shows a gender difference — with male babies more susceptible to maternal influence. And it even implicates experiences dating back to the mother’s own childhood.

The study, led by psychologist Michelle Bosquet Enlow, PhD, at Boston Children’s Hospital, may help explain why stress can have intergenerational effects within a family. It was published last month in the journal Psychoneuroendocrinology.

The researchers enrolled 151 socioeconomically diverse mothers and their infants, all born at Beth Israel Deaconess Medical Center in Boston. The mothers completed in-depth interviews during pregnancy. Cord blood was collected from the newborns so that their chromosomes could be examined — and in particular, the little caps at their tips known as telomeres.

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Families and data scientists build insights on Phelan-McDermid syndrome

querying stacks of data

This is the third year that Jacob Works has made the trip down to Boston Children’s Hospital from Maine. With research assistant Haley Medeiros, he looks at pictures, answers questions, manipulates blocks and mimes actions like knocking on a door. His father, Travis, and another research assistant look on through a window.

“At first, we had to practically bribe him with an iPad with every task,” Travis says. “This year he’s more excited, because he understands more and is more confident and able to share more.”

Jacob, 11, was diagnosed in 2011 with Phelan-McDermid Syndrome, a rare genetic condition that typically causes children to be born “floppy,” with low muscle tone, and to have little or no speech, developmental delay and, often, autism-like behaviors. At the time, Jacob was one of about 800 known cases. But through chromosomal microarray testing, introduced in just the past decade for children with autism symptoms, more cases are being picked up.

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Zeroing in on the fetal-to-adult hemoglobin switch and a new way to combat sickle cell disease

Normal red blood cell vs. sickle-shaped blood cell, which is found in sickle cell disease
Normal red blood cell vs. sickle-shaped blood cell.

It’s been known for more than 40 years that in rare individuals, lingering production of the fetal form of hemoglobin — the oxygen-transporting protein found in red blood cells — can reduce the severity of certain inherited blood disorders, most notably sickle cell disease and thalassemia. Typically, however, a protein called BCL11A switches off fetal hemoglobin production past infancy, but exactly how this happens has not been well understood until now.

In a new paper in Cell, researchers at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center have revealed how BCL11A controls the switch in the body’s production of fetal hemoglobin to adult hemoglobin. It does so by binding to a DNA sequence — made up of the bases T-G-A-C-C-A — that lies just in front of the fetal hemoglobin genes.

Another approach to curing sickle cell disease is already being evaluated in a new clinical trial at Dana-Farber/Boston Children’s. The novel gene therapy restores fetal hemoglobin production by genetically suppressing BCL11A, which prevents it from blocking fetal hemoglobin production. Learn more.

“Genetically modifying this TGACCA segment could be another possible strategy to cure sickle cell disease by blocking BCL11A’s ability to bind to this DNA site and switch off fetal hemoglobin production,” says Stuart Orkin, MD, senior author on the study.

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Snaps from the lab: From gene discovery to gene therapy for one rare disease

Will Ward’s birthday falls on Rare Disease Day (Feb. 28). That’s an interesting coincidence because he has a rare disease: X-linked myotubular myopathy (MTM), a rare, muscle-weakening disease that affects only boys. Originally on Snapchat, this video captures the Ward family’s recent visit to the lab of Alan Beggs, PhD to learn more about MTM research.

Beggs, director of the Manton Center for Orphan Disease Research at Boston Children’s Hospital, has known Will since he was a newborn in intensive care. In this lab walk-though you’ll see a freezer filled with muscle samples, stored in liquid nitrogen; muscle tissue under a microscope; gene sequencing to identify mutations causing MTM and other congenital myopathies and a testing station to measure muscle function in samples taken from animal models.

Beggs’s work, which began more than 20 years ago, led to pivotal studies in male Labrador retrievers who happen to have the same mutation and are born with a canine form of MTM. By adding back a healthy copy of the gene, Beggs’s collaborators got the dogs back on their feet running around again. (Read about Nibs, a female MTM carrier whose descendants took part in these studies.)

Based on the canine results, a clinical trial is now testing gene therapy in boys under the age of 5 with MTM. The phase I/II trial aims to enroll 12 boys and measure their respiratory and motor function and muscle structure after being dosed with a vector carrying a corrected MTM gene. In the meantime, observational and retrospective studies are characterizing the natural history of boys with MTM.

Learn more about the Manton Center for Orphan Disease Research.

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Breaking down brain disease one DNA break at a time

DNA breaks are depicted in this artistic renderingCells throughout the human body are constantly being damaged as a part of natural life, normal cellular processes, UV and chemical exposure and environmental factors — resulting in what are called DNA double-strand breaks. Thankfully, to prevent the accumulation of DNA damage that could eventually lead to cell dysfunction, cancer or death, the healthy human body has developed ways of locating and repairing the damage.

Unfortunately, these DNA repair mechanisms themselves are not impervious to genetic errors. Genetic mutations that disrupt DNA repair can contribute to devastating disease.

Across the early-stage progenitor cells that give rise to the human brain’s 80 billion neuronal cells, genomic alterations impacting DNA repair processes have been linked to neuropsychiatric disorders and the childhood brain cancer medulloblastoma. But until now, it was not known exactly which disruptions in DNA repair were involved.

A Boston Children’s Hospital team led by Frederick Alt, PhD, has finally changed that.

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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.

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Science and medicine in 2018: What’s the forecast?

2018 predictions for biomedicine

Vector consulted its many informants to find out which way the wind will blow in 2018. Here are their predictions for what to expect in genetics, stem cell research, immunology and more.

GENETICS

Gene-based therapies mature

We will continue to see successes in 2018 reflecting the maturation of gene therapy as a viable, generalizable platform for curing many rare diseases. Also, we will see exciting new applications of other maturing platforms, like CRISPR/Cas9 gene editing and oligonucleotide therapies for neurologic diseases, building on the success of nusinersen for spinal muscular atrophy.

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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.

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