Stories about: Frederick Alt

Creating custom brains from the ground up

building a custom brain
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Scientists studying how genetics impact brain disease have long sought a better experimental model. Cultures of genetically-modified cell lines can reveal some clues to how certain genes influence the development of psychiatric disorders and brain cancers. But such models cannot offer the true-to-form look at brain function that can be provided by genetically-modified mice.

Even then, carefully breeding mice to study how genes impact the brain has several drawbacks. The breeding cycles are lengthy and costly, and the desired gene specificity can only be verified — but not guaranteed — when mouse pups are born.

In today’s Nature, scientists from Boston Children’s Hospital and UC San Francisco describe a new way to create customized mouse models for studying the brain.

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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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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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Why evolution is the challenge — and the promise — in developing a vaccine against HIV

HIV surrounds and attacks a cell.
HIV surrounds and attacks a cell.

To fight HIV, the development of immunization strategies must keep up with how quickly the virus modifies itself. Now, Boston Children’s Hospital researchers are developing models to test HIV vaccines on a faster and broader scale than ever before with the support of the Bill & Melinda Gates Foundation.

“The field of HIV research has needed a better way to model the immune responses that happen in humans,” says Frederick Alt, PhD, director of the Boston Children’s Program in Cellular and Molecular Medicine, who is leading the HIV vaccine research supported by the Gates Foundation.

The researchers are racing against HIV’s sophisticated attack on the human immune system. HIV, the human immunodeficiency virus, mutates much faster than other pathogens. Within each infected patient, one virus can multiply by the billions.

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‘Hotspots’ for DNA breakage in neurons may promote brain genetic diversity, disease

DNA breakage brain
DNA breaks in certain genes may help brains evolve, but also can cause disease (Constantin Ciprian/Shutterstock)

As organs go, the brain seems to harbor an abundance of somatic mutations — genetic variants that arise after conception and affect only some of our neurons. In a recent study in Science, researchers found about 1,500 variants in each of neurons they sampled.

New research revealing the propensity of DNA to break in certain spots backs up the idea of a genetically diverse brain. Reported in Cell last month, it also suggests a new avenue for thinking about brain development, brain tumors and neurodevelopmental/psychiatric diseases.

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