Stories about: vaccines

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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Forecasting the convergence of artificial intelligence and precision medicine

Image of artificial DNA, which in combination with other artificial intelligence could contribute to an artificial model of the immune system
Will an artificial model of the immune system be the key to discovering new, precision vaccines?

This is part I of a two-part blog series recapping the 2018 BIO International Convention.

At the 2018 BIO International Convention last week, it was clear what’s provoking scientific minds in industry and academia — or at least those of the Guinness-world-record-making 16,000 people in attendance. Artificial intelligence, machine learning and their implications for tailor-made medicine bubbled up across all BIO’s educational tracks and a majority of discussions about the future state of biotechnology. Panelists from Boston Children’s Hospital also contributed their insights to what’s brewing at the intersection of these burgeoning fields.

Isaac Kohane, MD, PhD, former chair of Boston Children’s Computational Health and Informatics Program, spoke on a panel about how large-scale patient data — if properly harnessed and analyzed for health and disease trends — is a virtual goldmine for precision medicine insights. Patterns gleaned from population health data or electronic health records, for example, could help identify which subgroups of patients who might respond better to specific therapies.

According to Kohane, who is currently the Marion J. Nelson Professor of Biomedical Informatics and Pediatrics at Harvard Medical School (HMS), we will soon be leveraging artificial intelligence to go through patient records and determine exactly what doctors were thinking when they saw patients.

“We’ve seen again and again that data abstraction by artificial intelligence is better than abstraction by human analysts when performed at the scale of millions of clinical notes across thousands of patients,” said Kohane.

And based on what we heard at BIO, artificial intelligence will revolutionize more than patient data mining. It will also transform the way we design precision therapeutics — and even vaccines — from the ground up.

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Single-shot protection? Building a better hepatitis B vaccine for newborns

newborn vaccines
(Illustrations: Elena Hartley)

The hepatitis B vaccine is one of only three vaccines that are routinely given to newborns in the first days of life. But the current hepatitis B vaccine has limitations: multiple “booster” doses are needed, and it can’t be given to premature babies weighing less than 2 kg.

Annette Scheid, MD, a neonatologist at Brigham and Women’s Hospital, is interested in leveraging infant immune differences to create a better hepatitis B vaccine for newborns. “The reality is that we have to vaccinate several times,” she says. “But we all dream of a vaccine that you give only once.”

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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:

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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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How do cells release IL-1? The answer packs a punch, and could enable better vaccines

In hyperactivated immune cells, gasdermin D punches holes in the cell membrane that let IL-1 out — without killing the cell.

Interleukin-1 (IL-1), first described in 1984, is the original, highly potent member of the large family of cellular signaling molecules called cytokines that regulate immune responses and inflammation. It’s a key part of our immune response to infections, and also plays a role in autoimmune and inflammatory diseases. Several widely used anti-inflammatory drugs, such as anakinra, block IL-1 to treat rheumatoid arthritis, systemic inflammatory diseases, gout and atherosclerosis. IL-1 is also a target of interest in Alzheimer’s disease.

Yet until now, no one knew how IL-1 gets released by our immune cells.

“Most proteins have a secretion signal that causes them to leave the cell,” says Jonathan Kagan, PhD, an immunology researcher in Boston Children’s Hospital’s Division of Gastroenterology. “IL-1 doesn’t have that signal. Many people have championed the idea that IL-1 is passively released from dead cells: you just die and dump everything outside.”

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Science Seen: Tackling S. aureus by eavesdropping on infections

S. aureus vaccine messenger RNA transcriptome
This messenger RNA ‘heat map,’ generated from 50 patient samples, shows potential target proteins for a more effective S. aureus vaccine. The color scale indicates the magnitude of the transcription level, with red highest.

Staphylococcus aureus causes 11,000 deaths annually in the U.S. alone and is frequently antibiotic-resistant. It’s a leading cause of pneumonia, bloodstream infections, bone/joint infections and surgical site infections and the #1 cause of skin and soft tissue infections. Efforts to develop an S. aureus vaccine have so far failed: the vaccines don’t seem to be capturing the right ingredients to make people immune.

Kristin Moffitt, MD, in Boston Children’s Hospital’s Division of Infectious Diseases, took a step back and asked: “What proteins does S. aureus need to make to establish infection?” The answer, she reasoned, could point to new antigens to include in a vaccine.

The above image shows an early result from Moffitt’s investigation. It’s a “heat map” of the messenger RNA signature — a snapshot of the proteins S. aureus is potentially up-regulating during infection.

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How social media and a mumps outbreak teach us that vaccines build herd immunity

Mumps virus, pictured here, is usually preventable by vaccination.
The mumps virus, pictured here, has been spreading through Arkansas communities. Surprisingly, many affected people say they have received vaccinations to prevent it. Analyzing social media data helped a Boston Children’s Hospital team understand why so many people got sick.

Residents of Arkansas have been under siege by a viral threat that is typically preventable through vaccination. Since August 2016, more than 2,000 people have been stricken with mumps, an infection of the major salivary glands that causes uncomfortable facial swelling.

The disease is highly contagious but can usually be prevented by making sure that children (or adults) have had two doses of the measles-mumps-rubella (MMR) vaccine. But strangely, about 70 percent of people in Arkansas who got sick with mumps reported that they had received their two doses of the MMR vaccine.

So, members of the HealthMap lab, led by Chief Innovation Officer and director of the Computational Epidemiology Group at Boston Children’s Hospital, John Brownstein, PhD, asked, “Why did this outbreak take off?”

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Effective vaccination of newborns: Getting closer to the dream

newborn vaccines global health

In many parts of the world, babies have just one chance to be vaccinated: when they’re born. Unfortunately, newborns’ young immune systems don’t respond well to most vaccines. That’s why, in the U.S., most immunizations start at two months of age.

Currently, only BCG, polio vaccine and hepatitis B vaccines work in newborns, and the last two require multiple doses. But new research raises the possibility of one-shot vaccinations at birth — with huge implications for reducing infant mortality.

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Keeping up with HIV mutations: Building a nimble vaccine test system

AIDS vaccine
A new technology speeds up natural antibody “evolution” to create a nimble HIV vaccine test system. (Images: Wikimedia/Pixabay)

An AIDS vaccine able to fight any HIV strain has thus far eluded science. HIV frequently mutates its coat protein, dodging vaccine makers’ efforts to elicit sufficiently broadly neutralizing antibodies.

Yet sometimes HIV-infected people can produce such antibodies on their own. This usually requires years of exposure to the virus, allowing the immune system to modify its antibodies over time to keep up with HIV mutations. But the goal is generally achieved too late in the game to prevent them from being infected.

“Only a small fraction of patients are able to develop broadly neutralizing antibodies, and by the time they do, the virus has already integrated into the genomes of their T-cells,” says Ming Tian, PhD, of Boston Children’s Hospital’s Program in Cellular and Molecular Medicine (PCMM).

Tian is part of a group led by PCCM director Frederick Alt, PhD, that developed a technology to greatly speed up HIV development. Described today in Cell, the group’s method generates mouse models with built-in human immune systems. The model recapitulates what the human immune system does, only much more rapidly, enabling researchers to continuously test and tweak potential HIV vaccines.

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