Stories about: precision medicine

Genomic sequencing for newborns: Are parents receptive?

BabySeqCasie Genetti, MS, CGC is a licensed genetic counselor with the Manton Center for Orphan Disease Research at Boston Children’s Hospital. She is first author of a recently published paper on the BabySeq Project.

The idea of genomic sequencing for every newborn has many in the scientific community buzzing with excitement, while leaving others wary of the ethical and social implications. But what do the parents think? The BabySeq Project has been exploring parental motivations and concerns while assessing their willingness to participate in a pilot newborn sequencing study.

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Typing medulloblastoma: From RNA to proteomics and phospho-proteomics

medulloblastoma proteomics study
Medulloblastoma (CREDIT: ARMED FORCES INSTITUTE OF PATHOLOGY/WIKIMEDIA)

Medulloblastoma is one of the most common pediatric brain tumors, accounting for nearly 10 percent of cases. It occurs in the cerebellum, a complex part of the brain that controls balance, coordination and motor function and regulates verbal expression and emotional modulation. While overall survival rates are high, current therapies can be toxic and cause secondary cancers. Developing alternative therapeutics is a priority for the field.

As early as the 1990s, the lab of Scott Pomeroy, MD, PhD, neurologist-in-chief at Boston Children’s Hospital, discovered molecules in medulloblastoma tumors that could predict response to therapies. In 2010, Pomeroy and colleagues uncovered four distinct molecular subtypes of medulloblastoma.

The World Health Organization updated the brain tumor classification scheme in 2016 to include these molecular and genetic features. In the new scheme, tumor subtypes with a good molecular prognosis receive less radiation and chemotherapy. But the creation of targeted therapeutics has remained a challenge, since some of the genetic pathways implicated in these subtypes are found in non-cancerous cells.

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A perfect genetic hit: New gene mutation implicated in rare congenital diarrhea

Normal intestinal organoids (left) in contrast to intestinal organoids derived from patients (right) with a newly-discovered gene mutation linked to congenital diarrhea.
Normal intestinal organoids (left) in contrast to intestinal organoids derived from patients (right) with a newly-discovered gene mutation linked to congenital diarrhea.

When the 1-year-old boy arrived from overseas, he was relying on total parenteral nutrition — a way of bypassing the digestive system to provide nutrients and calories completely intravenously — to survive. From the time of his birth, he had experienced unexplainable diarrhea. Answers were desperately needed.

Sequencing his genes in search of clues, neonatologists and collaborators at the Manton Center for Orphan Disease Research at Boston Children’s Hospital identified a new gene mutation responsible for chronic congenital diarrhea — even finding a similar mutation in two other children as well.

Using patient-derived intestinal organoids in the laboratory, the team discovered that the newly-identified gene mutation, WNT2B, appears to stifle intestinal stem cells’ normal function and growth. The findings were published in the American Journal of Human Genetics.

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Precision medicine: Focus turns toward data sharing, costs, access

Precision Medicine 2018 at Harvard Medical School
(Paul Avillach via Twitter)

Precision medicine is often equated with high-tech, exquisitely targeted, million-dollar drug treatments. But at Precision Medicine 2018, hosted by Harvard Medical School’s Department of Biomedical Informatics (DBMI) this week, many of the speakers and panelists were more concerned about improving health for everyone and making better use of what we already have: data.

“We’re not going to make major changes in 21st century medicine without embracing data-driven approaches,” said HMS dean George Q. Daley in his opening remarks.

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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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Precision medicine for end-stage kidney failure? 40 percent of kids needing transplants have identifiable mutations

People forming a kidney shape - indicating that not all ESRD is alike and that it can have multiple genetic causes

In adults, end-stage renal disease, or ESRD, is most commonly a complication of diabetes or hypertension. In children, teens and young adults, it’s a different picture entirely. New research finds that more than half of people needing a kidney transplant before age 25 have a congenital anomaly of the kidney or urinary tract, and that 40 percent have an identifiable genetic cause of ESRD. Knowing these genetic underpinnings can inform better care for patients with kidney disease, says study leader Friedhelm Hildebrandt, MD, chief of the Division of Nephrology at Boston Children’s Hospital.

Hildebrandt and his colleagues drew on 263 families whose child received a new kidney at Boston Children’s between 2007 and 2017, before the age of 25. In 68 families, the team was able to perform whole-exome sequencing, comparing their DNA with a normal reference sample.

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Elusive epilepsy mutations begin to yield up their secrets

mosaic epilepsy mutations concept
Fawn Gracey illustration

Anti-seizure drugs don’t work in about a third of people with epilepsy. But for people with focal epilepsy, whose seizures originate in a discrete area of the brain, surgery is sometimes an option. The diseased brain tissue that’s removed also offers a rare opportunity to discover epilepsy-related genes.

Many mutations causing epilepsy have been discovered by testing DNA taken from the blood. But it’s becoming clear that not all epilepsy mutations show up on blood tests. So-called somatic mutations can arise directly in tissues like the brain during early prenatal development. Even within the brain, these mutations may affect only a fraction of the cells — those descended from the original mutated cell. This can create a “mosaic” pattern, with affected and unaffected cells sometimes intermingling.

One of the first such mutations to be described, by Ann Poduri, MD, MPH, and colleagues at Boston Children’s Hospital in 2012, was in Dante, a young boy who was having relentless daily seizures. The entire right side of Dante’s brain was malformed and enlarged, and he underwent a drastic operation, hemispherectomy, to remove it. Only later, studying brain samples from Dante and similar children, did Poduri find the genetic cause: a mutation in the gene AKT3. It affected only about a third of Dante’s brain cells. 

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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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Digital doctoring, big data and AI: Five takeaways

digital health

Big data and artificial intelligence are reshaping our world. Earlier this month, at Computefest 2018, organized by the Institute for Applied Computational Science at Harvard University, held the symposium, “The Digital Doctor: Health Care in an Age of AI and Big Data.” Speakers were:

  • Finale Doshi-Velez, PhD, Assistant Professor of Computer Science, Harvard University
  • Matt Might, Director, Hugh Kaul Personalized Medicine Institute, University of Alabama at Birmingham
  • John Brownstein, PhD, Chief Innovation Officer and Director, Computational Epidemiology Lab, Boston Children’s Hospital
  • Marzyeh Ghassemi, PhD, Visiting Researcher, Google’s Verily; Postdoctoral Fellow, Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology
  • Jennifer Chayes, Managing Director, Microsoft Research New England and New York City
  • Emery Brown, PhD, Professor of Medical Engineering and Computational Neuroscience, Massachusetts Institute of Technology

Here are Vector’s five takeaways from the symposium:

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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.

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