Author: Tom Ulrich

The changing nature of what it means to be “diagnosed”

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One of a series of posts honoring #RareDiseaseDay (Feb 28, 2015).

Historically, the starting point for making a rare disease diagnosis is the patient’s clinical profile: the set of symptoms and features that together define Diamond Blackfan anemia (DBA), Niemann-Pick disease or any of a thousand other conditions.

For example, anemia and problems absorbing nutrients are features of Pearson marrow pancreas syndrome (PS), whereas oddly shaped fingernails, lacy patterns on the skin and a proneness to cancer point to dyskeratosis congenita (DC).

The resulting diagnoses give the child and family an entry point into a disease community, and is their anchor for understanding what’s happening to them and others: “Yes, my child has that and here’s how it affects her. Does it affect your child this way too?”

But as researchers probe the relationships between genes and their outward expression—between genotype and phenotype—some families are losing that anchor. They may discover that their child doesn’t actually have condition A; rather, genetically they actually have condition B. Or it may be that no diagnosis matches their genetic findings.

What does that mean for patients’ care, and for their sense of who they are? 

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When HIV and TB coexist: Digging into the roots of IRIS

HIV (green dots) budding from a white blood cell. (CDC)
HIV (green dots) budding from a white blood cell. (CDC)

Millions of people worldwide suffer from co-infection with tuberculosis (TB) and HIV. While prompt antibiotic and antiretroviral treatment can be a recipe for survival, over the years, physicians have noticed something: two or three weeks after starting antiretrovirals, about 30 percent of co-infected patients get worse.

The reason: immune reconstitution inflammatory syndrome, or IRIS. Doctors think it represents a kind of immune rebound. As the antiretrovirals start to work, and the patient’s immune system begins to recover from HIV, it notices TB’s presence and overreacts.

“It’s as though the immune system was blanketed and then unleashed,” says Luke Jasenosky, PhD, a postdoctoral fellow with Anne Goldfeld, MD, of Boston Children’s Hospital’s Program in Cellular and Molecular Medicine. “It then says, ‘I can start to see things again, and there are a lot of bacteria in here.'”

Though potentially severe, even fatal, IRIS may actually be a good sign: there is evidence that patients who develop it tend to fare better in the long run. But why does it arise only in some patients?

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What we’ve been reading: Week of February 9, 2015

Children what we've been reading Flickr thomaslife https://www.flickr.com/photos/thomaslife/4508639159
(Photo: thomaslife/Flickr)

Vector’s picks of recent pediatric healthcare, science and innovation news.

Encryption wouldn’t have stopped Anthem’s data breach (MIT Technology Review)
Hackers got their hands on the personal information and Social Security numbers of 80 million people when they broke into the network of health insurer Anthem health. But encryption alone wouldn’t have been enough to keep those data safe.

Could a wireless pacemaker let hackers take control of your heart? (Science)
Medical devices like pacemakers, insulin pumps and defibrillators are getting ever smaller and more wirelessly connected. But are those connections secure enough?

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A simpler way to measure complex biochemical interactions

DNA nanoswitches electrophoresis Wesley Wong PCMM Wyss Institute
Do you really need complex high-end analytical equipment to study molecular interactions, or will an electrophoresis gel do the trick?

Life teems with interactions. Proteins bind. Bonds form between atoms, and break. Enzymes cut. Drugs attach to cell receptors. DNA hybridizes. Those interactions make the processes of life work, and capturing them has led to many medical advances.

“Determining which molecules interact, and measuring the strength of these interactions is fundamental for many areas of research, from drug discovery to understanding the mechanisms underlying disease,” says Wesley P. Wong, PhD, a biophysicist with Boston Children’s Hospital’s Program in Cellular and Molecular Medicine (PCMM), Harvard Medical School and the Wyss Institute for Biologically Inspired Engineering.

Technologies abound for studying molecular-level interactions quantitatively. But most are complex and expensive, requiring dedicated instruments and specific training on how to prep samples and run the experiments.

Wong and his team, including graduate student Mounir Koussa and postdoctoral fellows Ken Halvorsen, PhD (now at the RNA Institute) and Andrew Ward, PhD, have created an alternative method that democratizes the process. Using electrophoresis gels, found in just about any biomedical laboratory, they’ve developed what they call DNA nanoswitches. These switches let researchers make interaction measurements without complex instruments, at a cost of pennies per sample.

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Can breast cancer cells tell each other to metastasize?

Extracellular vesicles exosomes microRNA breast cancer metastasis
Breast cancer cells might be able to give each other the ability to metastasize using microRNAs packaged into extracellular vesicles similar to these exosomes. (Photo: Kourembanas Laboratory, Boston Children's Hospital)

Not all cancer cells are created equal. In fact, to call a cancer a cancer, in the singular, is something of a misnomer. Really, a patient could be said to have cancers, as every tumor is actually a mixture of cells with different mutations and capabilities.

One of those capabilities is the ability to escape the main tumor and spread, or metastasize, to other sites in the body. Not every cancer cell has this ability. But just like bacteria can share the ability to resist antibiotics, at least some cancer cells may be able to share the ability to spread.

According to a study by Judy Lieberman, MD, PhD, of Boston Children’s Hospital’s Program in Cellular and Molecular Medicine, breast cancer cells that can metastasize can tell those that can’t to turn that ability on. That conversation takes place via small pieces of RNA called microRNAs, delivered in microscopic packages called extracellular vesicles.

According to Lieberman, not only do her team’s data give insight into the metastatic process, they might also reveal the first example of cancer cells teaching each other.

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CES offers a glimpse into the connected health future

Bluetooth pacifier thermometer CES Consumer Electronics Show health gadgets wearables
A Bluetooth pacifier/thermometer? (Photo: Bluemaestro

A Bluetooth pacifier that takes a baby’s temperature. An iPhone otoscope. A smart yoga mat. And health & fitness trackers out the wazoo. That’s just a small sampling of the health-related technologies showcased at last week’s Consumer Electronics Show (or CES).

The Las Vegas-based annual trade fair, a weeklong playdate for gadgetphiles, largely focuses on TVs, computers, cameras, entertainment and mobile gear. This year it also had a robust health and biotech presence, with more than 300 health and biotech exhibitors.

“I witnessed literally hundreds of companies all vying for the wrists and attention of users,” Michael Docktor, MD, Boston Children’s Hospital’s clinical director of innovation and director of clinical mobile solutions, wrote on BetaBoston. “For me, it was a chance to see where medicine and health care are headed.”

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Is pediatric cancer research entering a “post-genomic” period?

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“Genome” has been the biggest word in cancer research in the last decade. Thanks largely to the high throughput and relatively low cost of “next generation” DNA-sequencing technologies, researchers have screened thousands of tumors for gene mutations that could explain their malignant properties and reveal possible treatment targets.

Sequencing of adult tumors has revealed a broad spectrum of cancer-causing gene mutations. Childhood tumors, by contrast, have turned out to be relatively simple from a genomic point of view. By and large, they harbor few mutations in genes that code for relatively “druggable” targets with discrete effects, like kinases.

“Pediatric tumors are very ‘pure,’ with very low mutation rates,” says Carlos Rodriguez-Galindo, MD, director of the Solid Tumor Center at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. “To really understand the nature of pediatric cancer, we need to turn to epigenetics and gene regulation.”

Rodriguez-Galindo is not alone in this view. There is a trend afoot in pediatric cancer research: the study of gene regulation and epigenetics is beginning to overshadow classic tumor genetics and genomics.

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Overturning dogma to open the black box of DIPG

pons DIPG brain tumor brainstem glioma

You can’t advance the care of a disease that you can’t study. And for 40 years, that was the case with a rare, uniformly fatal pediatric brain tumor called diffuse intrinsic pontine glioma, or DIPG.

DIPG isn’t like most brain tumors. Rather than forming a solid mass, it weaves itself among the nerve fibers of the pons—a structure in the brain stem that controls vital functions like breathing, blood pressure and heart rate—making it impossible to biopsy. At least, that’s been the dogma.

“DIPG is the only tumor that historically has not been biopsied, because it’s found in such a critical place in the brain,” says Mark Kieran, MD, PhD, director of the Brain Tumor Center at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. “In the 1970s and ‘80s, children with DIPG who underwent biopsy had multiple neurologic complications, so the dogma became ‘no biopsies.'”

As a result, research was stalled by a lack of available tumor tissue to study. To address this, Kieran and his colleagues Nalin Gupta, MD, and Michael Prados, MD, PhD, of the University of California, San Francisco, launched a new clinical trial of DIPG in 2012. The trial is leveraging advances in microsurgery and genomics to give researchers their first peek into the molecular nature of DIPGs.

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Quality assurance for genome editing

Chromosome breaks translocations gene editing CRISPR TALENs ZFNs zinc fingers Frederick Alt
When chromosomes break, the ends can join together in a number of ways, some of which can cause trouble. A new QA method could help researchers avoid making problematic breaks when using gene editing technologies like CRISPR.

Labs the world over are jumping onto the gene editing bandwagon (and into the inevitable patent arguments). And it’s hard to blame them. As these technologies have evolved over the last two decades starting with the zinc finger nucleases (ZFNs), followed by transcription activator-like effector nucleases (TALENs) and CRISPR—they’ve become ever more powerful and easier to use.

But one question keeps coming up: How precise are these systems? After all, a method that selectively mutates, deletes or swaps specific gene sequences (and now can even turn genes on) is only as good as its accuracy.

Algorithms can predict the likely “off-target” edits based on the target’s DNA sequence, but they’re based on limited data. “The algorithms are getting better,” says Richard Frock, PhD, a fellow in the laboratory of Frederick Alt, PhD, at Boston Children’s Hospital. “But you still worry about the one rare off-target effect that’s not predicted but falls in a coding region and totally debilitates a gene.”

Frock, Alt (who leads Boston Children’s Program in Cellular and Molecular Medicine, or PCMM), fellow Jiazhi Hu, PhD, and their collaborators recently turned a method first developed in Alt’s lab for studying broken chromosomes into a quality assurance tool for genome editing. As a bonus, the method—called high-throughput genome translocation sequencing (HTGTS)—also reveals the “collateral damage” gene editing methods might create in a cell’s genome, information that could help researchers make better choices when designing gene editing experiments.

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CRISPR gene editing is creating a buzz in Boston

Boston Globe CRISPR gene editing research

You have an immune system. Your cat has an immune system. And bacteria have an immune system, too—one that we’ve tapped to make one of the most powerful tools ever for editing genes.

The tool is called CRISPR (for “clustered regularly interspaced short palindromic repeats”), and it makes use of enzymes that “remember” viral genes and cut them out of bacterial genomes. Applied to bioengineering, CRISPR is launching a revolution. And the Boston Globe reported over the weekend that while researchers at the University of California at Berkeley first developed CRISPR, the technique is booming in labs around Boston.

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