Creative Minds: Can Diseased Cells Help to Make Their Own Drugs?

Matthew Disney

Matthew Disney

Matthew Disney grew up in a large family in Baltimore in the 1980s. While his mother worked nights, Disney and his younger brother often tagged along with their father in these pre-Internet days on calls to fix the microfilm machines used to view important records at hospitals, banks, and other places of business. Watching his father take apart the machines made Disney want to work with his hands one day. Seeing his father work tirelessly for the sake of his family also made him want to help others.

Disney found a profession that satisfied both requirements when he fell in love with chemistry as an undergraduate at the University of Maryland, College Park. Now a chemistry professor at The Scripps Research Institute, Jupiter, FL, Disney is applying his hands and brains to develop a treatment strategy that aims to control the progression of a long list of devastating disorders that includes Huntington’s disease, amyotrophic lateral sclerosis (ALS), and various forms of muscular dystrophy.

The 30 or so health conditions on Disney’s list have something in common. They are caused by genetic glitches in which repetitive DNA letters (CAGCAGCAG, for example) in transcribed regions of the genome cause some of the body’s cells and tissues to produce unwieldy messenger RNA molecules that interfere with normal cellular activities, either by binding other intracellular components or serving as templates for the production of toxic proteins.

The diseases on Disney’s list also have often been considered “undruggable,” in part because the compounds capable of disabling the lengthy, disease-causing RNA molecules are generally too large to cross cell membranes. Disney has found an ingenious way around that problem [1]. Instead of delivering the finished drug, he delivers smaller building blocks. He then uses the cell and its own machinery, including the very aberrant RNA molecules he aims to target, as his drug factory to produce those larger compounds.

Disney has received an NIH Director’s 2015 Pioneer Award to develop this innovative drug-delivery strategy further. He will apply his investigational approach initially to treat a common form of muscular dystrophy, first using human cells in culture and then in animal models. Once he gets that working well, he’ll move on to other conditions including ALS.

What’s appealing about Disney’s approach is that it makes it possible to treat disease-affected cells without affecting healthy cells. That’s because his drugs can only be assembled into their active forms in cells after they are templated by those aberrant RNA molecules.

Interestingly, Disney never intended to study human diseases. His lab was set up to study the structure and function of RNA molecules and their interactions with other small molecules. In the process, he stumbled across a small molecule that targets an RNA implicated in a rare form of muscular dystrophy. His niece also has a rare incurable disease, and Disney saw a chance to make a difference for others like her. It’s a healthy reminder that the pursuit of basic scientific questions often can lead to new and unexpectedly important medical discoveries that have the potential to touch the lives of many.

Reference:

[1] A toxic RNA catalyzes the in cellulo synthesis of its own inhibitor. Rzuczek SG, Park H, Disney MD. Angew Chem Int Ed Engl. 2014 Oct 6;53(41):10956-10959.

Links:

Disney Lab (The Scripps Research Institute, Jupiter, FL)

Disney NIH Project Information (NIH RePORTER)

NIH Director’s Pioneer Award Program

NIH Support: Common Fund; National Institute of Neurological Disorders and Stroke

Creative Minds: Of Arsenic and Misfolded Proteins

John Hanna

John Hanna

Taking out the trash is a must in every household. Inside our cells, it’s also essential because if defective proteins are not properly disposed of, they can accumulate and make a mess of the cell’s inner workings, leading to health problems.

John Hanna, a physician-scientist at Brigham and Women’s Hospital, Boston, is on a quest to study the cell’s trash disposal system in greater detail. In particular, this 2014 NIH Director’s Early Independence awardee wants to learn more about how cells identify proteins that need to be discarded, how such proteins are steered towards the molecular garbage can, and how, when the process breaks down, neurodegenerative conditions, cancers, and other diseases can arise.

That’s a complex challenge, so Hanna will start by zeroing in on one particular component of cellular waste management—the component that clears out proteins damaged by arsenic. Although arsenic is notorious for being the poison of choice in countless true crime shows and mystery novels, this semi-metallic element is found naturally in soil, water, air, and some foods.

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Brain Imaging: Tackling Chronic Traumatic Encephalopathy

Brain scans of CTE and AD

Caption: Left to right, brain PET scans of healthy control; former NFL player with suspected chronic traumatic encephalopathy (CTE); and person with Alzheimer’s disease (AD). Areas with highest levels of abnormal tau protein appear red/yellow; medium, green; and lowest, blue.
Credit: Adapted from Barrio et al., PNAS

If you follow the National Football League (NFL), you may have heard some former players describe their struggles with a type of traumatic brain injury called chronic traumatic encephalopathy (CTE). Known to be associated with repeated, hard blows to the head, this neurodegenerative disorder can diminish the ability to think critically, slow motor skills, and lead to volatile, even suicidal, mood swings. What’s doubly frustrating to both patients and physicians is that CTE has only been possible to diagnose conclusively after death (via autopsy) because it’s indistinguishable from many other brain conditions with current imaging methods.

But help might be starting to move out of the backfield toward the goal line of more accurate diagnosis. In findings published in the journal PNAS [1], NIH-supported scientists from the University of California, Los Angeles (UCLA) and the University of Chicago report they’ve made some progress toward imaging CTE in living people. Following up on their preliminary work published in 2013 [2], the researchers used a specially developed radioactive tracer that lights up a neural protein, called tau, known to deposit in certain areas of the brain in individuals with CTE. They used this approach on PET scans of the brains of 14 former NFL players suspected of having CTE, generating maps of tau distribution throughout various regions of the brain.

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Alzheimer’s-in-a-Dish: New Tool for Drug Discovery

Alzheimer's Disease in a dish

Caption: A plaque (orange) disrupts the normal network of human neurons (green) grown in a three-dimensional gel in the lab, mimicking the brain anatomy of Alzheimer’s patients.
Credit: Doo Yeon Kim and Rudolph E. Tanzi, Massachusetts General Hospital/ Harvard Medical School

Researchers want desperately to develop treatments to help the more than 5 million Americans with Alzheimer’s disease and the millions more at risk. But that’s proven to be extremely challenging for a variety of reasons, including the fact that it’s been extraordinarily difficult to mimic the brain’s complexity in standard laboratory models. So, that’s why I was particularly excited by the recent news that an NIH-supported team, led by Rudolph Tanzi at Boston’s Massachusetts General Hospital, has developed a new model called “Alzheimer’s in a dish.”

So, how did Tanzi’s group succeed where others have run up against a brick wall? The answer appears to lie in their decision to add a third dimension to their disease model.  Previous attempts at growing human brain cells in the lab and inducing them to form the plaques and tangles characteristic of Alzheimer’s disease were performed in a two-dimensional Petri dish system. And, in this flat, 2-D environment, plaques and tangles simply didn’t appear.

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Protein Pile-up: Common Cause of Brain Disease

Two images, one dark, one bright, resembling a finger.

Caption: Left: High levels of the toxic ataxin-1 protein have destroyed nerve cells in the cerebellum of a mouse, causing a severe disease. Right: Here researchers have genetically blocked the genes that normally produce high levels of ataxin-1. This prevents the disease from developing and keeps the brain healthy.
Credit: Harry Orr, Department of Laboratory Medicine and Pathology, University of Minnesota

With our aging population, more people are developing neurodegenerative disorders like Alzheimer’s and Parkinson’s disease. We currently don’t know how to prevent or cure these conditions, and their increasing prevalence not only represents a tragedy for affected individuals and their families, but also a looming public health and economic crisis.

Even though neurodegenerative diseases have varied roots—and affect distinct cell types in different brain regions—they do share something in common. In most of these disorders, we see some type of toxic protein accumulating in the brain. It’s as if the brain’s garbage disposal system is blocked, letting the waste pile up. In Huntington’s disease, huntingtin is the disease-causing protein. In spinocerebellar ataxia, it’s the ataxins. In Alzheimer’s, it’s beta-amyloid; in Parkinson’s, it’s α-synuclein. When garbage builds up in your kitchen, it’s a bad situation. When it’s in your brain, the consequences are deadly.

Last week, a team of NIH-funded researchers based at the Baylor College of Medicine in Texas and at the University of Minnesota revealed a clever way to identify genes that normally increase the levels of these rogue disease-causing proteins.

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