Snapshots of Life: Biological Bubble Machine

plasma membrane vesicles

Credit: Chi Zhao, David Busch, Connor Vershel, Jeanne Stachowiak, University of Texas at Austin

As kids, most of us got a bang out of blowing soap bubbles and watching them float around. Biologists have learned that some of our cells do that too. On the right, you can see two cells (greenish yellow) in the process of forming bubbles, or plasma membrane vesicles (PMVs). During this blebbing process, a cell’s membrane temporarily disassociates from its underlying cytoskeleton, forming a tiny pouch that, over the course of about 30 minutes, is “inflated” with a mix of proteins and lipids from inside the cell. After the PMVs are fully filled, these bubble-like structures are pinched off and released, like those that you see in the background. Certain cells constantly release PMVs, along with other types of vesicles, and may use those to communicate with other cells throughout the body.

This particular image, an entrant in the Biophysical Society’s 2017 Art of Science Image Contest, was produced by researchers working in the NIH-supported lab of Jeanne Stachowiak at the University of Texas at Austin. Stachowiak’s group is among the first to explore the potential of PMVs as specialized drug-delivery systems to target cancer and other disorders [1].

Until recently, most efforts to exploit vesicles for therapeutic uses have employed synthetic versions of a different type of vesicle, called an exosome. But Stachowiak and others have realized that PMVs come with certain built-in advantages. A major one is that a patient’s own cells could in theory serve as the production facility.

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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

Cardiometabolic Disease: Big Data Tackles a Big Health Problem

Cardiometabolic risk lociMore and more studies are popping up that demonstrate the power of Big Data analyses to get at the underlying molecular pathology of some of our most common diseases. A great example, which may have flown a bit under the radar during the summer holidays, involves cardiometabolic disease. It’s an umbrella term for common vascular and metabolic conditions, including hypertension, impaired glucose and lipid metabolism, excess belly fat, and inflammation. All of these components of cardiometabolic disease can increase a person’s risk for a heart attack or stroke.

In the study, an international research team tapped into the power of genomic data to develop clearer pictures of the complex biocircuitry in seven types of vascular and metabolic tissue known to be affected by cardiometabolic disease: the liver, the heart’s aortic root, visceral abdominal fat, subcutaneous fat, internal mammary artery, skeletal muscle, and blood. The researchers found that while some circuits might regulate the level of gene expression in just one tissue, that’s often not the case. In fact, the researchers’ computational models show that such genetic circuitry can be organized into super networks that work together to influence how multiple tissues carry out fundamental life processes, such as metabolizing glucose or regulating lipid levels. When these networks are perturbed, perhaps by things like inherited variants that affect gene expression, or environmental influences such as a high-carb diet, sedentary lifestyle, the aging process, or infectious disease, the researchers’ modeling work suggests that multiple tissues can be affected, resulting in chronic, systemic disorders including cardiometabolic disease.

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Precision Oncology: Nanoparticles Target Bone Cancers in Dogs

Timothy Fan and his dog Ember

Caption: Veterinary researcher Timothy Fan with his healthy family pet Ember.
Credit: L. Brian Stauffer

Many people share their homes with their pet dogs. Spending years under the same roof with the same environmental exposures, people and dogs have something else in common that sometimes gets overlooked. They can share some of the same diseases, such as diabetes and cancer. By studying these diseases in dogs, researchers can learn not only to improve care for people but for their canine friends as well.

As a case in point, an NIH-funded team of researchers recently tested a new method of delivering chemotherapy drugs for osteosarcoma, a bone cancer that affects dogs and people, typically teenagers and older adults. Their studies in dogs undergoing treatment for osteosarcoma suggest that specially engineered, bone-seeking nanoparticles might safely deliver anti-cancer drugs precisely to the places where they are most needed. These early findings come as encouraging news for the targeted treatment of inoperable bone cancers and other malignancies that spread to bone.

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Creative Minds: Engineering Targeted Breast Cancer Treatments

Photo of Debra Auguste

Debra Auguste

A few years ago, Debra Auguste, a chemical engineer then at Harvard University, was examining the statistics on breast cancer: the second most common cancer in women in the U.S. after lung cancer. She was disturbed to discover that of all the ethnic groups, African American women with breast cancer suffered the highest mortality rates—with 30.8% dying from the disease [1-3].

As an African American woman, Auguste was stunned by this correlation. She wondered whether there was some genetic aspect of breast cancer cells in African Americans that made these cancers more aggressive and more difficult to cure.

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