Manipulating Microbes: New Toolbox for Better Health?

Bacteroides thetaiotaomicron

Caption: Bacteroides thetaiotaomicron (white) living on mammalian cells in the gut (large pink cells coated in microvilli) and being activated by exogenously added compounds (small green dots) to express specific genes, such as those encoding light-generating luciferase proteins (glowing bacteria).
Credit: Janet Iwasa, Broad Visualization Group, MIT Media Lab

When you think about the cells that make up your body, you probably think about the cells in your skin, blood, heart, and other tissues and organs. But the one-celled microbes that live in and on the human body actually outnumber your own cells by a factor of about 10 to 1. Such microbes are especially abundant in the human gut, where some of them play essential roles in digestion, metabolism, immunity, and maybe even your mood and mental health. You are not just an organism. You are a superorganism!

Now imagine for a moment if the microbes that live inside our guts could be engineered to keep tabs on our health, sounding the alarm if something goes wrong and perhaps even acting to fix the problem. Though that may sound like science fiction, an NIH-funded team from the Massachusetts Institute of Technology (MIT) in Cambridge, MA, is already working to realize this goal. Most recently, they’ve developed a toolbox of genetic parts that make it possible to program precisely one of the most common bacteria found in the human gut—an achievement that provides a foundation for engineering our collection of microbes, or microbiome, in ways that may treat or prevent disease.

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Snapshots of Life: Host vs. Pathogen

Cryptoccocus neoformans

Caption: This scanning electron microscopy image shows mouse macrophages (green) interacting with a fungal cell (blue).
Credit: Sabriya Stukes and Hillary Guzik, Albert Einstein College of Medicine

Macrophages are white blood cells that generally destroy foreign invaders by engulfing them. It’s a tried-and-true strategy, but it doesn’t always work. Cryptoccocus neoformans, a deadly fungal pathogen commonly found in the feces of pigeons, can foil even the best macrophages. No one has captured this grand escape—but researchers are getting a whole lot closer to doing so.

Sabriya Stukes, an NIH-funded microbiologist at New York’s Albert Einstein College of Medicine, studies the interactions between C. neoformans and macrophages to determine how the former causes the lung infection cryptococcosis, which can be deadly for people with compromised immune systems. Stukes believes what makes C. neoformans so dangerous is that it can survive the acid death chamber inside macrophages—a situation that spells doom for most other pathogens. A big reason behind this fungus’s power of survival is its thick coat of polysaccharides, which serves as woolly-looking armor. Once a macrophage engulfs the fungus, this coat can give the white blood cell “indigestion,” prompting it to spit the fungus back into the lungs where it can cause disease.  Continue reading

Creative Minds: Meet a Theoretical Neuroscientist

Sean Escola

Sean Escola

Most neuroscientists make their discoveries in a traditional laboratory or clinical setting. Sean Escola, a theoretical neuroscientist at Columbia University in New York, just needs a powerful computer and, judging from his photo, a good whiteboard.

Using data that he and his colleagues have recorded from living brain cells, called neurons, Escola crunches numbers to develop rigorous statistical models that simulate the activity of neuronal circuits within the brain. He hopes his models will help to build a new neuroscience that brings into sharper focus how the brain’s biocircuitry lights up to generate sensations and thoughts—and how it misfires in various neurological disorders, particularly in mental illnesses.

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Cool Videos: Battling Bad Biofilms

Metabolomics of Bacterial BiofilmsPeriodically, I’ve posted some of the winners of the video competition to celebrate the Tenth Anniversary of the NIH Common Fund. After an intermission of several months, our scientific film fest is back to take another bow. This cool animation shows what some NIH-funded researchers are doing to address a serious health threat: hospital-acquired infections. Such infections can lead to hard-to-heal wounds, such as the foot sores that can trouble people with diabetes, and pressure ulcers in the elderly.

The stubbornness of such wounds owes, in part, to the infection-causing bacteria joining forces to improve their chances of survival within the injury. These microbes literally stick together to form microbial communities, called biofilms, that can resist antibiotics and evade our immune defenses. This strength in numbers has researchers pondering strategies that target the entire biofilm in innovative ways. One promising possibility involves exploiting metabolomics, which tracks the products produced by the bacterial troublemakers, and may provide new perspectives on how to battle this increasingly common healthcare problem.

The video was made by the laboratory of Mary Cloud Ammons at Montana State University in Bozeman. Ammons, who receives research support through the NIH Common Fund to study bacterial metabolomics, describes her work in this way: “The sixth leading cause of death in the United States is the result of hospital-acquired infections, which often result in nonhealing wounds colonized by communities of bacteria call biofilms. The research in our lab aims to uncover the mechanisms at the root of the deviation from the normal healing process that results in the development of chronic wounds. These metabolomic studies identify specific metabolite profiles that may be associated with pathogenicity in the chronic wound and could potentially be used in novel noninvasive diagnostics.”

Links:

Ammons Lab (Montana State University, Bozeman)

Ammons NIH Project Information (NIH RePORTER)

Common Fund (NIH)

Vaccine Research: New Tactics for Tackling HIV

HIV-infected Immune Cell

Caption: Scanning electron micrograph of an HIV-infected immune cell.
Credit: National Institute of Allergy and Infectious Diseases, NIH

For many of the viruses that make people sick—think measles, smallpox, or polio—vaccines that deliver weakened or killed virus encourage the immune system to produce antibodies that afford near complete protection in the event of an exposure. But that simple and straightforward approach doesn’t work in the case of human immunodeficiency virus (HIV), the virus that causes AIDS. In part, that’s because our immune system is poorly equipped to recognize HIV and mount an attack against the infection. To make matters worse, HIV has a habit of quickly mutating as it multiplies.That means, in order for an HIV vaccine to be effective, it must induce antibodies capable of fighting against a wide range of HIV strains. For all these reasons, the three decades of effort to develop an HIV vaccine have turned out to be enormously challenging and frustrating.

But now I’m pleased to report that NIH-funded scientists have taken some encouraging strides down this path. In two papers published in Science [1, 2] and one in Cell [3], researchers presented results of animal studies that support what most vaccine experts have come to suspect: the immune system is in fact capable of producing the kind of antibodies that should be protective against HIV, but it takes more than one step to get there. In effect, a successful vaccine strategy has to “take the immune system to school,” and it requires more than one lesson to pass the final exam. Specifically, what’s needed seems to be a series of shots—each consisting of a different engineered protein designed to push the immune system, step by step, toward the production of protective antibodies that will work against virtually all HIV strains.

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