Tag: kidney diseases

Bioethics Blogs

Protein Links Gut Microbes, Biological Clocks, and Weight Gain

Caption: Lipids (red) inside mouse intestinal cells with and without NFIL3.
Credit: Lora V. Hooper, University of Texas Southwestern Medical Center, Dallas

The American epidemic of obesity is a major public health concern, and keeping off the extra pounds is a concern for many of us. Yet it can also be a real challenge for people who may eat normally but get their days and nights mixed up, including night-shift workers and those who regularly travel overseas. Why is that?

The most obvious reason is the odd hours throw a person’s 24-hour biological clock—and metabolism—out of sync. But an NIH-funded team of researchers has new evidence in mice to suggest the answer could go deeper to include the trillions of microbes that live in our guts—and, more specifically, the way they “talk” to intestinal cells. Their studies suggest that what gut microbes “say” influences the activity of a key clock-driven protein called NFIL3, which can set intestinal cells up to absorb and store more fat from the diet while operating at hours that might run counter to our fixed biological clocks.

NFIL3 is a transcription factor, a protein that switches certain genes on and off. Earlier studies had focused on its role in immune cells, but a team led by Lora Hooper at the University of Texas Southwestern Medical Center, Dallas, discovered that NFIL3 is also found in cells in the inner lining, or epithelium, of the mouse small intestine.

Intriguingly, as reported recently in the journal Science [1], they noticed that NFIL3 levels were much lower in the intestines of “germ-free” mice that don’t have any gut microbes.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics Blogs

Snapshots of Life: Fighting Urinary Tract Infections

Source: Valerie O’Brien, Matthew Joens, Scott J. Hultgren, James A.J. Fitzpatrick, Washington University, St. Louis

For patients who’ve succeeded in knocking out a bad urinary tract infection (UTI) with antibiotic treatment, it’s frustrating to have that uncomfortable burning sensation flare back up. Researchers are hopeful that this striking work of science and art can help them better understand why severe UTIs leave people at greater risk of subsequent infection, as well as find ways to stop the vicious cycle.

Here you see the bladder (blue) of a laboratory mouse that was re-infected 24 hours earlier with the bacterium Escherichia coli (pink), a common cause of UTIs. White blood cells (yellow) reach out with what appear to be stringy extracellular traps to immobilize and kill the bacteria.

Valerie O’Brien, a graduate student in Scott Hultgren’s lab at Washington University, St. Louis, snapped this battle of microbes and white blood cells using a scanning electron microscope and then colorized it to draw out the striking details. It was one of the winners in the Federation of American Societies for Experimental Biology’s 2016 BioArt competition.

As reported last year in Nature Microbiology, O’Brien and her colleagues have evidence that severe UTIs leave a lasting imprint on bladder tissue [1]. That includes structural changes to the bladder wall and modifications in the gene activity of the cells that line its surface. The researchers suspect that a recurrent infection “hotwires” the bladder to rev up production of the enzyme Cox2 and enter an inflammatory state that makes living conditions even more hospitable for bacteria to grow and flourish.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics Blogs

Regenerative Medicine: Making Blood Stem Cells in the Lab

Caption: Arrow in first panel points to an endothelial cell induced to become hematopoietic stem cell (HSC). Second and third panels show the expansion of HSCs over time.
Credit: Raphael Lis, Weill Cornell Medicine, New York, NY

Bone marrow transplants offer a way to cure leukemia, sickle cell disease, and a variety of other life-threatening blood disorders.There are two major problems, however: One is many patients don’t have a well-matched donor to provide the marrow needed to reconstitute their blood with healthy cells. Another is even with a well-matched donor, rejection or graft versus host disease can occur, and lifelong immunosuppression may be needed.

A much more powerful option would be to develop a means for every patient to serve as their own bone marrow donor. To address this challenge, researchers have been trying to develop reliable, lab-based methods for making the vital, blood-producing component of bone marrow: hematopoietic stem cells (HSCs).

Two new studies by NIH-funded research teams bring us closer to achieving this feat. In the first study, researchers developed a biochemical “recipe” to produce HSC-like cells from human induced pluripotent stem cells (iPSCs), which were derived from mature skin cells. In the second, researchers employed another approach to convert mature mouse endothelial cells, which line the inside of blood vessels, directly into self-renewing HSCs. When these HSCs were transplanted into mice, they fully reconstituted the animals’ blood systems with healthy red and white blood cells.

As reported in Nature, both teams took advantage of earlier evidence showing that HSCs are formed during embryonic development from budding endothelial cells in the aorta.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics Blogs

Creative Minds: The Human Gut Microbiome’s Top 100 Hits

Michael Fishbach

Microbes that live in dirt often engage in their own deadly turf wars, producing a toxic mix of chemical compounds (also called “small molecules”) that can be a source of new antibiotics. When he started out in science more than a decade ago, Michael Fischbach studied these soil-dwelling microbes to look for genes involved in making these compounds.

Eventually, Fischbach, who is now at the University of California, San Francisco, came to a career-altering realization: maybe he didn’t need to dig in dirt! He hypothesized an even better way to improve human health might be found in the genes of the trillions of microorganisms that dwell in and on our bodies, known collectively as the human microbiome.

Fischbach is most interested in bacteria living in the human gut, especially the many species that generally live in harmony with us. These microbes produce thousands of small molecules, some so abundantly that they are absorbed into the bloodstream at levels comparable to a drug. Concentrations of these small molecules can vary dramatically from person to person, but researchers still don’t know exactly why.

Fischbach has received a 2016 NIH Director’s Pioneer Award to conduct research aimed at gaining a better understanding of the small molecules made by the human gut microbiome. He will begin by creating a “Top 100” list of its most-abundant molecules. Armed with this information, Fischbach’s team will set about assembling and growing beneficial communities of bacteria in the lab, with the ultimate aim of repopulating a sick person’s gut with a collection of microbes that make health-promoting small molecules.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics Blogs

Muscle Enzyme Explains Weight Gain in Middle Age

Thinkstock/tetmc

The struggle to maintain a healthy weight is a lifelong challenge for many of us. In fact, the average American packs on an extra 30 pounds from early adulthood to age 50. What’s responsible for this tendency toward middle-age spread? For most of us, too many calories and too little exercise definitely play a role. But now comes word that another reason may lie in a strong—and previously unknown—biochemical mechanism related to the normal aging process.

An NIH-led team recently discovered that the normal process of aging causes levels of an enzyme called DNA-PK to rise in animals as they approach middle age. While the enzyme is known for its role in DNA repair, their studies show it also slows down metabolism, making it more difficult to burn fat. To see if reducing DNA-PK levels might rev up the metabolism, the researchers turned to middle-aged mice. They found that a drug-like compound that blocked DNA-PK activity cut weight gain in the mice by a whopping 40 percent!

Jay H. Chung, an intramural researcher with NIH’s National Heart, Lung, and Blood Institute, had always wondered why many middle-aged people and animals gain weight even when they eat less. To explain this paradox, his team looked to biochemical changes in the skeletal muscles of middle-aged mice and rhesus macaques, whose stage in life would be roughly equivalent to a 45-year-old person.

Their studies, published recently in Cell Metabolism, uncovered evidence in both species that DNA-PK increases in skeletal muscle with age [1]. The discovery proved intriguing because the enzyme’s role in aging was completely unknown.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics Blogs

H3Africa: Fostering Collaboration

Caption: Pioneers in building Africa’s genomic research capacity; front, Charlotte Osafo (l) and Yemi Raji; back, David Burke (l) and Tom Glover.
Credit: University of Michigan, Ann Arbor

About a year ago, Tom Glover began sifting through a stack of applications from prospective students hoping to be admitted into the Master’s Degree Program in Human Genetics at the University of Michigan, Ann Arbor. Glover, the program’s director, got about halfway through the stack when he noticed applications from two physicians in West Africa: Charlotte Osafo from Ghana, and Yemi Raji from Nigeria. Both were kidney specialists in their 40s, and neither had formal training in genomics or molecular biology, which are normally requirements for entry into the program.

Glover’s first instinct was to disregard the applications. But he noticed the doctors were affiliated with the Human Heredity and Health in Africa (H3Africa) Initiative, which is co-supported by the Wellcome Trust and the National Institutes of Health Common Fund, and aims in part to build the expertise to carry out genomics research across the continent of Africa. (I am proud to have had a personal hand in the initial steps that led to the founding of H3Africa.) Glover held onto the two applications and, after much internal discussion, Osafo and Raji were admitted to the Master’s Program. But there were important stipulations: they had to arrive early to undergo “boot camp” in genomics and molecular biology and also extend their coursework over an extra term.

Both agreed and were soon put through the paces of performing basic lab techniques, hearing about the latest in DNA sequencing, learning the basics of designing genomic studies, and immersing themselves in their courses.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics Blogs

Cool Videos: Making Multicolored Waves in Cell Biology

Bacteria are single-cell organisms that reproduce by dividing in half. Proteins within these cells organize themselves in a number of fascinating ways during this process, including a recently discovered mechanism that makes the mesmerizing pattern of waves, or oscillations, you see in this video. Produced when the protein MinE chases the protein MinD from one end of the cell to the other, such oscillations are thought to center the cell’s division machinery so that its two new “daughter cells” will be the same size.

To study these dynamic patterns in greater detail, Anthony Vecchiarelli purified MinD and MinE proteins from the bacterium Escherichia coli. Vecchiarelli, who at the time was a postdoc in Kiyoshi Mizuuchi’s intramural lab at NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), labeled the proteins with fluorescent markers and placed them on a synthetic membrane, where their movements were then visualized by total internal reflection fluorescence microscopy. The proteins self-organized and generated dynamic spirals of waves: MinD (blue, left); MinE (red, right); and both MinD and MinE (purple, center) [1].

Dissecting how such patterns form outside of the cell is helping to unravel the oscillatory mechanism used inside the cell. While E. coli was the model used to produce this video—a recent winner in the Federation of American Societies for Experimental Biology’s BioArt contest, many other microbes have similar proteins.

Vecchiarelli, Mizuuchi, and their colleagues have gone on to uncover what they think are the foundational principles governing this dynamic pattern of protein self-organization that appears to regulate positioning spatially during bacterial cell division [2].

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics Blogs

Cool Videos: Flashes of Neuronal Brilliance

When you have a bright idea or suddenly understand something, you might say that a light bulb just went on in your head. But, as the flashing lights of this very cool video show, the brain’s signaling cells, called neurons, continually switch on and off in response to a wide range of factors, simple or sublime.

The technology used to produce this video—a recent winner in the Federation of American Societies for Experimental Biology’s BioArt contest—takes advantage of the fact that whenever a neuron is activated, levels of calcium increase inside the cell. To capture that activity, graduate student Caitlin Vander Weele in Kay M. Tye’s lab at the Picower Institute for Learning and Memory, Massachusetts Institute of Technology (MIT), Cambridge, MA, engineered neurons in a mouse’s brain to produce a bright fluorescent signal whenever calcium increases. Consequently, each time a neuron was activated, the fluorescent indicator lit up and the changes were detected with a miniature microscope. The brighter the flash, the greater the activity!

What’s amazing about this innovative system is it provides a unique view into the activity of individual neurons in the brains of living animals in real-time. In this particular video, the researchers assessed the activity of various neuronal subpopulations in the medial prefrontal cortex, which is a brain region involved in complex cognitive behaviors, while mice performed tasks accompanied by either rewards or punishments. In humans, many neuropsychiatric disorders, including addiction and depression, are characterized by an imbalance between the motivation to seek rewards and avoid punishment. Consequently, improving our fundamental understanding of how the mammalian brain works may be useful in developing new ways to help people with such disorders.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics Blogs

Built for the Future. Study Shows Wearable Devices Can Help Detect Illness Early

Caption: Stanford University’s Michael Snyder displays some of his wearable devices.
Credit: Steve Fisch/Stanford School of Medicine

Millions of Americans now head out the door each day wearing devices that count their steps, check their heart rates, and help them stay fit in general. But with further research, these “wearables” could also play an important role in the early detection of serious medical conditions. In partnership with health-care professionals, people may well use the next generation of wearables to monitor vital signs, blood oxygen levels, and a wide variety of other measures of personal health, allowing them to see in real time when something isn’t normal and, if unusual enough, to have it checked out right away.

In the latest issue of the journal PLoS Biology [1], an NIH-supported study offers an exciting glimpse of this future. Wearing a commercially available smartwatch over many months, more than 40 adults produced a continuous daily stream of accurate personal health data that researchers could access and monitor. When combined with standard laboratory blood tests, these data—totaling more than 250,000 bodily measurements a day per person—can detect early infections through changes in heart rate.

The study, led by Michael Snyder, a scientist at Stanford University, Palo Alto, CA, grew out of a larger ongoing clinical research study that tracks adults who are healthy or pre-diabetic for genomic and biochemical clues into health and disease. The researchers wondered whether adding wearables to the study could give them another window into the differences between early diabetes and health.

After evaluating more than 400 wearables, the team members settled on seven that were inexpensive and easy to use.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.

Bioethics Blogs

Happy New Year: Looking Back at 2016 Research Highlights

Happy New Year! While everyone was busy getting ready for the holidays, the journal Science announced its annual compendium of scientific Breakthroughs of the Year. If you missed it, the winner for 2016 was the detection of gravitational waves—tiny ripples in the fabric of spacetime created by the collision of two black holes 1.3 billion years ago! It’s an incredible discovery, and one that Albert Einstein predicted a century ago.

Among the nine other advances that made the first cut for Breakthrough of the Year, several involved the biomedical sciences. As I’ve done in previous years (here and here), I’ll kick off this New Year by taking a quick look of some of the breakthroughs that directly involved NIH support:

DNA analysis and human migration: I highlighted this intriguing advance on my blog last September. All humans trace their ancestry to Africa. But there has been considerable room for debate about exactly when and how many times modern humans departed Africa to take up residence in distant locations throughout the world.

Three new studies—two of which received NIH funding—helped to fill in some of those missing pages of our evolutionary history [1-3]. The genomic evidence suggests that the earliest human inhabitants of Eurasia came from Africa and began to diverge genetically at least 50,000 years ago. While the new studies differ somewhat in their conclusions, the findings also lend support to the notion that our modern human ancestors dispersed out of Africa primarily in a single migratory event. If an earlier and ultimately failed dispersion occurred, it left little trace in the genomes of people alive today.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.