Demystifying General Anesthetics

When Margaret Sedensky, now of Seattle Children’s Research Institute, started as an anesthesiology resident, she wasn’t entirely clear on how anesthetics worked. “I didn’t know, but I figured someone did,” she says. “I asked the senior resident. I asked the attending. I asked the chair. Nobody knew.”

For many years, doctors called general anesthetics a “modern mystery.” Even though they safely administered anesthetics to millions of Americans, they didn’t know exactly how the drugs produced the different states of general anesthesia. These states include unconsciousness, immobility, analgesia (lack of pain) and amnesia (lack of memory).

Stock image of a symphony.
Like the instruments that make up an orchestra, many molecular targets may contribute to an anesthetic producing the desired effect. Credit: Stock image.

Understanding anesthetics has been challenging for a number of reasons. Unlike many drugs that act on a limited number of proteins in the body, anesthetics interact with seemingly countless proteins and other molecules. Additionally, some anesthesiologists believe that anesthetics may work through a number of different molecular pathways. This means no single molecular target may be required for an anesthetic to work, or no single molecular target can do the job without the help of others.

“It’s like a symphony,” says Roderic Eckenhoff of the University of Pennsylvania Perelman School of Medicine, who has studied anesthesia for decades. “Each molecular target is an instrument, and you need all of them to produce Beethoven’s 5th.” Continue reading

Cracking a Ubiquitous Code

We asked the heads of our scientific divisions to tell us about some of the big questions in fundamental biomedical science that researchers are investigating with NIGMS support. This article is the third in an occasional series that explores these questions and explains how pursuing the answers could advance understanding of important biological processes.

Ubiquitin (Ub) molecules
Ubiquitin (Ub) molecules attached to proteins can form possibly hundreds of different shapes. Credit: NIGMS.

Researchers are on a quest to crack a code made by ubiquitin, a small protein that plays a big role in coordinating cellular function. By attaching to other proteins, ubiquitin determines what those proteins should do next.

Just as zip codes direct letters to specific towns, the ubiquitin code might direct one protein to help with DNA repair, another to assist in cell division, and a third to transport molecules into and out of cells. Continue reading

How Cells Manage Chance

We asked the heads of our scientific divisions to tell us about some of the big questions in fundamental biomedical science that researchers are investigating with NIGMS support. This article is the second in an occasional series that explores these questions and explains how pursuing the answers could advance understanding of important biological processes.

Sample slide, variability of mRNA in yeast cells
The number of copies of mRNA molecules (bright green) observed here in yeast cells (dark blue) fluctuates randomly. Credit: David Ball, Virginia Tech.

For some health conditions, the cause is clear: A single altered gene is responsible. But for many others, the path to disease is more complex. Scientists are working to understand how factors like genetics, lifestyle and environmental exposures all contribute to disease. Another important, but less well-known, area of investigation is the role of chance at the molecular level.

One team working in this field is led by John Tyson Exit icon at Virginia Tech. The group focuses on how chance events affect the cell division cycle, in which a cell duplicates its contents and splits into two. This cycle is the basis for normal growth, reproduction and the replenishment of skin, blood and other cells throughout the body. Errors in the cycle are associated with a number of conditions, including birth defects and cancer. Continue reading

How a Cell Knows Friend From Foe

We asked the heads of our scientific divisions to tell us about some of the big questions in fundamental biomedical science that researchers are investigating with NIGMS support. This article is the first in an occasional series that will explore these questions and explain how pursuing the answers could advance understanding of important biological processes.

Video screen shot showing different strains of amoeba cells in red and green.
This video shows different strains of amoeba cells in red and green. As cells move toward one another, they use two sets of proteins to recognize others from the same strain. When close relatives meet, their proteins match and the cells join together to form a multicellular structure. When cells from different strains meet, their proteins don’t match, so they can’t aggregate. Credit: Shigenori Hirose, Baylor College of Medicine.

Cells are faced with many decisions: When’s the best time to produce a new protein? To grow and split into two? To treat another cell as an invader? Scientists are working to understand how cells make these and many other decisions, and how these decisions contribute to health and disease.

An active area of research on cell decisions focuses on allorecognition, the ability of an organism to distinguish its own cells from those of another. Immune cells use a system called the major histocompatibility complex (MHC) to identify which cells belong to the body and which are foreign. The particular set of MHC proteins on the outer surface of a cell helps immune cells decide whether it does not belong and should be attacked.

But the system isn’t perfect. Invading pathogens can go undetected, and the body can mistake its own cells for intruders. Continue reading