Quickly matching the drug with the bug saves lives
| GAINESVILLE, Fla. - Regenerative medicine scientists at the University of Florida's McKnight Brain Institute have created a system in rodent models that for the first time duplicates neurogenesis - the process of generating new brain cells - in a dish.
Writing in today's (June 13) Proceedings of the National Academy of Sciences, researchers describe a cell culture method that holds the promise of producing a limitless supply of a person's own brain cells to potentially heal disorders such as Parkinson's disease or epilepsy.
"It's like an assembly line to manufacture and increase the number of brain cells," said Bjorn Scheffler, M.D., a neuroscientist with UF's College of Medicine. "We can basically take these cells and freeze them until we need them. Then we thaw them, begin a cell-generating process, and produce a ton of new neurons."
If the discovery can translate to human applications, it will enhance efforts aimed at finding ways to use large numbers of a person's own cells to restore damaged brain function, partially because the technique produces cells in far greater amounts than the body can on its own.
In addition, the discovery pinpoints the cell that is truly what people refer to when they say "stem cell." Although the term is used frequently to describe immature cells that are the building blocks of bones, skin, flesh and organs, the actual stem cell as it exists in the brain has been enigmatic, according to Dennis Steindler, Ph.D., executive director of the McKnight Brain Institute and senior author of the paper. Its general location was known, but it was an obscure species in a sea of cell types.
"We've isolated for the first time what appears to be the true candidate stem cell," said Steindler, a neuroscientist and member of UF's Program of Stem Cell Biology and Regenerative Medicine. "There have been other candidates, but in this case we used a special microscope that allows us to watch living cells over long periods of time through a method called live-cell microscopy, so we've actually witnessed the stem cell give rise to new neurons. Possibly a different method may come up to identify the mother of all stem cells, but we're confident this is it."
During experiments, scientists collected cells from mice and used chemicals to induce them to differentiate. During the process, they snapped images of the cells every five minutes for up to 30 hours and compiled the images into movies. Traditional ways to attempt neurogenesis have been unable to so closely duplicate the natural process. They also haven't allowed scientists to monitor the entire sequence of cell development from primitive states to functional neurons and expose the electrophysiological properties of the cells.
A little more than a decade ago, scientists came to realize that the brain continues to produce small amounts of new cells even in adulthood, overturning the belief that people are born with a fixed amount of brain cells that must last them throughout their lives.
In people, stem cells develop naturally into full-fledged brain cells as they travel through a neural pathway that begins deep within the brain in a region called the subventricular zone. The primitive cells mature along the way, finishing as neurons in a spot called the olfactory bulb.
In the laboratory cultures, the cells still move about, but the pathway is no longer important, showing that neurogenesis does not necessarily require the environmental cues of the host brain.
The natural development of stem cells in the brain is very similar to the lifelong production of blood cells in the human body called hematopoiesis, with "poiesis" derived from the Greek word meaning "to make."
Scientists in Steindler's lab noticed the similarities between primitive cell development in blood and in the brain in the late 1990s, calling the process "neuropoiesis."
"The exciting part is we are actually using methods that researchers involved with hematopoiesis used," Scheffler said. "Those researchers took primitive cells, put them in a dish and watched them perform. From
that, they learned vital information for clinical applications such as bone marrow transplants. Now we have a tool to do exactly the same thing."
By watching the cells perform, scientists can make judgments and influence the capacity of the cells to generate specific neurons.
"As far as regenerating parts of the brain that have degenerated, such as in Parkinson's disease, Huntington's disease and others of that nature, the ability to regenerate the needed cell type and placing it in the correct spot would have major impact," said Dr. Eric Holland, a neurosurgeon at Memorial Sloan-Kettering Cancer Center in New York who specializes in the treatment of brain tumors, but who is not connected to the research. "In terms of tumors, it's known that stem-like cells have characteristics much like cancer cells. Knowing what makes these cells tick may help by furthering our knowledge of the biology of the tumor."
Researchers create way to generate brain cells in lab
GAINESVILLE, Fla. - University of Florida researchers are resurrecting an old technology to more quickly and accurately identify potentially deadly bacterial infections in hospital patients.
Speed in identifying these bugs is crucial because bacteria such as E. coli can enter a patient's bloodstream and almost immediately become life-threatening, said Ken Rand, M.D., the director of clinical pathology at UF's College of Medicine. He presented his research findings today at the 105th annual American Society for Microbiology general meeting in Atlanta.
"The system we use can cut the time it takes to get a patient on the right antibiotic by 24 to 48 hours," said Rand, who is also the director of the clinical microbiology laboratory at Shands at UF medical center. "This can save lives and we would like to see it used in every hospital across the country."
Hospitals currently use a test that requires doctors to guess which antibiotic to use while they await the results of a blood draw and culture.
When doctors make an incorrect guess, patients may be prescribed antibiotics that do not fight the infection because the bacteria are resistant to them, which is like getting no antibiotics at all, Rand said.
To identify a bacterial type under current standard practice, it takes 18 to 24 hours before preliminary results come in and another 24 to 36 hours before the correct antibiotics can be identified. Rand's work shows that preliminary results gathered between 8 and 18 hours using the 30-year-old manual procedure known as the direct susceptibility method correlate well with final results that otherwise come days later.
If those highly accurate preliminary results are used to check a physician's initial guess, potential mistakes can be caught earlier and a patient's treatment can be corrected, he said.
"Not all antibiotics work for all bacteria. Unfortunately, there is no 'gorilla-micin' that can be used to attack any bug in the body," Rand said. "The best we can do is get the right drug to the patient as quickly as possible."
Looking at past studies, Rand found the mortality rate among patients hospitalized with a gram negative bloodstream infection was about 30 percent to 40 percent when there was a delay in giving the right antibiotic. Among patients who were treated with the right antibiotic from the beginning, the mortality rate fell to 20 percent.
Of the 34 patients Rand evaluated in a new UF study of the direct susceptibility method, 19 had bacterial infections that initially tested completely resistant to the type of antibiotic they were taking. When the final results came in, 17 of those 19 patients - half the cases studied - were confirmed to be infected with bacteria resistant to the prescribed drug.
Working with hospital pharmacists, Rand has developed a system that relies on the preliminary results to get infected patients on the right antibiotics within 18 hours. He said his goal is to cut that time to eight hours.
"In the first nine months of doing this, our mortality rate is just around 20 percent," Rand said. "So we think we are making a difference, but we know that we have to compare our (study) patients to our own (hospital) patients, not just to what is in the literature. But based on that, right now it looks like we are doing a good job."
Gregory Storch, M.D., director of the Microbiology Laboratory at the St. Louis Children's Hospital and a professor of pediatrics, medicine and molecular microbiology in the division of pediatric infectious disease at the Washington University School of Medicine, said the study results are exciting and many U.S. hospitals could immediately adopt the practice.
"In this era of elaborate and very expensive high-tech approaches, it is very nice to see an innovative use of existing technology that has the potential to improve patient outcomes," Storch said. "Another important component of this work is the close coordination of the microbiology laboratory and the pharmacy, which will help ensure that results generated in the laboratory are acted on without delay. This work may have immediate applicability in many U.S. hospitals."