While biologists have long known that the structure of adult animals follows a blueprint laid out in the early stages of embryonic development, classical biological experiments have provided only isolated "snapshots" of the development process, denying scientists a complete "movie" of it unfolding. Now, by combining experimental methods from physics and molecular biology, the team has replaced these snapshots with the movie, allowing them to see the first steps of blueprint formation in the fly embryo literally live and in color. The first of two papers in the July 13 issue of the scientific journal Cell describes the sophisticated techniques required to make these movies, techniques that could help scientists investigate a wide variety of biological systems.
In the second paper, the group poses a new question, never before asked by scientists studying embryos: How precisely can cells in the embryo read the blueprint? So precisely, the paper suggests, that a precious few molecules signaling a change can make a decisive difference.
"I think the prevailing view has been that cells accomplish all their functions using a complicated combination of mechanisms, each one of which is rather sloppy or noisy," said team member William Bialek, the John Archibald Wheeler/Battelle Professor in Physics. "This research, however, indicates that in the initial hours of a fly embryo's development, cells make decisions to become one part of the body or another by a process so precise that they must be close to counting every available signaling molecule they receive from the mother.”
Three hours into a fly embryo's development, it remains a single large cell with an unusual characteristic: Unlike other cells, which have a single nucleus, the embryo has thousands, each of which awaits a signal from the mother to form itself into a specialized cell. This signal arrives in the form of a droplet of protein called Bicoid that enters the embryo at one end and, like food coloring in water, diffuses out molecule by molecule through the nuclei. The concentration decreases with distance and forms the first blueprint that defines which part of the embryo will become the head and which the backside of the fly.
The team's findings indicate that two neighboring nuclei can determine their different places and functions within the embryo accurately if the concentration of Bicoid between them varies by only about 10 percent -- a quantity that on the scale of the tiny embryo amounts to only a few molecules of Bicoid.
"This signaling requires a sensitivity approaching the limits set by basic physical principles," Bialek said. "Perhaps more important than the answers we have found so far, this work has led us to sharpen the kinds of questions we ask about living cells as we try to understand them with the same kind of mathematical precision that we understand the rest of the physical world."
The two papers constitute the Ph.D. research of first author Thomas Gregor, who is now pursuing postdoctoral work in the Department of Physics at the University of Tokyo. The project was a collaboration among three Princeton faculty members: Bialek, David Tank (the Henry L. Hillman Professor in Molecular Biology and professor of physics) and Eric Wieschaus (the Squibb Professor in Molecular Biology and 1995 Nobel laureate for his earlier contributions to understanding the development of the fruit fly embryo). Gregor is available for comment at email@example.com.
-by Chad BoutinEngineered E. coli may lead to new drugs, detect pollutants
Hormones must be present in specific amounts to maintain health. For example, sufficient levels of the hormone estrogen are necessary for bone formation and reproduction, but too much of it has been implicated in premature puberty as well as the development of breast cancer and heart disease. The Princeton engineers hope that the bacteria can shed light on the way hormone-like compounds affect the body and eventually guide the development of drugs that can regulate hormone levels.
David Wood, an assistant professor of chemical engineering at Princeton, and Georgios Skretas, who earned his Ph.D. at Princeton in 2006 and is now at the University of Texas-Austin, designed the bacteria by linking the proteins that bind to estrogen, called estrogen receptors, with a protein required for growth in E. coli. This design allows the researchers to distinguish between compounds that stimulate the receptors and those that block them simply by observing bacterial cell growth. Since the bacteria respond quickly -- results are typically seen in about 15 hours under simple growth conditions -- they should be able to rapidly screen thousands of compounds that affect estrogen's activity, making an important contribution to the drug discovery process, Wood said.
When used to screen a small library of potential antioxidants, the bacteria identified two novel estrogen-mimicking compounds. Based upon bacterial growth in the presence of the mimics, the researchers predicted that one of the compounds would behave like estrogen in human cells, while the other would inhibit estrogen-related activity. The researchers confirmed their predictions with subsequent tests in human cells.
Although neither of the compounds turned out to be potent enough to make a good drug, the fact that the bacteria responded appropriately to the substances has made the researchers optimistic.
'Though these compounds themselves aren't likely to have pharmaceutical applications, the results prove that the system can work for drug-like compounds," Wood said. "Our system is also very good at detecting weakly binding substances, which is essential for the identification of hormone-like pollutants, which are found in many substances, including plastics and cosmetics."
In future work, the researchers plan to design bacteria that detect and respond to additional hormone-like compounds, including those that mimic or block the activity of testosterone, the stress hormone cortisol and thyroid hormone. This may advance the search for a nonsurgical treatment for Graves' disease, which is caused by the overabundance of thyroid hormone.
The findings were published online June 15 in the Journal of the American Chemical Society. The work was funded by the National Science Foundation and the Hellenic Secretariat for Research and Technology, and was completed in collaboration with researchers at the National Hellenic Research Foundation in Athens, Greece. Wood is available for comment at firstname.lastname@example.org or (609) 258-5721.
-by Hilary ParkerChoosy mating habits are costly to female iguanas, study shows
The behavior, which offers some of the first evidence that selecting a desirable partner is energetically costly for females, is surprising because it runs against conventional scientific wisdom.
Researchers often assume that choosiness demands comparatively little exertion from females. While males put a great deal of effort into courtship -- in the iguanas' case, they sidle up to the females, hunch their backs and walk sideways while rocking back and forth -- all the females have to do is amble into the males' territory, watch this flamboyant behavior and choose the male they want, while simply avoiding other suitors.
However, avoiding energetic but unwanted males is itself exhausting, said lead researcher Maren Vitousek, and it often results in smaller eggs whose young might be less likely to survive. The team found that over a month-long mating period, particularly choosy females lost as much as 25 percent of their body weight -- far more than the 14 percent lost by the average female. The longer they spent in the company of the attractive males, the more weight they lost. (Males lost 17 percent of their weight on average during the same period.)
Vitousek said that choosiness may also decrease a female's chances for survival. During the dry weather of El Niño years, marine iguanas have a hard time finding food, and those that start the season at a low body weight are less likely to live through it.
Why all this effort on the part of the females is worthwhile is unclear, because male iguanas do not seem to offer females anything other than fertilization for their eggs.
"It's possible that attractive males provide females with better genes, or perhaps other benefits that we have not yet identified," said Vitousek, a graduate student in Princeton's Department of Ecology and Evolutionary Biology. "We're certain they're not getting food, protection or better sunning spots from the males. Understanding the costs of being choosy should help to illuminate the process of sexual selection, which is one of the primary forces driving evolution."
The team's paper appears in the June 27 issue of the scientific journal, PLoS ONE (Public Library of Science ONE). Co-authors include scientists from Princeton University, Louisiana State University and the University of Birmingham. Vitousek is available for comment at email@example.com or (609) 924-2358.
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