Don’t believe me? Just look at this picture of squid embryos, taken by scientist Celeste Nelson. This image won first prize in the 2009 Art of Science exhibition.

This image was taken at the Woods Hole Marine Biological Laboratory in the summer of 2007.

Nelson said, “I was staring at these beautiful embryos under the microscope and wanted to capture an image of them to share with my colleagues and family. The embryos do continue to develop completely in the laboratory and will eventually hatch in the Petri dish.”

Prions are fascinating proteins – though their composition doesn’t change, they can adopt two shapes. One shape is innocuous; the other shape causes disease, such as scrapie in sheep, bovine spongiform encephalopathy in cattle (mad cow disease) and Creutzfeldt–Jakob disease in humans. These are incurable conditions where cells in the brain die, causing progressive dementia and death; upon examination, the brain is full of holes, like a sponge (hence the term ‘spongiform’).

In 1997 Stanley Prusiner won a Nobel Prize for discovering the prion protein and how its abnormal shape causes disease. However, we still don’t understand the function of the normally shaped prion protein, which is found throughout nature, in mammals, fish, yeast and fungi.

A new study using the zebrafish, a freshwater fish commonly used in developmental biology research, suggests that the normally shaped prion protein plays a crucial role in controlling how cells touch each other and communicate.

Edward Málaga-Trillo, Gonzalo P. Solis and colleagues from the University of Konstanz in Germany injected modified DNA into zebrafish embryos to reduce production of the two zebrafish prion proteins. When researchers reduced levels of prion protein 1, the embryos stopped growing during the gastrulation stage, when precursors to tissues and organs are formed. When researchers reduced levels of prion protein 2, the embryos developed beyond gastrulation and survived for several days, but had malformed brains and eyes. Producing more prion proteins than normal caused similar anatomical problems.

These defects could be rescued by injecting the modified DNA together with DNA that instructs cells to produce normal copies of prion proteins (with normal shapes). Even prion protein from mice could rescue development in zebrafish, suggesting that prion proteins from different animals have similar functions.

Further experiments showed that low levels of prion protein 1 cause cells in the embryo to lose their polygonal shape, become round, and detach from normally adherent cells. This abnormal cell shape and behavior likely caused the embryo to stop growing.

These results suggest that in zebrafish, prion proteins are required for normal development. Since zebrafish development is similar to mammalian development, it is likely that prions play a crucial role in the development of human embryos as well.

That’s the conventional ending, but this story has a twist. In 1992, scientists used genetic tricks to develop mice that were missing the prion protein. These mice “develop and behave normally.”

If zebrafish and mice are so similar, how do we explain this discrepancy?

It’s possible that when it comes to prions, zebrafish and mice are different. One argument is that prions are not essential for mouse development. This is the opinion of the committee that awards the Nobel Prize, which wrote “strangely enough, mice lacking the prion gene are apparently healthy, suggesting that the normal prion protein is not an essential protein in mice, its role in the nervous system remains a mystery.” However, this would not explain why prions from zebrafish and mice are similar, or why adding mouse prion can rescue zebrafish embryos deficient in zebrafish prions.

The other argument is that prions are so important for normal development that mice evolved redundancies, other proteins, not prions, that perform similar functions as prions. Málaga-Trillo and colleagues favor this idea, though it’s not clear why zebrafish lack an analogous backup system.

As with all good results, more research is required.

Source: “Regulation of Embryonic Cell Adhesion by the Prion Protein” by Edward Málaga-Trillo, Gonzalo P. Solis, Yvonne Schrock, Corinna Geiss, Lydia Luncz, Venus Thomanetz and Claudia A. O. Stuermer, published March 10 in PLoS Biology (doi:10.1371/journal.pbio.1000055).

Of the more than 3 billion bases, or individual units, of DNA in the human genome, less than 2 percent contain instructions for producing proteins. The genome regions that specify protein production are the genes (in science jargon genes are said to code for proteins); the rest of the DNA, the noncoding portions, have been dismissively referred to as junk.

Junk – obviously not a very scientific term – implies that because the DNA doesn’t code for proteins, it isn’t functional. (For a similar debate, see Norman Pace on purging “prokaryote” from science textbooks.)

In recent years, researchers proved that junk plays an important role in switching genes on and off. Identifying a gene is one thing, but knowing when it’s instructing a particular cell to produce proteins or when it’s remaining silent is crucial to understand how organisms develop and function.

Axel Visel wants to know how the genome decides which genes get turned on when. Raised and educated in Hannover, Germany, Visel also spent two years studying in the United States. After receiving his doctorate at Germany’s Max Planck Institute, Visel returned to the United States for a fellowship with Eddy Rubin and Len Pennacchio at the Lawrence Berkeley National Laboratory in California. Rubin and Pennacchio spearheaded the development of many tools to analyze genome sequences.

The portions of DNA that switch genes on are called promoters and enhancers. For a gene to be switched on, specialized proteins must bind to promoters and enhancers and coordinate with each other to transcribe RNA from the gene. That RNA is then translated into a protein. Promoters and enhancers don’t code for genes themselves; their only function is to regulate when and where genes are turned on – they are regulatory sequence.

Identifying regulatory sequence has been challenging. Promoters tend to be located adjacent to the genes they control, but enhancers are scattered throughout the genome, sometimes 1 million bases of DNA away from the gene they regulate.

Visel, Matthew Blow and their colleagues found a way to identify when enhancers are regulating genes. A protein called p300, produced throughout the body, is thought to bind to many enhancers. It’s also required for embryonic development, a crucial time when activated genes are literally building the body.

Visel dissected forebrain, midbrain and limb tissue from more than 150 mouse embryos and treated them with a chemical to strengthen the attachment between proteins and DNA. Normally the proteins bound to enhancers can be easily unbound, but the chemical linking prevents this. The DNA is then cut up into millions of pieces (DNA bound to protein is protected). Using antibodies, Visel and his colleagues purified only those pieces of DNA bound to p300 and then sequenced that DNA and identified it as a possible enhancer. This technique, called chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-seq), is not new, but using p300 as the bait was a clever twist.

To confirm these regions of DNA actually regulate gene expression, Visel and his colleagues identified analogous regions from human DNA, and genetically engineered mice such that the human DNA enhancer sequence was in a position to regulate a gene that produces a nontoxic protein that turns the cell blue. If the enhancer DNA regulated gene expression in the mouse embryo’s limb, but not in the brain, then the human version of the enhancer would turn only the mouse’s limbs blue.

In most cases, that’s what happened. (See photo.) This method is especially good because it’s large-scale, enabling scientists to study thousands of enhancers throughout the genome from any tissue during any time in an animal’s life. Visel and colleagues identified thousands of enhancers active in the brain and limbs of mouse embryos and verified more than 80 using genetically engineered mice. (For more on using transgenic mice to report gene expression, see Gianpaolo Rando’s blog.)

Visel is happy in the United States. Lawrence Berkeley National Laboratory provided help with his visa, but he is still stuck doing government paperwork. “It can all be done, but I wish one would have to spend less time on it.” Visel says “it would be nice” to return to Germany and be near friends and family, but the “stimulating scientific environment” at Berkeley enables him to pursue interesting projects.

As my graduate adviser used to say, if you put junk in, you get junk out. Clearly junk DNA is anything but.

Source: “ChIP-seq predicts tissue-specific activity of enhancers” by Axel Visel, Matthew J. Blow, Zirong Li, Tao Zhang, Jennifer A. Akiyama, Amy Holt, Ingrid Plajzer-Frick, Malak Shoukry, Crystal Wright, Feng Chen, Veena Afzal, Bing Ren, Edward M. Rubin and Len A. Pennacchio, published in the February 12 issue of Nature (doi:10.1038/nature07730, Visel and Blow contributed equally to this work).

Cutting steak across the grain keeps the meat tender. Cut with the grain and the natural fibers of the meat remain intact, making it tougher to chew. Those natural fibers are muscle, and how they grow in such an organized fashion – how they form a “grain” – was not well understood until the recent work of French biologist Jérôme Gros.

During his doctoral work at the Université de la Méditerranée in Marseille, Gros discovered that a gene called Wnt11 (pronounced wint) acts as a cue, directing muscle fibers to elongate in parallel. In elegant experiments using chicken embryos, Gros and colleagues showed that interfering with Wnt11 function caused the growing muscle fibers to appear disorganized. Transplanting cells that produce Wnt11 to a discrete region of normal, developing muscle caused the fibers to elongate parallel to the added Wnt11, in an organized fashion. Conversely, when Gros manipulated the developing muscle so that Wnt11 was produced throughout, the growing fibers became completely disorganized, growing every which way.

In April 2007 he moved to Boston for a postdoctoral fellowship at Harvard University in the laboratory of Cliff Tabin. (Gros only interviewed for positions in the United States and the United Kingdom to focus on speaking English.) He chose Tabin’s lab because he got a “good feeling” during the interview, and now Gros studies how embryonic cells move and organize to form limbs.

He said he found the transition “quite easy.” Harvard took care of his work visa, and he found an apartment in Boston while still in France, using the craigslist Web site. The most difficult challenge is “being apart from family.” He uses the Internet, particularly Skype, to keep in touch.

Gros says he is very happy as a postdoc. An eventual return to France depends on the stability of CNRS, France’s government-funded research organization. Gros is concerned that the French government is not committed enough to scientific research. As an example, he points to the lack of start up packages for young scientists establishing their laboratories, money they can use to buy expensive but necessary equipment. In the United States, such packages often run in the hundreds of thousands of dollars.

All things being equal, however, he said he would rather return to France. “The steaks are better.”

Source: “WNT11 acts as a directional cue to organize the elongation of early muscle fibers” by Jérôme Gros, Olivier Serralbo, and Christophe Marcelle, published in Nature, January 29, 2009.