Disposera-t-on un jour d’épiderme humain en quantité illimitée pour soigner les grands brûlés dès leur arrivée à l’hôpital ? Réalisée par une équipe d’I-Stem à Evry, la reconstitution d’un épiderme entier à partir de cellules souches embryonnaires humaines le laisse espérer (1). En effet, sous réserve de sa validation par essai sur l’homme, ce type d’épiderme pourrait être créé dans des unités de production fonctionnant en continu. Il constituerait ainsi une réserve transplantable à la demande. Car aujourd’hui, il faut trois semaines pour obtenir une surface suffisante d’épiderme par culture in vitro d’une partie indemne de la peau des patients. Mis à part ce problème de délai, ce type de greffe dite « autologue » fonctionne bien. La nouvelle méthode serait donc plutôt une alternative à la greffe de peau de cadavres qui protège le malade durant ces trois semaines critiques. « Compte tenu de l’immaturité immunologique des cellules souches embryonnaires, l’épiderme issu de notre technique ne devrait pas être rejeté pendant cette période, estime Marc Peschanski, directeur scientifique d’I-Stem. En outre, il serait produit en conditions sanitaires parfaitement contrôlées. »

Chronobiologie. Pour réussir cette première mondiale, les chercheurs ont exploité la capacité des cellules souches embryonnaires à se multiplier indéfiniment et à engendrer n’importe quel type de cellules différenciées. La première étape a donc consisté à mettre au point un environnement cellulaire et un traitement pharmacologique favorables à leur différenciation en kératinocytes. Ce sont en effet ces cellules qui permettent le renouvellement permanent de la peau. Les biologistes ont alors appliqué le traitement durant quarante jours, durée qu’il faut normalement à un embryon pour former son épiderme. « C’est sans doute ce respect de la chronobiologie qui nous a permis de réussir là où d’autres équipes avaient échoué, indique Marc Peschanski. In vitro, les kératinocytes ainsi obtenus ont généré un épiderme entier et parfaitement fonctionnel. Douze semaines  après sa greffe sur des souris au système immunitaire affaibli pour éviter un rejet, cet épiderme a présenté les mêmes caractéristiques qu’un épiderme humain adulte normal », ajoute le chercheur.

Essai clinique. Pour l’équipe de Marc Peschanski, le lancement d’un essai sur l’homme est techniquement réalisable dans un délai de deux ans. « Ces travaux constituent un superbe travail expérimental, mais de nombreuses étapes sont encore nécessaires, tempère toutefois Jean-Jacques Lataillade, responsable du département thérapie cellulaire à l'hôpital militaire Percy de Clamart, institution pionnière dans la greffe des grands brûlés. En effet, il faudra précisément évaluer les risques de rejet et d’apparition de tumeurs. Enfin, le challenge reste de produire une peau entière comprenant non seulement l’épiderme, mais aussi le derme. Ce dernier est en effet indispensable pour la réussite de la greffe autologue.

Jean-Philippe Braly

http://www.larecherche.fr/content/actualite-Sante/article?id=27178

(1) H. Guenou et al., The Lancet, 374, 1745, 2009.

Fossil feathers reveal dinosaurs' true colours

Pigment-storage sacs found in fossils give hints about hue.

http://www.nature.com/news/2010/100127/full/news.2010.39.html

Matt Kaplan

Sinosauropteryx may have had orange feathers and a stripey tail.Jim Robbins

Pristine fossils of dinosaur feathers from China have yielded the first clues about their colour.

A team of palaeontologists led by Michael Benton of the University of Bristol, UK, and Zhonghe Zhou of the Institute of Vertebrate Paleontology and Paleoanthropology in Beijing, has discovered ancient colour-producing sacs in fossilized feathers from the Jehol site in northeastern China that are more than 100 million years old.

These pigment-packed organelles, called melanosomes, have only been found in fossilized bird feathers before now.

The team discovered the melanosomes in fossils of the suborder Theropoda, the branch of the dinosaur family tree to which the flesh-eating species Velociraptor and Tyrannosaurus belong. However, it was not in these two iconic dinosaurs that the organelles were found, but in smaller species that ran around low to the ground with tiny feathers or bristles distributed across their bodies.

The team discovered two types of melanosome buried within the structure of the fossil feathers: sausage-shaped organelles called eumelanosomes that are seen today in the black stripes of zebras and the black masks of cardinal birds, and spherical organelles called phaeomelanosomes, which make and store the pigment that creates the rusty reds of red-tailed hawks and red human hair.

The team didn't find cell structures or machinery responsible for other colours, such as yellows, purples and blues. They suggest that dinosaur cells might have produced coloured pigments such as carotenoids and porphyrins, but that the proteins that make them degrade more rapidly than organelles, so do not leave a trace in fossils. Melanosomes, by contrast, are an integral part of a feather's tough protein structure so can survive for longer.

The team found pigment-storing eumelanosomes (left) and phaeomelanosomes (right) in the fossil feathers.University of Bristol.

"We always tell introductory palaeontology students that things like sound and colour are never going to be detected in the fossil record," says Benton. "Obviously that message needs to be reconsidered."

Fossils of one theropod dinosaur, Sinosauropteryx, reveal that it had light and dark feathered stripes along the length of its tail. The team found that feathers from the darker regions of the tail were packed with phaeomelanosomes, indicating they were russet-orange in colour. The lighter stripes could have been white, says Benton, but because some pigments degrade and don't leave a fossil signature, it is difficult to be sure.

Sinosauropteryx was not the only colourful feathered species. Another small theropod species, Sinornithosaurus, had feathery filaments that were dominated by either eumelanosomes or phaeomelanosomes, hinting that its individual feathers varied in colour between black and russet-orange.

Birds of a feather

A lot of questions have been raised about the structures that are found on the earliest of the feathered dinosaurs, such as Sinosauropteryx. Some palaeontologists argue that these bristle-like structures are actually fossilized connective tissue rather than early feathers.

However, says Benton, in modern birds — which evolved from the theropod dinosaurs — melanosomes are found only in the developing feathers and not in the connective tissue. The fact that the melanosomes in the dinosaur feathers are also found inside the bristles themselves resolves the debate, he says.

Samples were taken from a dark stripe near the base of Sinosauropteryx's tail.The Nanjing Institute

"This paper puts the nails in the coffin of arguments countering the feather nature of these structures," agrees Luis Chiappe, a palaeontologist at the Natural History Museum of Los Angeles County, California.

"It is deeply gratifying that this colour discovery is allowing us to finally agree that the structures on Sinosauropteryx were actually early feathers," says evolutionary ornithologist Richard Prum of Yale University in New Haven, Connecticut. "Now we can get on with studying their evolution."

In addition, the discovery of colour in the earliest feathers may also sway the biggest dinosaur debate of them all — what the feathers were actually being used for.

The tiny bristles on early feather-bearers could not have been used for flight, as some have suggested, because they would have provided no lift. But they could have served as insulation, or for display.

"It is looking increasingly likely to me that these dinosaurs were making a visual statement," says Benton. "What that statement was, we don't know, but you don't have a orange-and-white striped tail for nothing."

Hiding place for missing heritability uncovered

Rare mutations linked to disease may hide in common variants.

Brendan Maher

The genetic underpinnings of many diseases remain elusive, and computer simulations and experimental data suggest a reason why: the true culprit [coupable] may be masked by a more obvious suspect.

The findings, by David Goldstein, a geneticist at the Duke Institute for Genome Sciences & Policy in Durham, North Carolina, and his colleagues follow simulated genome-wide association (GWA) studies, in which genome variants among many individuals with and without a specific disease are compared and linked to the risk of developing the disorder.

The GWA technique is based, in part, on the assumption that diseases that are common in the population — such as diabetes and heart disease — are due to genetic factors that are also common. However, Goldstein speculated that rare mutations that are too low in frequency to be uncovered [à découvert] by GWA studies might be hiding within the common variants and throwing off the signal. His group's simulations back up this possibility. The results are published in PLoS Biology¹.

Leonid Kruglyak, a geneticist at Princeton University in New Jersey, says the work confirms what many had suspected. "I think everyone who thought hard about genome-wide association studies knew that this was a possibility," he says.

Many variations

The work addresses a concern that has been brewing in the genetics community for several years. More than 2,000 common variants have been linked to common diseases through GWA studies, but explain only a tiny fraction of the estimated heritability of these diseases.

Researchers have speculated as to the source of this 'missing heritability' (see 'The case of the missing heritibility'). One explanation is that a rare variant with a strong role in disease arises more frequently in people who share a common variant.

Goldstein and his colleagues looked at mock populations [populations modèles] of thousands of people. Some individuals had rare variants — mutations that occurred in 0.5–2% of the population — that were very likely to cause an unspecified disease. The authors simulated the genealogy of this population and ran GWA studies. They found common genetic variants that associated with the disease, but only a proportion of individuals with the common variant also had the rare variant that theoretically caused it. So, the association with the common variant was indirect. Goldstein calls it a "synthetic association".

Synthetic associations make it seem as if many people share a genetic sequence that confers some small risk of disease when, in fact, a few of those individuals have a rare variant that confers a much higher risk. This can lead to false assumptions [hypothèses] about the common variant, says Goldstein, it could also mean that rare variants account for much of the missing heritability of disease.

Hide and seek

Geneticists knew that many common variants picked out by GWA studies would be proxies — indicators of a genetic cause that might exist near the common variant or somewhere else in the genome — and, indeed, many of the associations made so far don't seem to have an explanation. Synthetic associations could be one factor at play. Goldstein speculates that, "a lot, and possibly the majority [of these unexplained associations], are due to, or at least contributed to, by this effect".

Goldstein and his colleagues also did a real-world experiment as a proof of the principle. They compared individuals with diseases caused by a single-gene mutation, such as sickle-cell anaemia or a genetic form of deafness [surdité], with a control population. Sure enough, in GWA studies on these populations, common variants seemed to associate with the disease, although in some cases these were as far as 2.5 million base pairs away from the known causative mutation.

Sarah Tishkoff, a geneticist at the University of Pennsylvania in Philadelphia, says "this may make it challenging to identify the functional variant within an association". Teri Manolio, a population geneticist at the National Human Genome Research Institute in Bethesda, Maryland, writes via email that "if their simulations are correct, and I suspect they are," they suggest researchers will have to sequence a lot of DNA, up to 10 million bases, surrounding common variants.

Goldstein says that the work suggests more whole-genome sequencing will be needed in more targeted populations of affected individuals and families. In a sense, he says the issues being raised signal the need for shift from the powerful statistics of GWA studies to work more focused on specific genes in affected families and how they function biologically. As Goldstein puts it, "the importance of the family has really come back again."

• References

  1. Dickson, S. P., Wang, K., Krantz, I., Hakonarson, H. & Goldstein, D. B. PLoS Biol. 8, e1000294 (2010).

http://www.nature.com/news/2010/100126/full/news.2010.33.htm