Los genes que regulan la personalidad (Redes 115)

El manual de instrucciones con el que se ensambla nuestra biología está escrito en el ADN. Pero, ¿es posible que los genes, del mismo modo que regulan el desarrollo de nuestro cuerpo, también influyan en nuestra personalidad? En este capítulo de Redes, Punset indaga sobre esta cuestión con Dean Hamer, genetista de los Institutos Nacionales de Salud de los Estados Unidos y divulgador científico. Hamer ha recopilado numerosas evidencias que sugieren que la felicidad, la espiritualidad, la orientación sexual y otros rasgos de la personalidad tendrían un componente genético.

Fuente: Redes para la Ciencia.

Rediseñaremos a los seres humanos (Redes 103)

Desde el origen de la vida, el azar y la selección natural han diseñado el ADN de todos los seres que han pasado por nuestro planeta. Sin embargo, la humanidad está dando los primeros pasos para controlar su propio futuro evolutivo. En el próximo capítulo de Redes, Gregory Stock, especialista en prever los desarrollos de la biotecnología, explica a Punset que estamos dando los primeros pasos para manipular nuestros genes, no solo para evitar las enfermedades, sino para mejorar nuestra especie. Fuente: Redes para la Ciencia

Alice Dreger: ¿es la anatomía destino?

Alice Dreger trabaja con personas en los márgenes de la anatomía, como son los gemelos siameses y las personas intersexuales. En su observación, a menudo, hay una línea borrosa entre hombres y mujeres, entre otras distinciones anatómicas. Lo que nos lleva a una gran pregunta: ¿por qué dejamos que nuestra anatomía determine nuestro destino?


Fuente: TED, Ideas Worth Spreading

The Secrets of Butterfly Wings

Gene search may unlock the mysteries of diversity


It’s a summer scene so common that we humans seldom stop to notice. A butterfly gingerly alights on a bush or a flower and unfolds its magnificent wings, revealing iridescent bands of blue.

For the Red-spotted Purple, one of New England’s prettiest butterflies, the display is a warning to hungry predators. Interested birds can see all they need to see to leave the butterfly alone.

In this case, however, predators are being duped; the Red-spotted Purple—Limenitis arthemis—is a gorgeous fake, a mimic that has co-opted the appearance of its toxic cousin, the Pipevine Swallowtail. How did such mimicry come about? How did one butterfly species so effectively usurp the warning signal of another?

Sean Mullen, a College of Arts & Sciences assistant professor of biology, is trying to find out. He and Harvard University evolutionary biologist Marcus Kronforst were awarded a $980,000 grant from the National Science Foundation in November 2010 to identify the specific genetic mutations responsible for mimetic wing pattern variation in three species of butterfly: Admirals (Limenitis), Swallowtails (Papilio), and Longwings (Heliconius).

There are approximately 18,000 species of butterflies on the planet, and Mullen says their wings are “some of the most diverse morphological appendages in the natural world.” Beyond their extraordinary beauty, wings play an important role in courtship, thermoregulation, predator avoidance, and, of course, locomotion.

This functional complexity belies a relatively simple two-dimensional structure. Butterfly wings are essentially a sheet of scales just one cell thick. Add this architectural simplicity to the fact that butterflies are easy to breed in a lab, he says, and they are a “phenomenal genetic model.”

Sometime in the last 200,000 years, the Red-spotted Purple (right, top) lost its stripes, literally, as a result of a genetic fluke. A butterfly emerged from its cocoon intact but, unlike the others in its Admiral family (below), it lacked the prominent white band through the middle of its wings.

Mullen points out that a wing pattern mutation such as this would typically cause a butterfly to stand out to its enemies. But this time the mutation offered an unforeseen advantage: the new, stripeless butterfly looked a lot like the Pipevine Swallowtail, whose poisonous effects were well known to predators.

“If you’re a bird, you learn quickly to avoid anything that’s big, black, with blue on the hind wings,” he says. The accidental mimic was thus blessed with a much greater chance of survival than its apparently nontoxic siblings, and consequently, with a greater chance that the fluke would become the norm.

Mullen and his team are making strides in their efforts to locate the mutation. They now know which chromosome (out of a possible 30) contains the gene that controls wing pattern. More specifically, they’ve identified which portion of that chromosome holds the answer.

“We have mapped one interval in the genome that we know the gene is in there somewhere,” he says. “It’s cool. It’s very cool.”

From here, Mullen will zero in even further. Using 1,000 butterfly genomes—many of the specially bred insects reside in his lab’s freezer—he will embark on a series of steps that combine genetic fine-mapping and next-generation DNA sequencing technology. Through this process, which, put simply, comes down to matching patterns, he will ultimately figure out which gene caused the butterfly’s appearance to change thousands of years ago.

Down the road, Mullen hopes we will know whether the wing patterns of all butterfly species are controlled by the same set of genes or by varying ones. In other words, does a common genetic architecture regulate the development of wing pattern or is it decided by several different architectures? The answer will help inform how scientists view the process of natural selection.

“Both outcomes would be really quite interesting,” Mullen says. One result would indicate predictability in evolution, he says, while the other would suggest flexibility.

If it turns out that all butterflies use the same set of core genes to establish wing pattern, that would imply a certain predictability in evolution. “You might expect, at the genetic level, that certain changes are going to produce certain shifts in appearance,” he says. “Predictable would be fantastic.”

If, on the other hand, very different genes control wing pattern, that would suggest evolutionary flexibility—that different genetic pathways can ultimately lead to the same changes in attributes.

“That would be exciting too,” says Mullen, “because it would suggest that the genomes of organisms are flexible enough that there are multiple solutions to common problems.”

Such knowledge will also have implications for larger issues, like genetic disease. “It’s important from our perspective as humans,” he says. “We’d like to know when we see a particular disease, is it going to be the same across all human populations?”

Mullen’s driving interest is understanding the history and origin of life and why it’s so varied. Studying the wing patterns of butterflies is one step toward unearthing answers to such larger questions. “You might actually be able to look at an entire group of organisms and begin to gain an understanding of why they’re so diverse and how they produce such amazing diversity,” he says. “That gets me really excited.”

Laura Davidson can be reached at ldavidso@bu.edu.

Fuente: Boston University.

Descubierto el mecanismo que relaciona la progesterona y el cáncer de mama hereditario

Dos investigadores del Centro de Regulación Genómica en Barcelona han descubierto un nuevo mecanismo por el que mutaciones en el gen BRCA1 pueden inducir el cáncer de mama.

El trabajo, que publica la revista Cancer Research, explica el mayor crecimiento células cancerosas con defectos de BRCA1 a dos niveles: por el aumento de la cantidad de receptor de progesterona que se encuentra en las células y por su mayor efecto sobre la expresión de genes que activan la proliferación celular.

Se conoce desde hace tiempo que la existencia de mutaciones en el gen BRCA1 pueden causar cáncer de mama en, aproximadamente, el 80% de los casos, así como cáncer de ovario en un 54% de los casos. Aunque este gen esté relacionado con otros tipos de cáncer, su gran especificidad para el cáncer de mama ha despertado un gran interés entre la comunidad científica y médica.

Una de las hipótesis más aceptadas para explicar esta especificidad de BRAC1 por desarrollar cáncer en tejidos con gran acción de hormonas femeninas, es el papel de este gen en la regulación de la actividad de dichas hormonas.
Los investigadores del Centro de Regulación Genómica, Miguel Beato y Verónica Calvo, describen en un trabajo publicado en la revista Cancer Research, el papel de BRCA1 en relación a una de las dos hormonas femeninas: la progesterona. Su trabajo, demuestra que BRCA1 tiene un papel crucial en el control de receptores de progesterona que se encuentran en las células.
“Cuando el gen BRCA1 está mutado y no se expresa bien, la célula tiene más receptores para progesterona por lo que aumenta su efecto sobre la proliferación celular”, explica Miguel Beato, responsable del trabajo y director del CRG. “Sabíamos que este gen tenía un papel importante en el cáncer de mama pero ahora sabemos cuál es uno de los mecanismos que utiliza”, añade Beato.

BRCA1 actúa a dos niveles, primero, sobre la cantidad de receptor de progesterona que se encuentra en las células y segundo, por el control de la expresión de los genes de progesterona.

Estos descubrimientos ponen de manifiesto la relación directa entre un exceso en los efectos celulares de progesterona y el riesgo de desarrollar cáncer de mama. Conocer este mecanismo de acción del gen BRCA1 permite comprender su importancia para desarrollo del cáncer de mama y ayudará a diseñar mejores terapias que actúen directamente sobre las moléculas implicadas.

Además, el trabajo de Miguel Beato y Verónica Calvo puede tener influencia a nivel de la prevención del cáncer. De manera similar a lo que ocurrió cuando se demostró la relación directa entre los niveles de estrógenos y el riesgo de desarrollar cáncer de mama, hecho que hizo que se modificaran los métodos anticonceptivos hormonales, quizás las aportaciones de estos investigadores sobre el papel de la progesterona también provocarán nuevos cambios en la prescripción de tratamientos anticonceptivos.

** Trabajo de referencia: Verónica Calvo and Miguel Beato. BRCA1 Counteracts Progesterone Action by Ubiquitination Leading to Progesterone Receptor Degradation and Epigenetic Silencing of Target Promoters. Cancer Research (2011), doi: 10.1158/0008-5472.CAN-10-3670.

** Agradecimientos: Este trabajo se ha realizado gracias a la Fundación Española Contra el Cáncer, el Ministerio de Ciencia e Innovación (BMC 2003-02902 y Consolider CSD2006-00049), el Departamento de Innovación, Universidad y Empresa de la Generalitat de Catalunya y el Insituto de Salud Carlos III.

Fuente: Centro de Regulación Genómica de Barcelona.

RNA dynamics deconstructed - Technique offers detailed view of how RNA levels change

RNA plays a critical role in directing the creation of proteins, but there is more to the life of an RNA molecule than simply carrying DNA’s message. One can imagine that an RNA molecule is born, matures, and, eventually, meets its demise. Researchers at the Broad Institute of Harvard and MIT have developed an approach that offers many windows into the life cycle of these essential molecules and will enable other scientists to investigate what happens when something in a cell goes wrong. They describe their approach, which offers high resolution and a comprehensive scope, in a Nature Biotechnology article published online on April 24.

“People are discovering more and more how the RNA life cycle is at the heart of problems we see in disease, but we actually understand a lot less about it than we understand about many other cellular processes,” said Aviv Regev, a core faculty member of the Broad Institute and a co-senior author on the paper.

Regev and her colleagues have developed a method that allows them to tease apart the different stages of this life cycle by measuring how much messenger RNA (mRNA) is produced and how much is degraded. The balance of these two processes contributes to the changes seen in RNA levels in a cell over time, much the way that birth and death rates contribute to a country’s total population.

RNA levels are dynamic — they change in response to certain stimuli. For this study, the researchers examined dendritic cells, which are involved in the body’s immune response, as a model. They exposed these cells to a stimulus that resembled a pathogen and then looked at RNA changes before and after exposure.

“We wanted to understand how cells regulate RNA levels, and if regulation happens at the step of producing the molecule, degrading the molecule, or processing it,” said Michal Rabani, first author of the paper and an MIT graduate student at the Broad. “Each of these steps can affect the level of active RNA molecules in cells. If you want to understand what happens when things go wrong, you have to understand how things work when they work as they should.”

The researchers’ approach allows them to look at a specific cell type and see changes in the expression of all genes. This combination of breadth and specificity offers a systematic view of how RNA changes over time. “If we want to look at specific neurons in the brain or a specific cell that’s lying between other kinds of cells in the lung, this technique allows us to zoom in on one process in one cell among a billion other cells. This is the case in many diseases, a short circuit in one specific cell type, and now we have a great tool to find it,” said Ido Amit, a co-senior author of the paper and a scientist at the Broad.

The scientists harnessed an existing technique to trace the fate of newly produced RNA and paired it with a new sequencing-based technology that counts molecules of mRNA. The results also gave the researchers a view of some of the in-between steps, during which mRNA is edited or processed — an unexpected but serendipitous finding. “That’s the beauty of sequencing: It has a very extensive view so it shows you things you didn’t expect to see,” said Regev.

A key aspect of the approach is that the researchers were able to take “snapshots” of RNA levels over very short time intervals. Strung together, these snapshots reveal not only how the amount of RNA changes, but also the short-lived, intermediate phases of the RNA life cycle that are otherwise impossible to detect. “This allows us many windows into the world of RNA,” said Amit.
One critical application of the new method is in following up on leads from disease studies, such as mutated genes in cancer or other diseases that impact the RNA life cycle. “In the past, you would know that there’s a mutation and there’s even a suspicion of what the gene does, but it would have been extraordinarily hard to see the effect of the mutation on these types of processes in the cell,” said Regev, who is also an assistant professor at MIT and an Early Career Scientist at the Howard Hughes Medical Institute. The researchers hope that their newly developed technique will enable others to gain deep insights into how gene mutations disrupt RNA levels, and in turn, what proteins are made.

“We’re decomposing these RNA levels, breaking them down into each separate step, so that we can understand what happens at each of these steps and how they interact with each other to produce the final readout,” said Rabani. “It’s a very complex system, but understanding it could eventually help us understand what goes wrong when things don’t work.”
This work was supported by the Richard Merkin Foundation for Stem Cell Research at the Broad Institute.

Fuente: Harvard University,

Europe comes together to develop cancer diagnostics based on genetics and protein chemistry

Uppsala University is participating in Europe’s largest academic-industry collaboration aimed at developing new diagnostic methods for, in the first instance, intestinal cancer. The collaboration represents an important step towards more efficient conversion of cancer research findings into patient benefit.
Approximately 60 researchers are comprised by the five-year OncoTrack project, which is being led by Bayer Healthcare Pharmaceuticals and the Max Planck Institute for Molecular Genetics in Berlin.

During the last few decades, the field of cancer research has produced notable progress in terms of treatment. Nevertheless, the significant differences that characterise tumours entail that even advanced therapies only help certain patients. The challenge is to diagnose tumour types and stages as accurately as possible so that the right drugs or combinations of drugs can be chosen in connection with treatment.

“The key factor in this connection is finding tumour-specific markers to improve diagnostics,” says Ulf Landegren, Professor of Molecular Medicine at the Rudbeck Laboratory, who is participating in the project together with his colleague Mats Nilsson, Professor of Molecular Diagnostics. “The collaboration aims at developing the required techniques and computer models.”

Tumour-specific markers would also make it possible to follow patient response in the course of treatment, providing an effective means of learning more about specific forms of cancer and evaluating treatment choices. The project will draw on advanced gene sequencing and protein analysis techniques developed in Uppsala and computer models that allow doctors to analyse large amounts of data about patients. The goal is to understand the connections between tumour characteristics and genetics, a starting point for the development of improved treatments.

“A collaboration of this kind between academia and industry provides decisive advantages for addressing the complicated task of using large-scale genetic analysis as a basis for choosing effective cancer treatments and for developing new medicines and treatment regimes,” says Mats Nilsson.

The other participating research teams are based in Germany, the UK, France and Austria.


Fuente: Uppsala University, Sweden.

Designing gene

Stephanie Mitchell/Harvard Staff Photographer

Harvard Professor Hopi Hoekstra (left) and research associate in the Department of Organismic and Evolutionary Biology Marie Manceau have found that a gene called agouti governs color patterns in deer mice, the most widespread mammal in North America, and may also be responsible for color pattern in a wide variety of species.

Scientists at Harvard University are moving closer to answering some age-old questions.

How did the leopard get its spots? How did the zebra get its stripes?

The answer may be a gene called agouti, which the Harvard team has found governs color patterns in deer mice, the most widespread mammal in North America. This gene, found in all vertebrates, may establish color pattern in a wide variety of species, a process that has been poorly understood at both the molecular and the evolutionary level.

“The question of how color patterns are established in vertebrates has been a black box,” says Marie Manceau, a research associate in Harvard’s Department of Organismic and Evolutionary Biology and lead author of a paper appearing this week in the journal Science. “Taking advantage of the simple color pattern of deer mice — which have a dark back and a light belly — we showed that small changes in the activity of a single pigmentation gene in embryos generate big differences in adult color pattern.”

Manceau and senior author Hopi E. Hoekstra found that color patterns in these mice rely on the establishment of an embryonic “pre-pattern” of agouti expression. In the mice they studied, this took place midway through gestation — just 12 days after conception, well before the first pigments are ever produced in the skin.

Agouti had previously been known to affect the type of pigment found in vertebrate fur, feathers, and scales: Little expression of the gene in adults results in the production of dark pigments, while robust agouti activity generally yields light pigment production. But Manceau and Hoekstra found that subtle changes in the gene’s embryonic activity can also make a profound difference in the distribution of pigments across the entire body.

“During embryogenesis, agouti is expressed in the belly, where it delays maturation of the cells that will eventually produce pigments,” says Hoekstra, John L. Loeb Associate Professor of the Natural Sciences at Harvard. “This leads to a lighter-colored belly in adults, which is the most common color pattern across a wide variety of vertebrates, from fish to antelope.”

Beyond color patterning, this study highlights how genetic and developmental mechanisms underlying trait variation can affect the evolution of natural diversity: Even small changes in agouti gene expression can establish a completely new color pattern. In deer mice, natural selection drives changes in the amount and place of agouti expression, which in turn results in new color patterns that can camouflage animals from visual predators in habitats including dark forests and light sandy beaches.

“It is hard not to speculate that agouti plays a role in generating more complex patterns — from stripes to spots — in a diversity of vertebrates,” Hoekstra says.

Manceau and Hoekstra now plan to continue researching the molecular basis of animals with more complex color patterns, such as zebra mice, chipmunks, thirteen-lined ground squirrels, and perhaps eventually even leopards and zebras.

“Are the same pre-patterning mechanisms we see in deer mice also involved in the formation and evolution of more complex pigment patterns, like the racing stripes of chipmunks?” Manceau asks. “That’s the exciting question now.”

Manceau and Hoekstra’s co-authors on the Science paper are Vera S. Domingues and Ricardo Mallarino, both of Harvard’s Department of Organismic and Evolutionary Biology. Their work was supported by the National Science Foundation and the Portuguese Foundation for Science and Technology.

Fuente: Harvard University.

The map of us

It has been described as “biology’s moonshot.” After 15 years of planning and work by public- and private-sector scientists at 20 centers in six countries, the Human Genome Project delivered what then-President Bill Clinton called “the most important, most wondrous map ever produced by humankind.”

What makes the Human Genome Map especially wondrous is its inward focus. It is the map of us, our portrait at the level of 21,000 genes.

To mark the 10th anniversary of the publication of that portrait, Harvard President Drew Faust will host a panel discussion on the project next week (Feb. 22) in Sanders Theatre.

The panel, featuring a leader of the original project, researchers who have benefited from the effort, and the head of the U.S. Food and Drug Administration, will consider the territory covered since the map was published in the scientific journals Nature and Science, and where researchers hope it will go in the future.

Because of the import of, and interest in, the Human Genome Project outcome and its long-range implications, USA Today, the nation’s largest-circulation newspaper, will be live-streaming the Sanders Theatre panel on its website beginning at 4 p.m. Tuesday. The video will also be available here.

While some observers have questioned whether the $3 billion project has contributed enough tangible benefits to humanity, many scientists say that its impact on genomic and medical research — indeed, on the very conduct of research — has been astounding.

“Today, we are learning at dizzying speed about the interplay of genes and environment in diabetes, heart disease, and other common conditions. In the past three years alone, more than 1,000 genetic risk factors have been found [an increase of perhaps 50-fold], contributing to more than 100 common diseases,” David M. Altshuler, a Harvard Medical School (HMS) professor of medicine and genetics, noted in a commentary in the latest issue of Tech Review. “Such advances would have come far later, if at all, without the Human Genome Project.”

When Altshuler was a student, he was taught “that the parts of the human genome not encoding proteins were ‘junk.’ Today, we know that this junk makes up three-quarters of our functional DNA. Parts of it help exquisitely control where and when genes are active in the body.

“I was taught,” he wrote, “that ‘genetic diseases,’ such as cystic fibrosis, are caused by mutation of a single gene, with only a small handful of these mutations known. Today, precise causes are known for 2,800 of these rare single-gene disorders.”

Altshuler and others have noted that the project also dramatically increased the sharing of scientific data across disciplines, touching off an exponential increase in cross-laboratory, cross-departmental and cross-institutional collaboration. “A body of knowledge is not its only legacy,” wrote Altshuler, who also is the director of the Program in Medical and Population Genetics at the Broad Institute of Harvard and MIT. “It changed the way biological research is performed.”

Writing on the “Initial Impact of the Sequencing of the Human Genome” in last week’s edition of Nature, Eric S. Lander, a leader of the project, president and director of the Broad, an HMS professor of systems biology, and a member of the panel, said that “the past decade has shown the power of genomic maps and catalogs for biomedical research. By providing a comprehensive scaffold, the human sequence made it possible for scientists to assemble often fragmentary information into landscapes of biological structure and function.”

But like the maps produced during the great age of global exploration from the 15th to mid-18th centuries — which proclaimed “here be dragons” in places that had yet to be fully explored — the information provided by the Human Genome Map contains many modern gaps that will only be filled as understanding of the project’s biological, social, and ethical ramifications grows.

The Sanders panel, which will take place at 4 p.m. on Feb. 22, will explore both what has been accomplished since the creation of the Human Genome Map and the ways in which science and society may replace the dragons with additional knowledge and policies. In addition to Lander, the panel will include:

Margaret Hamburg, the commissioner of food and drugs, U.S. Food and Drug Administration, Department of Health and Human Services;

M. Susan Lindee, chair and professor of history and sociology of science, University of Pennsylvania;
Vamsi Mootha, an associate professor of systems biology and of medicine at HMS, and an associate member of the Broad Institute;

Vicki L. Sato, a professor of the practice of molecular and cellular biology, Faculty of Arts and Sciences, and a professor of management practice at Harvard Business School, and former president of Vertex Pharmaceuticals.

The afternoon of Feb. 22 will be especially biology-rich at Harvard. In addition to the panel, C. David Allis, Joy and Jack Fishman Professor and head of the Laboratory of Chromatin Biology and Epigenetics at The Rockefeller University, will deliver a Dean’s Lecture at the Radcliffe Institute for Advanced Study on the related topic, “Beyond the Double Helix: Varying the ‘Histone Code.’ ”

Allis’ presentation, which will take place in the Radcliffe Gymnasium at 3 p.m., will explore the ways in which genes are turned on and off during development and the mechanisms involved in regulating those complex processes.

Fuente: Harvard Gazette, Harvard University

La genética personal topa con la patente

Diez años después de la secuenciación del genoma humano, el 20% de los genes está registrado - Los expertos alertan del peligro de entorpecer la medicina personalizada




Texto: Mónica González Salomone

En la mayoría de las enfermedades intervienen muchos genes a la vez, y es ahora, una década después de la secuenciación del genoma humano, cuando los investigadores empiezan a poder entender, en algunos casos, cómo funciona este concierto genético. Pero en el horizonte se vislumbran problemas. Alrededor de un 20% de los genes humanos están patentados. ¿Entorpecerán las patentes el desarrollo de la medicina personalizada, basada en pruebas diagnósticas que buscan no uno, sino muchos genes? Sentencias recientes han reabierto el debate. Mientras, sociedades científicas y la Administración estadounidense piden que las patentes se adapten a los nuevos tiempos.

Se cumplen ahora diez años de la publicación en las revistas Nature y Science del primer borrador del genoma humano, el libro de instrucciones del Homo sapiens. En este tiempo los investigadores se han dedicado a perfeccionarlo; a interpretar su significado; y a tratar de sacarle provecho médico. Y aquí hay unanimidad: lo mejor está aún por llegar.

Es cierto que los test genéticos para diagnosticar e incluso tratar cánceres se usan cada vez más. También son necesarios, por ejemplo, para seleccionar embriones en reproducción asistida. Recientemente, el Hospital Sant Pau en Barcelona anunció el nacimiento del primer niño en España sin mutaciones en el gen BRCA1 que causan el 5% de los tumores de mama. Pero esto es apenas la punta del iceberg.

En los años ochenta y noventa se tardaba una década o más en identificar un único gen. Así se encontraron el BRCA1, el de la enfermedad de Huntington o el de la fibrosis quística, entre otros. Ahora las técnicas de secuenciación leen millones de letras del genoma al día. "Dentro de poco se habrán secuenciado decenas de miles de genomas humanos", escribía Peter Donnelly, Director del Wellcome Trust Centre for Human Genetics (Oxford, Reino Unido), en el especial con que Science celebra el décimo cumpleaños del genoma humano. El resultado es que se conocen ya miles de genes implicados en cientos de enfermedades, y que se abre la vía a la tan anunciada -para algunos prematuramente- medicina personalizada.

Lo que llega es un cambio de paradigma. En un futuro próximo las pruebas genéticas para múltiples genes ayudarán a estimar la efectividad de los tratamientos para cada paciente, y sus efectos secundarios. "Los tests están atravesando una revolución", se afirmaba ya en 2010 en Nature.

"Cuando se secuenció el genoma humano, hace diez años, probablemente se le pedía más de lo que podía dar", dice Carlos López Otín, director en la Universidad de Oviedo de uno de los equipos participantes en el proyecto internacional Genoma del Cáncer. "Pero ahora la tecnología se ha desarrollado de forma extraordinaria, y está generando una cantidad de información genética abrumadora. Hoy ya no identificamos un gen, sino sus variantes, su interacción con otros genes, sus cambios patológicos...".

Pero muchos creen que las patentes de genes pueden ser un obstáculo para la medicina a medida. Entre los miles de genes patentados están alrededor de la mitad de los que se sabe que están implicados en tumores, y también muchos relacionados con otras enfermedades. En 2005, un estudio en Science contabilizaba 4.382 genes humanos bajo patente, de los 23.688 conocidos entonces en el genoma humano. La cuestión es: ¿se lanzarán las compañías al desarrollo de kits genéticos con múltiples genes si para ello deben hacer frente a una maraña de licencias? "La aplicación estricta de las patentes de genes podría hacer que los test genéticos cayeran en la trampa de una intrincada red de patentes (...). Esto amenaza con entorpecer la innovación", han afirmado los editorialistas de Nature.

La cuestión de las patentes de genes es una vieja herida sin cerrar. En los noventa, cuando las técnicas aceleraron el proceso de secuenciación, hubo un aluvión de solicitudes. Se intentaron patentar cientos de secuencias genéticas, incluso sin saber su función.Y muchos protestaron con argumentos éticos: ¿es patentable algo que forma parte del organismo? ¿Puede un gen ser de alguien?

Tanto EE UU como Europa respondieron sí, con una condición. Los genes humanos aislados fuera del organismo- sí son patentables, pero se debe conocer su función. "El gen en sí se ve como un producto químico, lo que aparece en la patente es una fórmula", dice Francisco Fernández Brañas, director de Biotecnología de la Oficina Europea de Patentes. "Es patentable siempre que su función esté descrita y que sea la solución a un problema, es decir, que sirva para tratar o diagnosticar una enfermedad, por ejemplo".

Esta condición, recogida en la directiva sobre patentes biotecnológicas de 1998 y las directrices de 2001 de la Oficina de Patentes de EEUU, hizo que disminuyeran las solicitudes. También la publicación del genoma humano -si la secuencia ya es conocida se incumple el requisito de novedad exigido en las patentes-. El mensaje era claro: el conocimiento de la secuencia de un gen no se premia con una patente, pero sí las aplicaciones de ese conocimiento. El fin último es estimular la innovación: "En el campo de la medicina si a una empresa no se le garantiza un cierto retorno nadie va a desarrollar nada", dice Fernández Brañas.

El problema ahora es que, a diez años vista, no está claro que las patentes hayan logrado su objetivo. "Hay muy pocas evidencias de que hayan promovido las innovaciones en el diagnóstico", escribió el mes pasado en Science Robert Cook-Deegan, experto en propiedad intelectual y genómica de la Universidad de Duke (EEUU).

Lo mismo opina Gert Mathijs, del Centro para la Genética Humana de la Universidad de Leuven (Bélgica), muy activo en la oposición a patentes de genes solicitadas en Europa: "Normalmente son importantes para favorecer el desarrollo de nuevas herramientas para el diagnóstico, pero hay evidencias de que pueden afectar negativamente a la oferta de servicios genéticos".

El pasado año el Departamento de Salud estadounidense publicó un informe que analizaba específicamente el efecto de las patentes de genes en el desarrollo de pruebas diagnósticas. Su conclusión es que los test genéticos no patentados, o comercializados bajo licencias no exclusivas, están mucho más difundidos que los test derivados de licencias exclusivas. La primera situación es, por ejemplo, la de los genes de la fibrosis quística y del cáncer colorrectal, para los que hay tests comercializados por más de cincuenta compañías.

El test de los genes BRCA1 y 2, por el contrario, es un monopolio derivado de una licencia otorgada en exclusiva por Myriad Genetics. Tras el informe de 2010, el Departamento de Salud de EE UU ha recomendado que las patentes de genes no se apliquen en el diagnóstico -tampoco en la investigación, pero esto ya era así-.

"Cuando hay miles de genes con un sinfín de propietarios, ¿cómo nos abriremos camino en el entresijo de patentes resultante para facilitar la aplicación de genotipados múltiples, o para analizar genomas completos?", se preguntaba James P. Evans, del departamento de Genética de la Universidad de Carolina del Norte y uno de los autores del informe, en la revista Genetics in Medicine.

Para muchos el problema no es tanto la patente en sí, sino la definición de lo que cubre y, sobre todo, la política de licencias. La Sociedad Europea de Genética Humana reconoce que las patentes deben "promover la innovación mediante una recompensa justa" a los inventores, pero recomienda "limitar su amplitud" y que las licencias para explotarlas no se concedan en exclusiva.

En este panorama, han vuelto a renacer las dudas éticas sobre la patentabilidad de los genes humanos. Hace un año, un juez de Nueva York invalidó las patentes de Myriad Genetics sobre BRCA1 y 2. En la sentencia, solo aplicable en una parte del estado de Nueva York, se considera a los genes "productos de la naturaleza" y por tanto no patentables. "Esta sentencia va en contra de toda la práctica de jurisprudencia en Europa y Estados Unidos, y la industria biotecnológica ha sido muy crítica", dice Fernández Brañas. "Se espera con mucho interés la decisión de la Corte Federal estadounidense, ante la que el caso ha sido recurrido".

Pero lo cierto es que no sólo quienes se oponen por motivos éticos a las patentes de genes ven en las del cáncer de mama hereditario un ejemplo a evitar. El test genético que Myriad comercializa de forma exclusiva en EE UU cuesta más de 2.000 euros. El grupo de pacientes, investigadores y médicos que interpuso la demanda en Nueva York afirmaba que la patente obstaculizaba la investigación y los tratamientos. No es la primera vez que Myriad Genetics está en el punto de mira. En Europa, ya en 2005, una coalición formada por instituciones médicas y de investigación, Greenpeace e incluso Holanda y Austria se opusieron a las patentes de BRCA1 y BRCA2 y lograron que la Oficina Europea de Patentes las denegara o redujera considerablemente el ámbito de protección.

"El proyecto genoma humano ya incluyó desacuerdos sobre la política de patentes", dice Cook-Degan en Science; "ahora los desacuerdos continúan, pero los efectos de la incertidumbre se hacen notar en las decisiones de inversión de compañías que decidirán qué tecnologías genómicas realmente se desarrollarán. Es importante reducir esta incertidumbre". Los derechos de propiedad intelectual no sólo tienen que ver con la Ley Sinde.

Fuente: El País

Un estudio identifica un oncogen que causa cáncer de piel y proliferación anormal de células madre

Investigadores del Centro de Regulación Genómica en colaboración con el Cold Spring Harbor Laboratory, identifican el gen p63 como oncogén que causa carcinoma escamoso y muestran cómo promueve la supervivencia de las células madre durante el desarrollo del tumor.

El trabajo, publicado en la revista Cell Stem Cell, presentó estos resultados el día 4 de febrero, Día Mundial del Cáncer.

Las células de carcinoma escamoso, es decir, cáncer en tejidos estratificados como por ejemplo, el de cabeza y cuello, piel y pulmón, acostumbran a tener más actividad del gen p63. Los científicos ya sabían que este gen se encuentra en las células tumorales pero su papel no estaba claro. Algunas evidencias apuntaban hacia una función promotora del cáncer mientras otras, por el contrario, sugieren que p63 podía ser un agente protector del cáncer.

Ha sido complicado desentrañar la función de p63 en el desarrollo tumoral debido a los múltiples subtipos o isoformas de la proteína resultante del gen. Bill Keyes, antes investigador del Cold Spring Harbor Laboratory de los Estados Unidos y ahora jefe del grupo Mecanismos de Cáncer y Senescencia en el Centro de Regulación Genómica de Barcelona, ya ayudó a describir el rol de una de las isoformas de p63 como gen protector del desarrollo del cáncer en un trabajo publicó recientemente la revista Nature Cell Biology. Ahora, su equipo del Centro de Regulación Genómica y el equipo liderado por la Dra. Alea Mills en el Cold Spring Harbor Laboratory, describen la función de otro subtipo de p63 en el desarrollo tumoral, respondiendo una pregunta pendiente desde hace tiempo y completando el rompecabezas de las funciones y roles de p63 en procesos de cáncer.

Células madre y cáncer
En el estudio, Keyes y colaboradores han observado que este gen promueve el desarrollo del tumor inhibiendo la senescencia, que es un mecanismo protector de tumores muy potente que normalmente previene que las células se conviertan en células cancerígenas. “Desgraciadamente existen algunos eventos genéticos que evitan la senescencia y presionan a la célula hacia el camino del cáncer. Eso es lo que ocurre cuando la variante ∆Np63∝ del gen se expresa a unos niveles más elevados de lo normal” explica la Dra. Mills. De todos modos, los investigadores han observado que las células que evitan la senescencia, muestran características en su crecimiento parecidas a las de las células madre normales.

“Todos tenemos células madre en nuestro cuerpo que se encargan de regenerar y mantener nuestros tejidos. Nosotros hemos visto que ∆Np63∝ fomenta una supervivencia anormal de la población de células madre de la piel llegando pues a forzar la aparición de un tumor” explica Bill Keyes, primer autor del trabajo. “Actualmente se está prestando mucha atención al paralelismo entre células madre y células cancerígenas. Mientras muchos investigadores estudian las células cancerígenas y las comparan con células madre normales, en este trabajo, hemos observado las células madre normales para entender cómo estas células podrían convertirse en cancerígenas” añade el Dr. Keyes.

El trabajo también revela un nuevo actor clave en todo el proceso, una proteína llamada Lsh. Esta proteína, que es muy importante para la remodelación de la cromatina y para diversos cambios epigenéticos, parece que sería esencial en los primeros estadios del proceso. “Descubrir, no sólo el papel del gen p63 en el cáncer sino también la implicación de la proteína Lsh, es muy excitante. Podría ser una muy buena diana sobre la que dirigir nuevos tratamientos para el cáncer de piel y otros cánceres en el futuro” manifiesta Keyes.

Trabajo de referencia: Keyes et al. ∆Np63∝ Is an Oncogene that Targets Chromatin Remodeler Lsh to Drive Skin Stem Cell Proliferation and Tumorgenesis, Cell Stem Cell (2011), doi:10.1016/j.stem.2010.12.009

Fuente: Centro de Regulación Genómica, Barcelona.

Un test genético determina el riesgo personalizado de cáncer de pulmón

La prueba, pionera en España, se realiza en el madrileño Hospital Moncloa y está indicada tanto para fumadores actuales como para personas que han fumado en los últimos 10 años.


El Hospital Moncloa de Madrid acaba de poner en marcha la implantación de un nuevo test genético -Pulmotest-, desarrollado por el laboratorio CGC Genetics y que tiene como finalidad la determinación del riesgo personalizado de desarrollar cáncer de pulmón asociado al tabaco.

El test, indicado tanto para fumadores actuales como para personas que han fumado en los últimos 10 años, determina el riesgo estratificado de desarrollar la enfermedad en función de las variantes genéticas encontradas en cada fumador. Así, un riesgo moderado se interpreta como que el paciente presenta un riesgo similar al del resto de la población fumadora de desarrollar un cáncer de pulmón (“y que es de hasta 15 veces más que el que tiene la población no fumadora”, precisó la doctora María Orera, directora médica de la CGC Genetics).

Por otro lado, un resultado que indique un riesgo alto significa que las posibilidades de desarrollar la enfermedad son entre 17 y 25 veces más altas que las de los no fumadores, mientras que si se determina que el riesgo es muy alto, se debe interpretar como que éste es entre 25 y 45 veces más elevado que el de la población no fumadora. La prueba, cuyos resultados se obtienen en dos semanas, se realiza a partir de unas gotas de sangre obtenidas mediante una pequeña punción, sin necesidad de que el paciente esté en ayunas.

Argumento eficaz para abandonar el tabaco

Esta nueva técnica, pionera en España, es fruto de los resultados arrojados por un meta-análisis sobre un total de 21 estudios en los que se han identificado qué marcadores están implicados en el riesgo de desarrollar cáncer de pulmón. “Creemos que esta prueba va a contribuir a que muchas personas dejen de fumar y, de hecho, en los estudios previos que se han realizado con este test se ha demostrado que más de la mitad de los fumadores han dejado el hábito al conocer el resultado y alrededor del 60% ha reducido el consumo de tabaco”, señaló la doctora Orera.

Por su parte, la neumóloga Sagrario Mayoralas, subdirectora Médica del Hospital Moncloa, destacó el importante papel que va a desempeñar esta técnica desde el punto de vista de proporcionar al paciente la motivación necesaria para dejar de fumar. “No es fácil abandonar el hábito tabáquico, pero el hecho de que cada paciente conozca de forma personalizada el riesgo derivado tanto del hábito tabáquico como de la carga genética supone un factor motivacional importante. No es lo mismo decirle a un paciente que el tabaco es malo en genérico que cuantificarle el riesgo exacto que tiene. En este sentido, esta nueva herramienta nos ayudará a hacer una adecuada prevención no solo ante el cáncer de pulmón, sino también frente a otras enfermedades asociadas al tabaquismo”.

Según la doctora Mayoralas, uno de cada diez fumadores crónicos desarrollará a lo largo de su vida un cáncer de pulmón. “Actualmente, más del 40% de la población española es fumadora, y el número de mujeres es cada vez mayor. Teniendo en cuenta que los niveles de supervivencia del cáncer de pulmón son bajos (sólo el 20% de los pacientes vive más de dos años después del tratamiento) y que se trata de un tumor que aún no se controla de forma lo suficientemente satisfactoria con las terapias actuales, cualquier medida que favorezca la decisión de iniciar el proceso de deshabituación tabáquica resulta muy útil”.

Se estima que cada año hay 19.000 nuevos casos de cáncer de pulmón y que actualmente unas 1.000 personas mueren semanalmente en nuestro país debido a complicaciones relacionadas con el hábito de fumar, nueve veces más que los fallecidos en accidentes de tráfico.
Los pacientes interesados en someterse a este test, cuyo precio es de 120 euros (“el gasto medio de un fumador en un mes”, tal y como precisó Eduardo Gaspar, director de CGC Genetics), pueden citarse a través del Servicio de Atención al Paciente del Hospital Moncloa y, también en alguno de los 52 laboratorios concertados que CGC Gentics tiene distribuidos en toda España.

Fuente: Revista Jano

Scientists find gene linked to congenital heart defect

by Kitta MacPherson

A gene that can cause congenital heart defects has been identified by a team of scientists, including a group from Princeton University. The discovery could lead to new treatments for those affected by the conditions brought on by the birth defect.

Princeton researchers focused on identifying and studying the gene in zebrafish embryos, and the team's work expanded to include collaborations with other groups studying the genetics of mice and people.

"This work really showcases the use of collaborative science and multiple model systems to better understand human disease," said Rebecca Burdine, an assistant professor of molecular biology at Princeton who led her team.

The newly discovered gene, called CCDC40 (for "coiled coil domain containing protein 40"), controls right-to-left patterning as tissues develop, a critical factor in the configuration and effectiveness of organs. Scientists found the gene by zeroing in on zebrafish and mice in which the placement, and sometimes the internal structure, of organs is disrupted or reversed. While these so-called "left-right patterning" defects occur very rarely in zebrafish and mice, they occur at high frequency in the animals with mutated CCDC40 genes. Their study will be published online in Nature Genetics on Dec. 5. A separate paper by another group identifying a sister gene, CCDC39, based on studies of genes in sheepdogs, appears in the same edition of the science journal.


Loss of the gene that produces the protein CCDC40 in zebrafish (identified here as the locke mutant) or mice (links mutant) leads to defects in the asymmetric placement of organs in the body. The organ placement of normal zebrafish and mice are seen in the upper left and right panels. In zebrafish embryos, the heart (dark region in upper left panel) is labeled showing the atrium (A) and the ventricle (V). Similarly, the view in the upper right shows the heart (RV, right ventricle) and other organs, stomach (S) and right and left lungs (RL and LL) in the proper places. The bottom left and right panels illustrate asymmetric placement of organs in zebrafish and mice embryos caused by the mutant gene. (Image courtesy of Rebecca Burdine and Irene Zohn)
"We used the strengths of different model organisms to gain an understanding of how a novel protein, produced by this new gene, functions," said Irene Zohn, who led a research group studying mice genetics at the Children's National Medical Center in Washington, D.C., and is one of the first authors on the CCDC40 study with Burdine's group. A third group, led by physician Heymut Omran and based at University Hospital in Freiburg, Germany, rounded out the team, with other individual participants located elsewhere. "These findings would not have been possible without the collaborations between the three groups," Zohn added.

The collaboration started several years ago when Zohn contacted Burdine, a renowned expert in the study of left-right patterning in animals. Developmental biologists such as Burdine investigate what factors contribute to patterns in vertebrates relating to symmetry and leading to where organs are placed in the spatial configuration of the body. In humans and many animals, for example, the heart is usually situated on the left side with the liver at its lower right. Flaws in left-right patterning can lead to congenital heart defects in humans.

It is estimated that one in 10,000 people have a condition known as situs inversus, when the left-to-right patterning in the body is switched. In most cases, there are no adverse consequences of this condition, but problems arise when perturbations in the patterning signals produce reversals within organs, including heart structures such as the aorta and pulmonary artery. In rare circumstances, the heart can be located on one side without any supporting structures around it such as arteries and veins. That condition can be fatal.

Zohn and her research team had found a gene in mice that, when mutated, appeared to lead to disruptions in left-right patterning causing heart defects. She asked Burdine if she could locate a similar gene in zebrafish. When Burdine studied the mouse gene found by Zohn's team and its location in the spool of genetic matter known as the genome, Burdine realized that her team knew of a gene mutation in zebrafish that was in the same general area of the zebrafish genome. Upon further study, however, Burdine and her team found that the mouse and zebrafish genes were not only in the same general area of their relative genomes -- they were the same gene.

At that point, the teams tracked where the genes were expressed in mice and fish to better understand their function. The groups found that the genes were specifically turned on in cells that produce motile cilia, important hair-like fibers that project from the surface of cells.

Burdine reasoned that zebrafish embryos with the mutated version of the gene also should possess some sort of defect in the cilia themselves. However, views of the cilia in zebrafish embryos through normal lab microscopes showed nothing beyond the ordinary.

For a closer look, Burdine employed a special transmission electron microscope. She examined the microscopic cilia in the zebrafish with the mutation in CCDC40 and compared those images with zebrafish with the normal gene. The cilia in the zebrafish with the mutations "were disrupted in their structure in a way I had never seen before," Burdine said.

She sent the images to Omran, who was treating people with a disorder known as primary ciliary dyskinesia or PCD. These patients suffer from a defect in the action of the cilia lining the respiratory tract. Normally, cilia beat rhythmically, moving mucus toward the throat. If cilia are impaired, however, they cannot reduce or remove mucus from the lungs, leaving people with the disorder susceptible to chronic recurrent respiratory infections, including bronchitis and pneumonia. Since motile cilia also are required for proper left-right patterning, these patients also often have defects in organ positioning.

Of the 26 patients with similar cilia structural defects tested by Omran, some 17 were found to have mutated versions of the gene CCDC40. In addition to the respiratory ciliary disorder, the patients also suffered from congenital heart defects. This finding provided evidence of a link between the cilia-induced respiratory disorder and the heart problems.

By knowing the gene and the properties conferred by its mutated version, scientists may be able to better treat those with the mutant gene and its accompanying respiratory disorders. Researchers eventually may be able to devise genetic repairs to impaired cilia, Burdine said. Because some congenital heart defects can be surgically repaired, it will be important for those individuals to understand whether or not they may be at risk for passing their defect on to their own children. In the future, it may be possible to screen for mutations in CCDC40 to help determine the risk of congenital heart defects.

In addition to Burdine, Princeton scientists on the paper included: Noriko Okabe, a former postdoctoral fellow; Kari Baker Lenhart and Jason McSheene, graduate students; and Jessica Sullivan-Brown, a former graduate student, all in the Department of Molecular Biology.

In the United States, teams included those at: the Children's National Medical Center in Washington, D.C.; the Howard Hughes Medical Institute at the University of Colorado in Denver; and the Sloan-Kettering Institute in New York. In Germany, teams included those at: the University Hospital Freiburg; the Klinik und Poliklinik für Kinder- und Jugendmedizin-Allgemeine Pädiatrie-Universitätsklinikum in Münster; Albert-Ludwigs-University in Freiburg; the Max Planck Institute for Plant Breeding Research in Köln; and the Max Planck Institute for Developmental Biology in Tübingen. Other groups were based at: the National Medical Center and the Pediatric Institute Svabhegy, both in Budapest, Hungary; and Copenhagen University Hospital in Denmark.

Support for the research included funding from the American Recovery and Reinvestment Act, the federal economic stimulus bill enacted last year, and also from the National Institute of Child Health and Human Development of the National Institutes of Health, the March of Dimes Foundation, the Spina Bifida Association, the German Human Genome Project and the Howard Hughes Medical Institute.

Fuente: Princeton University

Stefano Mancuso: Las raíces de la inteligencia de las plantas

Las plantas se comportan de maneras curiosamente inteligentes: luchan contra los depredadores, maximizan las oportunidades de alimentación... Pero, ¿podemos pensar que poseen realmente una forma propia de inteligencia? El botánico italiano Stefano Mancuso presenta evidencia intrigante.

Stefano Mancuso es fundador de un estudio sobre la "neurología" de las plantas, el cuál explora la señalización y la comunicación a todos los niveles de organización biológica, desde moléculas a genes, células y comunidades ecológicas.

Fuente: TED, Ideas Worth Spreading.

Two genes linked to common gynaecological disease

Two genetic variants have been identified that increase the risk of developing endometriosis, a common gynaecological disease. The study provides clues to the origin of this often very painful condition, which has a significant impact on the quality of life of many women.





The research was carried out at the University of Oxford, the Queensland Institute of Medical Research, Australia, and Brigham and Women's Hospital and Harvard Medical School in the USA. The findings are published in the journal Nature Genetics.

Endometriosis is a common gynaecological disease affecting an estimated 6–10% of all women in their reproductive years – an estimated 170 million women worldwide. In some cases, endometriosis will only cause minor symptoms and go undiagnosed. But in more severe cases, debilitating symptoms can have a profound effect on the woman’s life.

The condition is characterised by the growth of cells similar to those lining the womb on organs in the pelvis, such as the ovaries and bowel. These deposits can result in pelvic pain as well as infertility in some women, but why the deposits arise in the first place is as yet largely unknown.

A diagnosis can only be made reliably by looking into the pelvis with a laparoscope, which explains why it is common for years to pass before the diagnosis is made. Current treatments are limited to surgery and hormonal drugs that have numerous side-effects.

‘Endometriosis can be a painful and distressing condition that affects a significant number of women in their reproductive years,’ explains Dr Krina Zondervan of the Wellcome Trust Centre for Human Genetics and the Nuffield Department of Obstetrics and Gynaecology at Oxford University.

Endometriosis can be a painful and distressing condition that affects a significant number of women in their reproductive years
Dr Krina Zondervan
The researchers compared the genomes of over 5,500 women from the UK, Australia and the US who had been surgically diagnosed with endometriosis, with almost 10,000 healthy volunteers. They identified two new genetic variants that increase the risk of developing the disease, particularly moderate-severe forms.

‘We've known for some time that endometriosis is heritable, but until now we have been unable to find any robust genetic variants that influence a woman’s risk of developing the disease,’ says Dr Zondervan, who led the Wellcome Trust-funded study.

The first is a variant on chromosome 7 believed to be involved in regulating nearby genes, probably those involved in the development of the womb and its lining.

The second variant was found on chromosome 1, close to the gene WNT4. This is important for hormone metabolism and the development of the female reproductive tract, especially the ovaries, making it an important biological candidate for involvement in endometriosis.

‘Our study is a breakthrough because it provides the first strong evidence that variations in DNA make some women more likely to develop endometriosis,’ says Dr Zondervan. ‘We now need to understand the effect of these variations on cells and molecules in the body.’

Dr Stephen Kennedy, head of the Nuffield Department of Obstetrics and Gynaecology and joint senior author on the paper, adds: ‘We have great confidence that the results of this study will help towards developing less invasive methods of diagnosis and more effective treatments for endometriosis.’


Fuente: Oxford University.

El trabajo del Consorcio Internacional para el Genoma del Cáncer (ICGC), descrito en la Revista Nature.

El trabajo del Consorcio Internacional para el Genoma del Cáncer ha sido reconocido por la revista Nature en un artículo firmado por todas las instituciones participantes.

El Consorcio Internacional para el Genoma del Cáncer (ICGC) coordina estudios genómicos de alta capacidad en tumores de 50 diferentes tipos tumorales, escogidos por su importancia clínica o social a lo largo del globo. Estudios sistemáticos de más de 25.000 genomas de cáncer usando herramientas de genómica, epigenómica y transcriptómica están revelando el repertorio de mutaciones oncogénicas, permitiendo describir huellas de agentes mutagénicos, definiendo subtipos tumorales clínicamente relevantes, identificando nuevos marcadores pronósticos o terapéuticos y haciendo posible el desarrollo de nuevas terapias para cáncer. Un proyecto español, incorporando los principales centros de investigación en cáncer, en el que colaboran científicos del CNIO, forma parte del ICGC centrado en el análisis de la Leucemia Linfocítica crónica, la forma más frecuente de leucemia. El CNIO ha organizado recientemente el último Workshop anual del ICGC (22-23 Marzo 2010), reuniendo 129 científicos y representantes de todos los países participantes en el proyecto, considerado como el más ambicioso proyecto de investigación en cáncer.


Fuente: CNIO (Centro Nacional Investigaciones Oncológicas).

Mast cells: more than just allergy

"Mast cells are most commonly associated with allergies and anaphylactic shock, but the case of Stephanie Brown reported this week in the national press has raised the profile of another condition caused by mast cells: cutaneous mastocytosis".











Mast cells, a class of white blood cell, are characterised by their large granules. They are found in most tissues of the body particularly in boundary areas near the external environment – the skin, mucosa of the lungs and the digestive tract. Mast cells play a key role in inflammatory processes, releasing the contents of their granules in response to stimulation through direct contact, antibody cross-linking or activated complement proteins. The granules contain preformed chemical modulators, such as histamine and heparin, which cause blood vessels to relax leading to swelling and redness, as well as cytokines and lipid mediators that recruit other white blood cells to the site of inflammation.

The action of mast cells is most frequently associated with allergy and they play a central role in asthma, eczema and allergic rhinitis. Allergies result from the allergen (be it pollen or food) being bound by IgE antibodies on the surface of mast cells. Binding of the allergen results in cross-linking of the antibody and the activation of the mast cell. Activation leads to the release of its granules and inflammation. In severe cases this can lead to anaphylaxis, caused by degranulation of mast cells throughout the body leading to shock. This response, though best understood in terms of allergy, is thought to have evolved originally to defend the body against intestinal parasites such as the tapeworm.

Mastocytosis is a condition involving the accumulation of mast cells in a particular organ of the body, due to increased production of these cells in the bone marrow. A condition affecting people of all ages, mastocytosis is a heterogeneous condition in that it appears to have multiple causes. Several mutations in the gene c-Kit, a gene whose product is responsible for the survival and proliferation of white blood cells such as mast cells, have been identified in many but not all patients. Mastocytosis can be systemic, affecting the whole body, or cutaneous, affecting just the skin. Paediatric mastocytosis is generally restricted to the skin and often resolves itself once children reach adulthood.

In cutaneous mastocytosis activation of the accumulated mast cells causes the development of painful blisters over the entire skin surface. These skin lesions are known as urticaria pigmentosa and can be highly disfiguring. Activation of the mast cells in the skin can be triggered by many different events including touch, exercise, alcohol, insect stings or foods. Sufferers of systemic mastocytosis experience, in addition to skin lesions, gut pains, and vomiting due to mast cell activation in the gut. The liver, kidney and joints can also be affected. The specific symptoms of individual sufferers vary due to the heterogeneous nature of the condition.

Treatment of mastocytosis is tailored to individual patients depending on their symptoms and is based on controlling the symptoms. Antihistamines are commonly given to alleviate itching and redness, while adrenaline is provided to systemic patients who suffer anaphylactic reactions. Psoralen ultraviolet A (PUVA) therapy can be used, as in the case of Stephanie Brown, to alleviate itching and provide cosmestic improval.

Psoralen is a plant compound that increases the sensitivity of skin to UVA. The combination of Psoralen UVA treatment is used to treat a range of conditions affecting the skin such as psoriasis and eczema. The exact mechanism by which exposure to UVA resolves symptoms is unknown. UV is believed to suppress the body’s immune system in a mechanism involving regulatory T cells and vitamin D, a known regulator of the immune system. The recruitment of regulatory T cells to the skin would lower the extent of mast-cell activation in mastocytosis sufferers resulting in a decrease in the number of skin lesions. This treatment does not cure sufferers but alleviates symptoms. Sufferers may need to receive repeat treatments.

While there is no cure for mastocytosis, children often grow out of the condition with symptoms usually disappearing by adulthood. Hopefully this will be the case for Stephanie Brown as well.

References
Sunbed sessions cure toddler of painful blisters 5 Mar 2010 Telegraph.co.uk
www.ukmasto.co.uk

Fuente: British Society for Inmunology.

Stem cells and genetic programming : lessons from fundamental research

Female mammals carry two identical sex chromosomes, two X chromosomes, whilst males possess only a single X chromosome.

To avoid the effects of this imbalance, a mechanism is activated in females during embryonic development which ensures the silencing of the genes present on one of the two X chromosomes present in each cell. This mechanism ensures that cells of males and females express equally the genes present on the X chromosome.

The mechanisms responsible for this X-chromosome inactivation are under investigation in the unit of Mouse Molecular Genetics (Institut Pasteur/CNRS URA 2578), headed by Philip Avner. The scientists in this unit have previously identified three factors controlling directly the onset of this process in the embryo. In collaboration with the team of Dr.Ian Chambers at the University of Edinburgh, they have now characterised a further three factors implicated in a complementary second level of regulation.
Interestingly some of these factors have previously been shown to be able to induce adult cells of specialised tissues such as the skin to move towards the undifferentiated or stem cell state. When this ‘deprogrammation’ occurs in female cells it is accompanied by the reactivation of genes on the inactive X chromosome. This suggests that there are common molecular mechanisms between the reactivation of the inactive X and the process of reprogrammation/deprogrammation.

The discovery of scientists from the Institut Pasteur and CNRS by contributing to the identification of these underlying common regulatory mechanisms. underlines the importance of fundamental research for our understanding of the nature of the developmental plasticity of embryonic stem cells, an area of potential major interest for the development of novel therapeutics and public health.
_ _ _

These works received financial supports from the Agence Nationale de la Recherche Scientifique and the Epigenome European Network of Excellence.

Picture : The inactivated X-chromosom appears in green, via the non-coding ARN Xist, which covers it in the nucleus of each cell of female mammals. © Institut Pasteur

Scientists at the Institute Pasteur and CNRS have identified key regulatory factors controlling one of the critical developmental processes occurring during embryo development : X-inactivation, which ensures the silencing of the genes carried by one of the two X chromosomes present in all cells of female mammals. These regulatory factors are also implicated in maintaining the capacity of embryonic stem cells to give rise to the different tissues which form our organism, such as the skin, liver and brain. And these same regulatory factors are also capable of ‘reprogramming' the genomes of adult cells so that they lose their specialisation and return to the stem cell state. The research published in Nature contributes to our understanding of the fundamentals governing the stem cell state, a knowledge which will be necessary for controlling the differentiation of these cells and developing their use as a base for novel therapeutic stratégies.

Fuente: Instituto Pasteur.