Lego-like modular components make building 3-D 'labs-on-a-chip' a snap

Modular fluidic and instrumentation components developed by researchers at the University of Southern California Viterbi School of Engineering. Credit: USC Viterbi School of Engineering

Thanks to new LEGO-like components developed by researchers at the USC Viterbi School of Engineering, it is now possible to build a 3-D microfluidic system quickly and cheaply by simply snapping together small modules by hand.

Microfluidic systems are used in many fields including engineering, chemistry and biotechnology to precisely manipulate small volumes of fluids for use in applications such as 

• enzymatic or DNA analysis, 
• pathogen detection, 
• clinical diagnostic testing, and 
• synthetic chemistry. 

Traditionally, microfluidic devices are built in a cleanroom on a two-dimensional surface using the same technology developed to produce integrated circuits for the electronics industry.

Though tiny, designing, assembling and testing a new microfluidics system can take a lot of time and money. Building a single device can often require multiple iterations, each of which can take up to two weeks and several thousand dollars to manufacture. And the more complex the system, the higher the number of iterations needed.

"You test your device and it never works the first time," said Krisna Bhargava, materials science graduate student at the USC Viterbi School of Engineering. "If you've grown up to be an engineer or scientist, you've probably been influenced by LEGO at some point in your childhood. I think every scientist has a secret fantasy that whatever they're building will be as simple to assemble."

Frustrated that reproducing a simple microfluidic circuit could cost him so much time and money, Bhargava set out simplify the construction process. First, he identified the primitive elements commonly used in microfluidic systems, much like how circuitry is broken down in electrical engineering. Basic microfluidic functions would be separated into standardized modular components, not an entirely revolutionary concept. But then, he abandoned the two-dimensional method of building microfluidic devices altogether.

"The founders of the microfluidics field took the same approach as the semiconductor industry: to try to pack in as much integrated structure as possible into a single chip," explained Bhargava. "In electronics, this is important because a high density of transistors has many direct and indirect benefits for computation and signal processing. In microfluidics, our concerns are not with bits and symbolic representations, but rather with the way fluidics are routed, combined, mixed, and analyzed; there's no need to stick with continuing to integrate more and more complex devices."

Borrowing an approach from the electronics industry, which uses prototype boards to build circuits, Bhargava conceived of three-dimensional modular components that encapsulated the common elements of microfluidic systems, as well as a connector that could join the separate components together. Inspired by recent advancements in micron-scale 3D-printing, he and a USC Viterbi research team that included chemical engineering and materials science professor Noah Malmstadt and biomedical engineering graduate student Bryant Thompson, designed computer models for eight modular fluidic and instrumentation components (MFICs, pronounced "em-fix") that would each perform a simple operation. Examples are a "helix" component that can mix two fluid streams and a component that contains an integrated optical sensor for measuring the size of small droplets. The components constructed for this study are approximately 1 cm3, slightly smaller than a standard 6-sided die.

The team's development of these MFICs represents the first attempt to break a device into separate components that can be assembled, disassembled and re-assembled over and over.

RNA World 2.0

Most scientists believe that ribonucleic acid played a key role in the origin of life on Earth, but the versatile molecule isn’t the whole story.

© KEVIN HAND

The ubiquity and diverse functionality of ribonucleic acid (RNA) in today’s world suggest that the information polymer could well have been the leading player early on in the establishment of life on Earth, and, in theory, it’s a logical basis for primitive life. One can readily imagine that RNA, as a catalytic molecule capable of serving as a template for its own replication, might have reproduced itself and grown exponentially in the primordial environment. Perhaps such an RNA-based proto–life-form even replicated with an appropriate level of fidelity to allow natural selection to begin directing its evolution.

But there’s a snag: “The odds of suddenly having a self-replicating RNA pop out of a prebiotic soup are vanishingly low,” says evolutionary biochemist Niles Lehman of Portland State University in Oregon.

For decades, researchers from diverse fields have theorized—and argued—about how early life might have begun, and about what sparked the 3.5 billion years of evolution that led to the plethora of cell-based life that occupies almost every nook and cranny of modern Earth. Different camps emerged. So-called “metabolism first” researchers focus on understanding chemical cycles that may have materialized in a prebiotic environment and could have led to the synthesis of nucleotides and other organic molecules. Those subscribing to the theory of “genetics first” want to identify the first information molecule and understand how it arose, replicated, and evolved.

The RNA world, first posited by Francis Crick1 and others in the late 1960s, remains an attractive hypothesis. Many of the chemical hurdles that once challenged the laboratory synthesis of the molecule under presumed primordial conditions are being overcome, and in vitro evolution experiments are yielding RNA molecules that perform numerous functions, including copying themselves or other RNAs. “I don’t think there can be much doubt that RNA was a major central player as both a catalyst and an early replicator,” says Nick Lane, a biochemist at the University College London whose research falls under the “metabolism first” label. “So the RNA world is absolutely correct, as far as I’m concerned, in that.”

But the notion that RNA, on its own, spontaneously assembled and evolved on early Earth has fallen out of favor. More likely, whatever conditions spawned compounds as complex as nucleotides also generated other organics, perhaps early forms of modern amino acids and fatty acids, the constituent parts of proteins and membranes. “I’m not sure how many people anymore believe in a pure RNA world. I certainly don’t,” says Lane. “I think the field has drifted away from that, and there’s now an acknowledgment it had to be ‘dirty.’ ”

“I think most people would argue that there’s . . . more than just RNA,” agrees Matthew Powner, a “genetics first” origins-of-life researcher, also at University College London. (See “Matthew Powner: Origin Solver,” The Scientist, March 2014) “People have relaxed their opinions of the RNA world . . . from its original inception where RNA was fundamental to all parts of biology in the earliest form of life.”

Fellowships in Biochemistry, Cell Biology, Developmental Biology, Epigenetics, Immunobiology and Molecular Biology. Max Planck Institute

PhD overview

Our programme provides outstanding students with excellent research-oriented interdisciplinary training in Biochemistry, Cell Biology, Developmental Biology, Epigenetics, Immunobiology and Molecular Biology. We train students to become self-reliant and to acquire and utilize the knowledge necessary for their research project. Students have the chance to interact with experts in various fields both to extend their scientific knowledge and to learn critical thinking as well as acquire problem-solving skills.

The IMPRS-MCB fellows have 3 to 4 years to obtain their degree. Most of this time they work on their individually supervised research project. In addition to the experimental part all fellows have a possibility and are obliged to participate in curricular activities of the programme. These are:

• scientific and soft skills courses offered by the programme (see Curriculum)
• institute seminars
• PhD retreat
• supervision of junior students (master students or summer trainees)
• conference attendance
• career evenings

Our students are funded during the whole time of their PhD (3-4 years). The payment is sufficient for monthly living costs in Freiburg to be covered. There are no tuition fees to be paid.

Graphical overview of the curricular activities during your PhD

Figure Legend: Orange - activities related to research and the PhD project; Blue - courses; Green - scientific conference/retreats

ORIGINAL: Max Planck Institute

Biocombustible a partir de algas de aguas residuales

ORIGINAL: Noticias De La Ciencia
Jueves, 25 julio 2013

Investigadores de la Universidad de Antioquia (Colombia) y la Escuela Politécnica de Lausanne (EPFL, en Suiza) se unieron en un proyecto para producir biomasa de microalgas y captar biológicamente CO2 y así generar, posteriormente, metano para utilizarlo como combustible. “Las algas son capaces de utilizar las sales disueltas, presentes en las aguas residuales, y así aumentar la biomasa para después, mediante un tratamiento hidrotérmico, convertir esta biomasa en Metano” asegura Alejandro Acosta, investigador del Grupo de Biotransformación de la Universidad de Antioquia.

En Colombia se realiza el estudio relacionado con el uso de las aguas residuales del sector industrial y doméstico para el cultivo y aumento de la biomasa de microalgas; en Suiza se encargan de tomar esa biomasa y convertirla en gas metano al emplear una tecnología de gasificación hidrotérmica catalítica denominada SunCHem, desarrollada por EPFL.

“Ya se han realizado pruebas con otros materiales orgánicos diferentes a las algas provenientes, principalmente, de materiales maderables. Pero la velocidad de crecimiento es muy baja cuando se compara con la producción que podríamos lograr utilizando microalgas”, afirma Acosta.

Los ensayos experimentales se realizaron con microalgas cultivadas en la Planta de Tratamiento San Fernando, al Sur de Medellín. Ésta realiza dos procesos de tratamiento convencionales; con la captura de las sales que permanecen en las aguas, se empezará a realizar un tercer proceso de tratamiento que sólo es común en países industrializados.

Microalgas. (Foto: AGENCIENCIA)

“Así podrían verterse nuevamente las aguas minimizando el impacto ambiental al río y se aprovechan las microalgas para la generación de un biogás”, explica Acosta.

Además de la generación de combustible, las algas incidirán en el efecto del CO2 en el ambiente pues son fijadoras biológicas de este gas invernadero. (Fuente: AGENCIENCIA/DICYT)


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Two Mutations Found to Have Triggered Evolutionary Leap 500 Million Years Ago In Humans

ORIGINAL: 33rdSquare
June 24, 2013

Add caption

A research team led by a University of Chicago scientist has discovered two key mutations that sparked a hormonal revolution 500 million years ago.

Evolution, it seems, sometimes jumps instead of crawls.

A research team led by a University of Chicago scientist has discovered two key mutations that sparked a hormonal revolution 500 million years ago.

In a feat of "molecular time travel," the researchers resurrected and analyzed the functions of the ancestors of genes that play key roles in modern human reproduction, development, immunity and cancer. By re-creating the same DNA changes that occurred during those genes' ancient history, the team showed that two mutations set the stage for hormones like estrogen, testosterone and cortisol to take on their crucial present-day roles.

"Changes in just two letters of the genetic code in our deep evolutionary past caused a massive shift in the function of one protein and set in motion the evolution of our present-day hormonal and reproductive systems," said Joe Thornton, PhD, professor of human genetics and ecology & evolution at the University of Chicago, who led the study.

"If those two mutations had not happened, our bodies today would have to use different mechanisms to regulate pregnancy, libido, the response to stress, kidney function, inflammation, and the development of male and female characteristics at puberty," Thornton said.

The findings were published online in the Proceedings of the National Academy of Sciences.

Scripps Research Institute Scientists Discover How a Protein Finds Its Way

ORIGINAL: Scripps Research Institute

Katrin Karbstein.
Photo: TSRI

JUPITER, FL, April 29, 2013 – Proteins, the workhorses of the body, can have more than one function, but they often need to be very specific in their action or they create cellular havoc, possibly leading to disease.

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have uncovered how an enzyme co-factor can bestow specificity on a class of proteins with otherwise nonspecific biochemical activity.

The protein in question helps in the assembly of ribosomes, large macromolecular machines that are critical to protein production and cell growth. This new discovery expands scientists’ view of the role of co-factors and suggests such co-factors could be used to modify the activity of related proteins and their role in disease.

“In ribosome production, you need to do things very specifically,” said TSRI Associate Professor Katrin Karbstein, who led the study. “Adding a co-factor like Rrp5 forces these enzymes to be specific in their actions. The obvious possibility is that if you could manipulate the co-factor, you could alter protein activity, which could prove to be tremendously important.”

The new study, which is being published the week of April 29, 2013, in the online Early Edition of the Proceedings of the National Academy of Science, sheds light on proteins called DEAD-box proteins, a provocative title actually derived from their amino acid sequence. These proteins regulate all aspects of gene expression and RNA metabolism, particularly in the production of ribosomes, and are involved in cell metabolism. The link between defects in ribosome assembly and cancer and between DEAD-box proteins and cancer is well documented.

The findings show that the DEAD-box protein Rok1, needed in the production of a small ribosomal subunit, recognizes the RNA backbone, the basic structural framework of nucleic acids. The co-factor Rrp5 then gives Rok1 the ability to target a specific RNA sequence by modulating the structure of Rok1.

“Despite extensive efforts, the roles of these DEAD-box proteins in the assembly of the two ribosomal subunits remain largely unknown,” Karbstein said. “Our study suggests that the solution may be to identify their cofactors first.”

The first author of the study, “Cofactor-Dependent Specificity of a DEAD-box Protein,” is Crystal L. Young. Also a co-author of the paper is Sohail Khoshnevis.

The study was supported by National Institutes of Health Grant R01-GM086451 and the American Heart Association.

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.

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Tel: 858-784-2666

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Controlled Evolution In A Test Tube Produces Artificial Enzymes

ORIGINAL: PopSci

By Clay Dillow

01.31.2013

Artificial Enzymes From Evolution This visual explainer should clarify the process. University of Minnesota / Peggy Rinard

Researchers at the University of Minnesota have just created an artificial enzyme in a test tube by following the rules of natural selection.

This artificial enzyme likely resembles what enzymes looked like billions of years ago, when life began evolving.

Enzymes created in laboratories typically follow principles of rational enzyme design, in which researchers develop a preconceived idea of what an enzyme should be, model it on a computer, and then influence its development to produce the molecule that they want.

By contrast, this new enzyme, developed by Burckhard Seelig’s lab at UM’s College of Biological Sciences, was developed in the same way enzymes evolve in nature. A large quantity of candidate proteins were placed together in culture and screened with every successive generation for their ability to perform a desired function (in this case, joining two pieces of RNA together). Unlike rational enzyme design, this approach isn’t limited by what the researchers know about enzyme structure. All the researchers really need to know is what they want from the enzyme. Evolution finds the best way to get there.

Enzymes are manipulated for use in all kinds of things, from manufacturing processes to fuel refinement to the development of new food products. Industry uses both natural and artificial enzymes for specific purposes, as they catalyze the chemical reactions that generate desired processes and products. Now, the ability to generate enzymes by evolutionary means could lead to whole new applications for tailored enzymes that aren’t achievable with rational enzyme design.

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[PhysOrg]

Cultivos perennes garantizarán seguridad alimentaria

ORIGINAL: Instituto Humboldt

Jueves 11 de Octubre de 2012

Científicos de la Universidad de Rutgers (EE. UU.) le propusieron a investigadores de la UN desarrollar este tipo de plantíos para restaurar suelos y ofrecerle opciones alimentarias a la población.

Se denominan cultivos perennes a aquellos que tienen una vida útil de más de cinco años continuos (hasta de 25 años), como los mangos, los aguacates o las manzanas. 

Estos han sido pieza fundamental en la denominada revolución verde, un proceso que, según algunos investigadores, ha logrado prevenir la hambruna desde 1950 al incrementar sus prácticas en zonas de laderas, en donde hay mayor erosión de los suelos. 

Según el profesor Peter Kahn, doctor de la institución estadounidense: “la producción per cápita del grano anual llegó a su máximo hacia 1980, y ha estado bajando en todo el mundo, lo cual no es un buen panorama. Por eso, las plantas perennes se desarrollan para aumentar la productividad de la tierra, para garantizar la alimentación animal y humana y para proveer biocombustibles diferentes”. 

Por esta razón, los investigadores del Departamento de Bioquímica y Microbiología de esta prestigiosa universidad les propusieron a los científicos de la UN en Palmira desarrollar este tipo de plantas, para restaurar la tierra dañada y garantizar la seguridad alimentaria de los pequeños productores. 

“En algunos lugares en donde no podamos seguir usando cultivos, podemos utilizar árboles que tienen raíces profundas que ayudan al terreno a restaurarse. De esta manera, con el desarrollo de plantas perennes, podemos ayudar a los campesinos y pequeños productores del campo para que diversifiquen su comida y la de los animales, que les den también una rentabilidad adicional”, afirma el profesor Kahn. 

Para el científico estadounidense, el proyecto debe ser colombiano, aunque puede contar con recursos y asistencia técnica de su país. 

“Elegimos a Colombia porque es un laboratorio natural perfecto que tiene todos los tipos de suelos, desde selva tropical húmeda hasta nevados. Además, tiene científicos, agrónomos e investigadores talentosos y altamente capacitados mediante una educación de calidad. Por eso, nos acercamos a la UN”, asegura. 

Para la profesora Nora Cristina Mesa, decana de la Facultad de Ciencias Agropecuarias de la sede: “esta es una oportunidad que demuestra la importancia que tiene la Universidad para el desarrollo científico y tecnológico a nivel nacional e internacional”. 

La Oficina de Relaciones Internacionales e Interinstitucionales (ORI) de la sede espera firmar un convenio marco con la Universidad de Rutgers, a fin de impulsar, además de movilidad académica de estudiantes y docentes, proyectos de cooperación específicos que contribuyan al desarrollo de la nación.

Tomado de: www.agenciadenoticias.unal.edu.co

Why the Next UT-A&M Rivalry Could Be Fought in the Lab

ORIGINAL: NPR

BY TERRENCE HENRY

SEPTEMBER 14, 2012 | 1:54 PM

PHOTO BY MOSE BUCHELE

UT Research Engineer Robert Pearsal looks into a vat of algae.

Two teams, racing against the clock. A long-standing rivalry that up til now has been played on the football field. And at the end, the prize: gooey, stinky algae.

While the University of Texas and Texas A&M University football teams no longer play each other after A&M left the Big 12 conference for the SEC (beginning their membership with a loss to Florida last Saturday), there is a new rivalry between the two campuses: who can make algae into a commercially-viable fuel fastest.

The specifics are well over our pay grade, involving words like microfluidic and B. Braunii. But suffice to say that the idea behind all this research is to create a fuel from algae that can be used in combustion engines.

At UT, as we reported in a story in December, the Open Algae team is hard at work trying to commercialize algae biofuels.

And at A&M they’re aiming to do the same.

A new report by Texas A&M Agrilife Today says that a team at the university may be within four years of a commercially-viable, fuel-grade algae oil.

“The team, with a combined expertise from agriculture to engineering, has received a $2 million National Science Foundation grant to help hasten the process,” Agrilife Today writes.

TEXAS AGRILIFE RESEARCH PHOTO BY KATHLEEN PHILLIPS

A team at A&M recently received a $2 million grant to find ways to make algae biofuels commercially viable.

One of the collaborators on the project is Dr. Tim Devarenne, a Texas A&M AgriLife Research biochemist and collaborator on the project. He says that one benefit of algae isn’t just that it’s renewable, but also that it’s much less carbon intensive. “If we harvest algae and process them into fuels, we don’t emit any excess carbon into the atmosphere that is currently being emitted from petroleum fossil fuels,” he tells Agrilife Today.

If all goes well, the A&M team could partner with industry to make algae fuel commercially viable.

“If we can produce an alga that produces high amounts of oil and grows fast,” Devarenne says, “an industry partner could grow large amounts of it, extract the oil, convert that oil into gasoline or diesel fuel and sell it just like at a normal gasoline pump.”

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Algae can be grown using municipal wastewater, Devarenne says, or by using emissions from coal power plants. That means that carbon dioxide used to make algae fuel would come from existing carbon dioxide already in the atmosphere. The UT team has already produced biofuels from a sewage treatment plant outside of Austin.

And a recent study by UT found that it’s possible algae could produce 500 times more energy than it takes to grow. Oil and gas, by comparison, create 30 to 40 times as much energy as it takes to produce (i.e. drill) them, making algae potentially much more efficient to produce.

“Algae take CO2 out of the atmosphere to make the oil and then when we burn the oil as fuel, we just put that CO2 back into the atmosphere,” Devarenne tells Agrilife Today. “That is different from petroleum because the CO2 from petroleum has been stored underground for hundreds of millions of years and then we release that into the atmosphere when we burn fuels created from petroleum.”

You can read more about A&M’s project over at Agrilife Today.

Using Precisely-Targeted Lasers, Researchers Manipulate Neurons in Worms' Brains and Take Control of Their Behavior

ORIGINAL: Science Daily

Caenorhabditis elegans, adult hermaphrodite. (Credit: By Bob Goldstein, UNC Chapel Hill http://bio.unc.edu/people/faculty/goldstein/ (Own work) [CC-BY-SA-3.0], via Wikimedia Commons)

ScienceDaily (Sep. 23, 2012) — In the quest to understand how the brain turns sensory input into behavior, Harvard scientists have crossed a major threshold. Using precisely-targeted lasers, researchers have been able to take over an animal's brain, instruct it to turn in any direction they choose, and even to implant false sensory information, fooling the animal into thinking food was nearby.

As described in a September 23 paper published in Nature, a team made up of Sharad Ramanathan, an Assistant Professor of Molecular and Cellular Biology, and of Applied Physics, Askin Kocabas, a Post-Doctoral Fellow in Molecular and Cellular Biology, Ching-Han Shen, a Research Assistant in Molecular and Cellular Biology, and Zengcai V. Guo, from the Howard Hughes Medical Institute were able to take control of Caenorhabditis elegans -- tiny, transparent worms -- by manipulating neurons in the worms' "brain."

The work, Ramanathan said, is important because, by taking control of complex behaviors in a relatively simple animal -- C. elegans have just 302 neurons -we can understand how its nervous system functions..

"If we can understand simple nervous systems to the point of completely controlling them, then it may be a possibility that we can gain a comprehensive understanding of more complex systems," Ramanathan said. "This gives us a framework to think about neural circuits, how to manipulate them, which circuit to manipulate and what activity patterns to produce in them ."

"Extremely important work in the literature has focused on ablating neurons, or studying mutants that affect neuronal function and mapping out the connectivity of the entire nervous system. " he added. "Most of these approaches have discovered neurons necessary for specific behavior by destroying them. The question we were trying to answer was: Instead of breaking the system to understand it, can we essentially hijack the key neurons that are sufficient to control behavior and use these neurons to force the animal to do what we want?"

Before Ramanathan and his team could begin to answer that question, however, they needed to overcome a number of technical challenges.

Using genetic tools, researchers engineered worms whose neurons gave off fluorescent light, allowing them to be tracked during experiments. Researchers also altered genes in the worms which made neurons sensitive to light, meaning they could be activated with pulses of laser light.

The largest challenges, though, came in developing the hardware necessary to track the worms and target the correct neuron in a fraction of a second.

"The goal is to activate only one neuron," he explained. "That's challenging because the animal is moving, and the neurons are densely packed near its head, so the challenge is to acquire an image of the animal, process that image, identify the neuron, track the animal, position your laser and shoot the particularly neuron -- and do it all in 20 milliseconds, or about 50 times a second. The engineering challenges involved seemed insurmountable when we started. But Askin Kocabas found ways to overcome these challenges"

The system researchers eventually developed uses a movable table to keep the crawling worm centered beneath a camera and laser. They also custom-built computer hardware and software, Ramanathan said, to ensure the system works at the split-second speeds they need.

The end result, he said, was a system capable of not only controlling the worms' behavior, but their senses as well. In one test described in the paper, researchers were able to use the system to trick a worm's brain into believing food was nearby, causing it to make a beeline toward the imaginary meal.

Going forward, Ramanathan and his team plan to explore what other behaviors the system can control in C. elegans. Other efforts include designing new cameras and computer hardware with the goal of speeding up the system from 20 milliseconds to one. The increased speed would allow them to test the system in more complex animals, like zebrafish.

"By manipulating the neural system of this animal, we can make it turn left, we can make it turn right, we can make it go in a loop, we can make it think there is food nearby," Ramanathan said. "We want to understand the brain of this animal, which has only a few hundred neurons, completely and essentially turn it into a video game, where we can control all of its behaviors."

Funding for the research was provided by the Human Frontier Science Program, the NIH Pioneer Award and the National Science Foundation.

http://www.nature.com/nature/journal/vaop/ncurrent/full/nature11431.html

Genetic Mutation May Have Allowed Early Humans to Migrate Throughout Africa

ORIGINAL: ScienceDaily

ScienceDaily (Sep. 19, 2012) — A genetic mutation that occurred thousands of years ago might be the answer to how early humans were able to move from central Africa and across the continent in what has been called "the great expansion," according to new research from Wake Forest Baptist Medical Center.

A genetic mutation that occurred thousands of years ago might be the answer to how early humans were able to move from central Africa and across the continent in what has been called "the great expansion," according to new research. (Credit: © Sailorr / Fotolia)

By analyzing genetic sequence variation patterns in different populations around the world, three teams of scientists from Wake Forest Baptist, Johns Hopkins University School of Medicine and the University of Washington School of Medicine, Seattle, demonstrated that a critical genetic variant arose in a key gene cluster on chromosome 11, known as the fatty acid desaturase cluster or FADS, more than 85,000 years ago. This variation would have allowed early humans to convert plant-based polyunsaturated fatty acids (PUFAs) to brain PUFAs necessary for increased brain size, complexity and function. The FADS cluster plays a critical role in determining how effectively medium-chain PUFAs found in plants are converted to the long-chain PUFAs found in the brain.

This research is published online today in PLOS ONE.

Image: EVOLUTION

Archeological and genetic studies suggest that homo sapiens appeared approximately 180,000 years ago, but stayed in one location around bodies of water in central Africa for almost 100,000 years. Senior author Floyd H. "Ski" Chilton, Ph.D., professor of physiology and pharmacology and director of the Center for Botanical Lipids and Inflammatory Disease Prevention at Wake Forest Baptist, and others have hypothesized that this location was critical, in part, because early humans needed large amounts of the long-chain PUFA docosahexaenoic acid (DHA), which is found in shellfish and fish, to support complex brain function.

"This may have kept early humans tethered to the water in central Africa where there was a constant food source of DHA," Chilton said. "There has been considerable debate on how early humans were able to obtain sufficient DHA necessary to maintain brain size and complexity. It's amazing to think we may have uncovered the region of genetic variation that arose about the time that early humans moved out of this central region in what has been called the 'great expansion.'"

Once this trait arose, the study shows that it was under intense selective pressure and thus rapidly spread throughout the population of the entire African continent. "The power of genetics continually impresses me, and I find it remarkable that we can make inferences about things that happened tens of thousands of years ago by studying patterns of genetic variation that exist in contemporary populations," said Joshua M. Akey, Ph.D., lead scientist at the University of Washington.

This conversion meant that early humans didn't have to rely on just one food source, fish, for brain growth and development. This may have been particularly important because the genetic variant arose before organized hunting and fishing could have provided more reliable sources of long-chain PUFAs, Akey said.

To investigate the evolutionary forces shaping patterns of variation in the FADS gene cluster in geographically diverse populations, the researchers analyzed 1,092 individuals representing 15 different human populations that were sequenced as part of the 1000 Genome Project and 1,043 individuals from 52 populations from the Human Genome Diversity Panel database. They focused on the FADS cluster because they knew those genes code for the enzymatic steps in long-chain PUFA synthesis that are the least efficient.

Chilton said the findings were possible because of the collaboration of internationally recognized scientists from three distinct and diverse disciplines -- fatty acid biochemistry (Wake Forest Baptist), statistical genetics (Johns Hopkins) and population genetics (University of Washington). This new information builds on Chilton's 2011 research findings published in BMC Genetics that showed how people of African descent have a much higher frequency of the gene variants that convert plant-based medium-chain omega-6 PUFAs found in cooking oils and processed foods to long-chain PUFAs that cause inflammation. Compared to Caucasians, African Americans in the United States have much higher rates of hypertension, type 2 diabetes, stroke, coronary heart disease and certain types of cancer. "The current observation provides another important clue as to why diverse racial and ethnic populations likely respond differently to the modern western diet," Chilton said.

This research was supported by National Institutes of Health grants, P50 AT002782 and a Clinical and Translational Science Award grant to The Johns Hopkins Medical Institutions. Additional support was received from the Wake Forest Health Sciences Center for Public Health Genomics. Additional support came from the Mary Beryl Patch Turnbull Scholar Program and the MOSAIC initiative of Johns Hopkins University.

Chilton has a financial interest in and is a consultant for Gene Smart Health. His potential conflict of interest is being institutionally managed by Wake Forest Baptist and outside sponsors, as appropriate. No other authors have a conflict of interest.

First author is Rasika Mathias, Sc.D, assistant professor of medicine and epidemiology, Johns Hopkins; contributing authors include Hannah C. Ainsworth and Susan Sergeant, both of Wake Forest Baptist; Wenqing Fu, U of W; Dara G. Torgerson, University of California San Francisco; and Ingo Ruczinski and Kathleen C. Barnes of Johns Hopkins.

Expanding Database Enables Discoveries in Emerging Field of Metabolomics

ORIGINAL: The Scripps Research Institute

LA JOLLA, CA – September 10, 2012 – Over the last decade, metabolomics has emerged as the newest of the “omic” sciences (following genomics and proteomics) to provide comprehensive biochemical information about cellular metabolism. This new field has revealed that many of the chemicals involved in or produced through metabolism are currently unknown, but may play vital and previously unappreciated roles in human health and disease.

A major hurdle in profiling both unknown and known metabolic compounds (“metabolites”) has been the scarce amount of reference data. But a team from  The Scripps Research Institute  has developed a massive, searchable online metabolite database that is transforming the field and being widely used in research on countless conditions including cancer and chronic pain.

The researchers describe the newly expanded database, called METLIN, and its potential benefits in the September issue of the journal Nature Biotechnology.

Getting Off the Beaten Path

Scientists once focused on only the major metabolic highways, well-known pathways such as glycolysis and the Krebs Cycle. New metabolomic studies have shown that other pathways and metabolites, however, also play critical roles in fundamental biological processes and the progression of disease.

“For decades biochemical studies have targeted only a handful of canonical metabolites, and comprehensive profiling has been mostly limited to genes and proteins,” said Gary Patti, a former postdoctoral fellow at Scripps Research now an assistant professor at Washington University in St. Louis who helped develop the database. But now he says the new field of metabolomics has emerged with huge promise for medical and other advancements. “I think it’s a really exciting time because the insights being provided by metabolomics are in some cases affecting the way in which we think about fundamental biochemistry,” he said.

The sheer number and complexity of metabolites offer scientists a colossal challenge. While DNA studies of genes that code for proteins offer clues about how many proteins there are and their functions, there’s no such map for metabolites—which include a huge range of chemical types, from amino acids, carbohydrates, and steroids to large, complex fatty acids. No one knows how many metabolites there are in humans, though the number may well be over 100,000, and other organisms may have their own unique arrays.

Digging In

Metabolites can be isolated and analyzed from almost any biological specimen, including tissues, blood, urine, and tumors. The most sensitive technique for analyzing metabolites is mass spectrometry. By using cutting-edge mass spectrometric technologies, the molecular weight of thousands of metabolites can be measured within a few minutes. Previously, researchers might spend days combing databases and other sources of information to identify just one metabolite of interest.

“If you don’t have a database like METLIN, the value of metabomic data would be very limited because each study would require manual searches and ultimately fail to culminate in enough reference data to arrive at conclusive metabolite identifications,” said team leader Gary Siuzdak, a metabolomics expert at Scripps Research.

It was against this landscape that Siuzdak’s group recognized the need for a consolidated and expanded metabolite database to meet the group’s own needs as it struggled to understand key metabolic processes. Efforts to build such a resource began in 2004 and the database they dubbed METLIN was initially built upon slowly. Information was scarce and entered manually, sometimes after curating chemistry books manually for new structural information. Researchers in the lab would compete to see who could add the most in a week. Simultaneously, the lab also began cataloging experimental tandem mass spectrometry data on these compounds and established the first of such resources to provide structural information on metabolites that can be used to identify metabolites. 

Over the past few years, determined to accelerate their work, group members gained major momentum largely by partnering with companies like Sigma, Cayman, ChromaDex, as well as labs at Scripps Research (Boger), University of California, San Diego (Gerwick), the Joint BioEnergy Institute (Berkeley), and now Washington University (Patti) to facilitate acquisition of more molecules on which to generate tandem mass spectrometry data.

More than 10,000 Metabolites

Now METLIN includes more than 60,000 compounds with detailed, high-resolution tandem mass spectrometry information on more than 10,000 metabolites, by far the largest in the world. And the Siuzdak group is far from done. “METLIN is still growing as we speak,” said Ralf Tautenhahn, a senior research associate in Siuzdak’s lab and first author of the paper. “It’s a key tool for all our projects.” Once a metabolite is identified, researchers can begin working out how it functions in the body and in disease.

A key benefit of the database is that it goes beyond basic molecular weight—which might be the same for a range of different compounds. The tandem mass spectrometry data allows for a higher level of confidence in identifying these molecules from biological systems. This involves bombarding individual compounds with gas molecules, which causes them to break apart in unique ways. The weights of the resulting molecular fragments offer a sort of chemical signature for each metabolite that researchers can use to match unknowns more precisely.

Though you can search METLIN manually, the Scripps Research team has also developed software called XCMS Online that performs detailed automated searches. Users can input their own data and the coupled XCMS-METLIN system will come back with precise matches, or if there’s no direct match, it will identify structurally similar metabolites. “It really does accelerate the whole process of discovering new molecules associated with diseases and research in many different areas,” said Siuzdak.

Researchers identify biochemical functions for most of the human genome

ORIGINAL: MIT News

Anne Trafton, MIT News Office

New map finds genetic regulatory elements account for 80 percent of our DNA.

Only about 1 percent of the human genome contains gene regions that code for proteins, raising the question of what the rest of the DNA is doing. Scientists have now begun to discover the answer: About 80 percent of the genome is biochemically active, and likely involved in regulating the expression of nearby genes, according to a study from a large international team of researchers.

The consortium, known as ENCODE (which stands for “Encyclopedia of DNA Elements”), includes hundreds of scientists from several dozen labs around the world. Using genetic sequencing data from 140 types of cells, the researchers were able to identify thousands of DNA regions that help fine-tune genes’ activity and influence which genes are expressed in different kinds of cells.

Just as the sequencing of the human genome helped scientists learn how mutations in protein-coding genes can lead to disease, the new map of noncoding regions should provide some answers on how mutations in the regulatory elements lead to diseases such as lupus and diabetes, says Manolis Kellis, an associate professor of computer science at MIT, an associate member of the Broad Institute and an author of a paper describing the findings in the Sept. 5 online edition of Nature.

“Humans are 99.9 percent identical to each other, and you only have one difference in every 300 to 1,000 nucleotides,” Kellis says. “What ENCODE allows you to do is provide an annotation of what each nucleotide of the genome does, so that when it’s mutated, we can make some predictions about the consequences of the mutation.”

Kellis, who leads MIT’s Computational Biology Group, is one of the principal investigators involved in the Nature paper. The ENCODE collaboration is publishing about two dozen additional papers this week detailing the new results.

Mapping noncoding DNA

ENCODE was established in 2003 to extend our understanding of the human genome beyond protein-coding genes. One way to do that is by studying the chemical modifications of individual stretches of DNA, which control when genetic regions will be active. These modifications vary by cell type and can modify either DNA directly or the histone proteins that DNA wraps around.

To map these modifications, known collectively as the epigenome, the research groups had to collect many different kinds of data from different cell types. Some labs measured DNA or histone modifications, while others gauged the accessibility of different stretches of DNA by cutting it into fragments with enzymes. 

Kellis and his group were among the computational scientists leading the effort to analyze and integrate the huge amount of data generated by different labs. “Given that we were getting more than 1,000 data sets, we had to figure out ways to automatically calibrate experiments,” says Anshul Kundaje, a research scientist in MIT’s Computational Biology Group. “We developed an almost purely automated system that did all of this.”

The ENCODE researchers found that 80 percent of the genome experiences some kind of biochemical event, such as binding to proteins that regulate how often a neighboring gene is utilized. They also discovered that the same regulatory region can play different roles, depending on what type of cell it’s acting in.

The findings should have a major impact on scientists’ understanding of human biology and how genomic variations can cause disease, says Ben Raphael, an associate professor of computer science at Brown University.

“The most exciting part is now we’re getting a whole genome annotation of functional elements,” says Raphael, who was not part of the research team. “Every time you want to understand what a particular piece of the genome is doing, you can use the data from this project.”

Human variation

The researchers also studied the conservation of nucleotides — the A, T, C and G “letters” of DNA — in the newly identified regulatory regions. Nucleotides are conserved if they remain the same over long evolutionary periods, which can be measured by analyzing the variability between species, or among individuals within a species. 

A recent paper by Kellis and colleagues showed that 5 percent of noncoding DNA is conserved across mammals. In one of the ENCODE companion papers appearing online Sept. 5 in Science, Kellis and MIT postdoc Lucas Ward show that an additional 4 percent is conserved within the human lineage, suggesting that those elements control recently evolved traits, some of which are unique to humans.

When the researchers looked at the functions of genes near newly evolved regulatory regions, they found many genes that encode regulators that activate other genes. “Genes involved in the nerve growth pathway and color vision, both of which have been hypothesized to be recent innovations in the primate lineage, are enriched in human-constrained elements in non-conserved regions,” Ward says.

The researchers found that the most highly conserved nucleotides were also the ones most likely to be associated with disease when mutated. They also showed that variants associated with autoimmune diseases such as lupus and rheumatoid arthritis are located in regions active only in immune cells, while variants linked to metabolic diseases are in regions active only in liver cells.

In their next phase, the ENCODE researchers hope to determine just how those variations lead to human disease. 

“What we’ve done over this series of papers is effectively paint a set of reference annotations of common human genome function,” Kellis says. “Our next steps will be to personalize these maps — to basically ask how they vary naturally between individuals, by profiling different cell types from different people, and how their variation relates to human disease and complex human traits.”

In one follow-up project, Kellis and colleagues are comparing activity levels of regulatory elements in different cell types from the same person, across many individuals. Another project is looking at DNA modification patterns across the entire genome of many individuals, in hopes of identifying how variation of specific elements relates to disease.

The research was funded by the National Human Genome Research Institute.

Vanessa Restrepo Schild, con todos los talentos

ORIGINAL: Alma Mater - UNIVERSIDAD DE ANTIOQUIA

ALMA MATER N° 613, UNIVERSIDAD DE ANTIOQUIA

Medellín, septiembre de 2012

Vida Estudiantil

Cuando sea ‘grande’,  Restrepo Schild quiere adelantar el doctorado y el posdoctorado en biología molecular, específicamente en bioquímica y biofísica, los procesos que más le gustan y los que, dice, dan más explicaciones.

Se resiste a ser adulta, pues como los niños, su mente sigue formulándose preguntas sobre la vida, sobre la conformación y el funcionamiento de los organismos. Sobre todo.

Pero, para ser más precisos, esa propensión permanente a cuestionarse por la naturaleza de las cosas en realidad lo que revela es su modo de ser y de estar. Es científica desde chiquita y lo seguirá siendo, porque mantiene encendido el botón de la indagación, de la experimentación y del deseo por encontrar respuestas ciertas a los enigmas y salidas a los problemas que dificultan la existencia de las personas.

Su presente indica que es estudiante de biología e integrante del grupo de investigación Biotecnología de la Universidad de Antioquia, Mujer Joven Talento en Ciencia y Tecnología 2011, resultó seleccionada este año en la categoría como la mujer más destacada en toda la historia del concurso que promueve la Alcaldía de Medellíñ.

Cuando sea grande, por decirlo de alguna manera, piensa seguir siendo lo que constitutivamente es, una joven con alma de niña, que no se resigna a las respuestas dadas, ni a las fatalidades, ni al mundo que los mayores le quieren heredar.

Desde ya planea cursar doctorado y posdoctorado en biología molecular, de manera más específica en bioquímica y biofísica, campos científicos que considera le aportan más explicaciones satisfactorias a sus interrogantes y a sus búsquedas.

Ella quiere hacer su parte. Y lo está logrando. Y lo ha logrado. El reconocimiento de Mujer Joven Talento lo recibió por el proyecto "Mujer en la ciencia, una mirada social", que diseñó, acorde con su visión de la biotecnología, para mejorar la calidad de vida de las personas, en especial de quienes se encuentran en Situaciones vulnerables por el cambio climático u otros factores de riesgo.

Y con los porqué de los porqués a flor de piel sigue adelante. No ha cumplido los veinte años y ya cuenta con una patente registrada en la Superintendencia de Industria y Comercio sobre un diseño tecnológico que concibió en grado once, con el que se ganó la feria de la ciencia en Medellín y la feria nacional de la ciencia que organiza Colciencias.

En palabras simples, se trata de un reactor electrobiológico que, al tiempo que mitiga las inundaciones, mediante procesos biológicos transforma el agua en sus distintos estados y genera energía.

Pronto comenzará el cuarto semestre, pero aun recuerda su ingreso a la Universidad de Antioquia, que prefirió a la Universidad de los Andes a donde también pasó. Y eso por una motivación simple.

Desde que estaba en el colegio, el San José de la Salle, nada anhelaba tanto como poder estar en clase con la profesora Lucía Atehortúa, a quien conocía a través de la literatura por sus investigaciones en biotecnología.

Por eso, desde que llegó a la Universidad, en 2011, quiso no sólo tomar clases con la reconocida bióloga de la Facultad de Ciencias Exactas y Naturales, sino involucrarse desde el primer semestre a las actividades de Biotecnología, el grupo de investigación de excelencia que Atehortúa dirige.

Y como las clases con la profesora apenas aparecían en una etapa avanzada del programa, en el bloque de profundización, Vanessa, insistente como es, no quiso esperar, no podía esperar, y tocó a las puertas del laboratorio una y muchas veces hasta que la investigadora le abrió.

Al principio, quizá para sacársela de encima, la profesora Lucía Atehortúa le propuso diversos retos para montar un proyecto que ya traía entre manos. Uno a uno, paso a paso Vanessa resolvió los desafíos que el diseño de la iniciativa le iba presentando y desde entonces se ganó el derecho a ingresar tempranamente al grupo de Biotecnología.

Tempranamente, como todo lo que caracteriza su vida signada por la biología, un campo ajeno a la formación en derecho que recibió su mamá en la Universidad de Antioquia y a la ingeniería en la que se preparó su papá en la Facultad de Minas de la Universidad Nacional.

La biomimética ha guiado el pensar y el actuar de Vanessa. Por eso trabaja en biotecnología, que es el diseño de la tecnología a partir de la biología, porque sabe y está convencida de que la evolución nos lleva años de ventaja y en los organismos, que ya han solucionado muchos problemas para poder sobrevivir, están las claves. Foto: Luis Javier Londoño Balvín.

Sus progenitores, aunque sorprendidos al principio cuando Vanesa les dijo que su determinación era ser bióloga, respaldaron, por su puesto, la decisión. Al fin y al cabo, la biología es la carrera que integra todo lo que define su personalidad y con la que vibra y sueña día y noche: la curiosidad, la innovación, el preguntarse constante por la fisiología y por la conducta de los organismos.

Es decir, todo lo que le gusta y lo que espera analizar con más detalle cuando se adentre en la biología molecular, campo que quiere profundizar con la misma inquietud de niña, cuando salía por los alrededores a explorar las plantas, recolectar semillas y preguntarse y preguntarse y preguntarse.

"Me quedé como en la etapa infantil", dice, sonríe, y se explica: "la biología es la única que puede responderme todas mis preguntas, todo lo que quiero saber". Y saber que en el bachillerato le gustaba más la química, porque le brindaba un horizonte cognoscitivo más amplio, más desafiante, que no conseguía con la biología tradicional que le impartían.

Aunque, a decir verdad, es probable que su profesor o su profesora se hubieran sentido rebasados por las tantas preguntas que proponía esa muchachita flaca, sin maquillaje, tímida, ensimismada en los problemas de la ciencia y ajena al mundillo moderno, que es como decir casi todo el mundo, de las caderas anchas y de los senos vistosos en los que andaban preocupadas sus compañeras.

"Escogí la biología porque es muy amplia, y puedo visualizar algo macro y luego meterme a algo muy micro, muy específico", dice con la misma espontaneidad con la que informa que acaba de ganar una beca para jóvenes emprendedores auspiciada por linkedln, y cuyas clases, virtuales en su totalidad, las dirigirá el propio fundador de la famosoa red empresarial del mundo.

Y está feliz y orgullosa, porque por esa vía va a conocer los líderes mundiales que, como ella, ya se destacan en emprendimiento e innovación. De hecho ya ha tenido que disputarle el tiempo a los examenes parciales y finales en la Usniversidad para preparar, como sus compañeros de beca en África, India, Londres, work-sfiops en los que discuten cómo sacar el mejor provecho a esta nueva experiencia y oportunidad que les ofrece linkedln.

Pero eso sí, aunque uno se pregunte a qué horas esta joven científica estudia, diseña proyectos, hace trabajo de campo y laboratorio, dicta talleres, rinde informes a la Alcaldía, atiende, a cualquier hora, las demandas de una beca on line, se divierte y descansa, lo cierto es que el tiempo le alcanza para dormir ocho horas reglamentarias y para jugar con su mascota que, seguramente, se rinde primero que ella.

Aun así, el tiempo le alcanza, cómo no, para divulgar la ciencia, otra de las tantas pasiones y de los tantos talentos que la definen. Y lo hace no solo mediante los proyectos de innovación que diseña, o las ponencias, sino también a través de las tecnologías como su propio blogspot —http://vanessarschild.Blogspot.com — que actualiza en español y en inglés, idioma que aprendió desde pequeña cuando veía y escuchaba las caricaturas en la producción original. LJLB

ALMA MATER N°613 VERSIÓN IMPRESA