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Molecular snapshots of oxygen formation in photosynthesis

 

[2014-07-10] Researchers from Umeå University have explored two different ways that allow unprecedented experimental insights into the reaction sequence leading to the formation of oxygen molecules in photosynthesis. The two studies have been published in the scientific journal Nature Communications.

 

"The new knowledge will help improving present day synthetic catalysts for water oxidation, which are key components for building artificial leaf devices for the direct storage of solar energy in fuels like hydrogen, ethanol or methanol," says Johannes Messinger, Professor in Biological Chemistry and leader of the Artificial photosynthesis research group at Umeå University.

Every child learns at school that the oxygen we breathe is produced by photosynthesis in plants and by cyanobacteria that live in lakes and the oceans. However, exactly how that happens is still under intense research.

Oxygen formation in photosynthesis occurs in a reaction sequence that is completed within one thousandth of a second. Thus, it is not surprising that it has been so difficult to prove experimentally how precisely a catalyst consisting of four manganese ions and one calcium ion (Mn₄Ca cluster) performs this reaction sequence in photosystem II. Almost all molecular details we presently ‘know’ about the last critical steps are based on calculations. Johannes Messinger and his research group at Umeå University have now explored two different ways for obtaining experimental insight into the mechanism of oxygen formation.

In the first study, the researchers slowed down the reaction sequence more than 40-times by exchanging the calcium of the cluster against strontium, and a nearby chloride ion against an iodide ion.

"We could show that in the last short-lived intermediate state before oxygen formation, the two water molecules are ‘arrested’, meaning that they are more than 1000-times more tightly bound to the Mn₄Ca cluster than in all earlier states of the reaction. This stabilization is thought to be caused by a previously reported loss of a proton and to reflect a highly ordered arrangement that is required for the fast and energy efficient formation of oxygen from water."

The result was obtained using oxygen isotopic labelling and time-resolved membrane inlet mass spectrometry.

In the second study, Johannes Messinger and his collaborators used a X-ray free electron laser, Linac Coherent Light Source (Menlo Park, USA), that produces ultra-short  high-intensity x-ray pulses (10−15 of a second) to perform simultaneous x-ray crystallography and x-ray emission spectroscopy on suspensions of micrometer sized photosystem II crystals.

"With this technique we studied the same reaction sequence and we obtained ‘snap shots’ of the structure of the atoms for the different states of the cluster, including the short lived state investigated in the first study."

The data show that no large scale structural changes (> 0.5·10⁻¹⁰ m) occur in the Mn₄Ca cluster and the rest of the photosystem II complex during oxygen formation. The simultaneously collected X-ray emission data confirm that the “arresting” of the two bound water molecules, as observed in the mass spectrometric experiments, is not due to a change in the charge (oxidation state) of the manganese ions of the Mn₄Ca cluster, nor to the formation of a first bond between the oxygen atoms of the two water molecules.

"The study suggests that small structural changes occur together with the proton release, but we still need to further improve the resolution of our data to see exactly what happens."

The first study was performed in collaboration with two French researchers. The second study was performed within an international team of more than 40 researchers.

Artificial photosynthesis:

In the search for a clean and renewable energy source researchers at Umeå University are studying photosynthesis with the purpose to create artificial photosynthesis devices. Their aim is to understand and model the complex reactions that take place in plant chloroplasts during photosynthesis in order to mimic natural photosynthesis in an “artificial leaf”, an integrated unit that connects all important processes. If successful, it will be possible to convert water with the help of sunlight directly into oxygen and environmentally friendly energy carriers, for example into hydrogen gas.

Original articles in Nature Communications:

Study 1

Study 2

For more information please contact:

Johannes Messinger, Department of Chemistry at Umeå University Telephone: +46 090-786 59 33 E-mail: [email protected] www.solarfuels.se

Editor: Ingrid Söderbergh

Link to news: http://www.teknat.umu.se/english/news//.cid237790

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Page Editor: Ingrid Söderbergh                       2014-07-10

A first direct glimpse of photosynthesis in action

PUBLIC RELEASE DATE:

11-Jul-2014

 Contact: Dr. John Wray [email protected] 49-622-148-6277 Max-Planck-Gesellschaft

Researchers visualize the processes by which photosynthetic proteins split water into hydrogen and oxygen

An international team of researchers, including scientists from the Max Planck Institute for Medical Research in Heidelberg, has just a reported a major step in understanding photosynthesis, the process by which the Earth first gained and now maintains the oxygen in its atmosphere and which is therefore crucial for all higher forms of life on earth.

The researchers report the first direct visualization of a crucial event in the photosynthetic reaction, namely the step in which a specific protein complex, photosystem II, splits water into hydrogen and oxygen using energy provided by light. This is a catalytic process in which the molecules of photosystem II enable and promote the reaction without themselves being consumed. Given the very high sensitivity of photosystem II to radiation damage, the photosynthetic reaction cannot be followed by standard methods of structural investigation such as conventional time-resolved X-ray crystallography. It is, however, amenable to study using the very recently developed method of protein crystallography with free-electron lasers.

In this technique, exceedingly short but extremely intense pulses of X-rays are used to gather data from very small crystals. The pulses are so short, in fact, that they "outrun" most effects of radiation damage, including the complete annihilation of the sample that inevitably follows on much longer time scales. The technique is thus well suited for collecting data from highly sensitive systems such as this catalyzed splitting of water in photosynthesis. Crucial to the process is a special site within the photosystem-II-molecule that contains four manganese atoms and one calcium atom. The experimental measurements show large structural changes in this particular metal cluster, which elongates significantly.

The measurements were made at the SLAC National Accelerator Laboratory in Stanford, using the short and intense flashes from SLAC's X-ray laser, the Linac Coherent Light Source (LCLS). The international team from 18 different institutions was led by Petra Fromme (Arizona State University) and included, in addition to the Heidelberg group, members from SLAC and the University of Hamburg. The Heidelberg team contributed expertise on injecting a thick slurry (suspension) of crystals as a micron-sized jet of particles to be intersected by the femtosecond X-ray pulses from the free electron laser. Crucial to this injection was the design, manufacture and operation of a temperature-controlled, anti-settling device to allow uninterrupted sample injection over the course of many hours.  

This work is significant not only for its direct relevance to understanding photosynthesis, but also because it directly proves the feasibility of performing dynamic X-ray diffraction measurements at room temperature - in particular using free-electron lasers - to study mechanisms of the fast enzyme reactions that are characteristic of so many processes in living organisms.

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Original publication:

"Serial Time-resolved crystallography of photosystem II using a femtosecond X-ray laser"; Christopher Kupitz et al.; Nature, 2014; DOI: 10.1038/nature13453

Endoscope with an oxygen sensor detects pancreatic cancer

Pancreatic Cancer is one of the hardest cancers to detect and usually its progressed to the 4th stage-Walter Derzko

 

Endoscope with an oxygen sensor detects pancreatic cancer

Providing hope for earlier detection, Mayo Clinic says

JACKSONVILLE, Fla. — June 6, 3014 — An optical blood oxygen sensor attached to an endoscope is able to identify pancreatic cancer in patients via a simple lendoscopic procedure, according to researchers at Mayo Clinic in Florida.

The study, published in GIE: Gastrointestinal Endoscopy, shows that the device, which acts like the well-known clothespin-type finger clip used to measure blood oxygen in patients, has a sensitivity of 92 percent and a specificity of 86 percent.

MULTIMEDIA ALERT: Video and audio are available for download on the Mayo Clinic News Network.

That means, of 100 patients with pancreatic cancer, this sensor would detect 92 of them, based on the findings. And of 100 patients who don't have pancreatic cancer, the test would correctly identify them 86 percent of the time.

The device measures changes in blood flow in the tissues that are in the proximity to the pancreas, under the theory that tumors change the flow of blood flow in surrounding tissues because the tumors need oxygen to grow. The endoscope is passed into the stomach and the duodenum, where the measurements are taken. The pancreas lies just outside the duodenum.

"Although this is a small pilot study, the outcome is very promising. There is no test now available that can accurately identify pancreatic cancer at an early stage, short of removing some of the organ," says the study's senior investigator and gastroenterologist Michael Wallace, M.D., M.P.H. "We need new ways to detect pancreatic cancer effectively, and simply, as early as possible."

Now, more than 90 percent of pancreatic cancers are discovered at an advanced or metastatic stage with no effective therapy available. That explains why pancreatic cancer is the fourth most common cause of cancer deaths in the U.S., although it ranks 10th in occurrence.

"We are now confirming our findings in a much larger study, involving institutions in the U.S. and in Europe," Dr. Wallace says.

The technique is a very different way of looking at cancer detection, he says.

"What is quite unusual is that we were trying to sense changes that are not in the tumor itself but are in the nearby, normal-appearing tissues," he says. "It relies on a principle, now being increasingly acknowledged, called a cancer field effect. Instead of looking for the needle in the haystack, we now look at the haystack to see how it is different when there's a needle inside.

"The general concept is that cancers cause surrounding tissue to undergo changes in the flow of oxygen that are detectable, not visually or even under the microscope, but by this kind of sensor," Dr. Wallace says.

To test the ability of the sensor to recognize pancreatic cancer, researchers studied two groups — one in which 14 patients were already diagnosed with the cancer, and another in 10 cancer-free patients.

Dr. Wallace says the blood sensor endoscope is also being tested in colon and esophageal cancers.

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The study was funded by National Institutes of Health and National Cancer Institute, as well as the Mayo Clinic Foundation for Medical Education and Research.

About Mayo Clinic

Recognizing 150 years of serving humanity in 2014, Mayo Clinic is a nonprofit worldwide leader in medical care, research and education for people from all walks of life. For more information, visit 150years.mayoclinic.org, MayoClinic.org or newsnetwork.mayoclinic.org/.

Mitochondrial DNA of first Near Eastern farmers is sequenced for the first time

 

    

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  

                                            

Experts analysed samples from three sites located in the birthplace of Neolithic agricultural practices.

                                            

Sites are located in today’s Syria and date at about 8,000 BC.

                                            

Samples were obtained by the UAB research group and first processed by the UB research group.

                                            

The study is focused on the analysis of mitochondrial DNA —a type of non-Mendelian maternally inherited DNA— from the first Neolithic farmers.

                                            

The study provides a new framework to interpret the results of other studies about European Neolithic populations.

                    

                                          06/06/2014                                                                                            

Recerca                                                                                    

                                         

The mitochondrial DNA of the first Near Eastern farmers has been sequenced for the first time. In the research, published in the journal PLOS Genetics, experts analysed samples from three sites located in the birthplace of Neolithic agricultural practices: the Middle Euphrates basin and the oasis of Damascus, located in today’s Syria and date at about 8,000 BC.

The paper is signed by Daniel Turbón and Alejandro Pérez Pérez, from the Department of Animal Biology of the University of Barcelona (UB); Eva Fernández, from Liverpool John Moores University; Cristina Gamba, Eduardo Arroyo Pardo and Pedro Cuesta, from Complutense University of Madrid; Eva Prats, from the Spanish National Research Council, and Josep Anfruns and Miquel Molist, from the Universitat Autònoma de Barcelona (UAB). The study is focused on the analysis of mitochondrial DNA —a type of non-Mendelian maternally inherited DNA— from the first Neolithic farmers, by means of samples obtained by the UAB research group which were first processed by the UB research group.

                                                                                                                                                                                          

The Neolithic: a profound revolution in human societies

Agricultural and husbandry practices originated around 12,000 years ago in a region of the Near East known as the Fertile Crescent. This phenomenon, known as “Neolithic”, meant a profound social, cultural and economic transformation of human populations (agricultural production, sedentary farming lifestyle, origin of the first cities and modern societies, etc.).

Eva Fernández, first author of the article who got her PhD from UB, explains that “the Neolithic Revolution rapidly expanded from these territories into Europe, where the hunter-gatherer subsistence economy —prevailing till then— was replaced by an agropastoral producing system”. To know the nature of the diffusion of the Neolithic —in other words, to know if it was a population migration process or a cultural adoption— has been widely debated for the last fifty years. Different research fields, for instance archaeology, physical anthropology, linguistics and, more recently, human paleogenetics, have made contributions to the discussion.

The unknown genetics of first Near Eastern farmers

The genetic composition of first Neolithic populations was one of the mysteries of science till today, although some advances in European Neolithic populations’ genetics were made during the last decade. Professor Daniel Turbón points out that the results revealed by the study published in PLOS Genetics “are the first ones regarding first Near Eastern farmers; in other words, the genetic stock of original Neolithic”. However, it is important to remember that other data have been published about European first farmers, to be exact in Catalonia (by Cristina Gamba et al., 2012), the Basque Country (by Hervella et al.) and Germany (by Wolfgang Haak et al., 2010, and Brandt et al., 2013).

“Conclusions of previous studies —explains Turbón— are based on the comparison with current Near East populations, as first agricultural societies’ genetics have remained unknown until now”.

 

From the Near East to Europe

The study published in PLOS Genetics provides a new framework to interpret the results of other studies about European Neolithic populations, stress the authors. According to conclusions, genetic affinities have been observed between the mitochondrial DNA of first Neolithic populations and the DNA of first Catalan and German farmers. This suggests that probably Neolithic expansion took place through pioneer migrations of small groups of population. Moreover, the two main migration routes ―Mediterranean and European― might have been genetically linked.

“The most significant conclusion —highlights Eva Fernández— is that the degree of genetic similarity between the populations of the Fertile Crescent and the ones of Cyprus an Crete supports the hypothesis that Neolithic spread in Europe took place through pioneer seafaring colonization, not through a land-mediated expansion through Anatolia, as it was thought until now”.

 

How did the Neolithic Revolution spread?

Other scientific studies had already provided signs of an alternative scenario of Neolithic spread in Europe different from the one through Anatolia. According to Turbón, “recent archaeological finds have proved that the Neolithic arrived to Cyprus around 10,600 years ago, some years after the first documentation of agricultural practices in the Near East”. Architecture and burial models found in Cyprus’ sites are similar to the ones found in the Middle Euphrates basin, “that indicates a direct colonisation of these territories”, highlights the author. “Besides, spatial interpolation of radiocarbon dates from different Neolithic sites in the Near East and Europe also suggests a first seafaring expansion through Cyprus”, he concludes.

In order to support these conclusions, the scientific team aims at analysing a greater number of human Neolithic samples from other regions of the Fertile Crescent, and at increasing the number of genetic markers analysed in the samples.  

 

Photographies: Alejandro Pérez Pérez (UB) and Miquel Molist (UAB)

Short nanotubes target pancreatic cancer

 

Mike Williams

– June 5, 2014

 

 

Editor’s note: Links to images for download appear at the end of this release.

David Ruth 713-348-6327 [email protected]

Mike Williams 713-348-6728 [email protected]

 

Rice, MD Anderson scientists refine technique for attacking hard-to-reach tumors 

HOUSTON – (June 5, 2014) – Short, customized carbon nanotubes have the potential to deliver drugs to pancreatic cancer cells and destroy them from within, according to researchers at Rice University and the University of Texas MD Anderson Cancer Center.

Pristine nanotubes produced through a new process developed at Rice can be modified to carry drugs to tumors through gaps in blood-vessel walls that larger particles cannot fit through.

The nanotubes may then target and infiltrate the cancerous cells’ nuclei, where the drugs can be released through sonication – that is, by shaking them.

The research led by Rice chemist Andrew Barron was reported in the Royal Society of Chemistry’s Journal of Materials Chemistry B.

Most pancreatic cancer patients die within a year of diagnosis and have a five-year survival rate of 6 percent, partially because there is no method for early detection, according to the American Cancer Society. Tumors are often inoperable and pancreatic cancer cells are also difficult to reach with chemotherapy, said co-author Jason Fleming, a professor of surgical oncology at MD Anderson.

“These findings are encouraging because they offer a potential delivery solution for pancreatic cancer patients whose tumors resist standard chemotherapy,” Fleming said. “There are molecular and biological barriers to efficient delivery of chemotherapy to pancreatic cancer tumors, and these nanotubes might be able to make some of those irrelevant.”

Rice scientists made nanotubes pure enough to modify for the purpose and small enough to squeeze through the body’s defenses, Barron said. The researchers knew from previous work that nanotubes could be modified – a process called functionalization – to carry chemotherapy agents and release them at a controlled rate through sonication.

“This time, we were trying to work out how long the tubes should be and the extent of functionalization to maximize uptake by the cells,” Barron said.

Several discoveries were key, he said. First, Rice graduate student, alumnus and co-author Alvin Orbaek purified the carbon nanotubes of iron catalysts necessary to their growth by flushing them with chlorine. “Leftover iron particles damage the tubes through oxidation,” Barron said. “That makes subsequent use difficult.”

The next step was to cut the nanotubes down to size. Very long nanotubes are floppy and hard to deal with, Barron said. Enrico Andreoli, a postdoctoral research associate in Barron’s group and lead author of the paper, used a thermal process to chop them to an average length of 50 nanometers. (A human hair is about 100,000 nanometers wide.)

“Instead of ending up with a fluffy nanotube powder, we get something that looks like a hockey puck,” Barron said. “It’s not dense – it looks like a spongy puck – but you can cut it with a razor blade. You can weigh it and do accurate chemistry with it.”

Barron’s lab added polyethyleneimine (PEI) to the nanotube surfaces. In lab tests, the modified tubes were easily dispersed in liquid and able to pass through barriers into live cancer cells to infiltrate the nuclei. A small-molecule variant of PEI proved to be less toxic to cells than larger versions, Barron said.

“This research shows that the particles are small enough to get inside cells where you like them to be and that they may have an increased killing advantage – but that’s still unknown,” Fleming said.

Fleming, whose work focuses on improving drug delivery for pancreatic cancer, cautioned that more research is required. ”The next step will be to test this approach in mice that have allografts taken from human tumors,” he said. “The architecture of these tumors will more closely resemble that of human pancreatic cancer.”

Co-authors are Robert Hauge, a distinguished faculty fellow in chemistry, and Wade Adams, a senior faculty fellow in materials science and nanoengineering, both at Rice, and postdoctoral fellow Rei Suzuki and Manoop Bhutani, a professor of gastroenterology, hepatology and nutrition, both at MD Anderson. Barron is Rice’s Charles W. Duncan Jr.–Welch Professor of Chemistry and a professor of materials science and nanoengineering.

The Astellas Foundation for Research on Metabolic Disorders, the National Institutes of Health through MD Anderson’s Cancer Center Support Grant and the Robert A. Welch Foundation supported the research.

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Read the abstract at http://pubs.rsc.org/en/content/articlelanding/2014/tb/c4tb00778f#!divAbstract

Follow Rice News and Media Relations via Twitter @RiceUNews

Related Materials:

Barron Research Group: http://barron.rice.edu/Barron.html

The University of Texas MD Anderson Cancer Center: http://www.mdanderson.org

Images for download:

 

 

 

 

http://news.rice.edu/wp-content/uploads/2014/06/0609_PANCREATIC-1-WEB.jpg

Rice researchers found that chemotherapy agents attached to nanotubes are too large to go through the pores of normal blood vessels (left), but small enough to pass through the pores of cancer-related vessels. Once through, the customized nanotubes can be taken up by cancer cells to deliver their therapeutic cargoes. (Credit: Rei Suzuki/University of Texas MD Anderson Cancer Center)

 

 

 

 

http://news.rice.edu/wp-content/uploads/2014/06/0609_PANCREATIC-2-WEB.jpg

Laser confocal microscopy images show nanotubes combined with polyethyleneimine and fluorescent tags can be taken up by pancreatic cancer cells. The left image shows nanotubes with rhodamine B dye in the cells; the center image shows a DAPI-stained cell and the right image combines the two. (Credit: Enrico Andreoli/Rice University)

Located on a 300-acre forested campus in Houston, Rice University is consistently ranked among the nation’s top 20 universities by U.S. News & World Report. Rice has highly respected schools of Architecture, Business, Continuing Studies, Engineering, Humanities, Music, Natural Sciences and Social Sciences and is home to the Baker Institute for Public Policy. With 3,920 undergraduates and 2,567 graduate students, Rice’s undergraduate student-to-faculty ratio is 6.3-to-1. Its residential college system builds close-knit communities and lifelong friendships, just one reason why Rice has been ranked No. 1 for best quality of life multiple times by the Princeton Review and No. 2 for “best value” among private universities by Kiplinger’s Personal Finance. To read “What they’re saying about Rice,” go here.

- See more at: http://news.rice.edu/2014/06/05/short-nanotubes-target-pancreatic-cancer/#sthash.BKWR9D00.dpuf

Stanford scientists develop 'playbook' for reverse engineering tissue

 

 

STANFORD, Calif. — Consider the marvel of the embryo. It begins as a glob of identical cells that change shape and function as they multiply to become the cells of our lungs, muscles, nerves and all the other specialized tissues of the body.

Now, in a feat of reverse tissue engineering, Stanford University researchers have begun to unravel the complex genetic coding that allows embryonic cells to proliferate and transform into all of the specialized cells that perform myriad biological tasks.

A team of interdisciplinary researchers took lung cells from the embryos of mice, choosing samples at different points in the development cycle. Using the new technique of single-cell genomic analysis, they recorded what genes were active in each cell at each point. Though they studied lung cells, their technique is applicable to any type of cell.

"This lays out a playbook for how to do reverse tissue engineering," said Stephen Quake, PhD, the Lee Otterson Professor in the School of Engineering and a Howard Hughes Medical Institute investigator.

The researchers' findings are described in a paper published online April 13 in Nature. Quake, who also is a professor of bioengineering and of applied physics, is the senior author. The lead authors are postdoctoral scholars Barbara Treutlein, PhD, and Doug Brownfield, PhD.

The researchers used the reverse-engineering technique to study the cells in the alveoli, the small, balloon-like structures at the tips of the airways in the lungs. The alveoli serve as docking stations where blood vessels receive oxygen and deliver carbon dioxide.

Treutlein and Brownfield isolated 198 lung cells from mouse embryos at three stages of gestation: 14.5 days, 16.5 days and 18.5 days (mice are usually born at 20 days). They also took some lung cells from adult mice.

They used standard enzymatic techniques to dissolve the proteins that hold the lung cells together in tissue form, then sorted out the specific alveolar cell types that were the focus of their study.

Their next steps involved newer techniques at the heart of their reverse-engineering process.

Recall how eyedroppers work. Squeeze the rubber bulb to evacuate the air; plunge it into a solution to fill it with fluid; squeeze the bulb again to force the fluid out. In recent years, biotechnologists have used those basic principles to develop microfluidic devices of such precision that they can suck a single cell out of solution and isolate it in a chamber to study its genetic material.

Quake's lab has pioneered the use of microfluidic devices to study single cells. In this study, they used microfluidic devices to capture their 198 sample lung cells. Then they used single-cell genomic sequencing to measure which genes were active in each cell at each time.

How did they decode genomic activity in a single cell? DNA in the nucleus of every cell contains the full genome for that organism. That's why it's possible to build an organism from a single cell. But only some of those genes are active in any given cell at any given time. That's why lung cells are different than hair cells; each cell has a different set of active genes directing its functions.

Genes direct cellular activity by making or "expressing" messenger RNA. Each mRNA instructs the cell to make a particular protein. Cells are essentially a group of interacting proteins. Therefore knowing which mRNAs are active offers a lens into the function of that cell at the point when it was captured in the microfluidic device.

Using this process the Stanford researchers revealed for the first time precisely which genes regulate the development of these particular lung cells at each step along the way to mature alveoli.

One important finding involved the development of two key cell types at the tip of the alveoli, where the lung meets blood to perform the gas exchange that keeps us alive.

Alveolar type-1 cells are the flattest cells in the body. Blood cells dock alongside them to deliver oxygen or pick up carbon dioxide. The thinness of the cell is vital to facilitating this gas transfer.

Alveolar type-2 cells are compact and cuboidal. They secrete proteins to keep the alveoli from collapsing like empty balloons, so as to maintain the inner space through which oxygen and carbon dioxide can move.

Using single-cell genomics allowed the researchers to reverse engineer the development process to show how a single progenitor cell type gives rise to both of these different, mature alveolar cells.

The researchers also captured cells in transition from the progenitor to mature cell state, gaining crucial insights into the mechanism of alveolar cell differentiation.

Although this study focused on lung cells, the technique — capturing individual cells at different stages of embryonic development and assessing gene activity through mRNA sequencing — can be used to reverse-engineer other tissues.

In addition to studying embryonic development, the technique could be used in clinical settings. For instance, researchers could study differences between individual cells in a tumor, improving our understanding of the stages of cancers and leading to better, more targeted therapies.

"This technology represents a quantal leap forward in our ability to apprehend the full diversity of cell types in a given population, including rare ones that could have special functions," said Tushar Desai, MD, MPH, assistant professor of pulmonary and critical care medicine at Stanford and co-author of the paper. "Because a comprehensive molecular characterization of each type is achieved, including the signals they send and receive, a snapshot of the communication between individual cells will also emerge and may suggest attractive therapeutic targets in disease."

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The other Stanford co-authors of the paper are Mark Krasnow, MD, PhD, professor of biochemistry and an HHMI investigator; postdoctoral scholar Angela Wu, PhD; Norma Neff, PhD, genomics core director in the Department of Bioengineering; research assistant Gary Mantalas; and F. Hernan Espinoza, PhD, an HHMI research specialist.

The research was supported by the National Heart Lung and Blood Institute, the National Institutes of Health, the Parker B. Francis Foundation and the Howard Hughes Medical Institute.

The work was also supported by the Department of Bioengineering, which is jointly operated by the School of Engineering and the School of Medicine.

The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://mednews.stanford.edu. The medical school is part of Stanford Medicine, which includes Stanford Hospital & Clinics and Lucile Packard Children's Hospital Stanford. For information about all three, please visit http://stanfordmedicine.org/about/news.html.

The Stanford School of Engineering has been at forefront of innovation for nearly a century, creating pivotal technologies and businesses that have transformed the worlds of technology, medicine, energy and communications and laid the foundation for Silicon Valley. The school advances modern science and engineering through teaching and research. The school is home to nine departments, 245 faculty and more than 4,000 students, tackling the world's most pressing problems in areas like human health and environmental sustainability. For more information, visit http://engineering.stanford.edu.

Print media contact: Tom Abate at (650) 736-2245 ([email protected]) Broadcast media contact: M.A. Malone at (650) 723-6912 ([email protected])

Gene may predict if further cancer treatments are needed

 

		IMAGE:   This is a photo of Dr. Jerry Shay, University of Texas Southwestern Medical Center. Click here for more information.

DALLAS – March 28, 2014 – UT Southwestern Medical Center researchers are developing a new predictive tool that could help patients with breast cancer and certain lung cancers decide whether follow-up treatments are likely to help.

Dr. Jerry Shay, Vice Chairman and Professor of Cell Biology at UT Southwestern, led a three-year study on the effects of irradiation in a lung cancer-susceptible mouse model. When his team looked at gene expression changes in the mice, then applied them to humans with early stage cancer, the results revealed a breakdown of which patients have a high or low chance of survival.

The findings, published online in Clinical Cancer Research, offer insight into helping patients assess treatment risk. Radiation therapy and chemotherapy that can destroy tumors also can damage surrounding healthy tissue. So with an appropriate test, patients could avoid getting additional radiation or chemotherapy treatment they may not need, Dr. Shay said.

"This finding could be relevant to the many thousands of individuals affected by these cancers and could prevent unnecessary therapy," said Dr. Shay, Associate Director for Education and Training for the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. "We're trying to find better prognostic indicators of outcomes so that only patients who will benefit from additional therapy receive it."

Dr. Shay's study closely monitored lung cancer development in mice after irradiation. His group found some types of irradiation resulted in an increase in invasive, more malignant tumors. He examined the gene expression changes in mice well before some of them developed advanced cancers. The genes in the mouse that correlated with poor outcomes were then matched with human genes. When Dr. Shay's team compared the predictive signatures from the mice with more than 700 human cancer patient signatures, the overall survivability of the patients correlated with his predictive signature in the mice. Thus, the classifier that predicted invasive cancer in mice also predicted poor outcomes in humans.

His study looked at adenocarcinoma, a type of lung cancer in the air sacks that afflicts both smokers and non-smokers. The findings also predicted overall survival in patients with early-stage breast cancer and thus offer the same helpful information to breast cancer patients; however the genes were not predictive of another type of lung cancer, called squamous cell carcinoma. Other types of cancers have yet to be tested.

The American Cancer Society estimates the risk of developing lung cancer to be 1 in 13 for men and 1 in 16 for women, including both smokers and non-smokers. Lung cancer is the second most common cancer in both men and women, accounting for about 13 percent of all new cancers, and about 27 percent of cancer deaths. The American Cancer Society estimates more than 224,210 new cases of lung cancer and nearly 160,000 deaths from lung cancer will occur in 2014. Survival statistics vary depending on the stage of the cancer and when it is diagnosed.

Dr. Shay's research is paid for in part by a five-year grant from NASA, which helps fund cancer research due to cancer risks faced by astronauts during space missions.  The findings could lead to more individualized care and pave the way to better, more science-based care and decision making, he said.

"Personalized medicine is coming," Dr. Shay said. "I think this is the future – patients looking at their risks of cancer recurrence and deciding what to do next. We can better tailor the treatment to fit the individual. That's the goal."

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About UT Southwestern Medical Center 

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty includes many distinguished members, including five who have been awarded Nobel Prizes since 1985. Numbering more than 2,700, the faculty is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in 40 specialties to nearly 90,000 hospitalized patients and oversee more than 1.9 million outpatient visits a year.

One gene, many tissues

 

SISSA participating in an international study on genome expression

		IMAGE:   This image shows the Neurogenomics Laboratory of SISSA. Click here for more information.

Genes are the "code" for building the biological elements that form an organism. The DNA that makes up genes contains the instructions to synthesise proteins, but it's wrong to think that, for a given gene, these instructions are always the same for all parts of the organisms. In actual fact, the gene varies depending on the tissue where it is located (cerebral cortex, cerebellum, olfactory epithelium, etc.); in particular, what varies is the point in the "string" of code at which protein synthesis starts. This complexity complicates the work of scientists considerably, but projects like FANTOM come to their aid. FANTOM is in fact an international consortium that brings together several dozens of laboratories worldwide and has recently published a paper providing an exhaustive map of these specificities. The Neurogenomics Laboratory of SISSA, coordinated by Stefano Gustincich is among the participating laboratories.

"FANTOM has existed for about fourteen years and the published paper is the result of the fifth phase of the project," explains Stefano Gustincich. "Each of the participating laboratories sent in several biological samples all of which were examined using the same methodology".

In particular, the researchers used CAGE technology which, unlike more traditional methods, analyses only the first nucleotides of messenger RNA. Messenger RNA is a small piece of genetic material that the DNA uses to sythesize proteins, a sort of carbon copy of part of the information contained in the gene. Nucleotides are the small beads that make up the "string" of DNA and RNA. "By analysing the first nucleotides we are able to identify which sequence of gene starts the transcription. For any given gene, this sequence in fact changes depending on the tissue in which it is located. This way, we know where the gene starts to do its work" continues Gustincich. "Finding the beginning of the active portion also enables us to identify the 'promoter', that is, the DNA sequence that precedes the actual gene". The promoter changes from tissue to tissue, and it is the part that regulates the "active" portion of the gene. The FANTOM project has drawn up a list of all the promoters in human and mouse genomes.

"It's a huge task and the results described in this first paper are only the more general findings", continues Gustincich. "Soon, however, the work of each of the single laboratories will start to be published which will provide details about the single tissues and genes analysed". In the case of SISSA's Neurobiology Laboratory, the focus was on the genes of olfactory receptors which, surprisingly, are also present in the cells that synthesise dopamine and that die in Parkinson's disease.

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Simple blood test may predict if a child will become obese

 

Researchers at the Universities of Southampton, Plymouth and Exeter used the test to assess the levels of epigenetic switches in the PGC1a gene – a gene that regulates fat storage in the body.

Epigenetic switches take place through a chemical change called DNA methylation, which controls how genes work and is set during early life.

The Southampton team found that the test, when carried out on children at five years old, differentiates between children with a high body fat and those with a low body fat when they were older. Results showed that a rise in DNA methylation levels of 10 per cent at five years was associated with up to 12 per cent more body fat at 14 years. Results were independent of the child's gender, their amount of physical activity and their timing of puberty.

Dr Graham Burdge, of the University of Southampton who led the study with colleague Dr Karen Lillycrop, comments: "It can be difficult to predict when children are very young, which children will put on weight or become obese. It is important to know which children are at risk because help, such as suggestions about their diet, can be offered early and before they start to gain weight.

"The results of our study provide further evidence that being overweight or obese in childhood is not just due to lifestyle, but may also involve important basic processes that control our genes. We hope that this knowledge will help us to develop and test new ways to prevent children developing obesity which can be introduced before a child starts to gain excess weight. However, our findings now need to be tested in larger groups of children."

The study, which also involved Professor Terence Wilkin at the University of Exeter and Dr Joanne Hosking at Plymouth University, is published in the journal Diabetes. The researchers used DNA samples from 40 children who took part in the EarlyBird project, which studied 300 children in Plymouth from the age of five until they were 14 years old.

Led by Professor Wilkin, the study assessed the children in Plymouth each year for factors related to type 2 diabetes, such as the amount of exercise they undertook and the amount of fat in their body. A blood sample was collected and stored. The Southampton team extracted DNA from these blood samples to test for epigenetic switches.

Joanne Hosking, research fellow at Plymouth University, says: "This a unique longitudinal data set and we hope to gain even further insight by looking at what happens in these children beyond age 14 years and into adulthood."

Professor Wilkin says: "The EarlyBird study has already provided important information about the causes of obesity in children. Now samples stored during the study have provided clues about the role of fundamental processes that affect how genes work, over which a child has no control. This has shown that these mechanisms can affect their health during childhood and as adults."

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Stem cell study opens door to undiscovered world of biology

 

		IMAGE:   This photo shows Dr. Sean Morrison, Director of the Children's Research Institute and senior author of the study, right, and Dr. Robert A.J. Signer, a postdoctoral research fellow and the... Click here for more information.

DALLAS – March 9, 2014 – For the first time, researchers have shown that an essential biological process known as protein synthesis can be studied in adult stem cells – something scientists have long struggled to accomplish. The groundbreaking findings from the Children's Medical Center Research Institute at UT Southwestern (CRI) also demonstrate that the precise amount of protein produced by blood-forming stem cells is crucial to their function.

The discovery, published online today in Nature, measures protein production, a process known as translation, and shows that protein synthesis is not only fundamental to how stem cells are regulated, but also is critical to their regenerative potential.

"We unveiled new areas of cellular biology that no one has seen before," said Dr. Sean Morrison, Director of the Children's Research Institute, Professor of Pediatrics, and the Mary McDermott Cook Chair in Pediatric Genetics at UT Southwestern Medical Center. "No one has ever studied protein synthesis in somatic stem cells. This finding not only tells us something new about stem cell regulation, but opens up the ability to study differences in protein synthesis between many kinds of cells in the body. We believe there is an undiscovered world of biology that allows different kinds of cells to synthesize protein at different rates and in different ways, and that those differences are important for cellular survival."

Dr. Adrian Salic's laboratory at Harvard Medical School chemically modified the antibiotic puromycin in a way that made it possible to visualize and quantify the amount of protein synthesized by individual cells within the body. Dr. Robert A.J. Signer, a postdoctoral research fellow in Dr. Morrison's laboratory and first author of the study, realized that this reagent could be adapted to measure new protein synthesis by stem cells and other cells in the blood-forming system.

What they came across was astonishing, Dr. Morrison said. The findings suggested that different types of blood cells produce vastly different amounts of protein per hour, and stem cells in particular synthesize much less protein than any other blood-forming cells.

"This result suggests that blood-forming stem cells require a lower rate of protein synthesis as compared to other blood-forming cells," said Dr. Morrison, the paper's senior author.

Researchers applied the findings to a mouse model with a genetic mutation in a component of the ribosome – the machinery that makes proteins – and the rate of protein production was reduced in stem cells by 30 percent. The scientists also increased the rate of protein synthesis by deleting the tumor suppressor gene Pten in blood-forming stem cells. In both instances, stem cell function was noticeably impaired.

Together, these observations demonstrate that blood-forming stem cells require a highly regulated rate of protein synthesis, such that increases or decreases in that rate impair stem cell function.

"Amazingly, when the ribosomal mutant mice and the Pten mutant mice were bred together, stem cell function returned to normal, and we greatly delayed, and in some instances entirely blocked, the development of leukemia," Dr. Morrison said. "All of this happened because protein production in stem cells was returned to normal. It was as if two wrongs made a right."

Many diseases, including degenerative diseases and certain types of cancers, are associated with mutations in the machinery that makes proteins. However, why this is the case has yet to be understood. Discoveries such as this raise the possibility that changes in protein synthesis are necessary for the development of those diseases. 

"Many people think of protein synthesis as a housekeeping function, in that it happens behind the scenes in all cells," Dr. Signer said. "The reality is that a lot of housekeeping functions are highly regulated; they have just not been studied enough to recognize the difference among cells. I think what we are seeing with this study is just the tip of the iceberg, where the process of protein production is probably quite different in distinct cell types."

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