Freshly squeezed vaccines

4 06 2015

Microfluidic cell-squeezing device opens new possibilities for cell-based vaccines.

MIT researchers have shown that they can use a microfluidic cell-squeezing device to introduce specific antigens inside the immune system’s B cells, providing a new approach to developing and implementing antigen-presenting cell vaccines.

Such vaccines, created by reprogramming a patient’s own immune cells to fight invaders, hold great promise for treating cancer and other diseases. However, several inefficiencies have limited their translation to the clinic, and only one therapy has been approved by the Food and Drug Administration.

While most of these vaccines are created with dendritic cells, a class of antigen-presenting cells with broad functionality in the immune system, the researchers demonstrate in a study published in Scientific Reports that B cells can be engineered to serve as an alternative.

“We wanted to remove an important barrier in using B cells as an antigen-presenting cell population, helping them complement or replace dendritic cells,” says Gregory Szeto, a postdoc at MIT’s Koch Institute for Integrative Cancer Research and the paper’s lead author.

Darrell Irvine, a member of the Koch Institute and a professor of biological engineering and of materials sciences and engineering, is the paper’s senior author.

 

As cells pass through the CellSqueeze device at high speed, narrowing microfluidic channels apply a squeeze that opens small, temporary holes in the cells’ membranes. As a result, large molecules — antigens, in the case of this study — can enter before the membrane reseals. Courtesy of SQZ Biotech

A new vaccine-preparation approach

Dendritic cells are the most naturally versatile antigen-presenting cells. In the body, they continuously sample antigens from potential invaders, which they process and present on their cell surface. The cells then migrate to the spleen or the lymph nodes, where they prime T cells to mount an attack against cells that are cancerous or infected, targeting the specific antigens that are ingested and presented.

Despite their critical role in the immune system, dendritic cells have drawbacks when used for cell-based vaccines: They have a short lifespan, they do not divide when activated, and they are relatively sparse in the bloodstream.

B cells are also antigen-presenting cells, but in contrast to dendritic cells, they can proliferate when activated and are abundant in the bloodstream. However, their functionality is more limited: Whereas dendritic cells constantly sample antigens they encounter, a B cell is genetically programmed only to bind to a specific antigen that matches the receptor on its surface. As such, a B cell generally will not ingest and display an antigen if it does not match its receptor.

Using a microfluidic device, MIT researchers were able to overcome this genetically programmed barrier to antigen uptake — by squeezing the B cells.

Through “CellSqueeze,” the device platform originally developed at MIT, the researchers pass a suspension of B cells and target antigen through tiny, parallel channels etched on a chip. A positive-pressure system moves the suspension through these channels, which gradually narrow, applying a gentle pressure to the B cells. This “squeeze” opens small, temporary holes in their membranes, allowing the target antigen to enter by diffusion.

This process effectively loads the cells with antigens to prime a response of CD8 — or “killer” — T cells, which can then kill cancer cells or other target cells.

The researchers studied the squeezed B cells in culture and found that they could expand antigen-specific T cells at least as well as existing methods using antibody-coated beads. As proof of concept, the researchers then transferred squeezed B cells and antigen-specific T cells into mice, observing that the squeezed B cells could expand T cells in the spleen and in lymph nodes.

The researchers also say that this is the first method that decouples antigen delivery from B-cell activation. A B cell becomes activated when ingesting its antigen or when encountering a foreign stimulus that forces it to ingest nearby antigen. This activation causes B cells to carry out very specific functions, which has limited options for B-cell-based vaccine programming. Using CellSqueeze circumvents this problem, and by being able to separately configure delivery and activation, researchers have greater control over vaccine design.

Gail Bishop, a professor of microbiology at the University of Iowa Carver School of Medicine and director of the school’s Center for Immunology and Immune-Based Diseases, says that this paper presents a “creative new approach with considerable potential in the development of antigen-presenting cell vaccines.”

“The antigen-presenting capabilities of B cells have often been underestimated, but they are being increasingly appreciated for their practical advantages in therapies,” says Bishop, who was not involved in this research. “This new technical approach permits loading B cells effectively with virtually any antigen and has the additional benefit of targeting the antigens to the CD8 T-cell presentation pathway, thus facilitating the activation of the killer T cells desired in many clinical applications.”

 

Main squeeze

Armon Sharei, now a visiting scientist at the Koch Institute, developed CellSqueeze while he was a graduate student in the laboratories of Klavs Jensen, the Warren K. Lewis Professor of Chemical Engineering and a professor of materials science and engineering, and Robert Langer, the David H. Koch Institute Professor and a member of the Koch Institute. Sharei, Jensen, and Langer are also authors of this paper.

In a separate study published last month in the journal PLoS ONE, Sharei and his colleagues first demonstrated that CellSqueeze can deliver functional macromolecules into immune cells. The platform has benefits over existing delivery methods, including electroporation and genetically engineered viruses, which are limited to delivering nucleic acids. While nucleic acids can code a cell for a target antigen, these indirect methods have drawbacks: They have limited ability in coding for difficult-to-identify antigens, and using nucleic acids bears a risk for accidental genome editing. These methods are also toxic, and can cause cell damage and death. By delivering proteins directly into cells with minimal toxicity, CellSqueeze avoids these shortcomings and, in this new study, demonstrates promise as a versatile platform for creating more effective cell-based vaccines.

“Our dream is to spawn out a whole class of therapies which involve taking out your own cells, telling them what to do, and putting them back into your body to fight your disease, whatever that may be,” Sharei says.

After developing CellSqueeze at MIT, Sharei co-founded SQZ Biotech in 2013 to further develop and commercialize the platform. Just as the company has grown since then — now up to 13 employees — the device has also evolved. Sharei, now the company’s CEO, says that by improving the design and increasing the number of channels, the current generation has a throughput of 1 million cells per second.

 

Future steps

The researchers say they now plan to refine their B-cell-based vaccine to optimize distribution and function of the immune cells in the body. A B-cell-based approach could also reduce the amount of patient blood required to prepare a vaccine. At present, patients receiving cell-based vaccines must have blood drawn over several hours each time a new dose must be prepared.

Meanwhile, SQZ Biotech aims to reduce the footprint of its device, which could potentially lower the time and cost required to engineer cell-based vaccines.

“We envision a future system, if we can take advantage of its microfluidic nature, as a bedside or field-deployable device,” Sharei says. “Instead of shipping your cells off to this big, centralized facility, you could do it in your hospital or your doctor’s office.”

As the biology and technology become further refined, the authors say that their approach could potentially be a more efficient, more effective, and less expensive method for developing cell-based therapies for patients.

“Down the road, you could potentially get enough cells from just a normal syringe-based blood draw, run it through a bedside device that has the antigen you want to vaccinate against, and then you’d have the vaccine,” Szeto says.

This research was funded by the Kathy and Curt Marble Cancer Research Fund through the Koch Institute Frontier Research Program, the National Cancer Institute, the National Institute of General Medicine Sciences, and the Howard Hughes Medical Institute.

 

By Kevin Leonardi

 

Newsoffice.mit.edu [en línea] Cambridge, MA (USA): newsoffice.mit.edu, 04 de junio de 2015 [ref. 22 de mayo de 2015] Disponible en Internet: http://newsoffice.mit.edu/2015/cell-squeezing-device-vaccines-0522



Scientists unravel the complex brain mechanisms responsible for tinnitus

4 05 2015

Scientists have undertaken a unique study to help them unravel the complex brain mechanisms responsible for tinnitus.

Dr William Sedley, from Newcastle University’s Institute of Neuroscience

For the first time, researchers have recorded directly from the brain of someone with the condition to find the brain networks linked to causing the debilitating problem in order to gain a better understanding of the issue.

Dr William Sedley, from Newcastle University’s Institute of Neuroscience, co-led the international research with Dr Phillip Gander, from the University of Iowa in America. Their research contrasted brain activity during periods when tinnitus was relatively stronger and weaker.

The research was only possible because the 50-year-old man they studied required invasive electrode monitoring for epilepsy. He also happened to have a typical pattern of tinnitus, including ringing in both ears, in association with hearing loss.

Findings of the research, which are today (April 23) published in the Cell Press journal Current Biology, shed new light on the mechanisms of tinnitus and it is hoped that this will eventually lead to better treatments for patients.

The researchers found the expected tinnitus-linked brain activity, but they report that the unusual activity extended far beyond circumscribed auditory cortical regions to encompass almost all of the auditory cortex, along with other parts of the brain.

Dr Sedley said: “This is a big step forward in our understanding of tinnitus, as it is the first time we have been able to clearly associate the patient’s own subjective experience of tinnitus with direct and precise measurements of brain activity.

“Perhaps the most remarkable finding was that activity directly linked to tinnitus was very extensive, and spanned a large proportion of the part of the brain we measured from. In contrast, the brain responses to a sound we played that mimicked the tinnitus were localised to a tiny area.

“We hope that the extra amount of knowledge we have gained will indirectly help us to develop more treatments for patients in the future. For Newcastle University to collaborate with scientists in America reflects the great work that’s going on into this common condition.”

Approximately one in five people experience tinnitus, the perception of a sound – often described as ringing – that isn’t really there. In the UK it is estimated that around six million people have mild tinnitus, with around 600,000 experiencing it to the severity where their quality of life is affected.

The study may help to inform treatments such as neurofeedback, where patients learn to control their ‘brainwaves’, or electromagnetic brain stimulation, according to the researchers. A better understanding of the brain patterns associated with tinnitus may also help point towards new pharmacological approaches to treatment.

Dr Sedley, who also works for Newcastle Hospitals NHS Foundation Trust’s neurology department, added: “We now know that tinnitus is represented very differently in the brain to normal sounds, even ones that sound the same, and therefore these cannot necessarily be used as the basis for understanding tinnitus or targeting treatment.”

Studies on the patient took place in the University of Iowa’s Institute for Clinical and Translational Science, where patients requiring epilepsy surgery are often studied for up to two weeks with electrodes implanted in their brains, in order to locate the part of the brain responsible for the epilepsy so that it can be removed.

Dr Gander said: “It is such a rarity that a person requiring invasive electrode monitoring for epilepsy also has tinnitus that we aim to study every such person if they are willing.

“The sheer amount of the brain across which the tinnitus network is present suggests that tinnitus may not simply ‘fill in’ the ‘gap’ left by hearing damage, but also actively infiltrates beyond this into wider brain systems.”

The research was funded by the Wellcome Trust and Medical Research Council in the UK, and the National Institutes of Health in the USA. At present the research is based on a single patient, but over time the researchers are hopeful of being able to study more patients with tinnitus in a similar way.

Dr Ralph Holme, Action on Hearing Loss Head of Biomedical Research, said: “Tinnitus is a debilitating condition, for which there is currently no cure.

“We welcome investment and research into tinnitus as the mechanisms behind it are still not fully understood and more progress is needed to improve the chances of effective treatments in the future.”

 

Case study

Father-of-two Lindsay Waddell has suffered from tinnitus for 10 years and welcomes the new research.

The head gamekeeper has spent most of his life working on farms and believes the constant noise of heavy machinery has contributed towards his condition.

Mr Waddell, 64, from Middleton-in-Teesdale, County Durham, said: “My tinnitus has got worse over the years and it sounds like a constant hissing in my ears. Since I was a teenager I’ve been surrounded by the loud noise of farm machinery and I think this has damaged my hearing.

“I’m delighted that this research has been carried out as it’s a great step forward in understanding tinnitus, which will hopefully help lead to the development of new treatments in the future for those suffering the condition.

“Newcastle University is often leading the way with research and this is another example of that.”

 

 

Ncl.ac.uk [en línea] Newcastle (UK): ncl.ac.uk, 04 de mayo de 2015 [ref. 23 de abril de 2015] Disponible en Internet: http://www.ncl.ac.uk/press.office/press.release/item/scientists-unravel-the-complex-brain-mechanisms-responsible-for-tinnitus



Virus a possible cause of type 1 diabetes

23 04 2015

Researchers have found a virus in the pancreas of patients with type 1 diabetes. The discovery may offer the potential for both treatment and a vaccine.

 

The dark patches are viral components in the insulin-producing cells in the islets of Langerhans. Photo: DiViD.

Type 1 diabetes affects children and adolescents. The pancreas stops producing insulin. High blood glucose levels can lead to serious complications such as heart attack, stroke, vision loss, kidney failure and foot amputation.

Daily treatment involving multiple finger-prick blood tests to monitor glucose levels, four to six insulin injections or the use of an insulin pump, all put a great strain on the patient.

Unlike type 2 diabetes, it is not possible to regulate this form of diabetes by exercise or changes in diet. Only 29 per cent of patients achieve the recommended treatment goals that prevent complications.

For many years it has been suspected that a virus is a possible cause of type 1 diabetes. A new study has found a virus present in the pancreas of individuals who have recently been diagnosed with this type of diabetes.

The study was headed by Professor Knut Dahl-Jørgensen at the Faculty of Medicine, UiO, in collaboration with Lars Krogvold, research fellow at UiO and consultant paediatrician at Oslo University Hospital.

 

Professor Knut Dahl-Jørgensen at the University of Oslo heads the research group which is behind the discovery of a virus in the pancreas. Photo: UiO.

Common virus in an uncommon place

The researchers identified viral components in the insulin-producing cells in the islets of Langerhans.

The islets of Langerhans are hormone-producing groups of cells in the pancreas.

The virus that has been detected is in the group of enteroviruses.

Professor Dahl-Jørgensen explains:

“This is a type of virus that occurs frequently among the population. It can cause colds and stomach bugs but also serious infections in the brain and heart, for example”.

Enterovirus is normally found in the intestines and respiratory tract. In individuals with a genetic predisposition the virus has the ability to cause chronic infections.

“It is this type of infection that we have now identified in the insulin-producing cells in the pancreas”, says Dahl-Jørgensen.

 

Lars Krogvold, consultant paediatrician at OUS and research fellow at UiO. Photo: Private.

Vaccine and treatment

The next step will be to try to develop a vaccine.

The work will be done in an EU project in collaboration with two pharmaceutical companies which specialize in developing vaccines. The project will be headed by collaborative partners in Finland.

Lars Krogvold explains, “Producing new vaccines is a very slow business and extremely expensive. We have to make sure the vaccine is both safe and effective for patients and that adverse effects are minimized”.

The process usually takes more than five years, Krogvold adds.

New drugs to treat viral infections are constantly being developed. The hope is to start a project based on patients with newly diagnosed diabetes.

If those plans are realized, as early as next year patients could be participating in a clinical trial to test a combination of a new drug and a well-known drug.

“Our hope is that this can stop the destruction of the insulin-producing cells, and preserve the body’s residual insulin production capability. That will lessen the seriousness of the disease.

Insulin-producing cells have the ability to regenerate, so if we are very lucky some patients may be able to stop insulin therapy completely”, says Krogvold.

 

New research based on existing theory

An increase in the number of cases of type 1 diabetes was discovered in Norway after a viral epidemic. The number of new cases of type 1 diabetes is highest in the autumn and winter, when we have most virus infections.

Some years ago, researchers found a virus in the pancreas of a child who died of diabetes. Since then, signs of the virus have been identified in the blood of diabetes patients with greater frequency than in healthy individuals.

 

Earlier lack of evidence

“A virus consists of genetic material surrounded by a protein shell or capsid. We have detected specific proteins from the capsid by immunostaining tissue samples using special antibodies aimed at these proteins. Most importantly, we have also found the genetic material RNA, which is exclusively specific for this type of virus. In addition, changes have been found in genes that are involved in fighting viruses”, says Krogvold.

““Hitherto there were only indirect indications that a virus could trigger type 1 diabetes. We had no evidence to show that the virus is actually in the insulin-producing cells. To be able to say with certainty that diabetes is caused by a virus, the virus must be identified in the morbid cells, which is what we have done. We also have to show that antiviral treatment or vaccines help to remove it.”.

“If this is possible, we may be able to stop the process at an early stage and prevent the disease having such a serious progression, or preferably prevent it from arising in the first place”, says Dahl-Jørgensen in conclusion.

 

Reference

Lars Krogvold, et al. Detection of a low-grade enteroviral infection in the islets of Langerhans of living patients newly diagnosed with type 1 diabetes. American Diabetes Association, November 2014.

By Thomas Olafsen, information officer at UiO.

Published Dec 5, 2014 01:51 PM – Last modified Mar 23, 2015 12:58 PM

 

 

Med.uio.no [en línea] Oslo (NOR): med.uio.no, 23 de abril de 2015 [ref. 05 de diciembre de 2014] Disponible en Internet: http://www.med.uio.no/klinmed/english/research/news-and-events/news/2014/virus-possible-cause-of-type-1-diabetes.html

 



New synthetic technology for medicines and fine chemicals

20 04 2015

Direct continuous synthesis of medicines becomes possible

 

Sequential addition of starting materials enables continuous production of the final compound, rolipram. Credit: Shu Kobayashi
Read more at: http://phys.org/news/2015-04-synthetic-technology-medicines-fine-chemicals.html#jCp

A University of Tokyo research group has succeeded in synthesizing (R)- and (S)-rolipram, the active component of a medicine, in high yield with high selectivity by an innovative catalyzed flow fine synthesis instead of the traditional batch method used in the production of 99% of medicines.

Professor Shu Kobayashi’s group at the Graduate School of Science has developed highly active immobilized catalysts (heterogeneous catalysts) and demonstrated simple and highly efficient synthesis of (R)- and (S)-rolipram by an eight-step continuous flow reaction using multiple column reactors containing the immobilized catalysts.

Currently, the active components of medicines as well as other fine chemicals are synthesized by a repeated batch reaction method, in which all starting materials are mixed in reaction vessels and the desired compounds are extracted after the all reactions have finished. In this method excess energy and operational steps are needed and a significant amount of waste is generated.

Professor Kobayashi’s application of flow chemistry techniques to the production of fine chemicals using heterogeneous catalysts has resulted in simple method to synthesize (R)- and (S)-rolipram without requiring the isolation or purification of intermediates, without excess amount of energy, and without purification of products from catalysts.

Professor Kobayashi says “This new technology can be applied to not only other γ-aminobutyric acids and medicines but also various chemicals such as flavors, agricultural chemicals, and functional materials. In the future, if this innovative catalyzed flow fine synthesis is established as an original Japanese technology, we can hope for significant development of the chemical, pharmaceutical and related industries and recovery of high skill manufacturing in Japan.”

 

Paper

Tetsu Tsubogo, Hidekazu Oyamada, Shū Kobayashi, “Tetsu Tsubogo, Hidekazu Oyamada, Shū Kobayashi”, Nature Online Edition: 2015/4/16 (Japan time), doi: 10.1038/nature14343. 
Article link(Publication

Link

Graduate School of Science

Department of Chemistry, Graduate School of Science

Synthetic Organic Chemistry Laboratory, Department of Chemistry, Graduate School of Science

 

 

 

U-tokyo.ac.jp [en línea] Tokyo (JPN): u-tokyo.ac.jp, 20 de abril de 2015 [ref. 16 de abril de 2015] Disponible en Internet: http://www.u-tokyo.ac.jp/en/utokyo-research/research-news/new-synthetic-technology-for-medicines-and-fine-chemicals.html



Designed a Nicotine Vaccine that Provokes Robust Immune Response

23 02 2015

TSRI scientists design Nicotine Vaccine that provokes robust immune response

 Insights Could Help Scientists Develop Treatments for Smoking as Well as Other Addictions

 

Kim Janda is the Ely R. Callaway Jr. Professor of Chemistry and member of the Skaggs Institute for Chemical Biology at The Scripps Research Institute. (Photo by John Dole, courtesy of TSRI.)

When a promising nicotine vaccine failed in clinical trials a few years ago, scientists from The Scripps Research Institute (TSRI) were determined to keep trying to help smokers overcome their addiction.

Now the team has designed a more effective nicotine vaccine and proven that the structures of molecules used in vaccines is critical. The study was published recently in the Journal of Medicinal Chemistry.

“This study provides new hope that one could make a nicotine vaccine that succeeds in clinical trials,” said Kim Janda, the Ely R. Callaway Jr. Professor of Chemistry and member of the Skaggs Institute for Chemical Biology at TSRI.

 

Targeting Nicotine

According to the National Cancer Institute, smoking is the leading cause of eight types of cancer, including lung cancer and fast-moving pancreatic cancer.

Nicotine vaccines train the body to see nicotine as a foreign invader. To prompt this immune response, scientists have tried attaching nicotine derivatives called haptens to a larger carrier protein used in other approved vaccines.

The body reacts to the vaccine by creating antibodies to bind specifically to nicotine molecules. When a person later uses tobacco, the anti-nicotine antibodies stop the nicotine molecules from entering the central nervous system and ever reaching the brain.

Though a vaccine wouldn’t be a silver bullet—there would still be withdrawal symptoms—a person may be less motivated to relapse because the brain’s reward system could no longer react to nicotine.

The problem with the previous nicotine vaccine, which only worked in 30 percent of patients, was that it did not single out the most common form of nicotine for attack. Nicotine has two forms that look like mirror images of each other—one is a “right-handed” version and one is a “left-handed” version. Even though 99 percent of the nicotine found in tobacco is the left-handed version, the previous vaccine elicited antibodies against both.

Janda believes that was a waste of immune response. “This is a case where something very simple was overlooked,” he said.

 

Improving the Response

In the new study, the researchers elicited a more robust antibody response by creating a vaccine from only left-handed nicotine haptens. To do this, they prepared haptens as a 50-50 mixture and as pure right-handed or pure left-handed versions of nicotine, so they could use the two versions together or separately.

They tested both versions and the 50-50 mix in rat models, injecting the rats three times over 42 days. This series of “booster” shots gave the animals’ immune systems a chance to create an effective number of antibodies to respond to nicotine.

The researchers analyzed blood from the three experimental groups and found that the left-handed hapten elicited a much more effective immune response. Compared with the right-handed hapten vaccine, the left-handed hapten vaccine prompted the body to create four times as many antibodies against left-handed nicotine molecules. The 50-50 mix was only 60 percent as effective as the pure left-handed version.

“This shows that future vaccines should target that left-handed version,” said Jonathan Lockner, research associate in the Janda lab and first author of the new paper. “There might even be more effective haptens out there.”

The researchers believe purifying nicotine hapten mixtures is an important and practical step in creating future nicotine vaccines. Janda said considering molecule handed-ness is also critical for developing vaccines against other drugs of abuse, such as cocaine and heroin.

“This is just one area where we are looking outside the box to try to treat addiction,” Janda said.

In addition to Janda and Lockner, other authors of the paper, “A Conjugate Vaccine Using Enantiopure Hapten Imparts Superior Nicotine-Binding Capacity,” were Jenny M. Lively and Karen C. Collins of TSRI, and Janaína C. M. Vendruscolo and Marc R. Azar of Behavioral Pharma Inc. For more information, see http://pubs.acs.org/doi/abs/10.1021/jm501625j.

Funding for the research came from the Tobacco-Related Disease Research Program (20XT-0156).

 

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 two 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.

 

For information:
 Office of Communications 
Tel: 858-784-2666 
Fax: 858-784-8136 
press@scripps.edu

 

 

Scripps.edu [en línea] La Jolla, CA (USA): scripps.edu, 23 de febrero de 2015 [ref. 12 de enero de 2015] Disponible en Internet: http://www.scripps.edu/news/press/2015/20150112janda.html



Major cause of blindness linked to calcium deposits in the eye

16 02 2015

Microscopic spheres of calcium phosphate have been linked to the development of age-related macular degeneration (AMD), a major cause of blindness, by UCL-led research.

 

Thousands of hydroxyapatite spheres (magenta), each just a few microns across, are found in large drusen deposits within the eye (credit: Imre Lengyel, UCL)

AMD affects 1 in 5 people over 75, causing their vision to slowly deteriorate, but the cause of the most common form of the disease remains a mystery.* The ability to spot the disease early and reliably halt its progression would improve the lives of millions, but this is simply not possible with current knowledge and techniques.

The latest research, published in Proceedings of the National Academy of Sciences, has implicated tiny spheres of mineralised calcium phosphate, ‘hydroxylapatite’, in AMD progression. This not only offers a possible explanation for how AMD develops, but also opens up new ways to diagnose and treat the disease.

AMD is characterised by a build-up of mainly protein and fat containing deposits called ‘drusen’ in the retina, which can prevent essential nutrients from reaching the eye’s light-sensitive cells, ‘photoreceptors’. Photoreceptors are regularly recycled by cellular processes, creating waste products, but drusen can trap this ‘junk’ inside the retina, worsening the build-up. Until now, nobody understood how drusen formed and grew to clinically relevant size.

The new study shows that tiny calcium-based hydroxyapatite, commonly found in bones and teeth, could explain the origin of drusen. The researchers believe that these spheres attract proteins and fats to their surface, which build up over years to form drusen. Through post-mortem examination of 30 eyes from donors between 43 and 96 years old, the researchers used fluorescent dyes to identify the tiny spheres, just a few microns – thousandths of a millimetre – across.

“We found these miniscule hollow spheres inside all of the eyes and all the deposits that we examined, from donors with and without AMD,” explains Dr Imre Lengyel, Senior Research Fellow at the UCL Institute of Ophthalmology and Honorary Research Fellow at Moorfields Eye Hospital, who led the study. “Eyes with more of these spheres contained more drusen. The spheres appear long before drusen become visible on clinical examination.

“The fluorescent labelling technique that we used can identify the early signs of drusen build-up long before they become visible with current methods. The dyes that we used should be compatible with existing diagnostic machines. If we could develop a safe way of getting these dyes into the eye, we could advance AMD diagnoses by a decade or more and could follow early progression more precisely.”

Some of the mineral spheres identified in the eye samples were coated with amyloid beta, which is linked to Alzheimer’s disease. If a technique were developed to identify these spheres for AMD diagnosis, it may also aid early diagnosis of Alzheimer’s. Whether these spheres are a cause or symptom of AMD is still unclear, but their diagnostic value is significant either way. As drusen are hallmarks of AMD, then strategies to prevent build-up could potentially stop AMD from developing altogether.

“The calcium-based spheres are made up of the same compound that gives teeth and bone their strength, so removal may not be an option,” says Dr Lengyel. “However, if we could get to the spheres before the fat and protein build-up, we could prevent further growth. This can already be done in the lab, but much more work is needed before this could be translated into patients.”

“Our discovery opens up an exciting new avenue of scientific research into potential new diagnostics and treatments, but this is only the beginning of a long road.” says Dr Richard Thompson, the main international collaborator from the University of Maryland School of Medicine, USA.

The work was supported by the Bill Brown Charitable Trust, Moorfields Eye Hospital, Mercer Fund from Fight for Sight, and the Bright Focus Foundation. The UCL-led international collaboration involved researchers from the University of Maryland School of Medicine, Imperial College London, the University of Tübingen, George Mason University, Fairfax, and the University of Chicago.

 

Ucl.ac.uk [en línea] London (UK): ucl.ac.uk, 16 de febrero de 2015 [ref. 20 de enero de 2015] Disponible en Internet: http://www.ucl.ac.uk/news/news-articles/0115/200115-macular-degeneration-linked-to-calcium



Los glóbulos blancos “escanean” el torrente sanguíneo para provocar daño cardiovascular

18 12 2014

Un estudio publicado en Science y liderado por investigadores del CNIC descubre que los neutrófilos escanean activamente la sangre dentro de los vasos en busca de plaquetas activadas.

El estudio demuestra que muchos tipos de accidentes cardiovasculares, como el ictus o el choque séptico, se originan por la acción de los leucocitos que se activan por este mecanismo.

El estudio tiene importantes implicaciones para entender, y tratar, accidentes cardiovasculares de muy amplia índole.

 

Investigadores del CNIC han descubierto que un subtipo de los principales agentes defensivos del organismo, los leucocitos o glóbulos blancos, lleva a cabo un procedimiento de “escaneo” dentro de los vasos sanguíneos que desencadena múltiples tipos de accidentes cardiovasculares, incluyendo algunos tan comunes como el ictus, según publican hoy en la revista Science.

Si uno le preguntara a un médico que le prediga la probabilidad de que sufra un accidente cardiovascular, por ejemplo un ictus o un infarto de miocardio, este le contestaría que la respuesta no es simple porque no se conoce exactamente cómo se inician estos accidentes. Dirá también que existen ciertos marcadores que, no obstante, son altamente predictivos. Uno de estos marcadores es el nivel de un tipo específico de leucocitos –los neutrófilos- en la sangre. El otro, es la presencia de plaquetas activadas en el torrente sanguíneo, las cuales son responsables de la coagulación y contra las que se han desarrollado drogas tan conocidas como la aspirina. La pregunta desde el punto de vista biológico es si existe una relación meramente casual entre ambos marcadores, o si realmente es que ambos tipos celulares, neutrófilos y plaquetas, cooperan para iniciar un accidente vascular.

En colaboración con grupos de la universidad complutense, del departamento de Imagen Avanzada del CNIC, y grupos en Alemania, Estados Unidos y Japón, el equipo del Dr. Andrés Hidalgo, investigador del Departamento de Aterosclerosis, Imagen y Epidemiología del CNIC ha descubierto un sorprendente mecanismo que explica cómo ambos tipos de células, neutrófilos y plaquetas, cooperan para iniciar accidentes cardiovasculares.

Para escudriñar este fenómeno, los investigadores del grupo han mirado directamente dentro de los vasos sanguíneos de tejidos vivos con técnicas avanzadas de microscopia, las cuales permiten ver neutrófilos y plaquetas individuales durante el proceso inflamatorio. La primera sorpresa que se llevaron fue que los neutrófilos que se pegan al vaso inflamado extienden una especie de brazo o protrusión celular hacia el interior del vaso en la que se concentra una proteína altamente adhesiva. La segunda observación inesperada es que algunas de las plaquetas de la sangre se pegaban a esta la proteína presente en esta protrusión. Sorprendentemente, solo las plaquetas que estaban activadas (uno de estos marcadores predictivos de accidentes cardiovasculares) se adherían a esta estructura. La última observación, quizás la más sorprendente, es que esta proteína adhesiva es también capaz de mandar señales al neutrófilo para que inicie una respuesta inflamatoria. Esta respuesta es, en último término, la responsable del daño vascular.

Para investigar como este proceso puede subyacer a los accidentes vasculares referidos anteriormente, los investigadores indujeron ictus, choque séptico o daño pulmonar agudo en ratones en los que la proteína adhesiva estaba ausente o se había bloqueado, y se encontraron con que en todos ellos el grado de daño a los tejidos afectados (cerebro, hígado o pulmón) estaba significativamente reducido comparado con animales no tratados.

El trabajo explica antiguas observaciones clínicas, y tiene implicaciones que pueden ser inmediatas para entender cómo se originan muchos de los tipos de accidentes cardiovasculares más prevalentes en nuestra sociedad.

El trabajo también ilustra como el uso de técnicas de última generación nos ayuda a descubrir la elegancia de procesos biológicos previamente desconocidos, y que ahora pueden ser manipulados para prevenir o tratar enfermedades que de otra manera pueden ser devastadoras para la salud humana.

Sreeramkumar V, Adrover JM, Ballesteros I, Cuartero MI, Rossaint J, Bilbao I, Nácher M, Pitaval C, Radovanovic I, Fukui Y, McEver RP, Filippi MD, Lizasoain I, Ruiz-Cabello J, Zarbock A, Moro MA and Hidalgo A. Neutrophils scan for activated platelets to initiate inflammation. Science, In Press 2014.

Acceso al vídeo

 

 

 Cnic.es [en línea] Madrid (ESP): cnic.es, 18 de diciembre de 2014 [ref. 05 de diciembre de 2014] Disponible en Internet: https://www.cnic.es/es/noticias/index.php?id=3923



Dyslexia independent of IQ

11 12 2014

Brain-imaging study suggests that reading difficulties are the same regardless of overall intelligence — and that more children could benefit from support in school.

 

new brain-imaging study suggests that reading difficulties are the same regardless of overall intelligence. Photo: Patrick Gillooly

About 5 to 10 percent of American children are diagnosed as dyslexic. Historically, the label has been assigned to kids who are bright, even verbally articulate, but who struggle with reading — in short, whose high IQs mismatch their low reading scores. On the other hand, reading troubles in children with low IQs have traditionally been considered a byproduct of their general cognitive limitations, not a reading disorder in particular.

Now, a new brain-imaging study challenges this understanding of dyslexia. “We found that children who are poor readers have the same brain difficulty in processing the sounds of language whether they have a high or low IQ,” says John D. E. Gabrieli, MIT’s Grover Hermann Professor of Health Sciences and Technology and Cognitive Neuroscience, who performed the study with Fumiko Hoeft and colleagues at the Stanford University School of Medicine; Charles Hulme at York University in the U.K.; and Susan Whitfield-Gabrieli, also at MIT. “Reading difficulty is independent of other cognitive abilities.”

The study, which is forthcoming in the journal Psychological Science, could change how educators diagnose dyslexia, opening up reading support to more children who could benefit from it.

 

Rhymes and results

The researchers recruited 131 children, from 7 to 17 years old. According to a simple reading test and an IQ measure, each child was assigned to one of three groups: typical readers with typical IQs; poor readers with typical IQs; and poor readers with low IQs. All were shown pairs of words and asked to judge whether the words rhymed. (Rhymes are an effective way to probe dyslexics’ reading performance, since dyslexia is thought to entail difficulty connecting written words to sounds.) For some pairs, the researchers used words that rhyme but don’t share the same final letters — such as “bait” and “gate,” or “night” and “bite” — so that rhyme couldn’t be inferred simply from spelling. Using functional magnetic resonance imaging (fMRI), the researchers observed the activity in six brain regions known to be important for reading.

The results? Neural activity in the two groups of poor readers was indistinguishable. “The brain patterns could not have been more similar, whether the child had a high or low IQ,” Gabrieli says. Poor readers of all IQ levels showed significantly less brain activity in the six observed areas than typical readers, suggesting that reading difficulty is due to the same underlying neural mechanism, regardless of general cognitive ability.

 

Ditching diagnostic discrimination

The findings could have an important impact on both diagnosis and education for kids who struggle to read. Currently, Gabrieli says, many public school systems still require that a child have an otherwise normal IQ score to receive a diagnosis of dyslexia — essentially, that the label be reserved for children with a “reading difficulty that can’t be explained by anything else,” he says. But the new study suggests that even children with low IQ scores might benefit from treatment specific to dyslexia.

Jack Fletcher, a professor of psychology at the University of Houston Texas Medical Center Annex, says the study “adds to the evidence against” the notion that reading difficulty should be chalked up to general intellectual limitations in children with lower-than-average IQs. “Poor reading is poor reading,” he says. “IQ discrepancy doesn’t make much difference.”

Gabrieli, who says he hopes the new results will encourage educators to offer reading support to more struggling students, stresses the importance of diagnosing dyslexia and other behavioral disorders sooner rather than later. “Now, you basically diagnose dyslexia when a child seems miserable in school,” he says. “Maybe you could intervene before they ever get that way.”

 

 Emily Finn, MIT News Office

 

 

Newsoffice.mit.edu [en línea] Cambridge, MA (USA): newsoffice.mit.edu, 11 de diciembre de 2014 [ref. 23 de septiembre de 2011] Disponible en Internet: http://newsoffice.mit.edu/2011/dyslexia-iq-0923



SMUFIN: Detección Genética rápida y precisa de Tumores

4 12 2014

Un nuevo método computacional permite analizar los cambios genéticos en pacientes de cáncer en pocas horas

 

  • La prestigiosa revista Nature Biotechnology publica hoy SMUFIN, un nuevo método computacional capaz de detectar de forma sencilla, rápida y precisa alteraciones genéticas responsables de la aparición y progresión de tumores
  • SMUFIN localiza casi todos los tipos de cambios genómicos responsables de la aparición y progresión del cáncer, incluso las grandes reorganizaciones de cromosomas difícilmente detectables hasta ahora
  • Este nuevo método es un paso firme y realista hacia el horizonte de la medicina personalizada, en el que el análisis genómico de cada paciente ayudará a su diagnóstico y permitirá la selección de un tratamiento más eficaz y menos agresivo
  • SMUFIN supone una nueva forma de analizar genomas, también aplicable al estudio de las bases genéticas de muchas otras enfermedades prevalentes en nuestra sociedad

 

Un nuevo método computacional hace posible la detección rápida, precisa y sencilla de los cambios genómicos responsables de la aparición y progresión de tumores. Este método, llamado SMUFIN (por Somatic Mutations Finder), es capaz de analizar el genoma completo de un tumor y detectar sus mutaciones en pocas horas, y además consigue localizar alteraciones que hasta el momento permanecían ocultas incluso con métodos que requerían el uso de supercomputadores durante semanas.

La prestigiosa revista Nature Biotechnology publica hoy un artículo describiendo las características de SMUFIN, que ha sido desarrollado por el grupo de genómica computacional del Barcelona Supercomputing Center – Centro Nacional de Supercomputación (BSC-CNS) que lidera el Dr y Profesor de ICREA David Torrents, en colaboración con grupos de investigación del Hospital Clínic el Instituto de Investigación Biomédica August Pi i Sunyer (IDIBAPS) de Barcelona, el Instituto de Oncología de la Universidad de Oviedo (IUOPA), el European Molecular Biology Laboratory (EMBL, Heidelberg) y el Centro Nacional de Análisis Genómico (CNAG, Barcelona).

 

Una nueva forma de analizar genomas

Una de las principales novedades que aporta SMUFIN es que supone un cambio radical en el método de análisis de genomas. Hasta la fecha, la identificación de mutaciones responsables de la aparición de tumores ha implicado la comparación de genomas extraídos del tumor con genomas obtenidos de células sanas de mismo paciente a través de un genoma humano de referencia que se usa como guía. Este lento y complejo proceso conlleva una pérdida sustancial de información y dificulta la identificación de muchos tipos de mutaciones relevantes para el tumor. El análisis, además, se ejecuta sucesivamente con diferentes programas informáticos, cada uno de los cuales es capaz de detectar solamente determinados tipos de variaciones.

SMUFIN, en cambio, realiza una comparación directa entre el genoma de células sanas y el genoma de células tumorales de un mismo paciente y localiza prácticamente todas las mutaciones detectables a la vez sin tener que recurrir a varios programas. De esta manera el análisis resulta mucho más rápido y más completo.

 

Avances en el estudio de tumores agresivos

El artículo publicado en Nature Biotechnology refleja como SMUFIN, además de acelerar y abaratar el análisis, es capaz de descubrir alteraciones genéticas en tumores agresivos difíciles de detectar. El análisis mediante SMUFIN de dos tipos de tumores agresivos, uno sanguíneo (linfoma de células de nanto) y otro del sistema nervioso (Meduloblastoma Pediátrico), ha permitido encontrar, por primera vez y con una precisión superior al 90%, prácticamente todos los tipos de mutaciones ocurridas en sus genomas, incluidas alteraciones en la organización de los cromosomas que han permanecido ocultas a los métodos usados hasta la fecha. Esto supone el primer paso necesario para poder entender como afectan estas alteraciones cromosómicas a la evolución y a la agresividad del tumor.

 

Impulso a la investigación biomédica

Las características de SMUFIN posibilitarán a un gran número de grupos de investigación poder estudiar los genomas de sus pacientes de una forma que antes no les era accesible. Por otro lado, en manos de centros de supercomputación, SMUFIN permitirá detectar mutaciones en cientos y miles de genomas tumorales en pocos días. En este sentido, el BSC ya participa en la mayor iniciativa mundial de genómica del cáncer a través del Consorcio Internacional del Genoma del Cáncer (ICGC) ( www.icgc.org), en la que se pretende analizar los genomas de miles de pacientes para estudiar las bases genéticas de la aparición y la evolución de un gran número de tipos tumorales.

 

Impulso a la medicina personalizada

SMUFIN supone un paso firme y realista en el horizonte de la medicina personalizada, en la que el análisis del genoma de cada paciente facilitará su diagnóstico de forma más rápida y precisa, y permitirá el desarrollo y la aplicación de tratamientos personalizados más eficaces y menos agresivos que los actuales. Mientras que los métodos existentes hasta el momento resultan complejos, limitados y requieren días o semanas para el análisis completo de un genoma de tumor,  SMUFIN supone una opción realista en el proceso de la incorporación del análisis genómico al sistema sanitario, ya que es capaz de analizar, en pocas horas, un genoma de tumor de forma precisa y técnicamente sencilla.

 

Un desarrollo en el marco del CLL y el Programa Severo Ochoa

SMUFIN comenzó a desarrollarse en el Barcelona Supercomputing Center – Centro Nacional de Supercomputación, en el 2011, de la mano del equipo de genómica que es parte del Programa Conjunto BSC-CRG-IRB (Barcelona Supercomputing Center, Centre de Regulació Genòmica e Institut de Recerca Biomèdica Barcelona) de Biología Computacional.

El desarrollo se ha producido en dos entornos de investigación en los que participa  el centro. Uno es el Proyecto Genoma de la Leucemia Linfática Crónica, del que son directores científicos Elías Campo (Hospital Clínic, IDIBAPS) y Carlos López-Otín (Universidad de Oviedo) y que tiene como objetivo el estudio de la leucemia a través del análisis genómico de más de 500 pacientes. Este desarrollo también forma parte del Programa Nacional Severo Ochoa, con el que el Barcelona Supercomputing Center impulsa, entre otras, la creación de herramientas bioinformáticas capaces de gestionar y analizar grandes cantidades de datos biomédicos necesarios para posibilitar la medicina personalizada.

Artículo: http://www.nature.com/nbt/journal/v32/n11/full/nbt.3027.html

 

Sobre el BSC-CNS

El Barcelona Supercomputing Center – Centro Nacional de Supercomputación (BSC-CNS) es el centro líder de la supercomputación en España. Su especialidad es la computación de altas prestaciones, también conocida como HPC (High Performance Computing). Su función es doble: ofrecer infraestructuras y servicio en supercomputación a los científicos españoles y europeos, y generar conocimiento y tecnología para transferirlos a la sociedad.

El BSC-CNS es un Centro de Excelencia Severo Ochoa, miembro de primer nivel de la infraestructura de investigación europea PRACE (Partnership for Advanced Computing in Europe) y gestiona la Red Española de Supercomputación (RES).

 

Para más información:

BSC: Gemma Ribas, gemma.ribas@bsc.es / Tel: +34 620 429 956

 

 

 

 

Bsc.es [en línea] Barcelona (ESP): bsc.es, 04 de diciembre de 2014 [ref. 24 de octubre de 2014] Disponible en Internet: http://www.bsc.es/about-bsc/press/bsc-in-the-media/un-nuevo-método-computacional-permite-analizar-los-cambios



Typhoid gene unravelled

20 11 2014

People who carry a particular type of gene have natural resistance against typhoid fever according to new research published in Nature Genetics.

Lead researcher, Dr Sarah Dunstan from the Nossal Institute of Global Health at the University of Melbourne said the study is the first large-scale, unbiased search for human genes that affect a person’s risk of typhoid.

Typhoid is a health burden to lower income countries- www.ecofriend.com

Enteric fever, or typhoid fever as it more commonly known, is a considerable health burden to lower-income countries.

This finding is important because this natural resistance represents one of the largest human gene effects on an infectious disease.

“We screened the human genome to look for genes associated with susceptibility to, or resistance from typhoid.,” Dr Dunstan said.

“We found that carrying a particular form of the HLA-DRB1 gene provides natural resistance against typhoid fever.  This gene codes for a receptor that is important in the immune response, by recognising proteins from invading bacteria.”

Typhoid is contracted, by consuming food or water contaminated with the bacteria, Salmonella Typhi or Paratyphi. It has been estimated that typhoid causes 200,000 deaths a year globally, and infects 26.9 million people per year.

“If we can understand this natural mechanism of disease resistance, then we can use this knowledge to help develop improved vaccines for typhoid fever, but also potentially for other invasive bacterial disease,”

Better treatments and vaccines are needed for typhoid fever as the infecting bacteria are getting increasingly more resistant to antibiotic treatment, and the current vaccine is only moderately effective and does not protect against paratyphoid fever, which is increasing within Asia.

This work was conducted in patients from Vietnam with findings then replicated in independent patient cohorts from Vietnam and Nepal

The research collaboration was between the Genome Institute of Singapore and Oxford University Clinical Research Units in Vietnam and Nepal.

 

 

Newsroom.melbourne.edu [en línea] Melbourne (AUS): newsroom.melbourne.edu, 20 de noviembre de 2014 [ref. 10 de noviembre de 2014] Disponible en Internet: http://newsroom.melbourne.edu/news/typhoid-gene-unravelled