Cell mechanism discovered that may cause pancreatic cancer

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Researchers at Huntsman Cancer Institute (HCI) at the University of Utah have found that defects in how cells are squeezed out of overcrowded tissue to die, a process called extrusion, may be a mechanism by which pancreatic cancer begins. From these findings, they may have identified an effective way to reverse the defective extrusion’s effects without destroying normal tissues nearby. The results were published in the latest edition of the journal eLife.

The study focuses on the epithelia, tissues lining the cavities and surfaces of structures throughout the body, including organs such as the pancreas. It is already well-established that most solid tumors arise from this type of tissue.

The team analyzed previous published microarray data and found that a receptor for the lipid sphingosine 1-phosphate (S1P2) that is critical for the extrusion process, is significantly reduced in the most common type of pancreas cancer known as pancreatic ductal adenocarcinoma (PDAC), lung cancer, and some types of colon cancer–all aggressive cancers that resist treatment with chemotherapy.

Focusing on cells from PDAC tumors, the team found that reduced S1P2 levels led to reduced extrusion and cell death rates. About 50% of the cells did not extrude and formed masses, while most of the remaining ones extruded underneath instead of outside the cell layer.

“This kind of altered extrusion may be a common hallmark of invasive tumor types,” said Jody Rosenblatt, PhD, co-author of the study, associate professor in the Department of Oncological Sciences at the University of Utah School of Medicine, and an HCI investigator. “While the mechanisms that drive tumor cell invasion are not yet clear, the results suggest that S1P2-mediated extrusion may play an important role in metastatic cell invasion.”

Normally, signaling through S1P2 triggers epithelial cells to squeeze some cells out to die when overcrowding occurs in order to keep constant healthy numbers. “Usually, cells pop out, away from underlying tissue,” said Rosenblatt. “Looking at zebrafish, we found that when the S1P2 signal is disrupted, cells build up and form masses that resist cell death–even when it is triggered by chemotherapy–or they pop into underlying tissue where they can potentially invade. Also, some cells die without being extruded, creating poor barrier function in the epithelium, which could cause chronic inflammation.”

According to Rosenblatt, decades of previous research has established all these conditions–masses of cells, resistance to cell death, invasive activity, and chronic inflammation–as determining factors of cells becoming tumors and progressing into metastasis.

Normally, extruded cells ultimately die because survival signaling, which depends on a signal called focal adhesion kinase (FAK), is lost. The team tested whether defective extrusion could be bypassed by using inhibitors to FAK. Simply adding FAK inhibitors rescued cell death rates to normal, and surprisingly, eliminated the large cell masses and improved the barrier function.

“Some FAK inhibitors are already being tested in clinical trials for other types of cancers,” said Rosenblatt. “Hopefully, they may also be a better therapy for recalcitrant tumors such as pancreas cancers and some lung cancers.

“Our results so far have focused on the primary tumor or cells invading in culture. Now we need to see if we can target cells that have moved to other sites, or metastasized, with FAK inhibitors, since this is an important feature of pancreatic cancer. That’s the next phase of our study,” said Rosenblatt.

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The above story is based on materials provided by Huntsman Cancer Institute at the University of Utah.

Scientists find Ebola virus is mutating

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Researchers working at Institut Pasteur in France have found that the Ebola virus is mutating “a lot” causing concern in the African countries where the virus has killed over eight thousand people in just several months time. In speaking with the press, they report that multiple mutations of the virus have been observed, though it is still not clear what advantage it has given the virus, if any. They also reported that they have seen many cases of people infected with the virus that did not exhibit any symptoms, which might suggest that at least one of the mutations in the virus has led to infections that are less traumatic to their victim, but which are also likely more easily spread.

A scanning electron micrograph of Ebola virus budding from a cell (African green monkey kidney epithelial cell line). Photo Credit: NIAID

It is not unusual for a virus to mutate, of course, others do it all the time. Also, the Ebola virus is of a class (an RNA virus like HIV and influenza) that is able to evolve via mutations very quickly. The team in France pointed out that the virus has not shown any signs of a change in its mode of transmission—physical contact, which is of course good news—if it became transmissible through the, air for example, it could spread much quicker.

As the virus became evident, first in Guinea then other West African countries, researchers began studying it using techniques such as genetic sequencing which allows for tracking changes in the genetic make-up of the virus. To date, the team has studied approximately 20 samples from people in Guinea and is awaiting the arrival of approximately 600 more samples in the next few months. The World Health Organization reported that a similar study done in Sierra Leone indicated that the virus had mutated a lot in just the first month of the outbreak. It is hoped that such studies will help the medical community keep up with the virus as it changes by helping to diagnose new cases and treat those that are infected.

Meanwhile, officials monitoring the outbreak reported that there were fewer than 100 new cases over a single week period recently, the fewest since shortly after the outbreak began. The WHO also announced that it considers the outbreak to be entering a new phase—the main focus now is ending the epidemic.

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The above story is based on materials provided by WHO.

Latent HIV may lurk in ‘quiet’ immune cells

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Drugs for HIV have become adept at suppressing infection, but they still can’t eliminate it. That’s because the medication in these pills doesn’t touch the virus’ hidden reserves, which lie dormant within infected white blood cells. Unlock the secrets of this pool of latent virus, scientists believe, and it may become possible to cure – not just control – HIV.

Lillian Cohn (above) and her colleagues sequenced the sites in the genomes of infected cells where the virus had integrated. This allowed them to determine whether or not an infected cell had previously been copied as part of an immune response.

In a study published Thursday (January 29) in Cell, researchers lead by Michel C. Nussenzweig, Zanvil A. Cohn and Ralph M. Steinman Professor at Rockefeller University, and his collaborators describe new insights on which cells likely do, and do not, harbor this lurking threat.

“It has recently been shown that infected white blood cells can proliferate over time, producing many clones, all containing HIV’s genetic code. However, we found that these clones do not appear to harbor the latent reservoir of virus,” says study author Lillian Cohn a graduate student in Nussenzweig’s Laboratory of Molecular Immunology. “Instead our analysis points to cells that have never divided as the source of the latent reservoir.”

HIV belongs to a family of viruses that insert themselves directly into the host cell’s genome where they can hide out quietly after the initial infection. HIV mostly targets CD4 T lymphocytes, a type of T cell involved in initiating an immune response.

When HIV integrates itself into the genetic code of a CD4 T cell, it may produce an active infection, hijacking the cell to produce more copies of itself in order infect other cells, and killing it in the process. Antiretroviral drugs that suppress HIV infection work by disrupting this hijacking. But the virus may also fail to produce an active infection, remaining a quiet, tiny fragment of DNA tucked within the host cell’s genome. If so, the drugs have nothing to disrupt, and the infection remains latent.

Most often, however, what happens is actually something in between. While the virus does manage to get at least some of itself into the T cell’s genome, problems with the process leave it incapable of hijacking the cell to replicate itself. But those few successful integrations still do damage, and the resulting depletion in the victim’s immune system leaves him or her vulnerable to potentially fatal opportunistic infections years, or even decades, after the initial infection.

“If a patient stops taking antiretrovirals, the infection rebounds. It is truly amazing that the virus can give rise to AIDS 20 years after the initial infection,” says Cohn.

Researchers think the reservoir of latent virus may be hiding out in a type of CD4 T cell: long-lived memory cells that help the immune system remember particular pathogens. When these cells encounter a pathogen they have previously seen, they spur the proliferation of T cells tuned to recognize it, in a process called clonal expansion. Prior research has suggested clonal expansion is crucial to maintaining HIV’s latent reservoir.

Following up on work initiated by Mila Jankovic, a senior research associate in the lab, Cohn and her colleagues examined cloned and unique CD4 T cells in blood samples from 13 people infected with HIV. An analytical computational technique developed by Israel Tojal da Silva, a research associate in the lab, made it possible to identify integration sites into which HIV had inserted itself within individual cells.

“Given the size of the human genome, it is highly unlikely the virus would insert itself in exactly the same place more than once. So, if multiple cells contained virus with identical integration sites, we classified them as clones. Meanwhile if a cell had a unique integration site, one not shared with any other cell, then we assumed that cell was unique,” Cohn says.

The researchers tested 75 viral sequences taken from the expanded clones of cells to see if they had the potential to produce more of the virus. None could.

“While we cannot rule out the possibility that a rare clone of cells may contain an active virus, it appears most likely that latent reservoir – and the potential target for therapies meant to cure HIV – resides in the more rare single cells containing unique integrations,” Cohn says.

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The above story is based on materials provided by Rockefeller University.

Google is using synthetic skin to help early detection for cancer

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Last October, Google announced that it was working on magnetic nanoparticles that would seek out cancer cells in the bloodstream and report back to a smart wristband. Now, if this didn’t sound bizarre enough, it turns out the search giant is also using synthetic skin to develop the technology.

When Google first announced the project they didn’t discuss how the nanoparticles would relay their findings. But, in a video from The Atlantic, employees explain that they’ll be using light signals to talk to the wristband through the superficial veins on the underside of the wrist. Of course, shining lights through the skin means factoring in a range of skin types and colors, and so Google’s scientists have built fake arms with “the same autofluoresecence and biochemical components of real arms.” Thus the fake skin.

The video itself is well worth a watch and offers a tantalizing glimpse into the goings-on at Google X. Andrew Conrad, the head of Google’s Life Sciences department, also has a good response to those who might object that it’s weird having nanoparticles floating through your body constantly tracking you. “It’s way weirder,” says Conrad, “to have cancer cells floating through your body that are constantly trying to kill you.”

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Biomaterial Coating for Better Medical Implants

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A novel, bacteria-repelling coating material that could increase the success of medical implants has been created by researchers.

The material helps healthy cells ‘win the race’ to the medical implant, beating off competition from bacterial cells and thus reducing the likelihood of the implant being rejected by the body.

The first results of the material’s performance have been published today, 30 January, in IOP Publishing’s journal Biomedical Materials.

The failure rate of certain medical implants still remains high—around 40% for hip implants—due to the formation of biofilms when the implant is first inserted into the body.

This thin film is composed of a group of microorganisms stuck together and can be initiated by bacteria sticking to the implant. This prevents healthy cells from attaching and results in the body eventually rejecting the implant, potentially leading to serious complications for patients.

In their study, researchers from A*STAR (Agency for Science, Technology and Research) in Singapore, Nanyang Technological University and City University of Hong Kong produced a material that not only repelled bacteria but also attracted healthy cells.

The base of the material was made from polyelectrolyte multilayers onto which a number of specific bonding molecules, called ligands, were attached.

After testing various concentrations of different ligands, the researchers found that RGD peptide was particularly effective at inhibiting the attachment of bacterial cells and attracting healthy cells, compared with collagen, when attached to dextran sulfate and chitosan multilayers.

This combination was tested on cultures of healthy fibroblast cells and cultures of bacterial cells, in which two specific strains were used—E. coli and S. aureus.

The lead author of the research, Professor Vincent Chan from Nanyang Technological University, said: “The method we developed helped the host cells win the so called ‘race-for-surface’ battle, forming a confluent layer on the implant surface which protects it from possible bacterial adhesion and colonization.

“Medical implants currently have antibacterial silver coatings incorporated into them; however, the total amount of silver used must be very carefully controlled because high concentrations could kill mammalian cells and become toxic to the human body.

“The bio-selective coatings we’ve created do not have this problem as the materials used are non-toxic and the preparation process uses water as a solvent.

“At the moment this is just a ‘proof-of-concept’ study, so there is still a long way to go before the coating can be used on implants in clinical setting. In future studies we hope to firstly improve the long-term stability of the coating.”

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The above story is based on materials provided by IOP Publishing.

Growing functioning brain tissue in 3D

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Researchers at the RIKEN Center for Developmental Biology in Japan have succeeded in inducing human embryonic stem cells to self-organize into a three-dimensional structure similar to the cerebellum, providing tantalizing clues in the quest to recreate neural structures in the laboratory. One of the primary goals of stem-cell research is to be able to replace damaged body parts with tissues grown from undifferentiated stem cells. For the nervous system, this is a particular challenge because not only do specific neurons need to be generated, but they must also be coaxed into connecting to each other in very specific ways.

CALB and L7 are Purkinje-cell specific late markers are shown. GRID2 is a marker for a Purkinje-specific glutamate receptor. LHX5 is a marker for early Purkinje cells. Photo Credit: RIKEN

RIKEN researchers have taken up this challenge, and the work published in Cell Reports details how sequentially applying several signaling molecules to three-dimensional cultures of human embryotic stem cells prompts the cells to differentiate into functioning cerebellar neurons that self-organize to form the proper dorsal/ventral patterning and multi-layer structure found in the natural developing cerebellum.

Expanding from their previous studies with mice, the researchers first established that under specific conditions, culturing human embryonic stem cells with fibroblast growth factor 2 (FGF2) leads to neural differentiation particular to the midbrain/hindbrain region—the location of the cerebellum—within three weeks, and the expression of markers for the cerebellar plate neuroepithelium—the part of the developing nervous system specific for the cerebellum—within five. These cells also showed early markers that are specific to developing Purkinje cells, granule cells, or deep cerebellar projection neurons—all types of neurons only found in the cerebellum.

The researchers then looked for mature cerebellar neurons. They found that cells treated with FGF2 expressed late Purkinje-cell markers and developed structures characteristic of those cells. Electrophysiological recordings of these cells after culture for about 15 weeks revealed proper responses to currents and to inhibition of receptors needed for normal cerebellar signaling, indicating that function had developed along with structure. Some FGF2-treated cells also expressed markers for the rhombic lip—the structure from which granule cells develop and migrate, and a marker specific to migrating granule precursors by week seven. Moreover, cells were seen to migrate and extend fibers that bent to form the T-shape characteristic of granule cell parallel fibers.

Where these neurons form and how they locate in relation to each other is critical in the developing brain. Early in cerebellar development, particular cell types become distributed unevenly from top to bottom, creating a dorsal-ventral separation. Researchers tested several factors, and found that adding FGF19 around day 14 to the FGF2-treated cells caused several flat oval neuroepithelium to form by day 35, expressing dorsal-specific markers on the outside and ventral-specific markers on the inside. By adding stromal cell-derived factor 1 (SDF1) between days 28-35, they were able to generate a continuous neuroepithelial structure with dorsal-ventral polarity.

SDF1 also induced two other important structural changes. The dorsal region spontaneously developed three layers along the dorsal-ventral axis: the ventricular zone, a Purkinje-cell precursor zone, and a rhombic lip zone. At one end of the neuroepithelium, a region developed that was positive for markers of progenitors of granule and deep cerebellar nuclei projection neurons and negative for Purkinje-cell markers, and whose origins could be traced to the rhombic lip zone of the cerebellar plate.

Lead author Keiko Muguruma says that, “the principles of self-organization that we have demonstrated here are important for the future of developmental biology.” She added that, “attempts to generate the cerebellum from human iPS cells have already met with some success, and these patient-derived cerebellar neurons and tissues will be useful for modeling cerebellar diseases such as spinocerebellar ataxia.”

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Bioengineered antibody-based molecules show enhanced hiv-fighting abilities

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Capitalizing on a new insight into HIV’s strategy for evading antibodies—proteins produced by the immune system to identify and wipe out invading objects such as viruses—Caltech researchers have developed antibody-based molecules that are more than 100 times better than our bodies’ own defenses at binding to and neutralizing HIV, when tested in vitro. The work suggests a novel approach that could be used to engineer more effective HIV-fighting drugs.

“Based on the work that we have done, we now think we know how to make a really potent therapeutic that would not only work at relatively low concentrations but would also force the virus to mutate along pathways that would make it less fit and therefore more susceptible to elimination,” says Pamela Bjorkman, the Max Delbrück Professor of Biology and an investigator with the Howard Hughes Medical Institute. “If you were able to give this to someone who already had HIV, you might even be able to clear the infection.”

Antibodies generally attack a virus by binding with both of their “arms” to two of the spikes sticking up from the surface of the virus. Caltech researchers propose that HIV’s low spike density makes it hard for antibodies to do this. The biologists engineered antibody-based molecules that can bind to a single HIV spike with both arms and showed that the new molecules are more than 100 times better than naturally occurring antibodies at binding to and neutralizing HIV. Photo Credit: Lance Hayashida/Caltech Marketing & Communications and the Bjorkman Laboratory/Caltech

The researchers describe the work in the January 29 issue of Cell. Rachel Galimidi, a graduate student in Bjorkman’s lab at Caltech, is lead author on the paper.

The researchers hypothesized that one of the reasons the immune system is less effective against HIV than other viruses involves the small number and low density of spikes on HIV’s surface. These spikes, each one a cluster of three protein subunits, stick up from the surface of the virus and are the targets of antibodies that neutralize HIV. While most viruses are covered with hundreds of these spikes, HIV has only 10 to 20, making the average distance between the spikes quite long.

That distance is important with respect to the mechanism that naturally occurring antibodies use to capture their viral targets. Antibodies are Y-shaped proteins that evolved to grab onto their targets with both “arms.” However, if the spikes are few and far between—as is the case with HIV—it is likely that an antibody will bind with only one arm, making its connection to the virus weaker (and easier for a mutation of the spike to render the antibody ineffective).

To test their hypothesis, Bjorkman’s group genetically engineered antibody-based molecules that can bind with both arms to a single spike. They started with the virus-binding parts, or Fabs, of broadly neutralizing antibodies—proteins produced naturally by a small percentage of HIV-positive individuals that are able to fight multiple strains of HIV until the virus mutates. When given in combination, these antibodies are quite effective. Rather than making Y-shaped antibodies, the Caltech group simply connected two Fabs—often from different antibodies, to mimic combination therapies—with different lengths of spacers composed of DNA.

Why DNA? In order to engineer antibodies that could latch onto a spike twice, they needed to know which Fabs to use and how long to make the connection between them so that both could readily bind to a single spike. Previously, various members of Bjorkman’s group had tried to make educated guesses based on what is known of the viral spike structure, but the large number of possible variations in terms of which Fabs to use and how far apart they should be, made the problem intractable.

In the new work, Bjorkman and Galimidi struck upon the idea of using DNA as a “molecular ruler.” It is well known that each base pair in double-stranded DNA is separated by 3.4 angstroms. Therefore, by incorporating varying lengths of DNA between two Fabs, they could systematically test for the best neutralizer and then derive the distance between the Fabs from the length of the DNA. They also tested different combinations of Fabs from various antibodies—sometimes incorporating two different Fabs, sometimes using two of the same.

“Most of these didn’t work at all,” says Bjorkman, which was reassuring because it suggested that any improvements the researchers saw were not just created by an artifact, such as the addition of DNA.

But some of the fabricated molecules worked very well. The researchers found that the molecules that combined Fabs from two different antibodies performed the best, showing an improvement of 10 to 1,000 times in their ability to neutralize HIV, as compared to naturally occurring antibodies. Depending on the Fabs used, the optimal length for the DNA linker was between 40 and 62 base pairs (corresponding to 13 and 21 nanometers, respectively).

Taking this finding to the next level in the most successful of these new molecules, the researchers replaced the piece of DNA with a protein linker of roughly the same length composed of 12 copies of a protein called tetratricopeptide repeat. The end product was an all-protein antibody-based reagent designed to bind with both Fabs to a single HIV spike.

“That one also worked, showing more than 30-fold average increased potency compared with the parental antibodies,” says Bjorkman. “That is proof of principle that this can be done using protein-based reagents.”

The greater potency suggests that a reagent made of these antibody-based molecules could work at lower concentrations, making a potential therapeutic less expensive and decreasing the risk of adverse reactions in patients.

“I think that our work sheds light on the potential therapeutic strategies that biotech companies should be using—and that we will be using—in order to make a better antibody reagent to combat HIV,” says Galimidi. “A lot of companies discount antibody reagents because of the virus’s ability to evade antibody pressure, focusing instead on small molecules as drug therapies. Our new reagents illustrate a way to get around that.”

The Caltech team is currently working to produce larger quantities of the new reagents so that they can test them in humanized mice—specialized mice carrying human immune cells that, unlike most mice, are sensitive to HIV.

Along with Galimidi and Bjorkman, additional Caltech authors on the paper, “Intra-Spike Crosslinking Overcomes Antibody Evasion by HIV-1,” include Maria Politzer, a lab assistant; and Anthony West, a senior research specialist. Joshua Klein, a former Caltech graduate student (PhD ’09), and Shiyu Bai, a former technician in the Bjorkman lab, also contributed to the work; they are currently at Google and Case Western Reserve University School of Medicine, respectively. Michael Seaman of Beth Israel Deaconess Medical Center and Michel Nussenzweig of the Rockefeller University in New York are also coauthors. The work was supported by the National Institutes of Health through a Director’s Pioneer Award and a grant from the HIV Vaccine Research and Design Program, as well as grants from the Collaboration for AIDS Vaccine Discovery and the Bill and Melinda Gates Foundation. Nussenzweig is also an investigator with the Howard Hughes Medical Institute.

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The above story is based on materials provided by California Institute of Technology.

Healthy’ fat tissue could be key to reversing type 2 diabetes

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Preventing inflammation in obese fat tissue may hold the key to preventing or even reversing type 2 diabetes, new research has found.

Dr. Axel Kallies (L), Dr. Ajith Vasanthakumar and colleagues have found a signalling molecule could prevent inflammation in fat tissue, reversing symptoms of type 2 diabetes. Photo Credit: Walter and Eliza Hall Institute

Researchers from Melbourne’s Walter and Eliza Hall Institute, with colleagues from the RIKEN Institute, Japan, found they could ‘reverse’ type 2 diabetes in laboratory models by dampening the inflammatory response in fat tissue.

Dr Ajith Vasanthakumar, Dr Axel Kallies and colleagues from the institute discovered that specialised immune cells, called regulatory T cells (Tregs), played a key role in controlling inflammation in fat tissue and maintaining insulin sensitivity. The findings were published in the journal Nature Immunology.

More than 850,000 Australians are estimated to have type 2 diabetes, which is the most common type of diabetes, and its prevalence is rising. The disease is strongly linked with ‘lifestyle’ factors, such as being overweight or having high blood pressure. Long-term complications of type 2 diabetes include kidney, eye and heart disease, and there is no cure.

People with type 2 diabetes have reduced sensitivity to insulin, a hormone that normally triggers uptake of glucose by cells, and their cells no longer respond to insulin appropriately. This decrease in insulin sensitivity is thought to be a result of long-term, low-level inflammation of fat tissue in people who are obese.

Dr Vasanthakumar said Tregs acted as the guardians of the immune system, preventing the immune response from getting out-of-hand and attacking the body’s own tissues. “When Treg numbers are reduced, inflammatory diseases such as diabetes and rheumatoid arthritis can occur,” he said.

Recent studies have shown that fat tissue has its own unique type of Tregs, which disappear from fat tissue during obesity. “The fat tissue of obese people has lower numbers of Tregs than the fat tissue of people in a healthy weight range,” Dr Vasanthakumar said. “Without Tregs, inflammation-causing cell levels increase, and this rise in inflammation can lead to insulin resistance and high blood glucose levels, a classic hallmark of type 2 diabetes.”

The research team discovered a key hormone called IL-33 (interleukin-33) was able to selectively boost Treg populations in fat tissue, effectively halting the development of type 2 diabetes, or even reversing the disease in preclinical models.

“Treating fat tissues with IL-33 restored normal Treg cell levels, which reduced inflammation and decreased blood glucose levels,” Dr Vasanthakumar said. “Treatments that mimic IL-33 could have the potential to reduce obesity-related inflammation and type 2 diabetes.”

Dr Kallies said the research underscored the importance of ‘healthy’ fat tissue in maintaining a healthy body. “We can no longer think of fat tissue simply as energy storage,” Dr Kallies said.

“Fat tissue is increasingly being recognised as a crucial organ that releases hormones and regulates development. Keeping our fat tissue healthy is important for our general wellbeing, and our research highlights the important role it plays in preventing disease.”

The study was funded by the National Health and Medical Research Council, the Australian Research Council, the Sylvia and Charles Viertel Foundation and the Victorian Government.

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How are sea anemones so good at producing nerve cells?

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A research group has revealed how a seemingly simple animal is able to produce nerve cells throughout its entire body. A study published in the journal Development shows that the stem cells that a sea anemone uses to generate its nervous system are more similar to those of humans than expected.

Photo Credit: The Smithsonian Environmental Research Center

Nerve cells are found everywhere in our bodies, in our skin, in our guts, in our brains. But all these nerve cells were generated from only a small area of tissue when we were embryos.

In this tissue, neural stem cells give rise to nerve cells through a complicated process of cell division and stepwise specialization.

The nerve cells or their progenitor cells then move through the embryo to their final destination where they provide us with the ability to sense our environment, move our bodies and play chess.

Few of the stem cells that generate nerve cells when we are embryos, are still alive once we are adults, and it is therefore difficult for us to replace damaged nerve cells, for instance after an injury or a stroke.

Other animals are much better at replacing nerve cells, and among the champions of this are sea anemones – animals that do not have a brain and are only very distantly related to us.

A new study by Gemma Richards and Fabian Rentzsch has now shown that one of these animals, the starlet sea anemone Nematostella vectensis, uses stem cells that are surprisingly similar to ours to generate their nerve cells.

“Embryos of the sea anemone can generate nerve cells throughout their entire body and they can completely regenerate their nervous system as adults”, says postdoc Gemma Richards, the first author of the study.

Previously it was thought that this ability was based on a special type of stem cells in these animals, stem cells that can generate all kinds of cells, not only nerve cells.

“We have now been able to genetically label a specific group of cells in the sea anemone, and with this technique we can see that they build their nervous system from stem cells that exclusively generate nerve cells, resembling the way humans do this”, Richards explains.

The gene that has been used to label these neural stem cells is important for nerve cell formation in humans as well.

The Rentzsch group has now started to compare this process in more detail between sea anemones and other animals.

“There is no straight connection to nervous system regeneration in humans, but the question as to why these animals can do it so much better than we can, is of course in the back of our heads”, says Rentzsch.

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The above story is based on materials provided by Uni Research, Andreas R. Graven.

Scientists find gene vital to central nervous system development

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Scientists have identified a gene that helps regulate how well nerves of the central nervous system are insulated, researchers at Washington University School of Medicine in St. Louis report.

Healthy insulation is vital for the speedy propagation of nerve cell signals. The finding, in zebrafish and mice, may have implications for human diseases like multiple sclerosis, in which this insulation is lost.

Using Washington University’s zebrafish facility, graduate student Sarah Ackerman (left) and senior author Kelly Monk, PhD, identified a gene that regulates how well the wiring of the central nervous system is insulated. Photo Credit: Robert Boston

Nerve cells send electrical signals along lengthy projections called axons. These signals travel much faster when the axon is wrapped in myelin, an insulating layer of fats and proteins. In the central nervous system, the cells responsible for insulating axons are called oligodendrocytes.

The research focused on a gene called Gpr56, which manufactures a protein of the same name. Previous work indicated that this gene likely was involved in central nervous system development, but its specific roles were unclear.

In the new study, the researchers found that when the protein Gpr56 is disabled, there are too few oligodendrocytes to provide insulation for all of the axons. Still, the axons looked normal. And in the relatively few axons that were insulated, the myelin also looked normal. But the researchers observed many axons that were simply bare, not wrapped in any myelin at all.

Without Gpr56, the cells responsible for applying the insulation failed to reproduce themselves sufficiently, according to the study’s senior author, Kelly R. Monk, PhD, assistant professor of developmental biology. These cells actually matured too early instead of continuing to replicate as they should have. Consequently, in adulthood, there were not enough mature cells, leaving many axons without insulation.

Monk and her team study zebrafish because they are excellent models of the vertebrate nervous system. Their embryos are transparent and mature outside the body, making them useful for observing developmental processes.

“We first saw this defect in the developing zebrafish embryo,” said first author Sarah D. Ackerman, a graduate student in Monk’s lab. “But it’s not simply a temporary defect that only results in delayed myelination. When I looked at fish that were six months old, I still saw this problem of undermyelinated axons.”

In a companion paper in the same issue of Nature Communications, senior author Xianhua Piao, MD, PhD, of Harvard University, and her co-authors, including Monk, showed similar defects in mice without Gpr56. In past work, Piao also has shown evidence that human defects in Gpr56 lead to brain malformations related to a lack of myelin.

“These are nice studies that arrived at the same conclusion independently,” said Monk, who is also with the Hope Center for Neurological Disorders at Washington University. “Our Harvard colleagues used mouse models while we used fish models. And Dr. Piao’s research in human patients suggests that similar mechanisms are at work in people.”

Monk also said that Gpr56 belongs to a large class of cell receptors that are common targets for many commercially available drugs, making the protein attractive for further research. The investigators pointed out its possible relevance in treating diseases associated with a lack of myelin, with particular interest in multiple sclerosis.

“In the case of MS, there are areas where the central nervous system has lost its myelin,” Monk said. “At least part of the problem is that the precursor myelin-producing cells are recruited to that area, but they fail to become adult cells capable of producing nerve cell insulation. Now, we have evidence that Gpr56 modulates the switch from precursor to adult cell.”

In theory, if the precursor cells can be pushed to mature into adulthood, they may become capable of producing myelin. According to Monk and Ackerman, possible future work includes using the zebrafish model system as a drug-screening tool to search for small molecules that may flip that switch.

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The above story is based on materials provided by Washington University in St. Louis, Julia Evangelou Strait.

Pacemakers with Internet connection

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The healthcare sector is not escaping from the revolution in information and communications technologies. Thanks to the latest advances in microelectronics and communications technologies, it is not difficult to imagine a future with medical sensors connected to the Internet.

Pacemaker Photo Credit: Image courtesy of University of the Basque Country

Thanks to the Ladon security protocol developed by the UPV/EHU researcher Jasone Astorga in the 12T (Telematics Research and Engineering) research group, a little more progress has been made in the area of the remote monitoring of patients by means of implanted sensors. Ladon offers revolutionary features that make it possible to deploy applications that guarantee the privacy of sensors of this type, in other words, the medical information is only made available in response to legitimate, authorised requests.

The ageing of society needs new, more cost-effective solutions to improve the life quality of patients and cut the burden that is placed on the social welfare system. In modern western societies the fitting of pacemakers and implantable cardioverter defibrillators (ICDs) is growing rapidly. Devices of this type control heart rhythm and, if necessary, send an appropriate response to make the heart beat at the right rhythm. They also record heart activity patterns when abnormal heart rhythm is detected. This information is periodically checked and monitored by a doctor to plan future treatment. To do this, the information is transmitted in wireless mode to an external device. At the moment this communication is carried out in hospitals.

The main manufacturers of pacemakers and DCIs have started to market remote management devices. The remote monitoring of implantable, wireless medical sensors is a constantly advancing field which nevertheless still has clear shortcomings. The direct connection of medical sensors to the Internet is the next natural step in this evolution, and will enable doctors to obtain the information stored by the sensors at any moment and from any device connected to the Internet. Despite its great potential, the success of a monitoring system of this type is determined, among other things, by the protection of the privacy of the information transmitted. A researcher in the UPV/EHU’s Department of Communications Engineering has developed the Ladon security protocol, an efficient mechanism to authenticate, authorise and establish the end-to-end keys (keys for communication between the terminal used by the doctor and the patient’s device), which offers revolutionary features for sensors of this type.

Energy efficiency, memory space and latency

There are three key parameters in the development of new solutions for implantable medical sensors: energy consumption, memory space and latency. Energy efficiency is the most important design parameter for any protocol that has to work in these devices, since replacing the batteries used in them means opening up a wound in the patient’s chest. As the UPV/EHU researcher Jasone Astorga explained, it has been found that “the energy consumption of this Ladon protocol is negligible in comparison with the usual consumption of a pacemaker or ICD when applying its therapy (stimulating or defibrillating), and has no significant impact on how long the batteries last”. On the other hand, they have found that the deployment of this security application in the sensors has led to very little memory consumption. And finally, the latency incorporated by the protocol in the setting up of a secure communication is also less. All this turns it into a protocol suited to deploying functionalities to authenticate and control access in the sensors and for the setting up of a secret key that can be used to protect the confidentiality and integrity of the medical information transmitted over the wireless network.

Apart from its application in the remote monitoring of medical sensors, all the checks carried out in relation to the protocol lead to the conclusion that this is a protocol to authenticate, authorise and set up the keys that is right for use even in the securization of critical applications from the point of view of delay, like remote surgery, for example. In any case, the possibility of marketing this protocol for these purposes is still a long way off, as validations would have to be conducted on real pacemakers. “We have carried out our validation on a commercial sensor, not on a real pacemaker,” said the researcher. In other words, “one would have to conduct studies using real medical sensors and real patients,” explained Astorga. “In any case, we believe that it is a step forward down the road along which the remote monitoring of patients using implanted medical sensors can go on advancing.”

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Brain region vulnerable to aging is larger in those with longevity gene variant

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People who carry a variant of a gene that is associated with longevity also have larger volumes in a front part of the brain involved in planning and decision-making, according to researchers at UC San Francisco.

The finding bolsters their previous discovery that middle-aged and older people who carry a single copy of the KLOTHO allele, called KL-VS, performed better on a wide range of cognitive tests. When they modeled KL-VS in mice, they found this strengthened the connections between neurons and enhanced learning and memory.

KLOTHO codes for a protein, called klotho, which is produced in the kidney and brain and regulates many different processes in the body. About one in five people carry a single copy of KL-VS, which increases klotho levels and is associated with a longer lifespan and better heart and kidney function. A small minority, about 3 percent, carries two copies, which is associated with a shorter lifespan.

Examining Part of Prefrontal Cortex

In the current study, published Jan. 27, in Annals of Clinical and Translational Neurology, researchers scanned the brains of 422 cognitively normal men and women aged 53 and older to see if the size of any brain area correlated with carrying one, two or no copies of the allele.

They found that the KLOTHO gene variant predicted the size of a region called the right dorsolateral prefrontal cortex (rDLPFC), which is especially vulnerable to atrophy as people age. Deterioration in this area may be one reason why older people have difficulty suppressing distracting information and doing more than one thing at a time.

Researchers found that the rDLPFC shrank with age in all three groups, but those with one copy of KL-VS – about a quarter of the study group – had larger volumes than either non-carriers or those with two copies. Researchers also found that the size of the rDLPFC predicted how well the three groups performed on cognitive tests, such as working memory – the ability to keep a small amount of newly acquired information in mind – and processing speed. Both tests are considered to be good measures of the planning and decision-making functions that the rDLPFC controls.

“We’ve known for a long time that people lose cognitive abilities as they age, but now we’re beginning to understand that factors like klotho can give people a boost and confer resilience in aging,” said senior author Dena Dubal, MD, PhD, assistant professor of neurology at UCSF and the David A. Coulter Endowed Chair in Aging and Neurodegenerative Disease. “Genetic variation in KLOTHO could help us predict brain health and find ways to protect people from the devastating diseases that happen to us as we grow old, like Alzheimer’s and other dementias.”

Bigger Size Means Better Function

In statistical tests, the researchers concluded that the larger rDLPFC volumes seen in single copy KL-VS carriers accounted for just 12 percent of the overall effect that the variant had on the abilities tested.

However, the allele may have other effects on the brain, such as increasing levels or changing the actions of the klotho protein to enhance synaptic plasticity, or the connections between neurons. In a previous experiment, they found that raising klotho in mice increased the action of a cell receptor critical to forming memories.

“The brain region enhanced by genetic variation in KLOTHO is vulnerable in aging and several psychiatric and neurologic diseases including schizophrenia, depression, substance abuse and frontotemporal dementia,” said Jennifer Yokoyama, PhD, first author and assistant professor of neurology at UCSF. “In this case, bigger size means better function. It will be important to determine whether the structural boost associated with carrying one copy of KL-VS can offset the cognitive deficits caused by disease.”

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Stomach acid-powered micromotors get their first test in a living animal

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Researchers at the University of California, San Diego have shown that a micromotor fueled by stomach acid can take a bubble-powered ride inside a mouse. These tiny motors, each about one-fifth the width of a human hair, may someday offer a safer and more efficient way to deliver drugs or diagnose tumors.

Scanning electron microscopy image of the micromotors. Photo Credit: Jacobs School of Engineering/UC San Diego

The experiment is the first to show that these micromotors can operate safely in a living animal, said Professors Joseph Wang and Liangfang Zhang of the NanoEngineering Department at the UC San Diego Jacobs School of Engineering.

Wang, Zhang and others have experimented with different designs and fuel systems for micromotors that can travel in water, blood and other body fluids in the lab. “But this is the first example of loading and releasing a cargo in vivo,” said Wang. “We thought it was the logical extension of the work we have done, to see if these motors might be able to swim in stomach acid.”

Stomach acid reacts with the zinc body of the motors to generate a stream of hydrogen microbubbles that propel the motors forward. In their study published in the journal ACS Nano, the researchers report that the motors lodged themselves firmly in the stomach lining of mice. As the zinc motors are dissolved by the acid, they disappear within a few days leaving no toxic chemical traces.

When they loaded up the motors with a test “payload” of gold nanoparticles, Wang, Zhang and their coworkers found that more of these particles reached the stomach lining when carried by the motors, compared to when the particles alone were swallowed. The motors delivered 168 nanograms of gold per gram of stomach tissue, compared to the 53.6 nanograms per gram that was delivered through the traditional oral route.

“This initial work verifies that this motor can function in a real animal and is safe to use,” said Zhang.

In the experiment, the mice ingested tiny drops of solution containing hundreds of the micromotors. The motors become active as soon as they hit the stomach acid and zoom toward the stomach lining at a speed of 60 micrometers per second. They can self-propel like this for up to 10 minutes.This propulsive burst improved how well the cone-shaped motors were able to penetrate and stick in the mucous layer covering the stomach wall, explained Zhang. “It’s the motor that can punch into this viscous layer and stay there, which is an advantage over more passive delivery systems,” he said.

The researchers found that nearly four times as many zinc micromotors found their way into the stomach lining compared with platinum-based micromotors, which don’t react with and can’t be fueled by stomach acid.

Wang said it may be possible to add navigation capabilities and other functions to the motors, to increase their targeting potential. Now that his team has demonstrated that the motors work in living animals, he noted, similar nanomachines soon may find a variety of applications including drug delivery, diagnostics, nanosurgery and biopsies of hard-to-reach tumors.

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From Fiction To Science

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When a salamander loses a tail, it grows a new one. What’s the difference, biologist Peter Reddien wondered, between a wound that severs a salamander’s tail and one that severs a human spinal cord?

Peter Reddien believes human stem cells could one day be regulated to replace aged, damaged, and missing tissues. Photo Credits: Len Rubenstein

Tweaking a gene or injecting a drug to repair damaged or aging organs, muscles, nerves, or brain tissue is one of the most enticing medical scenarios imaginable — a scenario that Reddien, associate professor of biology and Howard Hughes Medical Institute investigator, hopes will one day make the leap from fiction to science.

Like salamanders, the ordinary flatworm — a small, mud-colored pond-dweller has the seemingly miraculous ability to regrow “every missing part of its body from tiny fragments of nervous systems, skin, — gut everything,” Reddien says.

While the creature’s regenerative ability — it can replace a decapitated head in less than a week and its entire body from a scrap only one-300th of its original size — has captured scientists’ interest for centuries, “there’s no good model using existing knowledge that explains how such dramatic regeneration could work,” Reddien says.

The Holy Grail of Reddien’s scientific career is to elucidate such a model. His fascination with the natural world dates to his childhood, when his home was flanked by the interstate and an unlikely pocket of beauty in North Dallas. His back yard bordered a creek in a wooded ravine where he’d wander barefoot, chasing frogs and snakes and keeping an eye out for raccoons, owls, and possums. He’d talk science with his mathematician father and art with his artist mother, and thought he might go into astrophysics. But after graduating from the University of Texas, buoyed by the new tools available for life scientists, he pursued a PhD at MIT in biology and then chose planaria — then not on many scientists’ radar — as a means to investigate regeneration.

Key to a flatworm’s regenerative ability is the neoblast, capable of transforming into any cell type in the adult animal. In planaria such as the flatworm, these stem cells have the potential to produce all new tissue — but how do they know what kind of replacements are needed?

Just last year, Reddien’s lab made the surprising finding that the genes that “instruct” cells at the wound site whether to start building a new head or a new tail are expressed in the muscle cells of the planarian body wall.

“Let’s say you cut off the head,” he says. Position control genes (PCGs) become active in the muscle cells at the wound site, providing a system of body coordinates and positional information that drives neoblasts to build a new head.

Reddien believes this “amazing, beautiful system” holds the key to understanding the molecular logic of regeneration.

“PCG expression is dynamic in muscle cells after injury, even in the absence of neoblasts, suggesting that muscle is instructive for regeneration,” he says. “We concluded that planarian regeneration involves two highly flexible systems: neoblasts that can generate any new cell type and muscle cells that provide positional instructions for the regeneration of any body region.”

Reddien believes we are in the midst of an explosion of basic biological discovery in which new tools for studying genes shared by the flatworms and humans could boost understanding of stem cells, holding out hope that one day human stem cells could be regulated to replace aged, damaged, and missing tissues.

Even humans “last longer than most machines we can build,” he says. “It’s amazing how good the body is at repairing its tissues, muscle, skin, blood vessels, peripheral nerves, bones — but there are limits on how much it can do.” With a boost from the ordinary flatworm, those limits might one day be redefined.

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The above story is based on materials provided by MIT, Deborah Halber.

Neurons in the Brain Tune into Different Frequencies for Different Spatial Memory Tasks

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Your brain transmits information about your current location and memories of past locations over the same neural pathways using different frequencies of a rhythmic electrical activity called gamma waves, report neuroscientists at The University of Texas at Austin.

The research, published in the journal Neuron on April 17, may provide insight into the cognitive and memory disruptions seen in diseases such as schizophrenia and Alzheimer’s, in which gamma waves are disturbed.

Previous research has shown that the same brain region is activated whether we’re storing memories of a new place or recalling past places we’ve been.

“Many of us leave our cars in a parking garage on a daily basis. Every morning, we create a memory of where we parked our car, which we retrieve in the evening when we pick it up,” said Laura Colgin, assistant professor of neuroscience and member of the Center for Learning and Memory in The University of Texas at Austin’s College of Natural Sciences. “How then do our brains distinguish between current location and the memory of a location? Our new findings suggest a mechanism for distinguishing these different representations.”

Memory involving location is stored in an area of the brain called the hippocampus. The neurons in the hippocampus that store spatial memories (such as the location where you parked your car) are called place cells. The same set of place cells are activated both when a new memory of a location is stored and, later, when the memory of that location is recalled or retrieved.

When the hippocampus forms a new spatial memory, it receives sensory information about your current location from a brain region called the entorhinal cortex. When the hippocampus recalls a past location, it retrieves the stored spatial memory from a subregion of the hippocampus called CA3.

The entorhinal cortex and CA3 transmit these different types of information using different frequencies of gamma waves. The entorhinal cortex uses fast gamma waves, which have a frequency of about 80 Hz (about the same frequency as a bass E note played on a piano). In contrast, CA3 sends its signals on slow gamma waves, which have a frequency of about 40 Hz.

Colgin and her colleagues hypothesized that fast gamma waves promote encoding of recent experiences, while slow gamma waves support memory retrieval.

They tested these hypotheses by recording gamma waves in the hippocampus, together with electrical signals from place cells, in rats navigating through a simple environment. They found that place cells represented the rat’s current location when cells were active on fast gamma waves. When cells were active on slow gamma waves, place cells represented locations in the direction that the rat was heading.

“These findings suggest that fast gamma waves promote current memory encoding, such as the memory of where we just parked,” said Colgin. “However, when we need to remember where we are going, like when finding our parked car later in the day, the hippocampus tunes into slow gamma waves.”

Because gamma waves are seen in many areas of the brain besides the hippocampus, Colgin’s findings may generalize beyond spatial memory. The ability for neurons to tune into different frequencies of gamma waves provides a way for the brain to traffic different types of information across the same neuronal circuits.

Colgin said one of the next steps in her team’s research will be to apply technologies that induce different types of gamma waves in rats performing memory tasks. She imagines that they will be able to improve new memory encoding by inducing fast gamma waves. Conversely, she expects that inducing slow gamma waves will be detrimental to the encoding of new memories. Those slow gamma waves should trigger old memories, which would interfere with new learning.

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Using stem cells to grow new hair

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In a new study from Sanford-Burnham Medical Research Institute (Sanford-Burnham), researchers have used human pluripotent stem cells to generate new hair. The study represents the first step toward the development of a cell-based treatment for people with hair loss. In the United States alone, more than 40 million men and 21 million women are affected by hair loss. The research was published online in PLOS One yesterday.

Scientists at Sanford-Burnham used iPSCs to grow new hair. Photo Credit: Sanford-Burnham Medical Research Institute

“We have developed a method using human pluripotent stem cells to create new cells capable of initiating human hair growth. The method is a marked improvement over current methods that rely on transplanting existing hair follicles from one part of the head to another,” said Alexey Terskikh, Ph.D., associate professor in the Development, Aging, and Regeneration Program at Sanford-Burnham. “Our stem cell method provides an unlimited source of cells from the patient for transplantation and isn’t limited by the availability of existing hair follicles.”

The research team developed a protocol that coaxed human pluripotent stem cells to become dermal papilla cells. They are a unique population of cells that regulate hair-follicle formation and growth cycle. Human dermal papilla cells on their own are not suitable for hair transplants because they cannot be obtained in necessary amounts and rapidly lose their ability to induce hair-follicle formation in culture.

“In adults, dermal papilla cells cannot be readily amplified outside of the body and they quickly lose their hair-inducing properties,” said Terskikh. “We developed a protocol to drive human pluripotent stem cells to differentiate into dermal papilla cells and confirmed their ability to induce hair growth when transplanted into mice.”

“Our next step is to transplant human dermal papilla cells derived from human pluripotent stem cells back into human subjects,” said Terskikh. “We are currently seeking partnerships to implement this final step.”

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Biological safety lock for genetically modified organisms

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The creation of genetically modified and entirely synthetic organisms continues to generate excitement as well as worry.

Scientists have genetically recoded a strain of E. coli to depend on a synthetic amino acid so the bacteria can’t survive outside the lab. Photo Credit: Jennifer Hinkle

Such organisms are already churning out insulin and other drug ingredients, helping produce biofuels, teaching scientists about human disease and improving fishing and agriculture. While the risks can be exaggerated to frightening effect, modified organisms do have the potential to upset natural ecosystems if they were to escape.

Physical containment isn’t enough. Lab dishes and industrial vats can break; workers can go home with inadvertently contaminated clothes. And some organisms are meant for use in open environments, such as mosquitoes that can’t spread malaria.

So attention turns to biocontainment: building in biological safeguards to prevent modified organisms from surviving where they’re not meant to. To do so, geneticists and synthetic biologists find themselves taking a cue from safety engineers.

“If you make a chemical that’s potentially explosive, you put stabilizers in it. If you build a car, you put in seat belts and airbags,” said George Church, Robert Winthrop Professor of Genetics at Harvard Medical School and core faculty member at the Wyss Institute.

And if you’ve created the world’s first genomically recoded organism, a strain of Escherichia coli with a radically changed genome, as Church’s group announced in 2013, you make its life dependent on something only you can supply.

Church and colleagues report Jan. 21 in Nature that they further modified their 2013 E. coli to incorporate a synthetic amino acid in many places throughout their genomes. Without this amino acid, the bacteria can’t perform the vital job of translating their RNA into properly folded proteins.

The E. coli can’t make this unnatural amino acid themselves or find it anywhere in the wild; they have to eat it in specially cooked-up lab cultures.

A separate team reports in Nature that it was able to engineer the same strain of E. coli to become dependent on a synthetic amino acid using different methods. That group was led by a longtime collaborator of Church’s, Farren Isaacs of Yale University.

The two studies are the first to use synthetic nutrient dependency as a biocontainment strategy, and suggest that it might be useful for making genetically modified organisms safer in an open environment.

In addition, “We now have the first example of genome-scale engineering rather than gene editing or genome copying,” said Church. “This is the most radically altered genome to date in terms of genome function. We have not only a new code, but also a new amino acid, and the organism is totally dependent on it.”

Church’s team, led by first authors Dan Mandell and Marc Lajoie, HMS research fellows in genetics, also made the E. coli resistant to two viruses, with plans to expand that list.

The modifications offer theoretically safer E. coli strains that could be used in biotechnology applications with less fear that they will be contaminated by viruses, which can be financially disastrous, or cause ecological trouble if they spill. (E. coli is one of the main organisms used in industry.)

Hooked on amino acids

Scientists have been exploring two main biocontainment methods, but each has weaknesses. Church was determined to fix them.

One method involves turning normally self-sufficient organisms like E. coli into auxotrophs, which can’t make certain nutrients they need for growth. Humans are auxotrophs, which is why we need to include vitamins and other “essential” nutrients in our diets.

Altering the genetics of E. coli so they can’t make a naturally occurring nutrient doesn’t always work, said Church, because some of them manage to scavenge the nutrient from their surroundings. He lowered that risk by making the E. coli dependent on a nutrient not found in nature.

Another pitfall of making auxotrophs is that some E. coli could evolve a way to synthesize the nutrient they need. Or they could acquire the ability while exchanging bits of DNA with other E. coli in a process called horizontal gene transfer.

Church believes his team protected against those possibilities because it had to make 49 genetic changes to the E. coli to make them dependent on the artificial nutrient. The chance one of the bacteria could randomly undo all of those changes without also acquiring a harmful mutation, he said, is incredibly slim.

Church’s solution also took care of concerns he had with another biocontainment technique, in which genetic “kill switches” make bacteria vulnerable to a toxin so spills can be quickly neutralized. “All you have to do to kill a kill switch is turn it off,” which can be done in any number of ways, Church said. Routing around the dependency on the artificial amino acid is much harder.

Church determined that another key to making a successful “synthetic auxotroph” was to ensure that the E. coli’s lives depended on the artificial amino acid. Otherwise, escaped E. coli could keep rolling along even if they couldn’t make or scavenge it. So his group targeted proteins that drive the essential functions of the cell.

“If you put it off on the periphery, like on the paint job of your car, the car will still run,” he explained. “You have to embed the dependency smack in the middle of the engine, like the crank shaft, so it now has a particular part you can only get from, say, one manufacturer in Europe.”

Building a safer bacterium

The need to choose a process essential to E. coli survival and a nutrient not found in nature “limited us to a small number of genes,” Church said. His team used computational tools to design proteins that might cause the desired “irreversible, inescapable dependency.” They took the best candidates, synthesized them and tested them in actual E. coli.

They ended up with three successful redesigned essential proteins and two dependent E. coli strains. “Using three proteins together is more powerful than using them separately,” Church said. He envisions future E. coli modified to require even more synthetic amino acids to make escape virtually impossible.

As it was, the escape rate—the number of E. coli able to survive without being fed the synthetic amino acid—was “so low we couldn’t detect it,” Church said.

The group grew a total of 1 trillion E. coli cells from various experiments, and after two weeks none had escaped. “That’s 10,000 times better than the National Institutes of Health’s recommendation for escape rate for genetically modified organisms,” said Church.

The weaknesses in Church’s methods remain to be seen. For now, he is satisfied with the results his group has obtained by pushing the limits of available testing.

“As part of our dedication to safety engineering in biology, we’re trying to get better at creating physically contained test systems to develop something that eventually will be so biologically contained that we won’t need physical containment anymore,” said Church.

In the meantime, he said, “we can use the physical containment to debug it and make sure it actually works.”

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How a cancer-causing virus blocks human immune response

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Scientists at The University of Texas at Austin and the University of California at San Francisco have revealed how a type of cancer-causing virus called Epstein-Barr virus (EBV) outwits the human body’s immune response. By helping explain why some cancer therapies fail, the discovery might lead to more effective treatments.

An Epstein-Barr virus erupting from an infected immune cell, called a B lymphocyte. Photo Credit: Analytical Imaging Facility at the Albert Einstein College of Medicine.

EBV, a virus of the herpes family, causes an estimated 200,000 cancers every year, including lymphomas, nasopharyngeal cancers and some stomach cancers. Better anti-viral drugs could help thousands of people suffering from these cancers.

Many viruses, including EBV, carry small molecules called microRNAs that they use to hijack natural processes in a host’s cells during an infection. Viral microRNAs are known to prevent host cell death, promote host cell growth and dampen the host cell’s viral defenses. However, scientists don’t yet know which viral microRNAs perform which functions.

Jennifer Cox, a graduate student working with Associate Professor Chris Sullivan at The University of Texas at Austin, identified microRNAs made by several herpes viruses that block a component of a human’s innate immune system called the interferon response. Immune cells within the body release interferon to prevent viral replication, and this often results in slower growth or death of infected host cells. The researchers found that several herpes viruses have independently evolved similar mechanisms to block the host’s interferon response.

“I was actually surprised that all these different viruses had converged on the same mechanism for blocking the body’s defenses,” said Sullivan. “As a biologist, I see this as evolutionary gold.”

Interferon is sometimes used in combination with chemotherapy to treat lymphomas. Although it is an effective treatment for some cancers, it does not significantly affect others. This latest research has demonstrated that EBV lymphoma cells are less susceptible to interferon therapy.

“This could explain the variability seen in the success of previous interferon-based cancer treatments,” said Cox. “While this work does not immediately identify new drugs, the fact that such different tumor viruses have converged on the same strategy makes this an exciting pursuit for future therapies against viral cancers.”

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Potential New Drug Target for Lung Cancer

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A new study by University of Kentucky Markey Cancer Center researchers suggests that targeting a key enzyme and its associated metabolic programming may lead to novel drug development to treat lung cancer.

Cancer cells undergo metabolic alterations to meet the increased energy demands that support their excess growth and survival. The Krebs cycle in the mitochondria of cells is used to supply both energy and building materials for cell growth. Two mitochondrial enzymes – pyruvate carboxylase (PC) and glutaminase replenish carbon to the Krebs cycle.

Published in the Journal of Clinical Investigation, the study collected metabolic data directly from more than 120 human lung cancer patients. Researchers Teresa Fan, Andrew Lane, and Richard Higashi, now part of UK’s Center for Environmental and Systems Biochemistry (CESB), worked with other collaborators to measure the in situ activity of these two enzymes in patients with early stage lung cancer. When they infused the patients with a glucose tagged with stable heavy atoms immediately prior to surgical removal of tumor tissue, they found that PC was selectively activated – in other words, PC expression may play an important role in the development of lung cancer.

By using molecular genetic tools to reduce the amount of PC in human lung cancer cells, the team observed decreased cell growth, a compromised ability to form colonies in soft agar (a gelatinous material specifically used to grow bacteria and other cells), and a reduced rate of tumor growth in mice. The loss of PC also induced widespread changes in the central metabolism of the cell, suggesting a role for PC in early stage metabolic reprogramming.

“We now know much more about metabolic reprogramming of cancerous tissues in human patients, particularly that the activation of pyruvate carboxylase is important to lung cancer cell growth and survival,” said Fan, UK professor of toxicology and faculty member of the Markey Cancer Center and CESB at the University of Kentucky. “Ultimately, figuring out how to target PC may help researchers develop new, more effective therapeutic strategies to improve upon current lung cancer treatments, which are limited and harmful.”

The team’s work was funded by the National Cancer Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institutes of Health (NIH)Common Fund. UK’s RC-SIRM is one of six NIH Common Fund-supported Regional Comprehensive Metabolomics Resource Centers. The overall mission of the Center is to enable cutting-edge approaches and to provide state-of-the art instrumentation for stable isotope-resolved metabolomics.

Unlike radioactive isotopes, stable isotopes do not decay, and they occur naturally in the body in low amounts. Enriching these isotopes with glucose or glutamine allows researchers to track the atoms through the metabolic transformation process, so researchers can backtrack to see what reactions have occurred and detect whether cancer cells have altered the metabolic pathway.

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New device allows deaf people to ‘hear with their tongue’

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Cochlear implants are expensive, invasive and are occasionally unsuitable for elderly patients – so scientists are working on a device which sends small electric shocks to the wearer’s tongue and allows them to ‘hear’ sounds

Cochlear implants have had great success in restoring hearing to deaf patients, but the surgery is invasive, expensive and not everyone is a suitable candidate.

Now a team from Colorado State University are working on a device which will allow deaf people to ‘hear’ simply by touching their tongue against a small Bluetooth-enabled device.

“It’s much simpler than undergoing surgery and we think it will be a lot less expensive than cochlear implants,” said John Williams, associate professor in the Department of Mechanical Engineering.

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Stem cells can become anything – but not without this protein

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How do stem cells preserve their ability to become any type of cell in the body? And how do they “decide” to give up that magical state and start specializing?

Mouse stem cells with two normally functioning copies of the Mof gene (left) have intact “stem-ness” — but that ability to self-renew is lost in cells in which one or both copies of Mof don’t work correctly (middle and right). Photo Credit: Dou laboratory, University of Michigan

If researchers could answer these questions, our ability to harness stem cells to treat disease could explode. Now, a University of Michigan Medical School team has published a key discovery that could help that goal become reality.

In the current issue of the prestigious journal Cell Stem Cell, researcher Yali Dou, Ph.D., and her team show the crucial role of a protein called Mof in preserving the ‘stem-ness’ of stem cells, and priming them to become specialized cells in mice.

Their results show that Mof plays a key role in the “epigenetics” of stem cells — that is, helping stem cells read and use their DNA. One of the key questions in stem cell research is what keeps stem cells in a kind of eternal youth, and then allows them to start “growing up” to be a specific type of tissue.

Dou, an associate professor of pathology and biological chemistry, has studied Mof for several years, puzzling over the intricacies of its role in stem cell biology.

She and her team have zeroed in on the factors that add temporary tags to DNA when it’s coiled around tiny spools called histones. In order to read their DNA, cells have to unwind it a bit from those spools, allowing the gene-reading mechanisms to get access to the genetic code and transcribe it. The temporary tags added by Mof act as tiny beacons, guiding the “reader” mechanism to the right place.

“Simply put, Mof regulates the core transcription mechanism – without it you can’t be a stem cell,” says Dou. “There are many such proteins, called histone acetyltransferases, in cells – but only MOF is important in undifferentiated cells.”

Dou and her team also have published on another protein involved in DNA transcription, called WDR5, that places tags that are important during transcription. But Mof appears to control the process that actually allows cells to determine which genes it wants to read – a crucial function for stem-ness. “Without Mof, embryonic stem cells lost their self-renewal capability and started to differentiate,” she explains.

The new findings may have particular importance for work on induced pluripotent stem cells – the kind of stem cells that don’t come from an embryo, but are made from “adult” tissue.

IPCS research holds great promise for disease treatment because it could allow a patient to be treated with stem cells made from their own tissue. But the current way of making IPSCs from tissue involves a process that uses a cancer-causing gene – a step that might give doctors and patients pause.

Dou says that further work on Mof might make it possible to stop using that potentially harmful approach. But further research will be needed.

What they will focus on is how Mof marks the DNA structures called chromatin to keep parts of the genome readily accessible. In stem cells, scientists have shown, many areas of DNA are kept open for access – probably because stem cells need to use their DNA to make many proteins that keep them from ‘growing up.’

Once a stem cell starts to differentiate, or become a certain specialized type of cell, parts of the DNA close up and aren’t as accessible. Many scientific teams have studied this “selective silencing” and the factors that cause stem cells to start specializing by reading only certain genes. But few have looked at the factors that facilitate broad-range DNA transcription to preserve stem-ness.

“Mof marks the areas that need to stay open and maintains the potential to become anything,” Dou explains. Its crucial role in many species is hinted at by the fact that the gene to make Mof has the same sequence in fruit flies and mice.

“If you think about stem cell biology, the self-renewal is one aspect that makes stem cells unique and powerful, and the differentiation is another,” says Dou. “People have looked a lot at differentiation to make cells useful for therapy in the future – but the stem cell itself is actually pretty fascinating. So far, Mof is the only histone acetyltransferase found to support the stemness of embryonic stem cells.”

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The above story is based on materials provided by University of Michigan Medical School.

How cancer turns good cells to the dark side

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BIOENGINEER.ORG http://bioengineer.org/how-cancer-turns-good-cells-to-the-dark-side/

Cancer uses a little-understood element of cell signaling to hijack the communication process and spread, according to Rice University researchers.

A new computational study by researchers at the Rice-based Center for Theoretical Biological Physics shows how cancer cells take advantage of the system by which cells communicate with their neighbors as they pass messages to “be like me” or “be not like me.”

Led by Rice biophysicists Eshel Ben-Jacob and José Onuchic, the researchers decode how cancer uses a cell-cell interaction mechanism known as notch signaling to promote metastasis. This mechanism plays a crucial role in embryonic development and wound healing and is activated when a delta or jagged ligand of one cell interacts with the notch receptor on an adjacent one.

Their open-access study appears this month in the Proceedings of the National Academy of Sciences. It follows a 2014 study in which the researchers mapped the flow of information through genetic circuits involved in cancer metastasis.

“At the heart of our new understanding is that the primary agents of metastasis are clusters of hybrid epithelial (nonmobile) and mesenchymal (migrating) cells,” Ben-Jacob said. “These, and not the fully mesenchymal cells, are the ‘bad actors’ of cancer progression that pose the highest risk. By acting together, these hybrid cancer cells have a better chance to evade the immune system during migration and can better survive while circulating in blood vessels.”

The multifaceted mechanism by which notch-delta-jagged signaling promotes cancer progression has been a mystery until now, Ben-Jacob said, but recent experimental studies have revealed the jagged ligand plays a critical role in tumor progression.

The new study provides a fresh theoretical framework for scientists who study the fates of cells. It shows the presence of jagged ligands can give rise to sender/receiver hybrid cells that send a signal — “be like me” — that is useful for embryonic development and healing, but can also be hijacked by cancer cells.

“We realized that hybrid cancer cells can take advantage of that characteristic to establish stable interactions and turn them into ‘assault teams’ that migrate together during metastasis,” Onuchic said.

The focus of research on notch signaling to date has been on notch-delta signaling alone, Ben-Jacob said. In that case, one cell (the sender) expresses high notch receptor and low delta ligand. The other (the receiver) expresses low notch and high delta. This situation leads the two cells to adopt opposite fates: to “be not like me.”

The first clues biologists had to notch-delta signaling came a century ago in studies of the wing formation of fruit flies. A visual manifestation of cell messaging is in the checkerboard or salt-and-pepper patterns seen in some organisms when cells tell their neighbors to be “not me” and adopt the opposite color. “Since jagged seemed to play a similar role to delta, the focus has been on notch-delta,” Ben-Jacob said. “We were motivated to look closer and focus on the effect of the differences between these ligands.”

“Cancer takes advantage of jagged proteins’ influence to form what are essentially migrating units of hybrid cancer stem cells,” Ben-Jacob said. Notch-jagged signaling also helps cells develop resistance to chemotherapy and radiotherapy and facilitates metastasis formation by promoting communications between cancer and stromal (connective tissue) cells at the new locations, he said.

Recent findings showed stromal cells in the tumor environment secrete jagged ligands. The Rice researchers found cancer cells hijack nearby stromal cells and prompt them to boost their production of the ligand, reinforcing the cancer’s chances of survival.

The researchers suggested cells’ internal expression of jagged may also increase the production and maintenance of therapy-resistant cancer stem cells.

“Because they have a high likelihood to acquire stem-like properties, when arriving at distant organs they utilize this cellular plasticity to differentiate and adapt to new conditions at the metastasis location,” said lead author Marcelo Boareto, a former visiting scholar at Rice and now a doctoral student at the University of Sao Paulo, Brazil.

The researchers said their model is a step toward deeper understanding of the signaling mechanisms cancer cells use to evade the immune system and treatment.

“Studying single cells cannot give us all the answers,” Onuchic said. “We need to understand the decisions made by the cells that are talking to each other.”

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The above story is based on materials provided by Rice University.

The brain’s electrical alphabet

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BIOENGINEER.ORG http://bioengineer.org/the-brains-electrical-alphabet/

The brain’s alphabet is a mix of rate and precise timing of electrical pulses: the observation was made by researchers at the International School for Advanced Studies (SISSA) of Trieste and the Italian Institute of Technology (IIT) of Rovereto, and has been published in the international journal Current Biology. The study shows that the nervous system features a “multichannel” language that makes up the neural code, or the alphabet that processes information in the brain.

Nerve signals consist of sequences of electrical pulses (“spikes”) that travel along communication channels, or neural circuits. What alphabet do these sequences use to transmit the information? In other words, what makes up the brain’s language? According to a new study published in Current Biology, the information is contained in both the rate and the precise, detailed temporal distribution of pulses. To distinguish one message from another, the rate of spikes varies over a relatively long time span of tens of milliseconds. This “spike rate code” has been known for many years. What’s new is the demonstration of a “spike timing code” operating on a millisecond scale. In addition, the research found that, contrary to what was thought until now, spike timing may be even more influential than spike rate, and that the two codes complement each other to form a more informative message. The study was coordinated by Mathew Diamond, professor at SISSA in Trieste, and Stefano Panzeri, research team leader at the Centre for Neuroscience and Cognitive Systems of the IIT in Rovereto.

“The two coding systems, one based on spike rate and the other on timing, give rise to multiple channels along the same transmission line”, explains Diamond. “If we take tactile sensation, for example, the brain uses these multiple channels to communicate aspects of the stimulus – intensity of the touch, texture of the surface, shape of the object and so on – which could not be conveyed by a single communication channel” adds Panzeri.

“We demonstrated that, contrary to what was believed until now, the exact timing of spikes encodes highly important information that complements and surpasses, in our experiments, the information conveyed by spike rate”, explains Diamond. “The timing of spikes for example, provides a greater amount of information since the potential number of messages exceeds that produced by rate alone. And the timing of spikes leads to the brain’s final interpretation of the stimulus”.

“Thanks to this discovery we have a greater understanding of how to imitate the brain’s language, and hence reproduce it”, concludes Stefano Panzeri. “We can, in fact, foresee developing robotic prostheses, such as limbs for amputees, capable of communicating with the brain in a complex, bi-directional manner, so as to restore not only motor function but also the senses, like the sense of touch”.

More in detail…

In the experiments conducted during the study rats explored surfaces of varying texture with their whiskers. Discrimination of the surface texture generated neural activity in the cortex of the brain, which the researchers recorded and analysed. The study showed not only that the spike timing conveyed a greater amount of information than spike rate alone, but also that the combination of the two channels was more accurate than either taken separately.

“We discovered that the brain encodes part of the information at very fast time scales, in particular in pulse sequences emitted with precision better than 5 milliseconds,” concludes Panzeri. “Another part of the information is instead encoded at a slower time scale, with the pulses transmitting the message over tens of milliseconds. The message is the same, of course, but it is read at two different resolutions, as if the brain were first viewing it through a naked eye and then through a magnifying glass” .

“Our results indicate that information transmitted through the detailed timing of spikes should not be underestimated, and that the nervous system communicates by opening several channels to convey every message”, comments Diamond. “This is probably one of the secrets underlying the richness of our perceptions”.

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The above story is based on materials provided by Sissa Medialab.