Potential ‘universal’ blood test for cancer discovered

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Researchers from the University of Bradford have devised a simple blood test that can be used to diagnose whether people have cancer or not.

The test will enable doctors to rule out cancer in patients presenting with certain symptoms, saving time and preventing costly and unnecessary invasive procedures such as colonoscopies and biopsies being carried out. Alternatively, it could be a useful aid for investigating patients who are suspected of having a cancer that is currently hard to diagnose.

Early results have shown the method gives a high degree of accuracy diagnosing cancer and pre-cancerous conditions from the blood of patients with melanoma, colon cancer and lung cancer. The research is published online in FASEB Journal, the US journal of the Federation of American Societies for Experimental Biology.

The Lymphocyte Genome Sensitivity (LGS) test looks at white blood cells and measures the damage caused to their DNA when subjected to different intensities of ultraviolet light (UVA), which is known to damage DNA. The results of the empirical study show a clear distinction between the damage to the white blood cells from patients with cancer, with pre-cancerous conditions and from healthy patients.

Professor Diana Anderson, from the University’s School of Life Sciences led the research. She said: “White blood cells are part of the body’s natural defence system. We know that they are under stress when they are fighting cancer or other diseases, so I wondered whether anything measureable could be seen if we put them under further stress with UVA light.We found that people with cancer have DNA which is more easily damaged by ultraviolet light than other people, so the test shows the sensitivity to damage of all the DNA – the genome – in a cell.”

The study looked at blood samples taken from 208 individuals. Ninety-four healthy individuals were recruited from staff and students at the University of Bradford and 114 blood samples were collected from patients referred to specialist clinics within Bradford Royal Infirmary prior to diagnosis and treatment. The samples were coded, anonymised, randomised and then exposed to UVA light through five different depths of agar.

The UVA damage was observed in the form of pieces of DNA being pulled in an electric field towards the positive end of the field, causing a comet-like tail. In the LGS test, the longer the tail the more DNA damage, and the measurements correlated to those patients who were ultimately diagnosed with cancer (58), those with pre-cancerous conditions (56) and those who were healthy (94).

“These are early results completed on three different types of cancer and we accept that more research needs to be done; but these results so far are remarkable,” said Professor Anderson. “Whilst the numbers of people we tested are, in epidemiological terms, quite small, in molecular epidemiological terms, the results are powerful. We’ve identified significant differences between the healthy volunteers, suspected cancer patients and confirmed cancer patients of mixed ages at a statistically significant level of P<0.001. This means that the possibility of these results happening by chance is 1 in 1000. We believe that this confirms the test’s potential as a diagnostic tool.”

Professor Anderson believes that if the LGS proves to be a useful cancer diagnostic test, it would be a highly valuable addition to the more traditional investigative procedures for detecting cancer.

A clinical trial is currently underway at Bradford Royal Infirmary. This will investigate the effectiveness of the LGS test in correctly predicting which patients referred by their GPs with suspected colorectal cancer would, or would not, benefit from a colonoscopy – currently the preferred investigation method.

The University of Bradford has filed patents for the technology and a spin-out company, Oncascan, has been established to commercialise the research.

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Researchers eliminate HIV from cultured human cells for first time

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The HIV-1 virus has proved to be tenacious, inserting its genome permanently into its victims’ DNA, forcing patients to take a lifelong drug regimen to control the virus and prevent a fresh attack. Now, a team of Temple University School of Medicine researchers has designed a way to snip out the integrated HIV-1 genes for good.

“This is one important step on the path toward a permanent cure for AIDS,” says Kamel Khalili, PhD, Professor and Chair of the Department of Neuroscience at Temple. Khalili and his colleague, Wenhui Hu, MD, PhD, Associate Professor of Neuroscience at Temple, led the work which marks the first successful attempt to eliminate latent HIV-1 virus from human cells. “It’s an exciting discovery, but it’s not yet ready to go into the clinic. It’s a proof of concept that we’re moving in the right direction,” added Dr. Khalili, who is also Director of the Center for Neurovirology and Director of the Comprehensive NeuroAIDS Center at Temple.

In a study published July 21 by the Proceedings of the National Academy of Sciences, Khalili and colleagues detail how they created molecular tools to delete the HIV-1 proviral DNA. When deployed, a combination of a DNA-snipping enzyme called a nuclease and a targeting strand of RNA called a guide RNA (gRNA) hunt down the viral genome and excise the HIV-1 DNA. From there, the cell’s gene repair machinery takes over, soldering the loose ends of the genome back together – resulting in virus-free cells.

“Since HIV-1 is never cleared by the immune system, removal of the virus is required in order to cure the disease,” says Khalili, whose research focuses on the neuropathogenesis of viral infections. The same technique could theoretically be used against a variety of viruses, he says.

The research shows that these molecular tools also hold promise as a therapeutic vaccine; cells armed with the nuclease-RNA combination proved impervious to HIV infection.

Worldwide, more than 33 million people have HIV, including more than 1 million in the United States. Every year, another 50,000 Americans contract the virus, according to the U.S. Centers for Disease Control and Prevention.

Although highly active antiretroviral therapy (HAART) has controlled HIV-1 for infected people in the developed world over the last 15 years, the virus can rage again with any interruption in treatment. Even when HIV-1 replication is well controlled with HAART, the lingering HIV-1 presence has health consequences. “The low level replication of HIV-1 makes patients more likely to suffer from diseases usually associated with aging,” Khalili says. These include cardiomyopathy – a weakening of the heart muscle – bone disease, kidney disease, and neurocognitive disorders. “These problems are often exacerbated by the toxic drugs that must be taken to control the virus,” Khalili adds.

Researchers based the two-part HIV-1 editor on a system that evolved as a bacterial defense mechanism to protect against infection, Khalili says. Khalili’s lab engineered a 20-nucleotide strand of gRNA to target the HIV-1 DNA and paired it with Cas9. The gRNA targets the control region of the gene called the long terminal repeat (LTR). LTRs are present on both ends of the HIV-1 genome. By targeting both LTRs, the Cas9 nuclease can snip out the 9,709-nucleotides that comprise the HIV-1 genome. To avoid any risk of the gRNA accidentally binding with any part of the patient’s genome, the researchers selected nucleotide sequences that do not appear in any coding sequences of human DNA, thereby avoiding off-target effects and subsequent cellular DNA damage.

The editing process was successful in several cell types that can harbor HIV-1, including microglia and macrophages, as well as in T-lymphocytes. “T-cells and monocytic cells are the main cell types infected by HIV-1, so they are the most important targets for this technology,” Khalili says.

The HIV-1 eradication approach faces several significant challenges before the technique is ready for patients, Khalili says. The researchers must devise a method to deliver the therapeutic agent to every single infected cell. Finally, because HIV-1 is prone to mutations, treatment may need to be individualized for each patient’s unique viral sequences.

“We are working on a number of strategies so we can take the construct into preclinical studies,” Khalili says. “We want to eradicate every single copy of HIV-1 from the patient. That will cure AIDS. I think this technology is the way we can do it.”

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Japan robot firm showcases thought-controlled suits

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A Japanese robot-maker shows off suits that the wearer can control just by thinking, as it says it is linking up with an industrial city promoting innovation.

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8.2 percent of our DNA is ‘functional’

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Only 8.2% of human DNA is likely to be doing something important – is ‘functional’ – say Oxford University researchers.

This figure is very different from one given in 2012, when some scientists involved in the ENCODE (Encyclopedia of DNA Elements) project stated that 80% of our genome has some biochemical function.

That claim has been controversial, with many in the field arguing that the biochemical definition of ‘function’ was too broad – that just because an activity on DNA occurs, it does not necessarily have a consequence; for functionality you need to demonstrate that an activity matters.

To reach their figure, the Oxford University group took advantage of the ability of evolution to discern which activities matter and which do not. They identified how much of our genome has avoided accumulating changes over 100 million years of mammalian evolution – a clear indication that this DNA matters, it has some important function that needs to be retained.

‘This is in large part a matter of different definitions of what is “functional” DNA,’ says joint senior author Professor Chris Pointing of the MRC Functional Genomics Unit at Oxford University. ‘We don’t think our figure is actually too different from what you would get looking at ENCODE’s bank of data using the same definition for functional DNA.

‘But this isn’t just an academic argument about the nebulous word “function”. These definitions matter. When sequencing the genomes of patients, if our DNA was largely functional, we’d need to pay attention to every mutation. In contrast, with only 8% being functional, we have to work out the 8% of the mutations detected that might be important. From a medical point of view, this is essential to interpreting the role of human genetic variation in disease.’

The researchers Chris Rands, Stephen Meader, Chris Ponting and Gerton Lunter report their findings in the journal PLOS Genetics. They were funded by the UK Medical Research Council and the Wellcome Trust.

The researchers used a computational approach to compare the complete DNA sequences of various mammals, from mice, guinea pigs and rabbits to dogs, horses and humans.

Dr Gerton Lunter from the Wellcome Trust Centre for Human Genetics at Oxford University, the other joint senior author, explained: ‘Throughout the evolution of these species from their common ancestors, mutations arise in the DNA and natural selection counteracts these changes to keep useful DNA sequences intact.’

The scientists’ idea was to look at where insertions and deletions of chunks of DNA appeared in the mammals’ genomes. These could be expected to fall approximately randomly in the sequence – except where natural selection was acting to preserve functional DNA, where insertions and deletions would then lie further apart.

‘We found that 8.2% of our human genome is functional,’ says Dr Lunter. ‘We cannot tell where every bit of the 8.2% of functional DNA is in our genomes, but our approach is largely free from assumptions or hypotheses. For example, it is not dependent on what we know about the genome or what particular experiments are used to identify biological function.’

The rest of our genome is leftover evolutionary material, parts of the genome that have undergone losses or gains in the DNA code – often called ‘junk’ DNA.

‘We tend to have the expectation that all of our DNA must be doing something. In reality, only a small part of it is,’ says Dr Chris Rands, first author of the study and a former DPhil student in the MRC Functional Genomics Unit at Oxford University.

Not all of the 8.2% is equally important, the researchers explain.

A little over 1% of human DNA accounts for the proteins that carry out almost all of the critical biological processes in the body.

The other 7% is thought to be involved in the switching on and off of genes that encode proteins – at different times, in response to various factors, and in different parts of the body. These are the control and regulation elements, and there are various different types.

‘The proteins produced are virtually the same in every cell in our body from when we are born to when we die,’ says Dr Rands. ‘Which of them are switched on, where in the body and at what point in time, needs to be controlled – and it is the 7% that is doing this job.’

In comparing the genomes of different species, the researchers found that while the protein-coding genes are very well conserved across all mammals, there is a higher turnover of DNA sequence in the regulatory regions as this sequence is lost and gained over time.

Mammals that are more closely related have a greater proportion of their functional DNA in common.

But only 2.2% of human DNA is functional and shared with mice, for example – because of the high turnover in the regulatory DNA regions over the 80 million years of evolutionary separation between the two species.

‘Regulatory DNA evolves much more dynamically that we thought,’ says Dr Lunter, ‘but even so, most of the changes in the genome involve junk DNA and are irrelevant.’

He explains that although there is a lot of functional DNA that isn’t shared between mice and humans, we can’t yet tell what is novel and explains our differences as species, and which is just a different gene-switching system that achieves the same result.

Professor Ponting agrees: ‘There appears to be a lot of redundancy in how our biological processes are controlled and kept in check. It’s like having lots of different switches in a room to turn the lights on. Perhaps you could do without some switches on one wall or another, but it’s still the same electrical circuit.’

He adds: ‘The fact that we only have 2.2% of DNA in common with mice does not show that we are so different. We are not so special. Our fundamental biology is very similar. Every mammal has approximately the same amount of functional DNA, and approximately the same distribution of functional DNA that is highly important and less important. Biologically, humans are pretty ordinary in the scheme of things, I’m afraid.

‘I’m definitely not of the opinion that mice are bad model organisms for animal research. This study really doesn’t address that issue,’ he notes.

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Combination Antiretroviral Therapy Helps Treat Hepatitis C in HIV Patients

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Treatment of HIV patients co-infected with the hepatitis C virus (HCV) with an anti-retroviral drug therapy not only tackles HIV, but also reduces HCV replication, according to a new study led by a University of Cincinnati researcher.

Kenneth Sherman, MD, PhD, Gould Professor of Medicine and Director in the UC Division of Digestive Diseases in the College of Medicine

The results were published Wednesday, July 23, 2014, in Science Translational Medicine

Previously, physicians treating co-infected patients worried that HIV antiretroviral therapy might injure the liver to the detriment of patient health, says Kenneth Sherman, MD, PhD, Gould Professor of Medicine and Director in the UC Division of Digestive Diseases in the College of Medicine.

Literature in the 2000s seemed to support that stance, prompting Sherman and the team of researchers from UC and elsewhere to intensively study the two-year experiences of 17 patients co-infected with HIV and hepatitis C. The patients received already approved HIV antiretroviral drug therapies, but underwent frequent evaluation and sampling of blood so that minor changes in the virus and the immune response could be captured.

In a subset of patients there was an initial increase in serum ALT (a marker of liver injury), hepatitis C or both during the first 16 weeks. However, over a period of 18 months researchers found that viral loads for HCV returned to what was expected in a mono-infected patient suffering from HCV without HIV, says Sherman. Initial liver injury actually resulted from effective HIV treatment and not from toxicity.

“The drop in HCV viral levels was a big surprise and not what we necessarily expected,” Sherman says.

In the United States, 200,000 to 300,000 people have HCV/HIV co-infection, while worldwide estimates range from 4 million to 8 million people, according to Sherman. Physicians can use Sherman’s study results to better plan treatment for HIV patients co-infected with hepatitis C.

“There is a complex interaction of biological effects when patients are infected with both HIV and the hepatitis C virus,” Sherman explains. “Initial response to HIV treatment results in a transient increase in HCV viral replication and evidence of liver injury. However, over time HIV suppression leads to reduced HCV replication.”

“This process is highly modulated by down regulation of the interferon-responsive gene family,” adds Sherman, who led the study. “The findings suggest that HIV suppression with antiretroviral medications play an important role in the management of individuals with HCV and HIV infection. It supports the concept that in those with HCV/HIV infection early and uninterrupted HIV therapy is a critical part of preventing liver disease.”

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Genetics of cancer: Non-coding DNA can finally be decoded

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Cancer is a disease of the genome resulting from a combination of genetic modifications (or mutations). We inherit from our parents strong or weak predispositions to developing certain kinds of cancer; in addition, we also accumulate new mutations in our cells throughout our lifetime. Although the genetic origins of cancers have been studied for a long time, researchers were not able to measure the role of non-coding regions of the genome until now. A team of geneticists from the University of Geneva (UNIGE), by studying tissues from patients suffering from colorectal cancer, have succeeded in decoding this unexplored, but crucial, part of our genome. Their results can be found in Nature.

To better understand how cancer develops, scientists strive to identify genetic factors – whether hereditary or acquired – that could serve as the catalyst or trigger for tumor progression. Until now, the genetic basis of cancers had only been examined in the coding regions of the genome, which constitutes only 2% of it. However, as recent scientific advances have shown, the other 98% is far from inactive: it includes elements that serve to regulate gene expression, and therefore should play a major role in the development of cancer.

In order to better understand this role, Louis-Jeantet professor Emmanouil Dermitzakis and his team, from the Department of Genetic and Developmental Medicine in UNIGE’s Faculty of Medicine, studied colorectal cancer, one of the most common and most deadly cancers. Indeed, each year, one million new cases are detected around the world, and for almost half of these patients, the disease will prove fatal. Using genome sequencing technology, the UNIGE geneticists compared the RNA between healthy tissue and tumor tissue from 103 patients, searching for regulatory elements present in the vast, non-coding portion of the genome that impact the development of colorectal cancer. The goal was to identify the effect, present only in cancerous tissue, of acquired mutations whose activation would have triggered the disease. This approach is totally new: it is the first study of this scale to examine the non-coding genome of cancer patients.

Unknown Mutations

The UNIGE team was able to identify two kinds of non-coding mutations that have an impact on the development of colorectal cancer. They found, on one hand, hereditary regulatory variants that are not active in healthy tissue, but are activated in tumors and seem to contribute to cancer progression. It shows that the genome we inherit not only affects our predisposition towards developing cancer, but also has an influence on its progression. On the other hand, the researchers identified effects of acquired mutations on the regulation of gene expression that affect the genesis and progression of colorectal tumors.

‘The elements responsible for the development and progression of cancers located in the non-coding genome are as important as those found in the coding regions of the genome. Therefore, analyzing genetic factors in our whole genome, and not only in the coding regions as it was done before, gives us a much more comprehensive knowledge of the genetics behind colorectal cancer,’ explains Halit Ongen, the lead author of this study. ‘We applied this completely innovative methodology to colorectal cancer, but it can be applied to understand the genetic basis of all sorts of cancers,’ underlines Professor Dermitzakis.

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Neuroprotective role of immune cell discovered

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A type of immune cell widely believed to exacerbate chronic adult brain diseases, such as Alzheimer’s disease and multiple sclerosis (MS), can actually protect the brain from traumatic brain injury (TBI) and may slow the progression of neurodegenerative diseases, according to Cleveland Clinic research published today in the online journal Nature Communications.

The research team, led by Bruce Trapp, PhD, Chair of the Department of Neurosciences at Cleveland Clinic’s Lerner Research Institute, found that microglia can help synchronize brain firing, which protects the brain from TBI and may help alleviate chronic neurological diseases. They provided the most detailed study and visual evidence of the mechanisms involved in that protection.

“Our findings suggest the innate immune system helps protect the brain after injury or during chronic disease, and this role should be further studied,” Dr. Trapp said. “We could potentially harness the protective role of microglia to improve prognosis for patients with TBI and delay the progression of Alzheimer’s disease, MS, and stroke. The methods we developed will help us further understand mechanisms of neuroprotection.”

Microglias are primary responders to the brain after injury or during illness. While researchers have long believed that activated microglia cause harmful inflammation that destroys healthy brain cells, some speculate a more protective role. Dr. Trapp’s team used an advanced technique called 3D electron microscopy to visualize the activation of microglia and subsequent events in animal models.

They found that when chemically activated, microglia migrate to inhibitory synapses, connections between brain cells that slow the firing of impulses. They dislodge the synapse (called “synaptic stripping”), thereby increasing neuronal firing and leading to a cascade of events that enhance survival of brain cells.

Trapp is internationally known for his work on mechanisms of neurodegeneration and repair in multiple sclerosis. His past research has included investigation of the cause of neurological disability in MS patients, cellular mechanisms of brain repair in neurodegenerative diseases, and the molecular biology of myelination in the central and peripheral nervous systems.

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Understanding How Neuro Cells Turn Cancerous

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A new understanding of the mechanism that makes neuro cells turn cancerous brings us nearer to a treatment for brain/neuro tumours

Scientists from the Sloan-Kettering Institute for Cancer Research in New York with the help of Plymouth University Peninsula Schools of Medicine and Dentistry have completed research which for the first time brings us nearer to understanding how some cells in the brain and nervous system become cancerous.

The results of their study are published in the prestigious journal Cancer Cell.

The research team led by Sloan-Kettering researchers studied a tumour suppressor called Merlin.

The results of the study have identified a new mechanism whereby Merlin suppresses tumours, and that the mechanism operates within the nucleus. The research team has discovered that unsuppressed tumour cells increase via a core signalling system, the hippo pathway, and they have identified the route and method by which this signalling occurs.

By identifying the signalling system and understanding how, when present, Merlin suppresses it, the way is open for research into drug therapies which may suppress the signalling in a similar way to Merlin.

Tumour suppressors exist in cells to prevent abnormal cell division in our bodies. The loss of Merlin leads to tumours in many cell types within our nervous systems. There are two copies of a tumour suppressor, one on each chromosome that we inherit from our parents. The loss of Merlin can be caused by random loss of both copies in a single cell, causing sporadic tumours, or by inheriting one abnormal copy and losing the second copy throughout our lifetime as is seen in the inherited condition of neurofibromatosis type 2 (NF2).

No effective therapy for these tumours exists, other than repeated invasive surgery aiming at a single tumour at a time and which is unlikely to eradicate the full extent of the tumours, or radiotherapy.

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Robot Revolution: Androids are coming

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The race is on to build robots for the consumer market. But are there consequences to co-existing with humanoid machines? 16×9 speaks to some of the world’s most brilliant people while exploring the Geminoid Project, Nao Robot, Baxter and Dr. Robot. For more info, please go to www.global16x9.com.

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Viral relics show cancer’s ‘footprint’ on our evolution

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Cancer has left its ‘footprint’ on our evolution, according to a study which examined how the relics of ancient viruses are preserved in the genomes of 38 mammal species.

Viral relics are evidence of the ancient battles our genes have fought against infection. Occasionally the retroviruses that infect an animal get incorporated into that animal’s genome and sometimes these relics get passed down from generation to generation – termed ‘endogenous retroviruses’ (ERVs). Because ERVs may be copied to other parts of the genome they contribute to the risk of cancer-causing mutations.

Now a team from Oxford University, Plymouth University, and the University of Glasgow has identified 27,711 ERVs preserved in the genomes of 38 mammal species, including humans, over the last 10 million years. The team found that as animals increased in size they ‘edited out’ these potentially cancer-causing relics from their genomes so that mice have almost ten times as many ERVs as humans. The findings offer a clue as to why larger animals have a lower incidence of cancer than expected compared to smaller ones, and could help in the search for new anti-viral therapies.

A report of the research is published in the journal PLOS Pathogens.

‘We set out to find as many of these viral relics as we could in everything from shrews and humans to elephants and dolphins,’ said Dr Aris Katzourakis of Oxford University’s Department of Zoology, lead author of the report. ‘Viral relics are preserved in every cell of an animal: Because larger animals have many more cells they should have more of these endogenous retroviruses (ERVs) – and so be at greater risk of ERV-induced mutations – but we’ve found this isn’t the case. In fact larger animals have far fewer ERVs, so they must have found ways to remove them.’

A combination of mathematical modelling and genome research uncovered some striking differences between mammal genomes: mice (c.19 grams) have 3331 ERVs, humans (c.59 kilograms) have 348 ERVs, whilst dolphins (c.281 kilograms) have just 55 ERVs.

‘This is the first time that anyone has shown that having a large number of ERVs in your genome must be harmful – otherwise larger animals wouldn’t have evolved ways of limiting their numbers,’ said Dr Katzourakis. ‘Logically we think this is linked to the increased risk of ERV-based cancer-causing mutations and how mammals have evolved to combat this risk. So when we look at the pattern of ERV distribution across mammals it’s like looking at the ‘footprint’ cancer has left on our evolution.’

ERVs that are immediately harmful to an animal tend not be passed on, what makes them troublesome is that having arrived at one location in a genome the replication process means they can be copied across, ‘jumping’, to somewhere else. ERVs can, for example, ‘jump’ into the middle of gene machinery responsible for suppressing tumours, damaging it and ratcheting up the risk of mutations turning into cancer.

‘We know that some cancers, such as t-cell leukaemia, are directly linked to retroviruses but a lot of the time ERVs contribute to the number of things that need to go wrong in cells for cancers to arise,’ said Dr Katzourakis. ‘As animals get bigger so the number of cells increases and there are more opportunities for things to go wrong, so there is an evolutionary pressure for larger animals to reduce the number of ERVs.’

Dr Gkikas Magiorkinis of Oxford University’s Department of Zoology, an author of the report, said: ‘We know that taller people have higher risk for some cancers, which fits our study about ERVs posing evolutionary pressure through cancer. Yet we still have no evidence that ERVs might have causal links with cancer in humans, even though they clearly cause cancers in other animals such as mice. We need to search in a more systematic way to see if ERVs cause cancer in humans, and our study suggests that viral pathogenic mechanisms in larger animals like humans would be more complex than those observed in smaller animals.’

The research suggests that larger creatures must have more effective anti-viral genes and resources than smaller ones and, if these can be identified, in the future it may be possible to mimic these mechanisms to produce new anti-viral therapies.

The new study is relevant to Peto’s Paradox, an observation made by Sir Richard Peto that the incidence of cancer does not appear to correlate with the number of cells in an organism. ‘Our work doesn’t solve Peto’s paradox as a whole but is has solved it in respect of infection,’ said Dr Katzourakis.

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Human platelets successfully generated using next-generation bioreactor

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Scientists at Brigham and Women’s Hospital (BWH) have developed a scalable, next-generation platelet bioreactor to generate fully functional human platelets in vitro. The work is a major biomedical advancement that will help address blood transfusion needs worldwide.

The study is published July 21, 2014 in Blood.

“The ability to generate an alternative source of functional human platelets with virtually no disease transmission represents a paradigm shift in how we collect platelets that may allow us meet the growing need for blood transfusions,” said Jonathan Thon, PhD, Division of Hematology, BWH Department of Medicine, lead study author.

According to the researchers, more than 2.17 million platelet units from donors are transfused yearly in the United States to treat patients undergoing chemotherapy, organ transplantation and surgery, as well as for those needing blood transfusions following a major trauma. However, increasing demand; a limited five-day shelf-life; and risk of contamination, rejection and infection have made blood platelet shortages common.

“Bioreactor-derived platelets theoretically have several advantages over conventional, donor-derived platelets in terms of safety and resource utilization,” said William Savage, MD, PhD, medical director, Kraft Family Blood Donor Center at Dana Farber Cancer Institute/Brigham and Women’s Hospital, who did not contribute to the study. “A major factor that has limited our ability to compare bioreactor platelets to donor platelets is the inefficiency of growing platelets, a problem that slows progress of clinical research. This study addresses that gap, while contributing to our understanding of platelet biology at the same time.”

Blood cells, such as platelets, are made in bone marrow. The bioreactor-a device that mimics a biological environment to carry out a reaction on an industrial scale-uses biologically inspired engineering to fully integrate the major components of bone marrow, modeling both its composition and blood flow characteristics. The microfluidic platelet bioreactor recapitulates features such as bone marrow stiffness, extracellular matrix composition, micro-channel size, and blood flow stability under high-resolution live-cell microscopy to make human platelets.

Application of shear forces of blood flow in the bioreactor triggered a dramatic increase in platelet initiation from 10 percent to 90 percent, leading to functional human platelets.

“By being able to develop a device that successfully models bone marrow represents a crucial bridge connecting our understanding of the physiological triggers of platelet formation to support drug development and scale platelet production,” said senior study author Joseph Italiano, Jr., PhD, Division of Hematology, BWH Department of Medicine, and the Vascular Biology Program at Boston Children’s Hospital.

In terms of next steps, the researchers would like to commence phase 0/I in human clinical trials in 2017.

“The regulatory bar is appropriately set high for blood products, and it is important to us that we show platelet quality, function and safety over these next three years since we’ll likely be recipients of these platelets ourselves at some point,” said Thon.

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Stem cells aid muscle repair and strengthening after resistance exercise

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A new study in mice reveals that mesenchymal (mezz-EN-chem-uhl) stem cells (MSCs) help rejuvenate skeletal muscle after resistance exercise.

University of Illinois kinesiology and community health professor Marni Boppart studies the mechanisms that enable muscles to recover and grow stronger after exercise. | Photo Credit: L. Brian Stauffe

By injecting MSCs into mouse leg muscles prior to several bouts of eccentric exercise (similar to the lengthening contractions performed during resistance training in humans that result in mild muscle damage), researchers were able to increase the rate of repair and enhance the growth and strength of those muscles in the exercising mice.

The findings, described in the journal Medicine and Science in Sports and Exercise, may one day lead to new interventions to combat age-related declines in muscle structure and function, said University of Illinois kinesiology and community health professor Marni Boppart, who led the research.

“We have an interest in understanding how muscle responds to exercise, and which cellular components contribute to the increase in repair and growth with exercise,” she said. “But the primary goal of our lab really is to have some understanding of how we can rejuvenate the aged muscle to prevent the physical disability that occurs with age, and to increase quality of life in general as well.”

MSCs occur naturally in the body and may differentiate into several different cell types. They form part of the stroma, the connective tissue that supports organs and other tissues.

MSCs also excrete growth factors and, according to the new study, stimulate muscle precursor cells, called satellite cells, to expand inside the tissue and contribute to repair following injury. Once present and activated, satellite cells actually fuse to the damaged muscle fibers and form new fibers to reconstruct the muscle and enhance strength.

“Satellite cells are a primary target for the rejuvenation of aged muscle, since activation becomes increasingly impaired and recovery from injury is delayed over the lifespan,” Boppart said. “MSC transplantation may provide a viable solution to reawaken the aged satellite cell.”

Satellite cells themselves will likely never be used therapeutically to enhance repair or strength in young or aged muscle “because they cause an immune response and rejection within the tissue,” Boppart said. But MSCs are “immunoprivileged,” meaning that they can be transplanted from one individual to another without sparking an immune response.

“Skeletal muscle is a very complex organ that is highly innervated and vascularized, and unfortunately all of these different tissues become dysfunctional with age,” Boppart said. “Therefore, development of an intervention that can heal multiple tissues is ideally required to reverse age-related declines in muscle mass and function. MSCs, because of their ability to repair a variety of different tissue types, are perfectly suited for this task.”

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Epigenetic tie to neuropsychiatric disorders found

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Dysfunction in dopamine signaling profoundly changes the activity level of about 2,000 genes in the brain’s prefrontal cortex and may be an underlying cause of certain complex neuropsychiatric disorders, such as schizophrenia, according to UC Irvine scientists.

This epigenetic alteration of gene activity in brain cells that receive this neurotransmitter showed for the first time that dopamine deficiencies can affect a variety of behavioral and physiological functions regulated in the prefrontal cortex.

The study, led by Emiliana Borrelli, a UCI professor of microbiology & molecular genetics, appears online in the journal Molecular Psychiatry.

“Our work presents new leads to understanding neuropsychiatric disorders,” Borrelli said. “Genes previously linked to schizophrenia seem to be dependent on the controlled release of dopamine at specific locations in the brain. Interestingly, this study shows that altered dopamine levels can modify gene activity through epigenetic mechanisms despite the absence of genetic mutations of the DNA.”

Dopamine is a neurotransmitter that acts within certain brain circuitries to help manage functions ranging from movement to emotion. Changes in the dopaminergic system are correlated with cognitive, motor, hormonal and emotional impairment. Excesses in dopamine signaling, for example, have been identified as a trigger for neuropsychiatric disorder symptoms.

Borrelli and her team wanted to understand what would happen if dopamine signaling was hindered. To do this, they used mice that lacked dopamine receptors in midbrain neurons, which radically affected regulated dopamine synthesis and release.

The researchers discovered that this receptor mutation profoundly altered gene expression in neurons receiving dopamine at distal sites in the brain, specifically in the prefrontal cortex. Borrelli said they observed a remarkable decrease in expression levels of some 2,000 genes in this area, coupled with a widespread increase in modifications of basic DNA proteins called histones – particularly those associated with reduced gene activity.

Borrelli further noted that the dopamine receptor-induced reprogramming led to psychotic-like behaviors in the mutant mice and that prolonged treatment with a dopamine activator restored regular signaling, pointing to one possible therapeutic approach.

The researchers are continuing their work to gain more insights into the genes altered by this dysfunctional dopamine signaling.

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Scientists map one of most important proteins in life

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Scientists reveal the structure of one of the most important and complicated proteins in cell division – a fundamental process in life and the development of cancer – in research published in Nature on Sunday.

Images of the gigantic protein in unprecedented detail will transform scientists’ understanding of exactly how cells copy their chromosomes and divide, and could reveal binding sites for future cancer drugs.

A team from The Institute of Cancer Research, London, and the Medical Research Council Laboratory of Molecular Biology in Cambridge produced the first detailed images of the anaphase-promoting complex (APC/C).

The APC/C performs a wide range of vital tasks associated with mitosis, the process during which a cell copies its chromosomes and pulls them apart into two separate cells. Mitosis is used in cell division by all animals and plants.

Discovering its structure could ultimately lead to new treatments for cancer, which hijacks the normal process of cell division to make thousands of copies of harmful cancer cells.

In the study, which was funded by Cancer Research UK, the researchers reconstituted human APC/C and used a combination of electron microscopy and imaging software to visualise it at a resolution of less than a billionth of a metre.

The resolution was so fine that it allowed the researchers to see the secondary structure – the set of basic building blocks which combine to form every protein. Alpha-helix rods and folded beta-sheet constructions were clearly visible within the 20 subunits of the APC/C, defining the overall architecture of the complex.

Previous studies led by the same research team had shown a globular structure for APC/C in much lower resolution, but the secondary structure had not previously been mapped. The new study could identify binding sites for potential cancer drugs.

Each of the APC/C’s subunits bond and mesh with other units at different points in the cell cycle, allowing it to control a range of mitotic processes including the initiation of DNA replication, the segregation of chromosomes along protein ‘rails’ called spindles, and the ultimate splitting of one cell into two, called cytokinesis. Disrupting each of these processes could selectively kill cancer cells or prevent them from dividing.

Dr David Barford, who led the study as Professor of Molecular Biology at The Institute of Cancer Research, London, before taking up a new position at the Medical Research Council Laboratory of Molecular Biology in Cambridge, said:

“It’s very rewarding to finally tie down the detailed structure of this important protein, which is both one of the most important and most complicated found in all of nature. We hope our discovery will open up whole new avenues of research that increase our understanding of the process of mitosis, and ultimately lead to the discovery of new cancer drugs.”

Professor Paul Workman, Interim Chief Executive of The Institute of Cancer Research, London, said: “The fantastic insights into molecular structure provided by this study are a vivid illustration of the critical role played by fundamental cell biology in cancer research.

“The new study is a major step forward in our understanding of cell division. When this process goes awry it is a critical difference that separates cancer cells from their healthy counterparts. Understanding exactly how cancer cells divide inappropriately is crucial to the discovery of innovative cancer treatments to improve outcomes for cancer patients.”

Dr Kat Arney, Science Information Manager at Cancer Research UK, said “Figuring out how the fundamental molecular ‘nuts and bolts’ of cells work is vital if we’re to make progress understanding what goes wrong in cancer cells and how to tackle them more effectively. Revealing the intricate details of biological shapes is a hugely important step towards identifying targets for future cancer drugs.”

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Clemson University bioengineering center lands $11 million for tissue research

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Clemson University has been awarded $11 million to expand a bioengineering center that helps mentor junior faculty members as they research how lab-grown tissue can treat some of the world’s most debilitating diseases, ranging from heart disease to spinal cord injuries.

Scientists expect the program will encourage an upward spiral that leads to more research dollars and helps boost the state’s growing medical-technology industry. Much of the center’s research will be done at the cutting-edge Patewood campus in Greenville.

The money comes from a National Institutes of Health (NIH) program that supports the Centers of Biomedical Research Excellence (COBRE) nationwide. The Clemson one is the South Carolina Bioengineering Center of Regeneration and Formation of Tissues (SC BioCRAFT).

Clemson University President James Clements made the announcement Wednesday, saying the grant is the largest from the NIH in the university’s history and brings the total NIH funding for the center to $20.3 million.

The $11 million will pay for maintaining and upgrading state-of-the-art facilities. It also will provide funds for five junior faculty to begin their research, said Naren Vyavahare, the SC BioCRAFT director and Hunter Endowed Chair of bioengineering.

The goal is to make the center self-sustaining, so that it can transition away from COBRE funding. Once the center is established, its researchers will be well-positioned to compete for funding from a range of federal and non-federal sources, Vyavahare said.

“This is seed money,” he said. “The whole idea behind the center is to fund and mentor junior faculty and make them successful. When they get their own major grant, we graduate them and bring new people in.

“This is a unique program to help early career investigators establish their research program quickly with the support of expert mentors and free access to world-class core facilities.”

Clemson researchers will collaborate with Dr. Roger Markwald of the Medical University of South Carolina, who is a co-principal investigator on the grant. Senior investigators Drs. Thomas Borg and Mark Kindy, both of MUSC, will provide biology expertise.

Support for the COBRE centers comes in three phases, each lasting five years. The new round of funding launches Clemson’s second phase. In the first phase, the university used the $9.3 million it received to start SC BioCRAFT.

Researchers at the center work on finding new ways to engineer cells and tissue to help the body function normally when someone gets sick or hurt. The field, regenerative medicine, holds the promise of eventually allowing scientists to grow vital organs in the lab for transplants.

“We’re on the right track,” President Clements said. “The NIH has invested more than $20 million in Clemson’s program since 2009. This level of funding is a great vote of confidence in our bioengineering faculty and their research.”

The funding strengthens the bond that Clemson and MUSC share through The Clemson-MUSC Joint Bioengineering Program.

A $60-million bioengineering building that recently opened on MUSC’s campus in Charleston houses the labs of five full-time Clemson faculty, including one involved in the grant.

“The new building and partnership underscore the growing statewide emphasis on bioengineering and regenerative medicine,” Markwald said. “Collaboration is key. We can accomplish more together than we can separately.”

SC BioCRAFT has been headquartered in Rhodes Engineering Research Center on Clemson’s main campus. The new round of funding will funnel more research to Clemson University Biomedical Engineering Campus (CUBEInC) at Greenville Health System’s Patewood Medical Campus.

Clinical mentors, including Eugene Langan, M.D. and Thomas Pace, M.D. from GHS, will help junior faculty keep their research clinically relevant.

CUBEInC opened nearly three years ago to serve as an economic engine that helps power the state’s medical technology industry. The campus’ 29,000 square feet includes world-class labs, a conference center and room for start-ups.

“It is gratifying that the NIH has recognized Clemson’s strength in bioengineering research,” said Larry Dooley, Clemson’s interim vice president for research. “The team at SC BioCRAFT has done very well in the first phase. It will be exciting to see what comes next.”

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Artificial Lung

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Researchers develop a compact artificial lung that could be worn in a fanny pack and received a $3.4 million federal grant to help make it happen.

Photo Credits:Trib Total Media

William Federspiel, a professor of bioengineering at the University of Pittsburgh, is leading a team that will use the grant from the National Institutes of Health, announced Tuesday, to replace technologies that keep those awaiting lung transplants or recovering from acute, chronic-lung failure bedridden and tethered to cumbersome machines to breathe.

“Lots and lots of people die of respiratory failure each day. A truly effective artificial lung would be a very important medical advance,” said Dr. Norman H. Edelman, chief medical officer for the American Lung Association, who is not involved with the research. “Transplants do work and are successful, but they are hard to come by. So having something to tide a patient over until a transplant would be an important advance.”

Thousands of people need such treatments to recover from lung disease. In the United States alone, experts estimate that 350,000 people a year die of lung disease; 150,000 more require medical care for it.

Federspiel’s team includes scientists and physicians from Pitt, UPMC, Carnegie Mellon University and Mississippi State University. In a laboratory on the South Side, researchers have assembled a small model of the device they hope to perfect.

The Paracorporeal Ambulatory Assist Lung, or PAAL, would remove blood through a plastic tube inserted into a vein, remove carbon dioxide from the blood and inject oxygen into it. The blood would be returned to the body through a second tube.

PAAL, which will weigh 3 to 5 pounds, likely would involve another year or two of development with a medical-device company before it is ready for clinical trial in humans, Federspiel said.

It’s a far cry from cumbersome, stationary machines now used to drain blood from the body, re-oxygenate it and return it to the bloodstream.

“Our wearable lung will allow lung patients to get up and moving within the hospital setting,” Federspiel said.

“Clinical literature indicates if you can get patients off sedation and up moving, you improve recovery from acute lung disease. And if they are a candidate for a lung transplantation, you can improve outcomes because you have healthier patients.”

The project takes place as researchers from the University of Maryland test an artificial lung on animals. Federspiel said the Pittsburgh lung would feature a different design, incorporating a spinning component that would mix oxygen in the blood like a spoon that stirs cream into coffee.

Edelman compared the development of a successful compact artificial lung to the device that kept former Vice President Dick Cheney alive while he awaited a heart transplant.

“Something like this could truly improve life for a certain subset of people,” Edelman said.

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Scientists criticize Europe’s $1.6B brain project

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Dozens of neuroscientists are protesting Europe’s $1.6 billion attempt to recreate the functioning of the human brain on supercomputers, fearing it will waste vast amounts of money and harm neuroscience in general.

The 10-year Human Brain Project is largely funded by the European Union. In an open letter issued Monday, more than 190 neuroscience researchers called on the EU to put less money into the effort to “build” a brain, and to invest instead in existing projects.

If the EU doesn’t adopt their recommendations, the scientists said, they will boycott the Human Brain Project and urge colleagues to do the same.

EU spokesman Ryan Heath called for patience, and said it was too early to say whether the project is a success because it had only been under way for nine months. He said the EU plans to rigorously review the scientific progress made and the project’s management every year.

Henry Markram, who heads the Human Brain Project at the Swiss Federal Institute for Technology in Lausanne, suggested those who signed the letter of protest did so because they didn’t understand the venture.

In an interview, he said the project, established in 2013, would bundle the work of some 100,000 neuroscientists worldwide the way that CERN, the European Organization for Nuclear Research, has done for particle physics. He acknowledged the brain project may have done a poor job telling scientists how they may benefit, even if they aren’t directly involved.

“I think we need to communicate more that it’s going to actually help them get more funding,” Markram said. “They feel that money is being taken away, that it’s going to distract from the important work that they’re doing. There is really not a threat.”

The Human Brain Project involves 112 institutions across Europe and the pooling, sharing and organization of their data on brain research. That information will be used to reconstruct the workings of a human brain on computers. “Only through simulations can you do some things that aren’t possible in the lab,” said Markram.

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Rats Use Whiskers Almost as Humans Use Fingers

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The way rats use their whiskers is more similar to how humans use their hands and fingers than previously thought, new research from the University of Sheffield has found.

Rats deliberately change how they sense their environment using their facial whiskers depending on whether the environment is novel, if there is a risk of collision and whether or not they can see where they are going.

Exploring rats move their long facial whiskers back and forth continuously while they are moving – a behaviour called “whisking”.

Scientists have known for a long time that movement of the whiskers provides these animals with a sense of touch that allows them to move around easily in the dark.

However, until now they did not know to what extent animals were able to deliberately control their whisker movement.

Academics from the Active Touch Laboratory in the University’s Department of Psychology used high-speed videography to study animals that had been trained over several days to run circuits for food.

By putting them in different scenarios – including putting unexpected obstacles in their way and removing visual cues – the team discovered strong evidence the creatures moved their whiskers in a purposeful way to safely navigate the course.

The study found that as animals got used to their environment, they moved quicker and altered their facial whisker movements – switching from broad exploratory whisker sweeps directed at nearby surfaces, such as the floor, to pushing their whisker forwards in order to detect obstacles and avoid collisions.

In environments where they were more likely to collide with objects, and without access to visual cues, animals moved more slowly but pushed their whiskers forward further. This suggests that they were aware on the increased risk of collisions and were acting more cautiously accordingly.

Professor Tony Prescott, Professor of Cognitive Neuroscience at the University of Sheffield, said: “A person moving around in the dark would likely use their hand and fingers to detect objects and obstacles in order to avoid banging into things. In a familiar environment, such as their own home, they might move faster pushing their hands out in front of them in case of unexpected collisions.

“This new research show that rats do much the same thing but using their facial whiskers. That is, they purposefully use their whisker to detect nearby objects and surfaces when moving slowly in unfamiliar environments, and push them out in front of themselves, to avoid collisions, when the environment is familiar and they want to move more quickly.

“All mammals except humans use facial whiskers as touch sensors. In humans we seem to have replaced this sense, in part, by being able to use our hand and fingers to feel our way.

“The rat puts its whiskers where it thinks it will get the most useful information, just as we do with our fingertips.”

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Bioengineered red blood cells could carry precious therapeutic cargo

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Whitehead Institute scientists have genetically and enzymatically modified red blood cells to carry a range of valuable payloads—from drugs, to vaccines, to imaging agents—for delivery to specific sites throughout the body.

“We wanted to create high-value red cells that do more than simply carry oxygen,” says Whitehead Founding Member Harvey Lodish, who collaborated with Whitehead Member Hidde Ploegh in this pursuit. “Here we’ve laid out the technology to make mouse and human red blood cells in culture that can express what we want and potentially be used for therapeutic or diagnostic purposes.”

The work, published this week in the Proceedings of the National Academy of Sciences (PNAS), combines Lodish’s expertise in the biology of red blood cells (RBCs) with biochemical methods developed in Ploegh’s lab.

RBCs are an attractive vehicle for potential therapeutic applications for a variety of reasons, including their abundance—they are more numerous than any other cell type in the body—and their long lifespan (up to 120 days in circulation). Perhaps most importantly, during RBC production, the progenitor cells that eventually mature to become RBCs jettison their nuclei and all DNA therein. Without a nucleus, a mature RBC lacks any genetic material or any signs of earlier genetic manipulation that could result in tumor formation or other adverse effects.

Exploiting this characteristic, Lodish and his lab introduced genes coding for specific slightly modified normal red cell surface proteins into early-stage RBC progenitors. As the RBCs approach maturity and enucleate, the proteins remain on the cell surface, where they are modified by Ploegh’s protein-labeling technique. Referred to as “sortagging,” the approach relies on the bacterial enzyme sortase A to establish a strong chemical bond between the surface protein and a substance of choice, be it a small-molecule therapeutic or an antibody capable of binding a toxin. The modifications leave the cells and their surfaces unharmed.

“Because the modified human red blood cells can circulate in the body for up to four months, one could envision a scenario in which the cells are used to introduce antibodies that neutralize a toxin,” says Ploegh. “The result would be long-lasting reserves of antitoxin antibodies.”

The approach has captured the attention of the U.S. military and its Defense Advanced Research Projects Agency (DARPA), which is supporting the research at Whitehead in the interest of developing treatments or vaccines effective against biological weapons.

Lodish believes the applications are potentially vast and may include RBCs modified to bind and remove bad cholesterol from the bloodstream, carry clot-busting proteins to treat ischemic strokes or deep-vein thrombosis, or deliver anti-inflammatory antibodies to alleviate chronic inflammation. Further, Ploegh notes there is evidence to suggest that modified RBCs could be used to suppress the unwanted immune response that often accompanies treatment with protein-based therapies. Ploegh is exploring whether these RBCs could be used to prime the immune system to allow patients to better tolerate treatment with such therapies.

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New reprogramming method makes better stem cells

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A team of researchers from the University of California, San Diego School of Medicine, Oregon Health & Science University (OHSU) and Salk Institute for Biological Studies has shown for the first time that stem cells created using different methods produce differing cells. The findings, published in the July 2, 2014 online issue of Nature, provide new insights into the basic biology of stem cells and could ultimately lead to improved stem cell therapies.

This image depicts scanning electron micrograph of cultured human neuron from induced pluripotent stem cell. Photo Credit: Mark Ellisman and Thomas Deerinck, National Center for Microscopy and Imaging Research, UC San Diego

Capable of developing into any cell type, pluripotent stem cells offer great promise as the basis for emerging cell transplantation therapies that address a wide array of diseases and conditions, from diabetes and Alzheimer’s disease to cancer and spinal cord injuries. In theory, stem cells could be created and programmed to replace ailing or absent cells for every organ in the human body.

The gold standard is human embryonic stem cells (ES cells) cultured from discarded embryos generated by in vitro fertilization, but their use has long been limited by ethical and logistical considerations. Scientists have instead turned to two other methods to create stem cells: Somatic cell nuclear transfer (SCNT), in which genetic material from an adult cell is transferred into an empty egg cell, and induced pluripotent stem cells (iPS cells), in which adult cells are reverted back to a stem cell state by artificially turning on targeted genes.

Until now, no one had directly and closely compared the stem cells acquired using these two methods. The scientists found they produced measurably different results. “The nuclear transfer ES cells are much more similar to real ES cells than the iPS cells,” said co-senior author Louise Laurent, PhD, assistant professor in the Department of Reproductive Medicine at UC San Diego. “They are more completely reprogrammed and have fewer alterations in gene expression and DNA methylation levels that are attributable to the reprogramming process itself.”

The development and use of iPS cells has grown exponentially in recent years, in no small part due to the fact that they can be generated from adult cells (often from the skin) by temporarily turning on a combination of four genes to induce the adult cells to return to a pluripotent state.

Laurent noted that iPS cell lines have been created from patients to model many different diseases and “the ability to make personalized iPS cells from a patient that could be transplanted back into that patient has generated excitement because it would eliminate the need for immunosuppression.”

The nuclear transfer method has been pioneered more recently by a team led by Shoukhrat Mitalipov, PhD, professor and director of the Center for Embryonic Cell and Gene Therapy at OSHU. The technique is similar to the process used in cloning, but the pluripotent cells are collected from early embryos before they develop into mature organisms.

For their comparisons, the researchers at UC San Diego, OSHU and Salk created four nuclear transfer ES cell lines and seven iPS cell lines using the same skin cells as the source of donor genetic material, then compared them to two standard human ES lines. All 13 cell lines were shown to be pluripotent using a battery of standard tests.

But closer analyses employing powerful genomic techniques to examine the DNA methylation – a fundamental biochemical process that helps turn genes on and off – and gene expression signatures of each cell line revealed key differences in stem cells created with the three methods. Specifically, the scientists found that the DNA methylation and gene expression patterns in nuclear transfer ES cells more closely resembled those of ES cells than did iPS cells, which revealed alterations apparently caused by the reprogramming process itself.

“If you believe that gene expression and DNA methylation are important, which we do, then the closer you get to the patterns of embryonic stem cells, the better,” said co-senior author Joseph R. Ecker, PhD, professor and director of Salk’s Genomic Analysis Laboratory. “Right now, nuclear transfer cells look closer to the embryonic stem cells than do the iPS cells.”

“I think these results show that the SCNT method is a far superior candidate for cell replacement therapies,” said Mitalipov, also a co-senior author of the Nature paper. “I truly believe that using this method of producing stem cells will someday help us cure and treat a wide range of diseases that are defeating us today.”

While nuclear transfer cells may be a better and more accurate representation of human ES cells than iPS cells, Laurent said there are significant barriers to their wider adoption and application. “Not only is nuclear transfer technically difficult, but federal funds cannot be used in experiments involving this procedure.”

On the other hand, she said, the findings could spur improvements in iPS cell reprogramming methods. “Our results have shown that widely used iPS cell reprogramming methods make cells that are similar to standard ES cells in broad strokes, but there are important differences when you look really closely. By using the egg cell to do the job, we can get much closer to the real thing. If we can figure out what factors in the egg drive the reprogramming process, maybe we can design a better iPS cell reprogramming method.”

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Researchers regrow corneas

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Researchers have identified a way to enhance regrowth of human corneal tissue to restore vision, using a molecule known as ABCB5 that acts as a marker for hard-to-find limbal stem cells. The research is also one of the first known examples of constructing a tissue from an adult-derived human stem cell.

This is a restored functional cornea following transplantation of human limbal stem cells to limbal stem cell-deficient mice. Photo Credit: Paraskevi Evi Kolovou, Bruce Ksander, and Natasha and Markus Frank

Boston researchers have identified a way to enhance regrowth of human corneal tissue to restore vision, using a molecule known as ABCB5 that acts as a marker for hard-to-find limbal stem cells. This work, a collaboration between the Massachusetts Eye and Ear/Schepens Eye Research Institute (Mass. Eye and Ear), Boston Children’s Hospital, Brigham and Women’s Hospital and the VA Boston Healthcare System, provides promise to burn victims, victims of chemical injury and others with damaging eye diseases. The research, published this week in Nature, is also one of the first known examples of constructing a tissue from an adult-derived human stem cell.

Limbal stem cells reside in the eye’s basal limbal epithelium, or limbus, and help maintain and regenerate corneal tissue. Their loss due to injury or disease is one of the leading causes of blindness. In the past, tissue or cell transplants have been used to help the cornea regenerate, but it was unknown whether there were actual limbal stem cells in the grafts, or how many, and the outcomes were not consistent.

In this study, researchers were able to use antibodies detecting ABCB5 to zero in on the stem cells in tissue from deceased human donors and use them to regrow anatomically correct, fully functional human corneas in mice.

“Limbal stem cells are very rare, and successful transplants are dependent on these rare cells,” says Bruce Ksander, Ph.D., of Mass. Eye and Ear, co-lead author on the study with post-doctoral fellow Paraskevi Kolovou, M.D. “This finding will now make it much easier to restore the corneal surface. It’s a very good example of basic research moving quickly to a translational application.”

ABCB5 was originally discovered in the lab of Markus Frank, M.D., of Boston Children’s Hospital, and Natasha Frank, M.D., of the VA Boston Healthcare System and Brigham and Women’s Hospital, co-senior investigators on the study, as being produced in tissue precursor cells in human skin and intestine. In the new work, using a mouse model developed by the Frank lab, they found that ABCB5 also occurs in limbal stem cells and is required for their maintenance and survival, and for corneal development and repair. Mice lacking a functional ABCB5 gene lost their populations of limbal stem cells, and their corneas healed poorly after injury.

“ABCB5 allows limbal stem cells to survive, protecting them from apoptosis [programmed cell death],” says Markus Frank. “The mouse model allowed us for the first time to understand the role of ABCB5 in normal development, and should be very important to the stem cell field in general.” according to Natasha Frank.

Markus Frank is working with biopharmaceutical industry to develop a clinical-grade ABCB5 antibody that would meet U.S. regulatory approvals. “A single lab cannot do a study like this,” says Natasha Frank, also affiliated with the Harvard Stem Cell Institute. “It integrates genetics, knockout mice, antibodies, transplantation — a lot of technical expertise that we were lucky came together in a very nice way.”

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A step closer to bio-printing transplantable tissues and organs: Study

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Researchers have made a giant leap towards the goal of ‘bio-printing’ transplantable tissues and organs for people affected by major diseases and trauma injuries, a new study reports.

Photo Credits: unknown

Scientists from the Universities of Sydney, Harvard, Stanford and MIT have bio-printed artificial vascular networks mimicking the body’s circulatory system that are necessary for growing large complex tissues.

“Thousands of people die each year due to a lack of organs for transplantation,” says study lead author and University of Sydney researcher, Dr Luiz Bertassoni.

“Many more are subjected to the surgical removal of tissues and organs due to cancer, or they’re involved in accidents with large fractures and injuries.

“Imagine being able to walk into a hospital and have a full organ printed – or bio-printed, as we call it – with all the cells, proteins and blood vessels in the right place, simply by pushing the ‘print’ button in your computer screen.

“We are still far away from that, but our research is addressing exactly that. Our finding is an important new step towards achieving these goals.

“At the moment, we are pretty much printing ‘prototypes’ that, as we improve, will eventually be used to change the way we treat patients worldwide.”

The research challenge – networking cells with a blood supply.

Cells need ready access to nutrients, oxygen and an effective ‘waste disposal’ system to sustain life. This is why ‘vascularisation’ – a functional transportation system – is central to the engineering of biological tissues and organs.

“One of the greatest challenges to the engineering of large tissues and organs is growing a network of blood vessels and capillaries,” says Dr Bertassoni.

“Cells die without an adequate blood supply because blood supplies oxygen that’s necessary for cells to grow and perform a range of functions in the body.”

“To illustrate the scale and complexity of the bio-engineering challenge we face, consider that every cell in the body is just a hair’s width from a supply of oxygenated blood.

“Replicating the complexity of these networks has been a stumbling block preventing tissue engineering from becoming a real world clinical application.”

But this is what researchers have now achieved.

What the researchers achieved

Using a high-tech ‘bio-printer’, the researchers fabricated a multitude of interconnected tiny fibres to serve as the mold for the artificial blood vessels.

They then covered the 3D printed structure with a cell-rich protein-based material, which was solidified by applying light to it.

Lastly they removed the bio-printed fibres to leave behind a network of tiny channels coated with human endothelial cells, which self organised to form stable blood capillaries in less than a week (see diagram below).

The study reveals that the bioprinted vascular networks promoted significantly better cell survival, differentiation and proliferation compared to cells that received no nutrient supply.

Significance of the breakthrough

According to Dr Bertassoni, a major benefit of the new bio-printing technique is the ability to fabricate large three-dimensional micro-vascular channels capable of supporting life on the fly, with enough precision to match individual patients’ needs.

“While recreating little parts of tissues in the lab is something that we have already been able to do, the possibility of printing three-dimensional tissues with functional blood capillaries in the blink of an eye is a game changer,” he says.

“Of course, simplified regenerative materials have long been available, but true regeneration of complex and functional organs is what doctors really want and patients really need, and this is the objective of our work.

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The above story is based on materials provided by University of Sydney.

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Muscle-powered bio-bots walk on command

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Engineers at the University of Illinois at Urbana-Champaign demonstrated a class of walking “bio-bots” powered by muscle cells and controlled with electrical pulses, giving researchers unprecedented command over their function. The group published its work in the online early edition of Proceedings of the National Academy of Science.

Tiny walking “bio-bots” are powered by muscle cells and controlled by an electric field. Photo Credit: Janet Sinn-Hanlon / Group@VetMed

“Biological actuation driven by cells is a fundamental need for any kind of biological machine you want to build,” said study leader Rashid Bashir, Abel Bliss Professor and head of bioengineering at the U. of I. “We’re trying to integrate these principles of engineering with biology in a way that can be used to design and develop biological machines and systems for environmental and medical applications. Biology is tremendously powerful, and if we can somehow learn to harness its advantages for useful applications, it could bring about a lot of great things.”

Bashir’s group has been a pioneer in designing and building bio-bots, less than a centimeter in size, made of flexible 3-D printed hydrogels and living cells. Previously, the group demonstrated bio-bots that “walk” on their own, powered by beating heart cells from rats. However, heart cells constantly contract, denying researchers control over the bot’s motion. This makes it difficult to use heart cells to engineer a bio-bot that can be turned on and off, sped up or slowed down.

The new bio-bots are powered by a strip of skeletal muscle cells that can be triggered by an electric pulse. This gives the researchers a simple way to control the bio-bots and opens the possibilities for other forward design principles, so engineers can customize bio-bots for specific applications.

“Skeletal muscles cells are very attractive because you can pace them using external signals,” Bashir said. “For example, you would use skeletal muscle when designing a device that you wanted to start functioning when it senses a chemical or when it received a certain signal. To us, it’s part of a design toolbox. We want to have different options that could be used by engineers to design these things.”

The design is inspired by the muscle-tendon-bone complex found in nature. There is a backbone of 3-D printed hydrogel, strong enough to give the bio-bot structure but flexible enough to bend like a joint. Two posts serve to anchor a strip of muscle to the backbone, like tendons attach muscle to bone, but the posts also act as feet for the bio-bot.

A bot’s speed can be controlled by adjusting the frequency of the electric pulses. A higher frequency causes the muscle to contract faster, thus speeding up the bio-bot’s progress as seen in this video.

“It’s only natural that we would start from a bio-mimetic design principle, such as the native organization of the musculoskeletal system, as a jumping-off point,” said graduate student Caroline Cvetkovic, co-first author of the paper. “This work represents an important first step in the development and control of biological machines that can be stimulated, trained, or programmed to do work. It’s exciting to think that this system could eventually evolve into a generation of biological machines that could aid in drug delivery, surgical robotics, ‘smart’ implants, or mobile environmental analyzers, among countless other applications.”

Next, the researchers will work to gain even greater control over the bio-bots’ motion, like integrating neurons so the bio-bots can be steered in different directions with light or chemical gradients. On the engineering side, they hope to design a hydrogel backbone that allows the bio-bot to move in different directions based on different signals. Thanks to 3-D printing, engineers can explore different shapes and designs quickly. Bashir and colleagues even plan to integrate a unit into undergraduate lab curriculum so that students can design different kinds of bio-bots.

“The goal of ‘building with biology’ is not a new one – tissue engineering researchers have been working for many years to reverse engineer native tissue and organs, and this is very promising for medical applications,” said graduate student Ritu Raman, co-first author of the paper. “But why stop there? We can go beyond this by using the dynamic abilities of cells to self-organize and respond to environmental cues to forward engineer non-natural biological machines and systems.

“The idea of doing forward engineering with these cell-based structures is very exciting,” Bashir said. “Our goal is for these devices to be used as autonomous sensors. We want it to sense a specific chemical and move towards it, then release agents to neutralize the toxin, for example. Being in control of the actuation is a big step forward toward that goal.”

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The above story is based on materials provided by University of Illinois at Urbana-Champaign.

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