Time filter

Source Type

Herlev, Denmark

News Article | September 12, 2016
Site: http://www.chromatographytechniques.com/rss-feeds/all/rss.xml/all

Our brains contain a surprising diversity of DNA. Even though we are taught that every cell in our body has the same DNA, in fact most cells in the brain have changes to their DNA that make each neuron a little different. Now researchers at the Salk Institute and their collaborators have shown that one source of this variation--called long interspersed nuclear elements or L1s--are present in 44 to 63 percent of healthy neurons and can not only insert DNA but also remove it. Previously, these L1s were known to be small bits of DNA called "jumping genes" that copy and paste themselves throughout the genome, but the researchers found that they also cause large deletions of entire genes. What's more, such variations can influence the expression of genes that are crucial for the developing brain. The findings, published September 12, 2016 in the journal Nature Neuroscience, may help explain what makes us each unique--why even identical twins can be so different from one other, for example--and how jumping genes can go awry and cause disease. "In 2013, we discovered that different neurons within the same brain have various complements of DNA, suggesting that they function slightly differently from each other even within the same person," says the study's senior investigator Rusty Gage, a professor in Salk's Laboratory of Genetics and holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases. "This recent study reveals a new and surprising form of variation that will help us understand the role of L1s, not only in healthy brains but in those affected by schizophrenia and autism." In 2005, Gage's team discovered L1s as a mechanism of genome diversity in the brain. However, it was not until it became possible to sequence the entire genome of a single cell that scientists could get a handle on the amount and nature of these variations. Using single-cell sequencing detailed in a 2013 Science paper, Gage's group showed that large chunks of DNA were inserted--or deleted--into the genomes of the cells. But even in that study the mechanisms responsible for causing insertions and deletions were unclear, making it difficult to decipher whether specific regions of the genome were more or less likely to be altered, as well as whether jumping genes were related to the deletions. In the new study, Gage, co-first authors Jennifer Erwin and Apuã Paquola, and collaborators developed a method to better capture the L1-associated variants in healthy neurons for sequencing and created a computational algorithm to distinguish the variations with greater accuracy than before. Using stem cells that are coaxed to differentiate into neurons in a dish, the team found that L1s are prone to DNA breaks. That's because a specific enzyme that chews through L1 spots in the genome is particularly active during differentiation. People inherit some L1s from their parents, and the enzyme appears to cut near these spots, the group found. "The surprising part was that we thought all L1s could do was insert into new places. But the fact that they're causing deletions means that they're affecting the genome in a more significant way," says Erwin, a staff scientist in Gage's group. Gage believes that diversity can be good for the brain--after all, about half of our brain cells have large chunks of missing or inserted DNA caused by L1s alone--but that too much of it can cause disease. Recent evidence has shown that neurons derived from individuals with schizophrenia or the rare autism-associated disorder Rett syndrome harbor more than normal amount of L1 variations in their genomes. In the new study, the team examined a schizophrenia-associated gene called DLG2, in which introducing L1 variations can change the gene's expression and subsequent maturation of neurons. The group plans to explore the role of L1 variations in other genes and their effects on brain activity and disease.

News Article
Site: http://www.nature.com/nature/current_issue/

In the 25 years that John Collinge has studied neurology, he has seen hundreds of human brains. But the ones he was looking at under the microscope in January 2015 were like nothing he had seen before. He and his team of pathologists were examining the autopsied brains of four people who had once received injections of growth hormone derived from human cadavers. It turned out that some of the preparations were contaminated with a misfolded protein — a prion — that causes a rare and deadly condition called Creutzfeldt–Jakob disease (CJD), and all four had died in their 40s or 50s as a result. But for Collinge, the reason that these brains looked extraordinary was not the damage wrought by prion disease; it was that they were scarred in another way. “It was very clear that something was there beyond what you'd expect,” he says. The brains were spotted with the whitish plaques typical of people with Alzheimer's disease. They looked, in other words, like young people with an old person's disease. For Collinge, this led to a worrying conclusion: that the plaques might have been transmitted, alongside the prions, in the injections of growth hormone — the first evidence that Alzheimer's could be transmitted from one person to another. If true, that could have far-reaching implications: the possibility that 'seeds' of the amyloid-β protein involved in Alzheimer's could be transferred during other procedures in which fluid or tissues from one person are introduced into another, such as blood transfusions, organ transplants and other common medical procedures. Collinge felt a duty to inform the public quickly. And that's what he did, publishing the study in Nature in September1, to headlines around the world. “Can you CATCH Alzheimer's?” asked Britain's Daily Mail, about the “potentially explosive new study”. Collinge has been careful to temper the alarm. “Our study does not mean that Alzheimer's is actually contagious,” he stresses. Carers won't catch it on the job, nor family members, however close. “But it raises concern that some medical procedures could be inadvertently transferring amyloid-β seeds.” Since then, the headlines have died away, but the academic work and discussion have taken off. Could seeds of amyloid-β proteins really be transmitted and, if so, are they harmless or do they cause disease? And could seeds of other related diseases involving misfolded proteins be transmitted in a similar way? In the past decade or so, evidence has been mounting for a controversial theory that rogue proteins, known collectively as amyloids and associated with diverse neurodegenerative diseases — from Alzheimer's to Parkinson's and Huntington's — might share some properties of prions, including their transmissibility. Collinge's data bolstered that theory. Urgent though these questions are, it could take years to find answers. The paper by Collinge and his colleagues has sparked a worldwide hunt for similar amyloid pathology in autopsied brains, and a small study2 published this January revealed a handful of related cases. Researchers are also trying to work out what the putative amyloid seeds look like, and whether different 'strains' of amyloids exist that are particularly damaging. Some researchers say that it is much too early to be alarmed. They point out that the number of patients in Collinge's study was tiny, that none had displayed symptoms of Alzheimer's disease before their death and that another toxic protein called tau also seems to be required to cause the condition. “We have to remember that there is no conclusive evidence that seeds of amyloids can transmit actual disease or that amyloids spread in the brain in a prion-like way,” says Pierluigi Nicotera, scientific director of the German Centre for Neurodegenerative Diseases in Bonn. “There may be other biological explanations.” Right now, there are few solid answers, but plenty of concerns. The sceptics worry that they might one day find themselves working under tight biosecurity regulations to handle proteins that they view as relatively innocuous. Others feel that the dangers may have been underestimated, and that scientists have a duty to investigate this as quickly as they can. “In my opinion, all amyloids should be considered dangerous until proven safe,” says prion and amyloid researcher Adriano Aguzzi at the University Hospital Zurich in Switzerland. A few decades ago, it was almost inconceivable that a protein, which has no genetic material or any other obvious way to self-replicate, could cause infectious disease. But that changed in 1982, when Stanley Prusiner, now at the University of California, San Francisco, introduced evidence for disease-causing prions, coining the term from the words 'proteinacious' and 'infectious'3. Prusiner showed that prion proteins (PrP) exist in a normal cellular form, and in a misfolded infectious form. The misfolded form causes the normal protein to also misfold, creating a cascade that overwhelms and kills cells4. It cause animal brains to turn into a spongy mess in scrapie, a disease of sheep, and in bovine spongiform encephalopathy (BSE or 'mad cow disease'), as well as in human prion diseases such as CJD. Prusiner and others also investigated how prions could spread. They showed that injecting brain extracts containing infectious prions into healthy animals seeds disease4. These prions can be so aggressive that in some cases, simply eating infected brains is sufficient to transmit disease. For example, many cases of variant CJD (vCJD) are now thought to have arisen in the United Kingdom in the 1990s after people ate meat from cattle that were infected with BSE. Since then, scientists have come to appreciate that many proteins associated with neurodegenerative diseases — including amyloid-β and tau in Alzheimer's disease and α-synuclein in Parkinson's disease — misfold catastrophically. Structural biologists call the entire family of misfolded proteins (including PrP) amyloids. Amyloid-β clumps into whitish plaques, tau forms ribbons called tangles and α-synuclein creates fibrous deposits called inclusions. A decade ago, these similarities prompted neuroscientist Mathias Jucker at the University of Tübingen in Germany to test whether injecting brain extracts containing misfolded amyloid-β into mice could seed an abnormal build-up of amyloid in the animals' brains. He found that it could, and that it also worked if he injected amyloids into the muscles5. “We saw no reason not to believe that if amyloid seeds entered the human brain, they would also cause amyloid pathology in the same way,” says Jucker. This didn't cause alarm at the time, because it wasn't clear how an amyloid seed from the brain of someone with Alzheimer's could be transferred into another person's body and find its way to their brain. To investigate that, what was needed was a group of people who had been injected with material from another person, and the opportunity to examine their brains in great detail, preferably when they were still relatively young and before they might have spontaneously developed early signs of Alzheimer's. The CJD brains provided just that opportunity. Between 1958 and 1985, around 30,000 people worldwide received injections of growth hormone derived from the pituitary glands of cadavers to treat growth problems. Some of the preparations were contaminated with the prion that causes CJD. Like all prion diseases, CJD has a very long incubation period, but once it gets going it rages through the brain, destroying all tissue in its wake and typically killing people from their late 40s onwards. According to 2012 statistics6, 226 people around the world have died from CJD as a result of prion-contaminated growth-hormone preparations. Collinge had not set out to find a link with Alzheimer's — it emerged as part of routine work at the National Prion Clinic in London, which he heads, and where around 70% of all people in the United Kingdom who die from prion-related causes are now autopsied. The clinic routinely looks for signs of all amyloid proteins in these brains to distinguish prion disease from other conditions. It was thanks to this routine work that the cluster of unusual cases emerged of people who had clearly died of CJD, but who also had obvious signs of amyloid pathology in their grey matter and cerebral blood vessels. As soon as he saw these brains, Collinge knew that he could get into stormy waters. Keen to strike a balance between warning of a possible public-health risk and causing unwarranted panic, he sketched a carefully worded press release that would go out from the National Prion Centre and set up hotlines for people who had been treated with growth hormone in the past. But no panic occurred: apart from one or two overwrought headlines, the news stories were fairly measured, he says. Only around ten people called the hotlines. For scientists, however, the paper was a red flag. “As soon as the paper came out we realized the health implications and started collecting slides and paraffin blocks from patients,” says Jiri Safar, director of the National Prion Disease Pathology Surveillance Center at Case Western Reserve University in Cleveland, Ohio. Like other pathologists in countries where people had died of CJD associated with medical procedures, he rushed to check the centre's archives of autopsied brains to see if any of them contained the ominous amyloid deposits. The answers are not yet in. Safar says that it has not proved easy to trace brain samples in the United States, but that he is working to do so with the National Institutes of Health and the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia. Charles Duyckaerts at the Pitié-Salpêtrière Hospital in Paris, France, has now examined brain tissues from around 24 patients and is likely to report the results later this year. A further 228 cases of CJD were caused by transplantation of prion-contaminated dura mater — the membrane surrounding the brain and spinal cord — prepared from cadavers around the world. Dura-mater preparations were regularly used in brain surgery as repair patches until the late 1990s. For the study2 published in January, Herbert Budka at the National Prion Diseases Reference Center at University Hospital Zurich and his colleagues examined the brains of seven such patients from Switzerland and Austria, and found that five had amyloid deposits in grey matter and blood vessels. In Japan, dementia researcher Masahito Yamada at Kanazawa University is making his way through a large number of such autopsy specimens and says that the 16 brains he has examined so far show signs of unusually high levels of amyloid deposition in cerebral blood vessels. Yet such case studies can only ever provide circumstantial evidence that seeds of amyloid-β were transferred during the treatments. And they cannot entirely rule out the possibility that the treatments themselves — or the patients' original medical conditions — caused the amyloid pathology. More-conclusive evidence would come from checking whether the original growth hormone and dura-mater preparations contained infectious amyloid seeds, by injecting them into animals and seeing whether this triggers disease. Most of these preparations, however, have long since disappeared. Collinge has access to some original samples of growth hormone stored by the UK Department of Health, and he is planning to analyse them for the presence of amyloid seeds and then inject them into mice. That work will take a couple of years to complete, he says. There is another hitch: no one knows for sure what size and shape the amyloid seeds might be. Jucker is hunting for them in an unusual source of human brain tissue that has nothing to do with CJD. A team in Bonn has collected frozen samples from more than 700 people with epilepsy who were operated on over the past 25 years to remove tissue that was driving their seizures. “It is the best source of fresh human brain tissue available at the moment,” says Jucker, who plans to scrutinize it carefully under the microscope for anything that might resemble tiny clumps or seeds of amyloid-β. The team also has records of the patients' cognitive skills, such as language and memory skills, before and at regular intervals after the operations. This should allow Jucker's team to correlate the presence of any amyloid-β seeds it finds with changes in the cognitive function of individual patients over time. Scientists have shown that tau and α-synuclein can also seed pathological features in mice. In two studies7, 8 from 2012, scientists injected fibrils of α-synuclein into the brains of mice already engineered to develop some of the characteristics of Parkinson's disease. This triggered the early onset of some of the signs and symptoms of Parkinson's, and eventually killed the animals. A third study9 showed that similar injections into normal mice caused some of the neurodegeneration typical of Parkinson's disease and the mice became less agile. In humans, α-synuclein would not necessarily turn out to be equally aggressive — mouse models of neurodegenerative diseases do not mimic human disease very closely — but scientists are taking the possibility seriously. If the transmissibility hypothesis proves true, the implications could be severe. Amyloids stick like glue to metal surgical instruments, and normal sterilization does not remove them, so amyloid seeds might possibly be transferred during surgery. The seeds might sit in the body for years or decades before spreading into plaques, and perhaps enabling the other pathological changes needed to induce Alzheimer's disease. Having amyloid plaques in cerebral blood vessels could be dangerous in another way, because they increase the risk that the vessel walls might break, leading to small strokes. But if common medical procedures really increased the risk of neurodegenerative disorders, then wouldn't that already have been detected? Not necessarily, says epidemiologist Roy Anderson at Imperial College London. “The proper epidemiological studies have not been done yet,” he says. They require very large and carefully curated databases of people with Alzheimer's disease, which include information about the development of symptoms and autopsy data. He and his team are now studying the handful of reliable databases that exist to tease out a signal that might associate medical procedures with Alzheimer's progression. The number of patients currently available may turn out to be too small to draw conclusions, he says, but a more definitive answer could emerge as the databases grow. Faced with so much uncertainty, some researchers and public-health agencies have adopted a wait-and-see approach. “We are right at the beginning of this story,” says Nicotera, “and if there is one message to come out right now it is that we need more work to see if this is a relevant mechanism.” The CDC and the European Centre for Disease Prevention and Control in Solna, Sweden, say that they are keeping a cautious eye on the issue. If further research does confirm that common neurodegenerative diseases are transmissible, what then? One immediate priority would be rigorous sterilization procedures for medical and surgical instruments that would destroy amyloids, in the way that extremely high temperatures and harsh chemicals destroy prions. Aguzzi says that funding agencies should put out calls now to researchers to develop cheap and simple sterilization methods. “It's not very sexy science, but it is urgently needed,” he says. He also worries about the safety of researchers working with amyloids — particularly α-synuclein. “I have nightmares that someone in my lab may catch Parkinson's,” he says. “While the story is in flux, our first duty is to protect lab workers.” The similarities between prions and other amyloids is throwing open other avenues of research. Prions can exist as distinct strains — proteins that have the same sequence of amino acids but misfold in different ways and have distinct biological behaviours10, much as different strains of a pathogenic virus can be aggressive or weak. The outbreak of vCJD in the United Kingdom in the 1990s was traced to BSE-contaminated meat because the prion strain was the same in both. Over the past few years, research in animals has shown that different strains of amyloid-β and α-synuclein exist11, 12. And a landmark paper13 in 2013 reported that strains of amyloid-β with different 3D structures were associated with different disease progression in two people with Alzheimer's. Structural biologist Robert Tycko, who led the work at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, is now looking at many more brain samples from such patients. Knowing the structures of pathological forms of amyloid seeds should help to design small molecules that bind to them and stop them doing damage, says biophysicist Ronald Melki at the Paris-Saclay Institute of Neuroscience, who works on α-synuclein strains. His lab is designing small peptides that target the seeds and mimic regions of 'chaperone' molecules, which usually bind to proteins and help them to fold correctly. Melki's small peptides mimic these binding regions, sticking to the amyloid proteins to stop them from aggregating further. In the research community, much of the agitation in response to Collinge's paper boils down to semantics. Some scientists do not like to use the word 'prion' in connection with the amyloids associated with common neurodegenerative diseases, or to describe any of their properties as 'prion-like' — because of its connotation of infectious, deadly disease. “The public has this perception of the word 'prion',” says Alzheimer's researcher Brad Hyman at Harvard Medical School in Boston, Massachusetts, and this matters, even if their ideas are wrong. “One of my patients told me that she wasn't getting any hugs any more from her husband who had read about the case in the media — that made me sad,” he says. Others, however, feel that it is helpful to consider prions and other amyloids as being part of a single spectrum of conditions involving proteins that misfold and misbehave. It means that researchers studying prion diseases and neurodegenerative diseases, who until recently had considered their disciplines to be separate, now find themselves tackling shared questions. Both fields are wary of raising premature alarm, even though they wonder what the future will bring. Jucker, only half-jokingly, says he could imagine a future in which people would go into hospital every ten years or so and get the amyloid seeds cleared out of their brains with antibodies. “You'd be good then to go for another decade.”

Wang Y.,Nordic Bioscience A S | Sorensen M.G.,Neurodegenerative Diseases | Zheng Q.,Nordic Bioscience A S | Zhang C.,Neurodegenerative Diseases | And 2 more authors.
International Journal of Alzheimer's Disease | Year: 2012

Drug development for dementias is significantly hampered by the lack of easily accessible biomarkers. Fluid biomarkers of dementias provide indications of disease stage, but have little prognostic value, cannot detect early pathological changes, and can only be measured in CSF (cerebrospinal fluid) which significantly limits their applicability. In contrast, imaging based biomarkers can provide indications of probability of disease progression, yet are limited in applicability due to cost, radiation and radio-tracers. These aspects highlight the need for other approaches to the development of biomarkers of dementia, which should focus on not only providing information about pathological changes, but also on being measured easily and reproducibly. For other diseases, focus on development of assays monitoring highly specific protease-generated cleavage fragments of proteins has provided assays, which in serum or plasma have the ability to predict early pathological changes. Proteolytic processing of brain proteins, such as tau, APP, and -synuclein, is a key pathological event in dementias. Here, we speculate that aiming biomarker development for dementias at detecting small brain protein degradation fragments of generated by brain-derived proteases specifically in blood samples could lead to the development of novel markers of disease progression, stage and importantly of treatment efficacy. © Copyright 2012 Y. Wang et al. Source

News Article
Site: http://www.nature.com/nature/current_issue/

An hour's drive from Kunming in southwestern China, past red clay embankments and sprawling forests, lies an unusual zoo. Inside the gated compound is a quiet, idyllic campus; a series of grey, cement animal houses stack up on the lush hillside, each with a clear plastic roof to let in the light. This is the Yunnan Key Laboratory of Primate Biomedical Research, and its inhabitants are some 1,500 monkeys, all bred for research. The serenity of the facility belies the bustle of activity within. Since it opened in 2011, this place has quickly become a Mecca for cutting-edge primate research, producing valuable disease models and seminal publications that have made its director, Ji Weizhi, a sought-after collaborator. Its campus houses a collection of gene-edited monkeys that serve as models of Duchenne muscular dystrophy, autism and Parkinson's disease. Ji plans to double the number of group leaders working there from 10 to 20 in the next 3 years, and to seek more international collaborations — he already works with scientists in Europe and the United States. “In terms of a technology platform, Ji is just way ahead,” says one collaborator, cardiologist Kenneth Chien at the Karolinska Institute in Stockholm. Ji is not alone in his ambitions for monkey research. With support from central and local governments, high-tech primate facilities have sprung up in Shenzhen, Hangzhou, Suzhou and Guangzhou over the past decade. Last month, the science ministry approved the launch of a facility at the Kunming Institute of Zoology that is expected to cost millions of dollars to build. These centres can provide scientists with monkeys in large numbers, and offer high-quality animal care and cutting-edge equipment with little red tape. A major brain project, expected to be announced in China soon, will focus much of its efforts on using monkeys to study disease. The enthusiasm stands in stark contrast to the climate in the West, where non-human-primate research is increasingly stymied by a tangle of regulatory hurdles, financial constraints and bioethical opposition. Between 2008 and 2011, the number of monkeys used in research in Europe declined by 28%, and some researchers have stopped trying to do such work in the West. Many have since sought refuge for their experiments in China by securing collaborators or setting up their own laboratories there. Some of the Chinese centres are even advertising themselves as primate-research hubs where scientists can fly in to take advantage of the latest tools, such as gene editing and advanced imaging. “It could be like CERN in Switzerland, where they set up a large facility and then people come from all over the world to get data,” says Stefan Treue, a neuroscientist who heads the German Primate Center in Göttingen, Germany. With China fast becoming a global centre for primate research, some scientists fear that it could hasten the atrophy of such science in the West and lead to a near monopoly, in which researchers become over-reliant on one country for essential disease research and drug testing. “Governments and politicians don't see this, but we face a huge risk,” says Erwan Bezard, who is director of the Institute of Neurodegenerative Diseases at the University of Bordeaux in France, and has set up his own primate-research company, Motac, in Beijing. Europe and the United States still have the lead in primate research, he says, but this could change as expertise migrates eastwards. “China will become the place where all therapeutic strategies will have to be validated. Do we want that? Or do we want to stay in control?” For decades, researchers have relied on monkeys to shed light on brain function and brain disease because of their similarity to humans. Growth in neuroscience research has increased demand, and although high costs and long reproductive cycles have limited the use of these animals in the past, new reproductive technologies and genetic-engineering techniques such as CRISPR–Cas9 are helping researchers to overcome these drawbacks, making monkeys a more efficient experimental tool. China has an abundance of macaques — the mainstay of non-human-primate scientific research. Although the population of wild rhesus macaques (Macaca mulatta) has declined, the number of farmed animals has risen. According to data from the Chinese State Forestry Administration, the number of businesses breeding macaques for laboratory use rose from 10 to 34 between 2004 and 2013, and the quota of animals that those companies could sell in China or overseas jumped from 9,868 to 35,385 over that time. Farm populations of marmosets, another popular research animal, are also on the rise. Most monkeys are shipped to pharmaceutical companies or researchers elsewhere in the world, but the growing appreciation among scientists of monkey models has prompted investment by local governments and private companies in dedicated research colonies. The country's 2011 five-year plan singled out primate disease models as a national goal; the science ministry followed up by pumping 25 million yuan (US$3.9 million) into the endeavour in 2014. Scientists visiting China are generally pleased with the care given to animals in these facilities, most of which have, or are trying to get, the gold-standard recognition of animal care — accreditation by AAALAC International. Ji's Yunnan Key Laboratory is the most active primate facility, but others are giving it competition. The new monkey facility at the Kunming Institute of Zoology was funded as part of the national development scheme for big science equipment that includes telescopes and supercomputers. The money will help the institute to double its colony of 2,500 cynomolgus monkeys (Macaca fascicularis) and rhesus macaques. Zhao Xudong, who runs the primate-research facility, says that the plan is to “set it up like a hospital, with separate departments for surgery, genetics and imaging”, and a conveyer belt to move monkeys between departments. There will be systems for measuring body temperature, heart rate and other physiological data, all to analyse the characteristics, or 'phenotypes', of animals, many of which will have had genes altered. “We are calling it the 'genotype versus phenotype analyser',” says Zhao. It will take ten years to finish, but he hopes to begin building this year and to start research within three. Other facilities, although smaller, are also expanding and diversifying. The Institute of Neuroscience in Shanghai plans to increase its population of 600 Old World monkeys to 800 next year and expand its 300-strong marmoset colony. Outside China, the numbers are heading in the opposite direction. Harvard Medical School closed its affiliated primate facility in May 2015 for 'strategic' reasons. Last December, the US National Institutes of Health decided to phase out non-human-primate experiments at one of its labs and subsequently announced that it would review all non-human-primate research that it funds. In Europe, researchers say, the climate is also growing colder for such research. Costs are a major disincentive. In 2008, Li Xiao-Jiang, a geneticist at Emory University in Atlanta, Georgia, helped to create the world's first transgenic monkey model of Huntington's disease1 with colleagues at Yerkes National Primate Research Centre. But Li says that it costs $6,000 to buy a monkey in the United States, and $20 per day to keep it, whereas the corresponding figures in China are $1,000 and $5 per day. “Because the cost is higher, you have to write a bigger grant, and then the bar will be higher when they judge it,” says Li. Funding agencies “really do not encourage large-animal research”. For Li, the solution was simple: go to China. He now has a joint position at the Institute of Genetics and Developmental Biology in Beijing, where he has access to around 3,000 cynomolgus monkeys at a farm in Guangzhou and some 400 rhesus monkeys at the Chinese Academy of Medical Sciences' monkey facility in Beijing. He has churned out a series of publications on monkeys with modified versions of the genes involved in Duchenne muscular dystrophy2 and Parkinson's disease3. Neuroscientist Anna Wang Roe says that red tape drove her to China. Roe's team at Vanderbilt University in Nashville, Tennessee, is attempting to work out how modules in the brain are connected, and she estimates that she and her colleagues have spent 25% of their time and a good deal of cash documenting the dosage and delivery-method for each drug they administered to their monkeys, as required by regulations. “We record something every 15 minutes,” she says. “It's not that it's wrong. It's just enormously time-consuming.” In 2013, impressed by the collaborative atmosphere at Zhejiang University in Hangzhou, she proposed that it build a neuroscience institute. The next day the university agreed, and she soon had a $25-million, 5-year budget. “Once the decision is made, you can start writing cheques,” she says. She is now closing her US laboratory to be the director of the Zhejiang Interdisciplinary Institute of Neuroscience and Technology, where she hopes to open a suite of the latest brain-analysis tools, including a powerful new 7-tesla functional magnetic resonance imaging device that she says will give images of the primate brain at unprecedented resolution. Bob Desimone was similarly impressed with the speed at which China moves. As a neuroscientist who heads the McGovern Institute for Brain Research at the Massachusetts Institute of Technology in Cambridge, in January 2014, he had a 'meet and greet' with the mayor of Shenzhen. In March, the mayor donated a building on the Shenzhen Institute of Advanced Technology campus for a monkey-research facility, and the centre's soon-to-be director, Liping Wang, promised that it would be ready by summer. Thinking that impossible, Desimone bet two bottles of China's prized mind-numbing liquor, maotai, that it wouldn't be done in time. He lost. The group raised most of the $10 million needed from city development grants, along with a small input from McGovern, and soon the first animals were being installed in the Brain Cognition and Brain Disorder Research Institute. “This place just makes things happen quickly,” Desimone says. But money and monkeys alone are not enough to lead to discovery. Researchers say that China is short on talented scientists to take advantage of the opportunities provided by animal research. That's why the organizers of the country's new primate centres hope to attract an influx of foreigners to permanent posts or as collaborators. So far, many of those moving to China have been Chinese or foreigners with a previous connection to the country, but others are expressing interest, says neuroscientist Guoping Feng, also at the McGovern Institute. Already, the Shenzhen primate centre has recruited from Europe and the United States, and Desimone says that it will be “an open technology base. Anyone who wants to work with monkeys can come.” The rapid spread of CRISPR–Cas9 and TALEN gene-editing tools is likely to accelerate demand for monkey research: they are turning the genetic modification of monkeys from a laborious and expensive task into a relatively quick, straightforward one. Unlike engineered mice, which can be bred and sent around the world, “monkeys are difficult to send, so it will be easier for the PI or postdoc to go there”, says Treue. Already, competition is fierce as researchers are racing for the low-hanging fruit — engineering genes with established roles in human disease or development. Almost all reports of gene-edited monkeys produced with these techniques have come from China. Desimone predicts that the pursuit of monkey disease models “could give China a unique niche to occupy in neuroscience”. The cages of Ji's facility are already full of the products of gene editing. One troop of animals has had a mutation genetically engineered into the MECP2 gene, which has been identified as the culprit in humans with Rett's syndrome, an autism spectrum disorder. An animal sits listless and unresponsive, holding tight to the bars of the cage as her normal twin sister crawls all over her. In another cage, a monkey with the mutation pumps its arm, reminiscent of repetitive behaviour seen in the human disorder. Some incessantly suck their thumbs. “I've never seen that in a monkey before — never so constant,” says Ji. Among the range of other disease models in Ji's menagerie are monkey versions of cardiovascular disease, which he is working on in collaboration with the Karolinska Institute. And last year, Ji made the world's first chimeric monkeys using embryonic stem cells4, an advance that could make the production of genetically modified animals even easier. The question now is whether these genetically modified monkeys will propel understanding of human brain function and dysfunction to a higher level. “You can't just knock out one gene and be sure you'll have human-like disease phenotype,” says Ji. Researchers see an opportunity to understand human evolution as well as disease. Su Bing, a geneticist at the Kunming Institute of Zoology, is working with Ji to engineer monkeys that carry the human version of a gene called SRGAP2, which is thought to endow the human brain with processing power by allowing the growth of connections between neurons. Su also plans to use CRISPR–Cas9 to introduce human versions of MCPH1, a gene related to brain size, and the human FOXP2 gene, which is thought to give humans unique language ability. “I don't think the monkey will all of a sudden start speaking, but will have some behavioural change,” predicts Su. Although the opportunities are great, there are still obstacles for scientists who choose to locate their animal research in China. Trying to keep a foot in two places can be challenging, says Grégoire Courtine, a spinal-cord-injury researcher based at the Swiss Federal Institute of Technology in Lausanne, who travels almost monthly to China to pursue his monkey research at Motac. He has even flown to Beijing, done a couple of operations on his experimental monkeys, then returned that night. “I'm 40 years old, I have energy in my body. But you need to really will it,” he says. Another downside, says Li, is that policies can change suddenly in China. “There is uncertainty. That makes us hesitate to commit,” says Li, who has retained his post at Emory University. And the immunity that China's primate researchers have had to animal-rights activism could start to erode, warns Deborah Cao, who researches law at Griffith University in Brisbane, Australia, and last year published a book on the use of animals in China5. People are starting to use Chinese social-media sites to voice outrage at the abuse of animals, Cao says. China has competition in its bid to dominate primate research, too. Japan has launched its own brain project focused on the marmoset as a model: the animal reaches sexual maturity in a year and a half, less than half the time it takes a macaque. Some research facilities in China are now building marmoset research colonies — but Japan is considered to be several years ahead. And some researchers want to ensure that such work continues outside Asia. Courtine says that he's “fighting to keep alive” a monkey-research programme he has at Fribourg, Switzerland, because he thinks it's important to have a division of labour. “Research that requires quantity, I'll do in China. I would like to do sophisticated work in Fribourg,” he says. Back at his primate centre in Yunnan, Ji is sure that such work is already taking place. His dream, he says is “to have an animal like a tool” for biomedical discovery. He knows there is a lot of competition in this field, especially in China. But he feels confident: “The field is wide, and there are many, many projects we can do.”

Discover hidden collaborations