Posts tagged science
Articles and news from the latest research reports.
Brain Cancer: Hunger for Amino Acids Makes It More Aggressive
An enzyme that facilitates the breakdown of specific amino acids makes brain cancers particularly aggressive. Scientists from the German Cancer Research Center (DKFZ) discovered this in an attempt to find new targets for therapies against this dangerous disease. They have reported their findings in the journal “Nature Medicine”.
To fuel phases of fast and aggressive growth, tumors need higher-than-normal amounts of energy and the molecular building blocks needed to build new cellular components. Cancer cells therefore consume a lot of sugar (glucose A number of tumors are also able to catabolize the amino acid glutamine, an important building block of proteins. A key enzyme in amino acid decomposition is isocitrate dehydrogenase (IDH). Several years ago, scientists discovered mutations in the gene coding for IDH in numerous types of brain cancer. Very malignant brain tumors called primary glioblastomas carry an intact IDH gene, whereas those that grow more slowly usually have a defective form.
“The study of the IDH gene currently is one of the most important diagnostic criteria for differentiating glioblastomas from other brain cancers that grow more slowly,” says Dr. Bernhard Radlwimmer from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ). “We wanted to find out what spurs the aggressive growth of glioblastomas.” In collaboration with scientists from other institutes including Heidelberg University Hospital, Dr. Martje Tönjes and Dr. Sebastian Barbus from Radlwimmer’s team compared gene activity profiles from several hundred brain tumors. They aimed to find out whether either altered or intact IDH show further, specific genetic characteristics that might help explain the aggressiveness of the disease.
The researchers found a significant difference between the two groups in the highly increased activity of the gene for the BCAT1 enzyme, which in normal brain tissue is responsible for breaking down so-called branched-chain amino acids. However, Radlwimmer’s team discovered, only those tumor cells whose IDH gene is not mutated produce BCAT1. “This is not surprising, because as IDH breaks down amino acids, it produces ketoglutarate – a molecule which BCAT1 needs. This explains why BCAT1 is produced only in tumor cells carrying intact IDH. The two enzymes seem to form a kind of functional unit in amino acid catabolism,” says Bernhard Radlwimmer.
Glioblastomas are particularly dreaded because they aggressively invade the healthy brain tissue that surrounds them. When the researchers used a pharmacological substance to block BCAT1’s effects, the tumor cells lost their invasive capacity. In addition, the cells released less of the glutamate neurotransmitter. High glutamate release is responsible for severe neurological symptoms such as epileptic seizures, which are frequently associated with the disease. When transferred to mice, glioblastoma cells in which the BCAT1 gene had been blocked no longer grew into tumors.
“Altogether, we can see that overexpression of BCAT1 contributes to the aggressiveness of glioblastoma cells,” Radlwimmer says. The study suggests that the two enzymes, BCAT1 and IDH, cooperate in the decomposition of branched-chain amino acids. These protein building blocks appear to act as a “food source” that increases the cancer cells’ aggressiveness. Branched-chain amino acids also play a significant role in metabolic diseases such as diabetes. This is the first time that scientists have been able to show the role of these amino acids in the growth of malignant tumors.
“The good news,” sums up Radlwimmer, “is that we have found another target for therapies in BCAT1. In collaboration with Bayer Healthcare, we have already started searching for agents that might be specifically directed against this enzyme.” The researchers also plan to investigate whether BCAT1 expression may serve as an additional marker to diagnose the malignancy of brain cancer.
Genes Involved in Birth Defects May Also Lead to Mental Illness
Gene mutations that lead to major birth defects may also cause subtle disruptions in the brain that contribute to psychiatric disorders such as schizophrenia, autism, and bipolar disorder, according to new research by UC San Francisco scientists.
Over the past several years, researchers in the laboratory of psychiatrist Benjamin Cheyette, MD, PhD, have shown that mutations in a gene called Dact1 cause cell signaling networks to go awry during embryonic development. Researchers observed that mice with Dact1 mutations were born with a range of severe malformations, including some reminiscent of spina bifida in humans.
This new study was designed to explore whether Dact1 mutations exert more nuanced effects in the brain that may lead to mental illness. In doing so, Cheyette, John Rubenstein, MD, PhD, and colleagues in UCSF’s Nina Ireland Laboratory of Developmental Neurobiology used a genetic technique in adult mice to selectively delete the Dact1 protein only in interneurons, a group of brain cells that regulates activity in the cerebral cortex, including cognitive and sensory processes. Poor function of interneurons has been implicated in a range of psychiatric conditions.
As reported in the June 24 online issue of PLOS ONE, researchers found that the genetically altered interneurons appeared relatively normal and had managed to find their proper position in the brain’s circuitry during development. But the cells had significantly fewer synapses, the sites where communication with neighboring neurons takes place. In additional observations not included in the new paper, the team also noted that the cells’ dendrites – fine extensions that normally form bushy arbors studded with synapses – were poorly developed and sparsely branched.
“When you delete this gene function after initial, early development – just eliminating it in neurons after they’ve formed – they migrate to the right place and their numbers are correct, but their morphology is a little off,” Cheyette said. “And that’s very much in line with the kinds of pathology that people have been able to identify in psychiatric illness.
"Neurological illnesses tend to be focal, with lesions that you can identify or pathology you can see on an imaging study," Cheyette explained. "Psychiatric illnesses? Not so much. The differences are really subtle and hard to see.”
Key Gene’s Role in Development of Human Nervous System
The Dact1 protein is part of a fundamental biological system known as the Wnt (pronounced “wint”) signaling pathway. Interactions among proteins in the Wnt pathway orchestrate many processes essential to life in animals as diverse as fruit flies, mice and humans, including the proper development of the immensely complex human nervous system from a single fertilized egg cell.
One way the Wnt pathway manages this task is by maintaining the “polarity” of cells during development, said Cheyette, “a process of sequestering, increasing the concentration of one set of proteins on one side of the cell and a different set of proteins on the other side of the cell.” Polarity is particularly important as precursor cells transform into nerve cells, Cheyette said, because neurons are “the most polarized cells in the body,” with specialized input and output zones that must wind up in the proper spots if the cells are to function normally.
Cheyette said his group is now conducting behavioral experiments with the mice analyzed in the new PLOS ONE paper and with genetically related mouse lines to test whether these mice have behavioral abnormalities in sociability, sensory perception, anxiety or motivation that resemble symptoms in major psychiatric disorders.
He also hopes to collaborate with UCSF colleagues on follow-up experiments to determine whether the activity of neurons lacking Dact1 is impaired in addition to the structural flaws identified in the new study and prior published work from his lab.
Meanwhile, as-yet-unpublished findings from human genetics research conducted by Cheyette’s group suggest that individuals with autism are significantly more likely than healthy comparison subjects to carry mutations in a Wnt pathway gene called WNT1.
“Just because a gene plays an important role in the embryo doesn’t mean it isn’t also important in the brain later, and might be involved in psychiatric pathology,” said Cheyette. “When these genes are mutated, someone may look fine, develop fine and have no obvious medical problems at birth, but they may also develop autism in childhood or have a psychotic break in adulthood and develop schizophrenia.”
'Out-of-body' virtual experience could help social anxiety
New virtual imaging technology could be used as part of therapy to help people get over social anxiety according to new research from the University of East Anglia (UEA).
Research published today investigated for the first time whether people with social anxiety could benefit from seeing themselves interacting in social situations via video capture.
The experiment gave participants the chance to experience social interaction in the safety of a virtual environment by seeing their own life-size image projected into specially scripted real-time video scenes.
UEA researchers, led by Dr Lina Gega from UEA’s Norwich Medical School and MHCO’s Northumberland Talking Therapies, worked with Xenodu Virtual Environments to create more than 100 different social scenarios – such as using public transport, buying a drink at a bar, socialising at a party, shopping, and talking to a stranger in an art gallery.
The researchers tested whether this sort of experience could become a valuable part of Cognitive Behavioural Therapy (CBT) by including an hour-long session midway through a 12-week CBT course.
Dr Gega said: “People with social anxiety are afraid that they will draw attention to themselves and be negatively judged by others in social situations. Many will either avoid public places and social gatherings altogether, or use safety behaviours to cope – such as not making eye contact and being guarded or hyper-vigilant towards others.
“Paradoxically, this sort of behaviour draws attention to people with social anxiety and feeds into their beliefs that they don’t fit in.
“We wanted to see whether practising social situations in a virtual environment could help.”
Paul Strickland from Xenodu, the company behind the virtual environment system, said: “Our system uses video capture to project a user’s life-size image on screen so that they can watch themselves interacting with custom-scripted and digitally edited video clips.
“It isn’t a head-mounted display – which anxious people may find uncomfortable,” he added. “Instead, the user observes from an out-of-body perspective. They can then simultaneously view themselves and interact with the characters of the film.”
Dr Gega’s project focused on six socially anxious young men recovering from psychosis who also have debilitating social anxiety. The participants engaged with a range of scenarios, some of which were designed to feature rude and hostile people. The virtual environments encouraged participants to practice small-talk, maintain eye contact, test beliefs that they wouldn’t know what to say, and resist safety behaviour such as looking at the floor or being hyper-vigilant.
The main benefits of using these virtual environments in therapy was that it helped participants notice and change anxious behaviours in a safe, controlled environment which could be rehearsed over and over again. Participants were found to drop safety behaviours and take greater social risks. And while realistic to an extent, the ‘fake’ feeling of staged scenarios in itself proved to be a virtue.
“It helped the participants question their interpretation of social cues,” said Dr Gega. “For example, if they thought that one of the characters was looking at them ‘funny’ they could immediately see that there must be an alternative explanation because the scenarios were artificial.
“Another useful aspect of the system is that it can be tailored to address specific fears in social situations - for example a fear of performance, intimacy, or crowds,” she added.
“Two of the patients said that the system felt “weird and surreal”, so the element of having an out-of-body experience is something to study further in future – particularly because psychosis itself is defined by a distorted perception of reality.
“This research explored the feasibility and potential added value of using virtual environments as part of CBT. The next stage would be to carry out a randomised, controlled comparison of CBT with and without the virtual environment system to test whether using the system as a therapy tool leads to greater or quicker symptom improvement.”
Mr Strickland added: “I hope our technology can help make a difference to the lives of people experiencing social anxiety and other specific anxiety conditions for which controlled exposure to feared situations is part of therapy. It is particularly versatile because it doesn’t need technical expertise to set up and use. And the library of scenarios can be built on to capture different types of exposure environments needed in day-to-day clinical practice.”
‘Virtual Environments Using Video Capture for Social Phobia with Psychosis’ is published by the journal Cyberpsychology, Behaviour and Social Networking.
Pleasure Response from Chocolate: You Can See it in the Eyes
The brain’s pleasure response to tasting food can be measured through the eyes using a common, low-cost ophthalmological tool, according to a study just published in the journal Obesity. If validated, this method could be useful for research and clinical applications in food addiction and obesity prevention.
Dr. Jennifer Nasser, an associate professor in the department of Nutrition Sciences in Drexel University’s College of Nursing and Health Professions, led the study testing the use of electroretinography (ERG) to indicate increases in the neurotransmitter dopamine in the retina.
Dopamine is associated with a variety of pleasure-related effects in the brain, including the expectation of reward. In the eye’s retina, dopamine is released when the optical nerve activates in response to light exposure.
Nasser and her colleagues found that electrical signals in the retina spiked high in response to a flash of light when a food stimulus (a small piece of chocolate brownie) was placed in participants’ mouths. The increase was as great as that seen when participants had received the stimulant drug methylphenidate to induce a strong dopamine response. These responses in the presence of food and drug stimuli were each significantly greater than the response to light when participants ingested a control substance, water.
“What makes this so exciting is that the eye’s dopamine system was considered separate from the rest of the brain’s dopamine system,” Nasser said. “So most people– and indeed many retinography experts told me this– would say that tasting a food that stimulates the brain’s dopamine system wouldn’t have an effect on the eye’s dopamine system.”
This study was a small-scale demonstration of the concept, with only nine participants. Most participants were overweight but none had eating disorders. All fasted for four hours before testing with the food stimulus.
If this technique is validated through additional and larger studies, Nasser said she and other researchers can use ERG for studies of food addiction and food science.
“My research takes a pharmacology approach to the brain’s response to food,” Nasser said. “Food is both a nutrient delivery system and a pleasure delivery system, and a ‘side effect’ is excess calories. I want to maximize the pleasure and nutritional value of food but minimize the side effects. We need more user-friendly tools to do that.”
The low cost and ease of performing electroretinography make it an appealing method, according to Nasser. The Medicare reimbursement cost for clinical use of ERG is about $150 per session, and each session generates 200 scans in just two minutes. Procedures to measure dopamine responses directly from the brain are more expensive and invasive. For example, PET scanning costs about $2,000 per session and takes more than an hour to generate a scan.
(Image: Scott Thornburg)
New research points to potential treatment strategies for multiple sclerosis
Myelin, the fatty coating that protects neurons in the brain and spinal cord, is destroyed in diseases such as multiple sclerosis. Researchers have been striving to determine whether oligodendrocytes, the cells that produce myelin, can be stimulated to make new myelin. Using live imaging in zebrafish to track oligodendrocytes in real time, researchers reporting in the June 24 issue of the Cell Press journal Developmental Cell discovered that individual oligodendrocytes coat neurons with myelin for only five hours after they are born. If the findings hold true in humans, they could lead to new treatment strategies for multiple sclerosis.
"The study could help improve our understanding of the triggers needed to encourage cells to produce myelin," says senior author Dr. David Lyons, of the University of Edinburgh, UK. For example, if scientists could determine what is blocking the cells from making myelin after five hours, they might be able to remove that blockage. Alternatively, treatments could focus on creating more new oligodendrocytes rather than trying to stimulate existing oligodendrocytes.
Dr. Lyons and his team used zebrafish to study the formation of myelin sheaths by oligodendrocytes because this laboratory animal is transparent at early stages of its development, which allows investigators to directly observe cells within the organism. It is also known that zebrafish and humans have very similar genes, and these similarities extend to more than 80% of the genes associated with human disease. Zebrafish therefore respond in very similar ways to most drugs used for therapeutic purposes in humans.
"In the future, zebrafish will be used to identify new genes and drugs that can influence myelin formation and myelin repair," says Dr. Lyons.
(Source: eurekalert.org)
Absence of Gene Leads to Earlier, More Severe Case of Multiple Sclerosis
A UC San Francisco-led research team has identified the likely genetic mechanism that causes some patients with multiple sclerosis (MS) to progress more quickly than others to a debilitating stage of the disease. This finding could lead to the development of a test to help physicians tailor treatments for MS patients.
Researchers found that the absence of the gene Tob1 in CD4+ T cells, a type of immune cell, was the key to early onset of more serious disease in an animal model of MS.
Senior author Sergio Baranzini, PhD, a UCSF associate professor of neurology, said the potential development of a test for the gene could predict the course of MS in individual patients.
The study, done in collaboration with UCSF neurology researchers Scott Zamvil, MD, and Jorge Oksenberg, PhD, was published on June 24 in the Journal of Experimental Medicine.
MS is an inflammatory disease in which the protective myelin sheathing that coats nerve fibers in the brain and spinal cord is damaged and ultimately stripped away – a process known as demyelination. During the highly variable course of the disease, a wide range of cognitive, debilitating and painful neurological symptoms can result.
In previously published work, Baranzini and his research team found that patients at an early stage of MS, known as clinically isolated syndrome, who expressed low amounts of Tob1 were more likely to exhibit further signs of disease activity – a condition known as relapsing-remitting multiple sclerosis – earlier than those who expressed normal levels of the gene.
The current study, according to Baranzini, had two goals: to recapitulate in an animal model what the researchers had observed in humans, and uncover the potential mechanism by which it occurs.
The authors were successful on both counts. They found that when an MS-like disease was induced in mice genetically engineered to be deficient in Tob1, the mice had significantly earlier onset compared with wild-type mice, and developed a more aggressive form of the disease.
Subsequent experiments revealed the probable cause: the absence of Tob1 in just CD4+ T cells. The scientists demonstrated this by transferring T cells lacking the Tob1 gene into mice that had no immune systems but had normal Tob1 in all other cells. They found that the mice developed earlier and more severe disease than mice that had normal Tob1 expression in all cells including CD4+.
“This shows that Tob1 only needs to be absent in this one type of immune cell in order to reproduce our initial observations in mice lacking Tob1 in all of their cells,” said Baranzini.
Personalized Treatments for MS Patients
The researchers also found the likely mechanism of disease progression in the Tob1-deficient mice: higher levels of Th1 and Th17 cells, which cause an inflammatory response against myelin, and lower levels of Treg cells, which normally regulate inflammatory responses. The inflammation results in demyelination.
The research is significant for humans, said Baranzini, because the presence or absence of Tob1 in CD4+ cells could eventually serve as a prognostic biomarker that could help clinicians predict the course and severity of MS in individual patients. “This would be useful and important,” he said, “because physicians could decide to switch or modify therapies if they know whether the patient is likely to have an aggressive course of disease, or a more benign course.”
Ultimately, predicted Baranzini, “This may become an example of personalized medicine. When the patient comes to the clinic, we will be able to tailor the therapy based on what the tests tell us. We’re now laying the groundwork for this to happen.”
(Source: ucsf.edu)
NMR advance brings proteins into the open
A key protein interaction, common across all forms of life, had eluded scientists’ observation until a team of researchers cracked the case by combining data from four different techniques of nuclear magnetic resonance spectroscopy.
When working a cold case, smart investigators try something new. By taking a novel approach to nuclear magnetic resonance spectroscopy — a blending of four techniques — scientists have been able to resolve a key interaction between two proteins that could never be observed before. They report on their findings the week of June 24, 2013, in Proceedings of the National Academy of Sciences (PNAS).
The interaction, which the team first described, is nearly universal across all of life. A protein machine called a chaperone takes hold of a disordered smaller protein to help it find its proper folded conformation. In this case, the team set up test-tube experiments where they hoped to watch the capsule-shaped bacterial chaperone GroEL capture a disordered amyloid β (Aβ) protein, a molecule that in humans is central in Alzheimer’s disease.
The two proteins are well studied, but the motions they go through when they first meet — when the open GroEL capsule captures its target — have been invisible to scientists. Electron microscopy and X-ray crystallography are only good for taking snapshots of easily frozen moments in time. NMR is capable of sensing the interactions and kinetics of protein handshakes as they occur, but in some cases any single technique can provide only hints and whispers of what’s going on.
Brown University biologist Nicolas Fawzi, who was a postdoctoral researcher in the group of Marius Clore at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) within the National Institutes of Health (NIH), worked with co-authors and NIDDK researchers David Libich, Jinfa Yang and Marius Clore to piece together the story of the proteins by combining four different NMR techniques. They figured out what each one could tell them about the interaction and built the case presented in PNAS.
“None of the four techniques alone gave us sufficient information,” said Fawzi, assistant professor of medical science in Brown’s Department of Molecular Pharmacology, Physiology, and Biotechnology. “Only by using them all together would we be able to figure out the structure and motions of Aβ when it was bound to GroEL. By having four indirect measurements together, that was able to give us a complete picture.”
The researchers acted like a team of detectives working on a case in which no single witness saw everything. Instead they found three witnesses, each with something different to contribute, and then one more that could corroborate some of what the others revealed and rule out other possibilities. The NMR techniques they used were lifetime line broadening, Carr-Purcell-Meinboom-Gill (CPMG) relaxation dispersion spectroscopy, and exchange-induced chemical shifts.
“The fourth technique we employed was Dark-state Exchange Saturation Transfer (DEST) spectroscopy, which we had developed in my lab at the NIH in 2011,” said Clore, also the paper’s corresponding author. “We were able to more effectively conduct our research by using that tool to corroborate and extend the information afforded by the other three measurements.”
Bouncing with the chaperone
The mystery debated among molecular biologists was what the GroEL chaperone requires of its captives at the moment they engage. Does it force them into a particular conformation? Does it hold on tightly while it closes its capsule lid around the smaller protein, or does the captive stay in motion at all?
What the team observed is that the GroEL is a permissive captor. It bound Aβ at just two “hydrophobic” sites, leaving the smaller protein to otherwise dangle in a variety of conformations. It also didn’t keep it bound the entire time, letting it instead detach and re-bind. Essentially Aβ would bounce off and on within GroEL’s binding cavity.
“By using these four techniques together we were able to extract information about the structure of the protein while it binds as well as how fast it comes on and off and what it’s doing at each position,” Fawzi said. “Instead of forming more particular structure upon binding it appears to retain great conformational heterogeneity.”
The lifetime line broadening technique, for example, told them that the Aβ was interacting with something big (GroEL), while the CPMG and chemical shift observations combined to show the length of time Aβ spent on GroEL before unbinding, as well as the structural details of Aβ when it was bound to GroEL. DEST provided information that could confirm much of the story of the other techniques.
Fawzi said GroEL’s laid-back approach could be a matter of being able to bind many different proteins in disordered conformations, but also of saving energy. Forcing proteins into a specific conformation just to make and sustain the initial capture would require more energy than it’s worth.
Eventually, in moments after those the team resolved in this study, GroEL closes its lid and encapsulates its target proteins fully, Fawzi said. That’s when it invests in forcing them to fold the right way.
For molecular and structural biologists, the newly proven blend of NMR techniques could open a number of other cold cases of elusive interactions.
“We can now look at how these big machines can do their job while they are working,” Fawzi said. “This is not just limited to this GroEL machine.”
Defects in brain cell migration linked to mental retardation
A rare, inherited form of mental retardation has led scientists at Washington University School of Medicine in St. Louis to three important “travel agents” at work in the developing brain.
The agents — two individual proteins and a tightly bound cluster of four additional proteins — make it possible for brain neurons to travel from the area where they are born to other brain regions where they will reside permanently and integrate into neuronal circuits. Inhibiting any of these proteins in embryonic mice reduces the ability of neurons, which process and transmit information, to reach their final destinations and, presumably, to hardwire the brain.
“That kind of misplacement of brain cells is likely to seriously disrupt mental functions,” said Azad Bonni, MD, PhD, the Edison Professor and chairman of the Department of Anatomy and Neurobiology. “This is just one of many ways that brain development can go awry. To understand intellectual disability and develop treatments, we need to understand the many problems that can arise as the brain develops and its circuitry is established.”
The results appeared June 19 in Neuron.
The new work began as an inquiry into PHF6, a gene that is mutated in patients with Börjeson-Forssman-Lehmann syndrome. This disorder causes mental retardation, developmental delays and skeletal abnormalities. More than a decade ago, scientists identified a link between the condition and PHF6, but they did not know what the gene did in the brain.
Bonni’s laboratory added green fluorescent protein to brain cells to track their development and movement in embryonic mice. Then the researchers inhibited PHF6 in some mice.
In normal mice, as expected, brain neurons migrated from the ventricular zone, where they were born, to the cortical plate, the precursor site of the cerebral cortex. In the mature brain, the cerebral cortex is responsible for higher brain functions such as processing of sensory data, attention and decision-making. In mice whose brain cells lacked PHF6, many brain cells either stayed in the ventricular zone or only completed part of their journey.
In a series of additional experiments, Bonni’s research group showed that the PHF6 protein operates in the nucleus of brain neurons, the command center of the cell. The scientists found that the PHF6 protein interacts with the PAF1 complex, a tightly bound cluster of four proteins that regulates programs of gene expression. This cluster then turns on a cell surface protein called neuroglycan C in brain neurons.
If any of these factors were inhibited, mouse brain neurons were unable to complete their normal migration. The researchers could “rescue” the neurons by restoring the missing protein, allowing the cells to complete their journey.
Disrupting proper brain structure and organization may not be the only problem caused by the PHF6 mutation. A portion of patients with Börjeson-Forssman-Lehmann syndrome also have epilepsy.
In tests in mice, Bonni’s group found that the misplaced brain neurons were more excitable. This might result from changes in the activity of other proteins regulated by PHF6 and could make the brain more susceptible to seizures.
The researchers also learned that increasing the production of neuroglycan C in brain neurons overcomes the harmful effects of PHF6 loss on the migration of neurons.
“Cell surface proteins such as neuroglycan C are in good position to help cells move through their environment,” Bonni said. “The protein’s position on the cell surface of neurons also one day might make it an accessible target for drug treatments for developmental cognitive disorders.”
Bonni suspects there might be additional problems in brain cells that develop without normal PHF6 and that errors in the gene might even impair function in neurons that make it to their final destinations. Further studies are underway.
(Source: genetics.wustl.edu)
Dream of regenerating human body parts gets a little closer
Damage to vital organs, the spinal cord, or limbs can have an enormous impact on our ability to move, function – and even live. But imagine if you could restore these tissues back to their original condition and go on with life as normal.
Well, this is the dream for regenerative medicine. And while humans missed out on these abilities in the evolutionary lottery, a recent study in mice shows we’re making small progress to achieving this dream.
Learning from animals
Nature has provided the animal kingdom with many different ways to achieve perfect regeneration. Some amphibians – such as salamanders – are famous for their superhero-like ability to regenerate heart, brain, spinal cord, tail and can even whole limb tissue throughout their life.
Although organ and spinal cord regeneration are clinically important and worthy of intense research investment, regrowing whole limbs provides a flagship example of perfect regeneration in the salamander.
It has been known for more than a hundred years that if a salamander loses a limb, it grows right back. This process is extremely precise and removal of the limb at the shoulder regrows a full limb, but removal at the wrist only regrows the missing hand portion.
Interestingly, there does not seem to be a limit on how many times they can perform this clever trick and each time the limb comes back perfect.
But mammals (including humans and mice) seem to have missed out on this important skill. The question of how to enhance the regenerative capabilities in humans, either by adding the missing ingredients, or activating these latent abilities currently lies wide open.
Extending regeneration to mammals
Mammals currently only have the capacity to regenerate the very tip of their finger. But the result is far from perfect. A range of studies in mice have shown the digit-tip regrowth is severely restricted. Removal of the very tip of the mouse digit will be replaced, but removal of the tissue a small distance further up the digit and closer to nail bed (the equivalent to a human cuticle), will fail to regrow.
Last week, a group of researchers from the United States and Japan published work extending our understanding of the mechanism by which a resident stem cell population within the mouse digit tip nail bed can be activated to induce digit tip regeneration. In other words, we can now grow more of the digit back in mice and possibly more of the human finger.
Resident stem cells are specialised cells found at various locations within the body. When activated, these cells multiply and then transform into other cell types required to replace worn out cells under conditions of normal tissue maintenance.
This work builds on previous studies identifying the stem cell population in the nail bed by unveiling a signalling mechanism that could be exploited to enhance the amount of tissue that could be regrown. The potential for repair after injury appears very limited in many tissues and organs. Understanding how to enhance stem cell activation in these tissues may stimulate repair not previously thought possible.
The ability to switch on and mobilise resident stem cells in regeneration will be important in a wide range of new therapies, particularity for organs affected by injury or disease. On a world stage, momentum is currently growing for these types of strategies. It is clear that once refined, these approaches are sure to have a profound influence on many different aspects of clinical medicine, opening up the possibility of replacing diseased or injured tissues.
We may be some way off from the dream of replacing whole limbs in humans but recent progress confirms that by deepening our understanding of stem cell activation, we can directly unlock more regeneration in mammals than normally possible.
Sugar solution makes tissues see-through
Japanese researchers have developed a new sugar and water-based solution that turns tissues transparent in just three days, without disrupting the shape and chemical nature of the samples. Combined with fluorescence microscopy, this technique enabled them to obtain detailed images of a mouse brain at an unprecedented resolution.
The team from the RIKEN Center for Developmental biology reports their finding today in Nature Neuroscience.
Over the past few years, teams in the USA and Japan have reported a number of techniques to make biological samples transparent, that have enabled researchers to look deep down into biological structures like the brain.
“However, these clearing techniques have limitations because they induce chemical and morphological damage to the sample and require time-consuming procedures,” explains Dr. Takeshi Imai, who led the study.
SeeDB, an aqueous fructose solution that Dr. Imai developed with colleagues Drs. Meng-Tsen Ke and Satoshi Fujimoto, overcomes these limitations.
Using SeeDB, the researchers were able to make mouse embryos and brains transparent in just three days, without damaging the fine structures of the samples, or the fluorescent dyes they had injected in them.
They could then visualize the neuronal circuitry inside a mouse brain, at the whole-brain scale, under a customized fluorescence microscope without making mechanical sections through the brain.
They describe the detailed wiring patterns of commissural fibers connecting the right and left hemispheres of the cerebral cortex, in three dimensions, for the first time. They also report that they were able to visualize in three dimensions the wiring of mitral cells in the olfactory bulb, which is involved the detection of smells, at single-fiber resolution.
“Because SeeDB is inexpensive, quick, easy and safe to use, and requires no special equipment, it will prove useful for a broad range of studies, including the study of neuronal circuits in human samples,” explain the authors.