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Crionica, inmortalidad y transhumanismo
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Researchers Repair Brain Damage in Mice With Stem Cell Transplants
The human brain is a biological wonder with considerable skills. Regeneration, unfortunately, isn’t one of them.
Save for one tiny V-shaped region within the hippocampus, the human brain’s ability to rebuild itself is nearly nonexistent. When neurons die, there’s no backup reserve of cells to replace them. Brain trauma — a blow to the head, a stroke, or neurodegeneration — can be brutally final. You’re not getting lost neurons back.
An obvious solution is to supply a broken brain with additional neurons, like swapping a broken stick of RAM with a new one. But a single neuron forms thousands of intricate connections to others near and far, and often these connections are established early in development.
Can a foreign transplant really assimilate into mature neuronal networks after injury and automatically repair broken circuitry? According to a new study recently published in Nature, the answer is a promising yes.
In mice with brain lesions, a German team showed that within two months of transplantation, foreign embryonic neurons matured and fully incorporated into an existing network within the hosts’ visual brain region.
Amazingly, the adoptee neurons were nearly indistinguishable from the brain’s native ones — they carried the right information, established functional input and output circuitries, and performed the functions of the damaged neurons.
“To date, this is the most comprehensive study of the circuit integration of transplanted neurons into the adult brain, and the only study so far to follow the integration of individual cells throughout their life span in the new host,” says study author Susanna Falkner, a PhD student at the Max Planck Institute of Neurobiology to Singularity Hub.
It’s a tour de force demonstration of brain plasticity that gives hope to cell transplantation therapies for devastating brain disorders like traumatic brain injury, Parkinson’s and Alzheimer’s disease.
Plug in, wire up
Cell transplantation studies are nothing new, but almost all previous studies used infant animals rather than adults as hosts.
“Early postnatal brains are still developing and thus are much more plastic and receptive for grafts,” explains Falkner.
Although a handful of attempts at grafting stem cells into adult mice brains have been published, so far no one has convincingly demonstrated that the grafts could mature and function in a foreign brain.
To start off, the team used a powerful laser to precisely damage a small bit of brain tissue within a mouse’s visual cortex.
The scientists picked the brain region with care. “We know so much about the functions of the nerve cells in this region and the connections between them that we can readily assess whether the implanted nerve cells actually perform the tasks normally carried out by the network, ” explains study author Dr. Mark Hübener.
They then isolated immature neurons from the outermost layer of mice embryos and labeled them with a fluorescent protein tag. Under the microscope, these tags light up in brilliant reds and greens, which makes the transplanted cells easily distinguishable from the host’s native neurons. Using a long, thin needle, the embryonic neurons were then injected straight into the damaged mouse cortex.
The team next carefully crafted a “cranial window” by removing parts of the skull above the injection site and fitting it with a clear glass panel. This way, scientists were able to observe individual neurons for long periods of time through the window without harming the delicate cortex or risking infection.
Over the course of just a month, the transplanted neurons sprouted long, tortuous branches characteristic of cortical neurons. Tiny mushroom-shaped structures called spines popped up on the neurons’ output wires (dendrites), a process often seen in normal brain development. Since synapses grow on these bulbous spines, this suggested that the transplants were actively forming connections with other neurons in the brain.
And they sure did.
Neuronal transplants (blue) connect with host neurons (yellow) in the adult mouse brain in a highly specific manner, rebuilding neural networks lost upon injury. Image credit: Sofia Grade (LMU/Helmholtz Zentrum München)
One month after transplantation, the team mapped the newly added neurons’ connectome — what brain regions they projected to and which regions they received information from. Not only was the wiring exquisitely accurate, with some extending across the entire brain, the strengths of those connections were also similar to those formed by the laser-ablated neurons.
“The very fact that the cells survived and continued to develop was very encouraging,” says Hübener. “But things got really exciting when we took a closer look at the electrical activity of the transplanted cells.”
Neurons from a part of the visual cortex called V1 are very picky about what sorts of stimuli they respond to. For example, a neuron may only fire when it detects black-and-white lines presented at a 45-degree angle, but not at any other angles. This is called tuning, which develops early in life. Promiscuous V1 neurons are bad news — without selective activation, they pump noise into the circuit.
By 15 weeks after transplantation, the new neurons adopted the functional quirks of V1 neurons, consistently responding more strongly towards certain line orientations than others. They remained fully functional for the entire year-long duration of the study.
“These findings demonstrate that the implanted nerve cells have integrated with high precision into a neuronal network into which, under normal conditions, new nerve cells would never have been incorporated,” explains lead author Dr. Magdalena Götz at the Ludwig-Maximilians University in Munich, Germany.
Cell replacement therapy
So what does this mean for repairing a degenerating human brain?
“This proof-of-principle study shows that…the lesioned adult brain is still capable of integrating new building blocks,” says Falkner. “Neuronal replacement therapies may be realistic, at least at times when a sufficient part of the pre-existing neuronal network is still available.”
Cell replacement therapy has been tried in Parkinson’s disease for at least two decades, but with mixed results. Impure sources of donor cells, pre-implant processing, suboptimal grafting procedures and side effects could all contribute, explains Falker.
Then there’s the issue that real-world brain injuries aren’t so sterile and precise. A whack to the head, for example, can trigger inflammatory and other signals that turn the brain into a hostile environment unreceptive to neuron implants.
But the team is hopeful that their regime can help in those situations as well.
“We are doing this now in more realistic models, in models of traumatic and ischemic brain injury and all I can say is that it looks pretty good,” says Götz.
Supply is also a problem — isolating neurons from aborted fetuses isn’t a practical solution — but recent advances in cell reprogramming could be a readily available answer.
Scientists can already directly turn skin cells into neurons, for example. Other groups have also shown that glia cells — the other major cell type in the brain — can shed their identity and transform into neurons under the right conditions. Then there are iPSCs, in which a patient’s skin cell is deprogrammed into stem cells and further developed into neurons.
It’s becoming more possible to get defined mixtures of cells to match the afflicted cell type in the diseased brain, says Falkner.
“Once neurons die, there is, at the moment, no real therapy to make these neurons come back. Surely, at some point in the future, these approaches will be used in the clinic,” says Götz.
Researchers Repair Brain Damage in Mice With Stem Cell Transplants
The human brain is a biological wonder with considerable skills. Regeneration, unfortunately, isn’t one of them.
Save for one tiny V-shaped region within the hippocampus, the human brain’s ability to rebuild itself is nearly nonexistent. When neurons die, there’s no backup reserve of cells to replace them. Brain trauma — a blow to the head, a stroke, or neurodegeneration — can be brutally final. You’re not getting lost neurons back.
An obvious solution is to supply a broken brain with additional neurons, like swapping a broken stick of RAM with a new one. But a single neuron forms thousands of intricate connections to others near and far, and often these connections are established early in development.
Can a foreign transplant really assimilate into mature neuronal networks after injury and automatically repair broken circuitry? According to a new study recently published in Nature, the answer is a promising yes.
In mice with brain lesions, a German team showed that within two months of transplantation, foreign embryonic neurons matured and fully incorporated into an existing network within the hosts’ visual brain region.
Amazingly, the adoptee neurons were nearly indistinguishable from the brain’s native ones — they carried the right information, established functional input and output circuitries, and performed the functions of the damaged neurons.
“To date, this is the most comprehensive study of the circuit integration of transplanted neurons into the adult brain, and the only study so far to follow the integration of individual cells throughout their life span in the new host,” says study author Susanna Falkner, a PhD student at the Max Planck Institute of Neurobiology to Singularity Hub.
It’s a tour de force demonstration of brain plasticity that gives hope to cell transplantation therapies for devastating brain disorders like traumatic brain injury, Parkinson’s and Alzheimer’s disease.
Plug in, wire up
Cell transplantation studies are nothing new, but almost all previous studies used infant animals rather than adults as hosts.
“Early postnatal brains are still developing and thus are much more plastic and receptive for grafts,” explains Falkner.
Although a handful of attempts at grafting stem cells into adult mice brains have been published, so far no one has convincingly demonstrated that the grafts could mature and function in a foreign brain.
To start off, the team used a powerful laser to precisely damage a small bit of brain tissue within a mouse’s visual cortex.
The scientists picked the brain region with care. “We know so much about the functions of the nerve cells in this region and the connections between them that we can readily assess whether the implanted nerve cells actually perform the tasks normally carried out by the network, ” explains study author Dr. Mark Hübener.
They then isolated immature neurons from the outermost layer of mice embryos and labeled them with a fluorescent protein tag. Under the microscope, these tags light up in brilliant reds and greens, which makes the transplanted cells easily distinguishable from the host’s native neurons. Using a long, thin needle, the embryonic neurons were then injected straight into the damaged mouse cortex.
The team next carefully crafted a “cranial window” by removing parts of the skull above the injection site and fitting it with a clear glass panel. This way, scientists were able to observe individual neurons for long periods of time through the window without harming the delicate cortex or risking infection.
Over the course of just a month, the transplanted neurons sprouted long, tortuous branches characteristic of cortical neurons. Tiny mushroom-shaped structures called spines popped up on the neurons’ output wires (dendrites), a process often seen in normal brain development. Since synapses grow on these bulbous spines, this suggested that the transplants were actively forming connections with other neurons in the brain.
And they sure did.
Neuronal transplants (blue) connect with host neurons (yellow) in the adult mouse brain in a highly specific manner, rebuilding neural networks lost upon injury. Image credit: Sofia Grade (LMU/Helmholtz Zentrum München)
One month after transplantation, the team mapped the newly added neurons’ connectome — what brain regions they projected to and which regions they received information from. Not only was the wiring exquisitely accurate, with some extending across the entire brain, the strengths of those connections were also similar to those formed by the laser-ablated neurons.
“The very fact that the cells survived and continued to develop was very encouraging,” says Hübener. “But things got really exciting when we took a closer look at the electrical activity of the transplanted cells.”
Neurons from a part of the visual cortex called V1 are very picky about what sorts of stimuli they respond to. For example, a neuron may only fire when it detects black-and-white lines presented at a 45-degree angle, but not at any other angles. This is called tuning, which develops early in life. Promiscuous V1 neurons are bad news — without selective activation, they pump noise into the circuit.
By 15 weeks after transplantation, the new neurons adopted the functional quirks of V1 neurons, consistently responding more strongly towards certain line orientations than others. They remained fully functional for the entire year-long duration of the study.
“These findings demonstrate that the implanted nerve cells have integrated with high precision into a neuronal network into which, under normal conditions, new nerve cells would never have been incorporated,” explains lead author Dr. Magdalena Götz at the Ludwig-Maximilians University in Munich, Germany.
Cell replacement therapy
So what does this mean for repairing a degenerating human brain?
“This proof-of-principle study shows that…the lesioned adult brain is still capable of integrating new building blocks,” says Falkner. “Neuronal replacement therapies may be realistic, at least at times when a sufficient part of the pre-existing neuronal network is still available.”
Cell replacement therapy has been tried in Parkinson’s disease for at least two decades, but with mixed results. Impure sources of donor cells, pre-implant processing, suboptimal grafting procedures and side effects could all contribute, explains Falker.
Then there’s the issue that real-world brain injuries aren’t so sterile and precise. A whack to the head, for example, can trigger inflammatory and other signals that turn the brain into a hostile environment unreceptive to neuron implants.
But the team is hopeful that their regime can help in those situations as well.
“We are doing this now in more realistic models, in models of traumatic and ischemic brain injury and all I can say is that it looks pretty good,” says Götz.
Supply is also a problem — isolating neurons from aborted fetuses isn’t a practical solution — but recent advances in cell reprogramming could be a readily available answer.
Scientists can already directly turn skin cells into neurons, for example. Other groups have also shown that glia cells — the other major cell type in the brain — can shed their identity and transform into neurons under the right conditions. Then there are iPSCs, in which a patient’s skin cell is deprogrammed into stem cells and further developed into neurons.
It’s becoming more possible to get defined mixtures of cells to match the afflicted cell type in the diseased brain, says Falkner.
“Once neurons die, there is, at the moment, no real therapy to make these neurons come back. Surely, at some point in the future, these approaches will be used in the clinic,” says Götz.
Researchers Repair Brain Damage in Mice With Stem Cell Transplants
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Writing the First Human Genome by 2026 Is Synthetic Biology’s Grand Challenge
A “top secret" meeting of scientists was held at the Langone Medical Center on Halloween 2015. Their aim? To kickstart a new Human Genome Project and build a functional human genome from the base pairs up by 2026.
“There's only one grand challenge in synthetic biology. Only one. And it's to write a human genome. And we have to do that,” said Autodesk Fellow Andrew Hessel at Singularity University’s Exponential Medicine 2016 conference.
Like the first Human Genome Project before it — which resulted in the first fully sequenced human genome — writing a human genome from scratch is an audacious goal. Hessel said a number of organizations are already writing DNA, and we can fabricate million-pair DNA constructs. But the human genome contains three billion base pairs.
We’re a long way from writing DNA on that scale.
“It took a year to design the yeast genome, even though there were barely any changes made to [it]. So, we need better design tools,” Hessel said.
Work on the yeast genome is the most advanced thing going on in synthetic biology. It's been pushing the field forward, but not as fast as Hessel would like. His career was hugely influenced by the race to map the first human genome in the 90s and early 2000s, and he thought to himself — now we need something like that for synthetic biology.
That's why Hessel and fellow scientists are pushing for a new Human Genome Project focused on synthetic biology — something to spark people’s imagination. That “top secret” meeting and a subsequent white paper made just the splash they were looking for.
“Two hundred news organizations picked up the story, and we got ninety two million page impressions in the first week,” Hessel said. “Everybody suddenly knew about the secret meeting to synthesize the human genome.”
Andrew Hessel at Exponential Medicine.
Though interest in the project is high, it’s just the beginning.
“This is really hard work...trying to go from DNA to packaged chromosome put into a cell and functional is hard. I don't want to gloss over the technical challenges,” Hessel said.
Hessel’s work at Autodesk is focused on making more effective design tools. He started writing viruses two years back, and it took weeks to get the DNA. Now, he’s writing more complicated viruses to fight cancer. The larger the amount of DNA, the longer it takes to assemble.
But there are a number of fields, from health and medicine to electronics (DNA is an excellent medium for long-term information storage), creating big incentives to speed development. Hessel is excited at the prospects.
Though it’s still early, he thinks 2026 for a fully engineered human genome is realistic if synthetic biology follows an exponential pace like genome sequencing did.
“So, a new genome race is starting, ladies and gentlemen,” Hessel said. “It's starting now. It's still in the organizational phase, but it is going to accelerate and, guaranteed, by 2026, we're going to succeed.”
As for the more controversial aspects of the project, like the worry the work may result in synthetic humans? The intentions behind this project are not to produce synthetic babies.
"We couldn't advocate that," Hessel said.
It’s more about pushing the science and technology necessary to build a whole human genome — but no more. And he has a personal motivation too.
“I’m doing this because I want my daughter to literally have the best nanomedicine in the future, the best diagnostics, the best treatments,”Hessel said. “I hope you realize that by 2026, it's a completely different game.”
Writing the First Human Genome by 2026 Is Synthetic Biology's Grand Challenge
A “top secret" meeting of scientists was held at the Langone Medical Center on Halloween 2015. Their aim? To kickstart a new Human Genome Project and build a functional human genome from the base pairs up by 2026.
“There's only one grand challenge in synthetic biology. Only one. And it's to write a human genome. And we have to do that,” said Autodesk Fellow Andrew Hessel at Singularity University’s Exponential Medicine 2016 conference.
Like the first Human Genome Project before it — which resulted in the first fully sequenced human genome — writing a human genome from scratch is an audacious goal. Hessel said a number of organizations are already writing DNA, and we can fabricate million-pair DNA constructs. But the human genome contains three billion base pairs.
We’re a long way from writing DNA on that scale.
“It took a year to design the yeast genome, even though there were barely any changes made to [it]. So, we need better design tools,” Hessel said.
Work on the yeast genome is the most advanced thing going on in synthetic biology. It's been pushing the field forward, but not as fast as Hessel would like. His career was hugely influenced by the race to map the first human genome in the 90s and early 2000s, and he thought to himself — now we need something like that for synthetic biology.
That's why Hessel and fellow scientists are pushing for a new Human Genome Project focused on synthetic biology — something to spark people’s imagination. That “top secret” meeting and a subsequent white paper made just the splash they were looking for.
“Two hundred news organizations picked up the story, and we got ninety two million page impressions in the first week,” Hessel said. “Everybody suddenly knew about the secret meeting to synthesize the human genome.”
Andrew Hessel at Exponential Medicine.
Though interest in the project is high, it’s just the beginning.
“This is really hard work...trying to go from DNA to packaged chromosome put into a cell and functional is hard. I don't want to gloss over the technical challenges,” Hessel said.
Hessel’s work at Autodesk is focused on making more effective design tools. He started writing viruses two years back, and it took weeks to get the DNA. Now, he’s writing more complicated viruses to fight cancer. The larger the amount of DNA, the longer it takes to assemble.
But there are a number of fields, from health and medicine to electronics (DNA is an excellent medium for long-term information storage), creating big incentives to speed development. Hessel is excited at the prospects.
Though it’s still early, he thinks 2026 for a fully engineered human genome is realistic if synthetic biology follows an exponential pace like genome sequencing did.
“So, a new genome race is starting, ladies and gentlemen,” Hessel said. “It's starting now. It's still in the organizational phase, but it is going to accelerate and, guaranteed, by 2026, we're going to succeed.”
As for the more controversial aspects of the project, like the worry the work may result in synthetic humans? The intentions behind this project are not to produce synthetic babies.
"We couldn't advocate that," Hessel said.
It’s more about pushing the science and technology necessary to build a whole human genome — but no more. And he has a personal motivation too.
“I’m doing this because I want my daughter to literally have the best nanomedicine in the future, the best diagnostics, the best treatments,”Hessel said. “I hope you realize that by 2026, it's a completely different game.”
Writing the First Human Genome by 2026 Is Synthetic Biology's Grand Challenge
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Scientists Say the Clock of Aging May Be Reversible
Impaired muscle repair in mice, left, compared with improved muscle regeneration seen after reprogramming. CreditThe Salk Institute for Biological Studies
At the Salk Institute in La Jolla, Calif., scientists are trying to get time to run backward.
Biological time, that is. In the first attempt to reverse aging by reprogramming the genome, they have rejuvenated the organs of mice and lengthened their life spans by 30 percent. The technique, which requires genetic engineering, cannot be applied directly to people, but the achievement points toward better understanding of human aging and the possibility of rejuvenating human tissues by other means.
The Salk team’s discovery, reported in the Thursday issue of the journal Cell, is “novel and exciting,” said Jan Vijg, an expert on aging at the Albert Einstein College of Medicine in New York.
Leonard Guarente, who studies the biology of aging at M.I.T., said, “This is huge,” citing the novelty of the finding and the opportunity it creates to slow down, if not reverse, aging. “It’s a pretty remarkable finding, and if it holds up it could be quite important in the history of aging research,” Dr. Guarente said.
The finding is based on the heterodox idea that aging is not irreversible and that an animal’s biological clock can in principle be wound back to a more youthful state.
The aging process is clocklike in the sense that a steady accumulation of changes eventually degrades the efficiency of the body’s cells. In one of the deepest mysteries of biology, the clock’s hands are always set back to zero at conception: However old the parents and their reproductive cells, a fertilized egg is free of all marks of age.
Ten years ago, the Japanese biologist Shinya Yamanaka amazed researchers by identifying four critical genes that reset the clock of the fertilized egg. The four genes are so powerful that they will reprogram even the genome of skin or intestinal cells back to the embryonic state. Dr. Yamanaka’s method is now routinely used to change adult tissue cells into cells very similar to the embryonic stem cells produced in the first few divisions of a fertilized egg.
Scientists next began to wonder if the four Yamanaka genes could be applied not just to cells in glassware but to a whole animal. The results were disastrous. As two groups of researchers reported in 2013 and 2014, the animals all died, some because their adult tissue cells had lost their identity and others from cancer. Embryonic cells are primed for rapid growth, which easily becomes uncontrolled.
But at the Salk Institute, Juan Carlos Izpisua Belmonte had been contemplating a different approach. He has long been interested in regeneration, the phenomenon in which certain animals, like lizards and fish, can regenerate lost tails or limbs. The cells near the lost appendage revert to a stage midway between an embryonic cell, which is open to all fates, and an adult cell, which is committed to being a particular type of cell, before rebuilding the missing limb.
This partial reprogramming suggested to him that reprogramming is a stepwise process, and that a small dose of the Yamanaka factors might rejuvenate cells without the total reprogramming that converts cells to the embryonic state.
With Alejandro Ocampo and other Salk researchers, Dr. Izpisua Belmonte has spent five years devising ways to deliver a nonlethal dose of Yamanaka factors to mice. The solution his team developed was to genetically engineer mice with extra copies of the four Yamanaka genes, and to have the genes activated only when the mice received a certain drug in their drinking water, applied just two days a week.
The Salk team worked first with mice that age prematurely, so as to get quick results. “What we saw is that the animal has fewer signs of aging, healthier organs, and at the end of the experiment we could see they had lived 30 percent longer than control mice,” Dr. Izpisua Belmonte said.
Juan Carlos Izpisua Belmonte of the Salk Institute in La Jolla, Calif., has long been interested in regeneration, the phenomenon in which certain animals, like lizards and fish, can regenerate lost tails or limbs.CreditConcepcion Rodriguez Esteban/The Salk Institute for Biological Studies
The team also saw improved organ health in normal mice but, because the mice are still living, could not yet say if longevity was extended.
Dr. Izpisua Belmonte believes these beneficial effects have been obtained by resetting the clock of the aging process. The clock is created by the epigenome, the system of proteins that clads the cell’s DNA and controls which genes are active and which are suppressed.
When an egg develops into a whole animal, the epigenome plays a critical role by letting a heart cell, say, activate just the genes specific to its role but switching off all the genes used by other types of cells. This process lets the embryo’s cells differentiate into all the various types of cells required by the adult body.
The epigenome is also involved throughout life in maintaining each cell and letting it switch genes on and off as required for its housekeeping duties. The epigenome itself is controlled by agents that add or subtract chemical groups, known as marks, to its proteins.
Only in the last few years have biologists come to realize that the state of the epigenome may be a major cause of aging. If the epigenome is damaged, perhaps by accumulating too many marks, the cell’s efficiency is degraded.
Dr. Izpisua Belmonte sees the epigenome as being like a manuscript that is continually edited. “At the end of life there are many marks and it is difficult for the cell to read them,” he said.
What the Yamanaka genes are doing in his mice, he believes, is eliminating the extra marks, thus reverting the cell to a more youthful state.
The Salk biologists “do indeed provide what I believe to be the first evidence that partial reprogramming of the genome ameliorated symptoms of tissue degeneration and improved regenerative capacity,” Dr. Vijg said.
But he cautioned the fast-aging mice used in the study might not be fully representative of ordinary aging.
Dr. Guarente said it was more likely that the Yamanaka genes were not erasing the epigenomic marks directly, but rather were activating the genes which are responsible for the immense health and vitality of embryonic cells. This gene activation is a natural function of the Yamanaka factors. It is these embryonic pro-health genes that are rejuvenating the tissues in the mice, Dr. Guarente suggested, and causing changes in the epigenome through their activity.
Thomas A. Rando, an expert on stem cells and aging at Stanford, said that it should be possible in theory to uncouple the differentiation program and the aging process, and that “if that’s what’s happening, this is the first demonstration of that.”
Dr. Izpisua Belmonte said he was testing drugs to see if he could achieve the same rejuvenation as with the Yamanaka factors. The use of chemicals “will be more translatable to human therapies and clinical applications,” he said.
http://www.nytimes.com/2016/12/15/s...et-clock-of-aging-for-mice-at-least.html?_r=1
Ageing process may be reversible, scientists claim
New form of gene therapy shown to produce rejuvenating effect in mice, although scientists say human clinical applications are decade away
Discovery raises the prospect of a new approach to healthcare in which ageing itself is treated, rather than the various diseases associated with it. Photograph: Dimitri Otis/Getty Images
Wrinkles, grey hair and niggling aches are normally regarded as an inevitable part of growing older, but now scientists claim that the ageing process may be reversible.
The team showed that a new form of gene therapy produced a remarkable rejuvenating effect in mice. After six weeks of treatment, the animals looked younger, had straighter spines and better cardiovascular health, healed quicker when injured, and lived 30% longer.
Juan Carlos Izpisua Belmonte, who led the work at the Salk Institute in La Jolla, California, said: “Our study shows that ageing may not have to proceed in one single direction. With careful modulation, ageing might be reversed.”
The genetic techniques used do not lend themselves to immediate use in humans, and the team predict that clinical applications are a decade away. However, the discovery raises the prospect of a new approach to healthcare in which ageing itself is treated, rather than the various diseases associated with it.
The findings also challenge the notion that ageing is simply the result of physical wear and tear over the years. Instead, they add to a growing body of evidence that ageing is partially – perhaps mostly – driven by an internal genetic clock that actively causes our body to enter a state of decline.
The scientists are not claiming that ageing can be eliminated, but say that in the foreseeable future treatments designed to slow the ticking of this internal clock could increase life expectancy.
“We believe that this approach will not lead to immortality,” said Izpisua Belmonte. “There are probably still limits that we will face in terms of complete reversal of ageing. Our focus is not only extension of lifespan but most importantly health-span.”
Wolf Reik, a professor of epigenetics at the Babraham Institute, Cambridge, who was not involved in the work, described the findings as “pretty amazing” and agreed that the idea of life-extending therapies was plausible. “This is not science fiction,” he said.
On the left is muscle tissue from an aged mouse. On the right is muscle tissue from an aged mouse that has been subjected to “reprogramming”. Photograph: Salk Institute
The rejuvenating treatment given to the mice was based on a technique that has previously been used to “rewind” adult cells, such as skin cells, back into powerful stem cells, very similar to those seen in embryos. These so-called induced pluripotent stem (iPS) cells have the ability to multiply and turn into any cell type in the body and are already being tested in trials designed to provide “spare parts” for patients.
The latest study is the first to show that the same technique can be used to partially rewind the clock on cells – enough to make them younger, but without the cells losing their specialised function.
“Obviously there is a logic to it,” said Reik. “In iPS cells you reset the ageing clock and go back to zero. Going back to zero, to an embryonic state, is probably not what you want, so you ask: where do you want to go back to?”
The treatment involved intermittently switching on the same four genes that are used to turn skin cells into iPS cells. The mice were genetically engineered in such a way that the four genes could be artificially switched on when the mice were exposed to a chemical in their drinking water.
The scientists tested the treatment in mice with a genetic disorder, called progeria, which is linked to accelerated ageing, DNA damage, organ dysfunction and dramatically shortened lifespan.
After six weeks of treatment, the mice looked visibly younger, skin and muscle tone improved and they lived 30% longer. When the same genes were targeted in cells, DNA damage was reduced and the function of the cellular batteries, called the mitochondria, improved.
“This is the first time that someone has shown that reprogramming in an animal can provide a beneficial effect in terms of health and extend their lifespan,” said Izpisua Belmonte.
Crucially, the mice did not have an increased cancer risk, suggesting that the treatment had successfully rewound cells without turning them all the way back into stem cells, which can proliferate uncontrollably in the body.
The potential for carcinogenic side-effects means that the first people to benefit are likely to be those with serious genetic conditions, such as progeria, where there is more likely to be a medical justification for experimental treatments. “Obviously the tumour risk is lurking in the background,” said Reik.
The approach used in the mice could not be readily applied to humans as it would require embryos to be genetically manipulated, but the Salk team believe the same genes could be targeted with drugs.
“These chemicals could be administrated in creams or injections to rejuvenate skin, muscle or bones,” said Izpisua Belmonte. “We think these chemical approaches might be in human clinical trials in the next ten years.”
The findings are published in the journal Cell.
- This article was amended on 16 December 2016. A previous version erroneously gave Wolf Reik’s affiliation as the University of Cambridge. This has now been corrected to the Babraham Institute, Cambridge.
Ageing process may be reversible, scientists claim
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An anti-CRISPR for gene editing
December 8, 2016
This visual abstract depicts the finding that naturally occurring inhibitors of CRISPR-Cas9 can block genome editing in cultured human cells, providing a means to spatially, temporally, and conditionally control Cas9 activity. Credit: Pawluk et al./Cell 2016
Researchers have discovered a way to program cells to inhibit CRISPR-Cas9 activity. "Anti-CRISPR" proteins had previously been isolated from viruses that infect bacteria, but now University of Toronto and University of Massachusetts Medical School scientists report three families of proteins that turn off CRISPR systems specifically used for gene editing. The work, which appears December 15 in Cell, offers a new strategy to prevent CRISPR-Cas9 technology from making unwanted changes.
"Making CRISPR controllable allows you to have more layers of control on the system and to turn it on or off under certain conditions, such as where it works within a cell or at what point in time," says lead author Alan Davidson, a phage biologist and bacteriologist at the University of Toronto. "The three anti-CRISPR proteins we've isolated seem to bind to different parts of the Cas9, and there are surely more out there."
CRISPR inhibitors are a natural byproduct of the evolutionary arms race between viruses and bacteria. Bacteria use CRISPR-Cas complexes to target and cut up genetic material from invading viruses. In response, viruses have developed proteins that, upon infection, can quickly bind to a host bacterium's CRISPR-Cas systems, thus nullifying their effects.
Anti-CRISPR proteins are attractive experimentally because they offer one solution for preventing potential off-target effects. Research in mice has shown that such mistakes may be rare when using CRISPR-Cas9 technology, but even the occasional error could be a serious problem when being used therapeutically in humans.
"CRISPR-Cas9 in ancillary cells, tissues, or organs is at best useless and at worst a safety risk," says co-author and collaborator Erik J. Sontheimer, a professor in the RNA Therapeutics Institute at the University of Massachusetts Medical School. "But if you could build an off-switch that keeps Cas9 inactive everywhere except the intended target tissue, then the tissue specificity will be improved."
"Knowing we have a safety valve will allow people to develop many more uses for CRISPR," says co-author Karen Maxwell, an assistant professor in biochemistry who is also at the University of Toronto. "Things that may have been too risky previously might be possible now."
While the work will be of great interest to those studying gene editing and gene drives, Davidson's team is also curious to follow up on the biology of how bacterial CRISPRs and viral anti-CRISPRs interact.
"We didn't set out to find anti-CRISPRs, we were just trying to understand how phages incorporate themselves into bacterial genomes and stumbled onto something that I think will be important for biotechnology," Davidson says.
"We were being observant and following a path that we didn't know where it could lead, and it's just been a very fun and exciting story."
Explore further: Video: Genetically modified humans? CRISPR/Cas 9 explained
More information: Cell, Pawluk et al.: "Naturally occurring off-switches for CRISPR-Cas9" http://www.cell.com/cell/fulltext/S0092-8674(16)31589-6 , DOI: 10.1016/j.cell.2016.11.017
Journal reference: Cell
Provided by: Cell Press
Read more at: https://phys.org/news/2016-12-anti-crispr-gene.html#jCp
Off-switch for CRISPR-Cas9 gene editing system discovered
December 29, 2016
Credit: NIH
UC San Francisco researchers have discovered a way to switch off the widely used CRISPR-Cas9 gene-editing system using newly identified anti-CRISPR proteins that are produced by bacterial viruses. The technique has the potential to improve the safety and accuracy of CRISPR applications both in the clinic and for basic research.
The new study, published in Cell on Dec. 29, 2016, was led by Benjamin Rauch, PhD, a post-doctoral researcher in the laboratory of Joseph Bondy-Denomy, PhD, who is a UCSF Sandler Faculty Fellow in the Department of Microbiology and Immunology.
CRISPR-Cas9 evolved in bacteria as an immune system to protect against viral infections, but in the past decade it has excited both researchers and the general public as a general-use gene editing system, enabling scientists to quickly and efficiently modify genetic information and tweak gene activity in virtually any organism.
Many hope CRISPR will speed efforts to directly treat genetic disorders, among many other applications, but for the most part the technology has not yet proven quite precise enough, making occasional unintended edits along with the intended ones. Researchers and bioethicists also worry that the technology's very power and ease of use raise the possibility that it could potentially cause harm, either intentionally or by accident.
The newly discovered anti-CRISPR proteins—which are the first to work against the type of CRISPR-Cas9 system most commonly used by laboratories and the burgeoning gene editing industry—could help resolve both problems, Bondy-Denomy says, enabling more precise control in CRISPR applications but also providing a fail-safe to quickly block any potentially harmful uses of the technology.
To find such a switch, Bondy-Denomy and Rauch turned to the same billion-year arms race between viruses and bacteria that produced the CRISPR system itself:
"Just as CRISPR technology was developed from the natural anti-viral defense systems in bacteria, we can also take advantage of the anti-CRISPR proteins that viruses have sculpted to get around those bacterial defenses," Rauch said.
How it was done: identifying "self-targeting" bacteria
In order to discover an anti-CRISPR protein that would work against the type of CRISPR-Cas9 system most labs now use, which depends on a protein called SpyCas9 as its targeted DNA clippers, the researchers came up with a clever trick: They reasoned that they should be able to identify bacteria with inactivated CRISPR systems by looking for evidence of so-called "self-targeting"—bacterial strains where some virus had successfully gotten through the Cas9 blockade and inserted its genes into the bacterial genome. The team hypothesized that these phages must encode some anti-CRISPR agent, or else Cas9 would kill the bacteria by cutting its own genome where the viral DNA had been inserted.
"Cas9 isn't very smart," Bondy-Denomy said. "It's not able to avoid cutting the bacterium's own DNA if it is programmed to do so. So we looked for strains of bacteria where the CRISPR-Cas9 system ought to be targeting its own genome - the fact that the cells do not self-destruct was a clue that the whole CRISPR system was inactivated."
Using a bioinformatics approach designed by Rauch, the team examined nearly 300 strains of Listeria, a bacterial genus famous for its role in food-borne illness, and found that three percent of strains exhibited "self-targeting". Further investigation isolated four distinct anti-CRISPR proteins that proved capable of blocking the activity of the Listeria Cas9 protein, which is very similar to SpyCas9.
Additional experiments showed that two of the four anti-CRISPR proteins—which the researchers dubbed AcrIIA2 and AcrIIA4—worked to inhibit the ability of the commonly used SpyCas9 to target specific genes in other bacteria - such as E. coli - as well as in engineered human cells. Together, the results suggest that AcrIIA proteins are potent inhibitors of the CRISPR-Cas9 gene editing system as it has been adopted in labs around the world.
"The next step is to show in human cells that using these inhibitors can actually improve the precision of gene editing by reducing off-target effects," Rauch said. "We also want to understand exactly how the inhibitor proteins block Cas9's gene targeting abilities, and continue the search for more and better CRISPR inhibitors in other bacteria."
Off-switch could improve accuracy and safety of many CRISPR applications
Rauch and Bondy-Denomy believe the ability to deactivate SpyCas9 will make CRISPR-based gene editing much safer and more precise by resolving the ongoing problem of unintended "off-target" gene modifications, which become more likely the longer the CRISPR gene editing machinery remains active in target cells.
The discovery could also be a boon for scientists using newer CRISPR techniques pioneered in part at UCSF - such as CRISPR interference and CRISPR activation—which use Cas9 not to modify gene sequences but to precisely tune their activity up and down. Using anti-CRISPR proteins, researchers could boost or block gene activity temporarily, potentially even synchronizing choreographed bursts of activity from sets of interconnected genes across the genome, which could be key to studying and treating complex, multi-gene diseases.
CRISPR inhibitors could also prove to be a valuable safeguard, the researchers say, enabling scientists to quickly halt any application of CRISPR gene editing outside the lab.
"Researchers and the public are reasonably concerned about CRISPR being so powerful that it potentially gets put to dangerous uses," Bondy-Denomy said. "These inhibitors provide a mechanism to block nefarious or out-of-control CRISPR applications, making it safer to explore all the ways this technology can be used to help people."
Explore further: An anti-CRISPR for gene editing
More information: Cell, DOI: 10.1016/j.cell.2016.12.009
Journal reference: Cell
Provided by: University of California, San Francisco
Read more at: https://phys.org/news/2016-12-off-switch-crispr-cas9-gene.html#jCp
December 8, 2016
This visual abstract depicts the finding that naturally occurring inhibitors of CRISPR-Cas9 can block genome editing in cultured human cells, providing a means to spatially, temporally, and conditionally control Cas9 activity. Credit: Pawluk et al./Cell 2016
Researchers have discovered a way to program cells to inhibit CRISPR-Cas9 activity. "Anti-CRISPR" proteins had previously been isolated from viruses that infect bacteria, but now University of Toronto and University of Massachusetts Medical School scientists report three families of proteins that turn off CRISPR systems specifically used for gene editing. The work, which appears December 15 in Cell, offers a new strategy to prevent CRISPR-Cas9 technology from making unwanted changes.
"Making CRISPR controllable allows you to have more layers of control on the system and to turn it on or off under certain conditions, such as where it works within a cell or at what point in time," says lead author Alan Davidson, a phage biologist and bacteriologist at the University of Toronto. "The three anti-CRISPR proteins we've isolated seem to bind to different parts of the Cas9, and there are surely more out there."
CRISPR inhibitors are a natural byproduct of the evolutionary arms race between viruses and bacteria. Bacteria use CRISPR-Cas complexes to target and cut up genetic material from invading viruses. In response, viruses have developed proteins that, upon infection, can quickly bind to a host bacterium's CRISPR-Cas systems, thus nullifying their effects.
Anti-CRISPR proteins are attractive experimentally because they offer one solution for preventing potential off-target effects. Research in mice has shown that such mistakes may be rare when using CRISPR-Cas9 technology, but even the occasional error could be a serious problem when being used therapeutically in humans.
"CRISPR-Cas9 in ancillary cells, tissues, or organs is at best useless and at worst a safety risk," says co-author and collaborator Erik J. Sontheimer, a professor in the RNA Therapeutics Institute at the University of Massachusetts Medical School. "But if you could build an off-switch that keeps Cas9 inactive everywhere except the intended target tissue, then the tissue specificity will be improved."
"Knowing we have a safety valve will allow people to develop many more uses for CRISPR," says co-author Karen Maxwell, an assistant professor in biochemistry who is also at the University of Toronto. "Things that may have been too risky previously might be possible now."
While the work will be of great interest to those studying gene editing and gene drives, Davidson's team is also curious to follow up on the biology of how bacterial CRISPRs and viral anti-CRISPRs interact.
"We didn't set out to find anti-CRISPRs, we were just trying to understand how phages incorporate themselves into bacterial genomes and stumbled onto something that I think will be important for biotechnology," Davidson says.
"We were being observant and following a path that we didn't know where it could lead, and it's just been a very fun and exciting story."
Explore further: Video: Genetically modified humans? CRISPR/Cas 9 explainedMore information: Cell, Pawluk et al.: "Naturally occurring off-switches for CRISPR-Cas9" http://www.cell.com/cell/fulltext/S0092-8674(16)31589-6 , DOI: 10.1016/j.cell.2016.11.017
Journal reference: Cell
Provided by: Cell Press
Read more at: https://phys.org/news/2016-12-anti-crispr-gene.html#jCp
Off-switch for CRISPR-Cas9 gene editing system discovered
December 29, 2016
Credit: NIH
UC San Francisco researchers have discovered a way to switch off the widely used CRISPR-Cas9 gene-editing system using newly identified anti-CRISPR proteins that are produced by bacterial viruses. The technique has the potential to improve the safety and accuracy of CRISPR applications both in the clinic and for basic research.
The new study, published in Cell on Dec. 29, 2016, was led by Benjamin Rauch, PhD, a post-doctoral researcher in the laboratory of Joseph Bondy-Denomy, PhD, who is a UCSF Sandler Faculty Fellow in the Department of Microbiology and Immunology.
CRISPR-Cas9 evolved in bacteria as an immune system to protect against viral infections, but in the past decade it has excited both researchers and the general public as a general-use gene editing system, enabling scientists to quickly and efficiently modify genetic information and tweak gene activity in virtually any organism.
Many hope CRISPR will speed efforts to directly treat genetic disorders, among many other applications, but for the most part the technology has not yet proven quite precise enough, making occasional unintended edits along with the intended ones. Researchers and bioethicists also worry that the technology's very power and ease of use raise the possibility that it could potentially cause harm, either intentionally or by accident.
The newly discovered anti-CRISPR proteins—which are the first to work against the type of CRISPR-Cas9 system most commonly used by laboratories and the burgeoning gene editing industry—could help resolve both problems, Bondy-Denomy says, enabling more precise control in CRISPR applications but also providing a fail-safe to quickly block any potentially harmful uses of the technology.
To find such a switch, Bondy-Denomy and Rauch turned to the same billion-year arms race between viruses and bacteria that produced the CRISPR system itself:
"Just as CRISPR technology was developed from the natural anti-viral defense systems in bacteria, we can also take advantage of the anti-CRISPR proteins that viruses have sculpted to get around those bacterial defenses," Rauch said.
How it was done: identifying "self-targeting" bacteria
In order to discover an anti-CRISPR protein that would work against the type of CRISPR-Cas9 system most labs now use, which depends on a protein called SpyCas9 as its targeted DNA clippers, the researchers came up with a clever trick: They reasoned that they should be able to identify bacteria with inactivated CRISPR systems by looking for evidence of so-called "self-targeting"—bacterial strains where some virus had successfully gotten through the Cas9 blockade and inserted its genes into the bacterial genome. The team hypothesized that these phages must encode some anti-CRISPR agent, or else Cas9 would kill the bacteria by cutting its own genome where the viral DNA had been inserted.
"Cas9 isn't very smart," Bondy-Denomy said. "It's not able to avoid cutting the bacterium's own DNA if it is programmed to do so. So we looked for strains of bacteria where the CRISPR-Cas9 system ought to be targeting its own genome - the fact that the cells do not self-destruct was a clue that the whole CRISPR system was inactivated."
Using a bioinformatics approach designed by Rauch, the team examined nearly 300 strains of Listeria, a bacterial genus famous for its role in food-borne illness, and found that three percent of strains exhibited "self-targeting". Further investigation isolated four distinct anti-CRISPR proteins that proved capable of blocking the activity of the Listeria Cas9 protein, which is very similar to SpyCas9.
Additional experiments showed that two of the four anti-CRISPR proteins—which the researchers dubbed AcrIIA2 and AcrIIA4—worked to inhibit the ability of the commonly used SpyCas9 to target specific genes in other bacteria - such as E. coli - as well as in engineered human cells. Together, the results suggest that AcrIIA proteins are potent inhibitors of the CRISPR-Cas9 gene editing system as it has been adopted in labs around the world.
"The next step is to show in human cells that using these inhibitors can actually improve the precision of gene editing by reducing off-target effects," Rauch said. "We also want to understand exactly how the inhibitor proteins block Cas9's gene targeting abilities, and continue the search for more and better CRISPR inhibitors in other bacteria."
Off-switch could improve accuracy and safety of many CRISPR applications
Rauch and Bondy-Denomy believe the ability to deactivate SpyCas9 will make CRISPR-based gene editing much safer and more precise by resolving the ongoing problem of unintended "off-target" gene modifications, which become more likely the longer the CRISPR gene editing machinery remains active in target cells.
The discovery could also be a boon for scientists using newer CRISPR techniques pioneered in part at UCSF - such as CRISPR interference and CRISPR activation—which use Cas9 not to modify gene sequences but to precisely tune their activity up and down. Using anti-CRISPR proteins, researchers could boost or block gene activity temporarily, potentially even synchronizing choreographed bursts of activity from sets of interconnected genes across the genome, which could be key to studying and treating complex, multi-gene diseases.
CRISPR inhibitors could also prove to be a valuable safeguard, the researchers say, enabling scientists to quickly halt any application of CRISPR gene editing outside the lab.
"Researchers and the public are reasonably concerned about CRISPR being so powerful that it potentially gets put to dangerous uses," Bondy-Denomy said. "These inhibitors provide a mechanism to block nefarious or out-of-control CRISPR applications, making it safer to explore all the ways this technology can be used to help people."
Explore further: An anti-CRISPR for gene editingMore information: Cell, DOI: 10.1016/j.cell.2016.12.009
Journal reference: Cell
Provided by: University of California, San Francisco
Read more at: https://phys.org/news/2016-12-off-switch-crispr-cas9-gene.html#jCp
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Tiny 3D printed biobots could dispense drug doses from inside your body
Jan 5, 2017 | By Benedict
Samuel Sia, a professor of biomedical engineering at New York City’s Columbia University, has developed a 3D printed biobot that can be implanted in the body to release controlled doses of drugs. The amazing device can be controlled from outside the body using only magnets.
For patients who have been diagnosed with cancer, treatment options are often few and far between, and in many serious cases, starting an intense course of chemotherapy becomes a necessity rather than a choice. But despite being a powerful weapon against cancer, chemotherapy takes its toll on the body in a number of ways: chronic pain, nausea, fatigue, hair loss, and the chance of infertility are just some of the adverse effects that chemotherapy can present. Fortunately, scientists are working hard to develop more effective ways of delivering chemotherapy drugs, including a new 3D printing method that involves fabricating squishy, “clockwork” micromachines that deliver precise drug doses from within the body.
These exciting new micromachines, or “biobots,” have been developed at the laboratory of Samuel Sia, a professor of biomedical engineering at New York City’s Columbia University. Sia and his research team recently published their findings in Science Robotics, where they explain how they have developed “a fast manufacturing method that can produce features in biocompatible materials down to tens of micrometers in scale, with intricate and composite patterns in each layer.” With this manufacturing method, the scientists have been able to create tiny devices that can release drugs into the body via magnetic signals.
Going into the laboratory with the goal of creating these drug-dispensing micromachines, the Columbia biomedical engineers first needed to develop a special way of creating that machine. For this, they turned to 3D printing, developing a one-off machine that can deposit layers of hydrogel to form solid, rubbery shapes.
Next came the challenge of creating the tiny devices themselves. For this part, the researchers could use a tried and tested mechanism to operate their biobots: clockwork. Amazingly, the hydrogel-based micromachines really do function like a timepiece—each squishy device is a kind of Geneva drive, a gear mechanism capable of regular rotation, and clicks forward when an external magnet is directed at it. The “gear” of the device is just a squishy component containing iron nanoparticles, and each click causes one of six chambers to line up with a hole and dispense medicine through it.
Creating these 3D printed biobots was a challenge for Sia’s team for several reasons. For starters, the tiny devices needed to be soft and flexible enough to be compatible with the human body. But they also needed to be robust enough to withstand the rough and tumble of the body’s insides: “If your material is collapsing like jello, it’s hard to make robots out of it,” Sia told IEEE Spectrum. “It has to be stiff enough to work like a tiny implantable machine.”
With tiny devices like these, doctors could someday deliver drugs such as chemotherapy treatments with a much higher level of precision—potentially reducing some of the adverse effects of the powerful drugs. They could also be used to regulate hormones or perform other important tasks from within the body. Importantly, Sia and his team have already tested out the 3D printed robotic devices on mice, and with great success. (A device implanted in a mouse can be seen in the image below.)
The researchers implanted the biobots into a number of mice with bone cancer, releasing controlled doses of a chemotherapy drug through the 3D printed devices. Simultaneously, other mice suffering from bone cancer were given the same drug through conventional methods. According to the researchers, tumors grew slower, more tumor cells died off, and fewer healthy cells were damaged in the mice fitted with the 3D printed biobots.
The squishy 3D printed devices therefore represent a massive opportunity for medical professionals, potentially serving as a new way to deliver critical treatments to the body. First, however, Sia’s team (or another group of researchers) might need to find a more precise way to control the device. Although the magnetic system currently in place works a charm in the laboratory, it remains possible that a powerful magnet from another source might accidentally trigger the devices within the body, releasing drugs at the wrong time and in the wrong dosage.
For now, Sia will continue to look for other ways in which the 3D printed micromachines can be used to benefit patients. “I’m confident that we’ll find something useful,” he said.
Tiny 3D printed biobots could dispense drug doses from inside your body
Jan 5, 2017 | By Benedict
Samuel Sia, a professor of biomedical engineering at New York City’s Columbia University, has developed a 3D printed biobot that can be implanted in the body to release controlled doses of drugs. The amazing device can be controlled from outside the body using only magnets.
For patients who have been diagnosed with cancer, treatment options are often few and far between, and in many serious cases, starting an intense course of chemotherapy becomes a necessity rather than a choice. But despite being a powerful weapon against cancer, chemotherapy takes its toll on the body in a number of ways: chronic pain, nausea, fatigue, hair loss, and the chance of infertility are just some of the adverse effects that chemotherapy can present. Fortunately, scientists are working hard to develop more effective ways of delivering chemotherapy drugs, including a new 3D printing method that involves fabricating squishy, “clockwork” micromachines that deliver precise drug doses from within the body.
These exciting new micromachines, or “biobots,” have been developed at the laboratory of Samuel Sia, a professor of biomedical engineering at New York City’s Columbia University. Sia and his research team recently published their findings in Science Robotics, where they explain how they have developed “a fast manufacturing method that can produce features in biocompatible materials down to tens of micrometers in scale, with intricate and composite patterns in each layer.” With this manufacturing method, the scientists have been able to create tiny devices that can release drugs into the body via magnetic signals.
Going into the laboratory with the goal of creating these drug-dispensing micromachines, the Columbia biomedical engineers first needed to develop a special way of creating that machine. For this, they turned to 3D printing, developing a one-off machine that can deposit layers of hydrogel to form solid, rubbery shapes.
Next came the challenge of creating the tiny devices themselves. For this part, the researchers could use a tried and tested mechanism to operate their biobots: clockwork. Amazingly, the hydrogel-based micromachines really do function like a timepiece—each squishy device is a kind of Geneva drive, a gear mechanism capable of regular rotation, and clicks forward when an external magnet is directed at it. The “gear” of the device is just a squishy component containing iron nanoparticles, and each click causes one of six chambers to line up with a hole and dispense medicine through it.
Creating these 3D printed biobots was a challenge for Sia’s team for several reasons. For starters, the tiny devices needed to be soft and flexible enough to be compatible with the human body. But they also needed to be robust enough to withstand the rough and tumble of the body’s insides: “If your material is collapsing like jello, it’s hard to make robots out of it,” Sia told IEEE Spectrum. “It has to be stiff enough to work like a tiny implantable machine.”
With tiny devices like these, doctors could someday deliver drugs such as chemotherapy treatments with a much higher level of precision—potentially reducing some of the adverse effects of the powerful drugs. They could also be used to regulate hormones or perform other important tasks from within the body. Importantly, Sia and his team have already tested out the 3D printed robotic devices on mice, and with great success. (A device implanted in a mouse can be seen in the image below.)
The researchers implanted the biobots into a number of mice with bone cancer, releasing controlled doses of a chemotherapy drug through the 3D printed devices. Simultaneously, other mice suffering from bone cancer were given the same drug through conventional methods. According to the researchers, tumors grew slower, more tumor cells died off, and fewer healthy cells were damaged in the mice fitted with the 3D printed biobots.
The squishy 3D printed devices therefore represent a massive opportunity for medical professionals, potentially serving as a new way to deliver critical treatments to the body. First, however, Sia’s team (or another group of researchers) might need to find a more precise way to control the device. Although the magnetic system currently in place works a charm in the laboratory, it remains possible that a powerful magnet from another source might accidentally trigger the devices within the body, releasing drugs at the wrong time and in the wrong dosage.
For now, Sia will continue to look for other ways in which the 3D printed micromachines can be used to benefit patients. “I’m confident that we’ll find something useful,” he said.
Tiny 3D printed biobots could dispense drug doses from inside your body
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Entrevista de Materia_ciencia a Aubrey de Grey:
Presento en Madrid el libro 'El próximo paso: la vida exponencial' de BBVA Openmind, del que es autor. Se puede descargar en El próximo paso: la vida exponencial
Presento en Madrid el libro 'El próximo paso: la vida exponencial' de BBVA Openmind, del que es autor. Se puede descargar en El próximo paso: la vida exponencial
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Una 'start-up' afirma tener una técnica de edición genética aún mejor que CRISPR
Las afirmaciones de Homology Medicines de ser capaz de editar ADN con virus han conseguido que recaude casi 110 millones de euros. Algunos científicos creen que su técnica es imposible, otros la consideran "impresionante"
El sistema de edición genética CRISPR es el tema más candente en biología, gracias a su facilidad para modificar las letras del ADN y a su potencial para curar enfermedades genéticas. ¿Podría existir alguna tecnología aún más sencilla? Tal vez una capaz de editar genes sin tener que utilizar CRISPR para nada.
La start-up Homology Medicines asegura que sabe como hacerlo. La compañía de Massachusetts (EEUU) ha recaudado unos 107 millones de euros para tratar enfermedades genéticas mediante virus que, según afirma, son capaces de reparar eficazmente los genes humanos por su propia cuenta.
Si su afirmación es cierta, Homology puede haber dado con la forma más segura y sencilla para modificar los genes en el cuerpo humano hasta la fecha. Una técnica que no requiere cortar las hebras de ADN de una persona, como lo hace CRISPR.
Disponer de una tecnología mejor que CRISPR tendría un gran impacto, pero los resultados científicos de Homology aún no están aceptados totalmente. De hecho, en declaraciones a MIT Technology Review, varios científicos afirman que creen que, probablemente, sus afirmaciones son incorrectas.
"Lo sorprendente es que esta empresa recaudara tanto dinero para algo que la comunidad científica considera falso", alerta el investigador de la Universidad de Washington en Seattle (EEUU) David Russell. El experto apostilla: "Creo que sólo se trata de la histeria que hay con la edición genética".
Ahora mismo, encontrar mejores maneras de alterar los genes de una persona para eliminar una enfermedad puede ser la investigación médica más importante, además de una de las más lucrativas. A finales de agosto, la Administración de Alimentos y Medicamentos de los Estados Unidos aprobó lo que denominó la "primera terapia génica" del país, un tratamiento de la compañía Novartis que utiliza células inmunitarias modificadas genéticamente para tratar la leucemia. Los medicamentos como éste podrían generar miles de millones en ventas con el tiempo.
Gran demanda
Los métodos tradicionales de terapia génica sólo pueden añadir genes, a menudo al azar, mediante virus que los introducen en las células. La edición genética, por el contrario, se refiere a tecnologías nuevas y potentes que también eliminan o revisan las letras del ADN. A veces es llamada "terapia génica 2.0".
CRISPR es el sistema de edición de genes más versátil que se conoce de momento. Para editar un genoma, utiliza una nucleasa, una enzima proteica que rompe la doble hélice del ADN. Ese daño provoca reparaciones de emergencia dentro de la célula, un fenómeno que los científicos aprovechan para cambiar las letras en el código de ADN.
La afirmación más llamativa de Homology es que asegura tener una manera de hacer que esta edición ocurra sin agregar una nucleasa y, por lo tanto, sin romper la hebra de ADN. Imagínese una cirugía sin bisturí o a un sastre sin tijeras.
Parece imposible pero, de hecho, el primero en demostrar el fenómeno fue el propio Russell en 1998. Si una cadena de ADN introducida por un virus coincide en gran medida con la de un gen concreto (esta semejanza se denomina "homología"), a veces puede intercambiarse por ella cuando una célula se divide. Por lo tanto, una mutación de ADN se puede reemplazar por una secuencia correcta, o editada.
El problema es que estas reparaciones provocadas por virus son muy poco frecuentes, y el proceso es fortuito y aún incomprendido.En algunos tipos de células, sólo una de cada 1.000 células se edita, una cantidad insuficiente para pensar en tratar la mayoría de las enfermedades con este método. Por eso, la edición de virus nunca ha sido ampliamente adoptada por los desarrolladores de fármacos.
Pero Homology afirma que ha encontrado una manera de hacerlo mucho mejor. En mayo de este año, en la reunión anual de expertos en terapia génica y celular, investigadores del laboratorio de la científica fundadora de la compañía, Saswati Chatterjee, del Centro Médico Nacional de la Ciudad de la Esperanza (California), proclamaron haber encontrado virus capaces de editar hasta el 50% de las células en un tubo de ensayo con un gen que las hace brillar.
"El santo grial siempre fue conseguir editar genes con un vector viral sencillo y sin nucleasa. No hay corte del ADN, la toxicidad es mínima, y no hay problemas con la entrega. Si se llega al 50%, sería la mejor técnica de edición de genes creada jamás", afirma Russell. Pero también está seguro de que ese resultado es demasiado bueno para ser verdad. Otros científicos se mostraron también escépticos. El especialista en edición genética de la Universidad de Stanford (EEUU) Matthew Porteus, que asistió a la charla y trabaja en CRISPR, coincide: "Muchos de nosotros no estábamos convencidos de que los resultados presentados estuvieran respaldados por los datos que presentaban".
Nuevos virus
La compañía dio el pistoletazo de salida después de que Chatterjee comenzara a extraer muestras de médula ósea para detectar rastros de virus, llamados AAV (virus adeno-asociados en español), que se usan en la terapia génica convencional.
Este nuevo tipo de virus es valioso por sí mismo porque cada uno puede ayudar a los científicos a contagiar órganos específicos, como el cerebro y el hígado. La creciente variedad de nuevos virus es una de las razones por las que la terapia génica es cada vez más eficaz, permitiendo que los genes se añadan a ciertas células, pero no a otras. Chatterjee encontró 17 nuevos tipos de virus y expidió patentes de ellos.
El director asociado del Instituto Altius de Ciencias Biomédicas en Seattle (EEUU), Fyodor Urnov, se lamenta: "Es uno de esos experimentos en los que te fustigas y dices: '¿Por qué no pensé yo en eso?'"
Pero Chatterjee añadió otra afirmación que dejó a los inversores boquiabiertos. Dijo que sus virus eran también editores de genes de primera división. "Eso prendió el comienzo de la compañía", cuenta el CEO de Homology y ejecutivo de biotecnología, Arthur Tzianabos.
Si la edición eficiente puede ser llevada a cabo con sólo un virus, ésta combinaría el poder de CRISPR con la simplicidad de los métodos de terapia génica. "Esto implicaría que sólo se necesitarían inyecciones para hacer la corrección genética en el cuerpo, y esto sería un gran salto", dice Tzianabos, y añade: "Creemos que es más fácil de desarrollar, menos complicado y más preciso".
Los inversores que perdieron el tren de CRISPR estaban especialmente interesados en pasar a la acción. Algunos de los nombres detrás de la inversión de Homology Medicines son 5AM Ventures y ARCH Venture Partners, ambos grupos de capital de riesgo bien conocidos. Los esfuerzos realizados por MIT Technology Review para hablar con los socios de ambos fondos no tuvieron éxito.
El especialista de la Universidad de Harvard (EEUU) en reparación del ADN Stephen Elledge fue contratado por Homology como asesor científico y está de acuerdo en que aún hay preguntas abiertas. "No está claro qué es lo que han encontrado que lo hace mejor; podrían estar recibiendo más ADN, o podría ser algo relacionado con el virus. Eso no está resuelto totalmente", explica. Pero asegura que los datos que ha visto hasta la fecha le parecen "impresionantes".
Tzianabos explica que Homology todavía está llevando a cabo la investigación en el laboratorio para confirmar y ampliar sus resultados. El CEO admite: "Siempre hay escepticismo cuando aparece algo nuevo, y lo nuestro es muy novedoso. Reconozco que es una tecnología bastante precoz y que sale de un laboratorio académico. Nuestro trabajo consiste en industrializar el proceso".
Por su parte, Chatterjee adelanta que los datos detallados de su laboratorio, que ha presentado para que sean publicados, deberían calmar los ánimos de los que dudan de sus afirmaciones. La investigadora afirma. "No hay fundamentos para sostener que nuestras conclusiones no son posibles".
Otras empresas emergentes también están persiguiendo la edición de virus, aunque ninguna afirma hacerlo de forma tan eficiente. Russell dirige una compañía llamada Universal Cells que está tratando de hacer suministros personalizados de células para trasplantes. Otra empresa, LogicBio, ha recaudado alrededor algo más de 42 millones de euros y quiere utilizar la edición con virus para tratar a los niños que sufren enfermedades hepáticas hereditarias.
Tzianabos explica que, a la larga, Homology Medicines quiere utilizar su método de edición genética viral para tratar la anemia de células falciformes, un problema sanguíneo causada por un pequeño error genético y que también es un objetivo de científicos de CRISPR como Porteus.
Por su parte, Porteus sostiene que de momento sigue apostando por CRISPR. El experto concluye: "Ya hay bastante trabajo duro que hacer como para estar preocupándonos por una ratonera mejor.Mejorar en CRISPR requerirá algo muy especial".
Una 'start-up' afirma tener una técnica de edición genética aún mejor que CRISPR
Las afirmaciones de Homology Medicines de ser capaz de editar ADN con virus han conseguido que recaude casi 110 millones de euros. Algunos científicos creen que su técnica es imposible, otros la consideran "impresionante"
- por Antonio Regalado | traducido por Patricia R. Guevara
- 07 Septiembre, 2017
El sistema de edición genética CRISPR es el tema más candente en biología, gracias a su facilidad para modificar las letras del ADN y a su potencial para curar enfermedades genéticas. ¿Podría existir alguna tecnología aún más sencilla? Tal vez una capaz de editar genes sin tener que utilizar CRISPR para nada.
La start-up Homology Medicines asegura que sabe como hacerlo. La compañía de Massachusetts (EEUU) ha recaudado unos 107 millones de euros para tratar enfermedades genéticas mediante virus que, según afirma, son capaces de reparar eficazmente los genes humanos por su propia cuenta.
Si su afirmación es cierta, Homology puede haber dado con la forma más segura y sencilla para modificar los genes en el cuerpo humano hasta la fecha. Una técnica que no requiere cortar las hebras de ADN de una persona, como lo hace CRISPR.
Disponer de una tecnología mejor que CRISPR tendría un gran impacto, pero los resultados científicos de Homology aún no están aceptados totalmente. De hecho, en declaraciones a MIT Technology Review, varios científicos afirman que creen que, probablemente, sus afirmaciones son incorrectas.
"Lo sorprendente es que esta empresa recaudara tanto dinero para algo que la comunidad científica considera falso", alerta el investigador de la Universidad de Washington en Seattle (EEUU) David Russell. El experto apostilla: "Creo que sólo se trata de la histeria que hay con la edición genética".
Ahora mismo, encontrar mejores maneras de alterar los genes de una persona para eliminar una enfermedad puede ser la investigación médica más importante, además de una de las más lucrativas. A finales de agosto, la Administración de Alimentos y Medicamentos de los Estados Unidos aprobó lo que denominó la "primera terapia génica" del país, un tratamiento de la compañía Novartis que utiliza células inmunitarias modificadas genéticamente para tratar la leucemia. Los medicamentos como éste podrían generar miles de millones en ventas con el tiempo.
Gran demanda
Los métodos tradicionales de terapia génica sólo pueden añadir genes, a menudo al azar, mediante virus que los introducen en las células. La edición genética, por el contrario, se refiere a tecnologías nuevas y potentes que también eliminan o revisan las letras del ADN. A veces es llamada "terapia génica 2.0".
CRISPR es el sistema de edición de genes más versátil que se conoce de momento. Para editar un genoma, utiliza una nucleasa, una enzima proteica que rompe la doble hélice del ADN. Ese daño provoca reparaciones de emergencia dentro de la célula, un fenómeno que los científicos aprovechan para cambiar las letras en el código de ADN.
La afirmación más llamativa de Homology es que asegura tener una manera de hacer que esta edición ocurra sin agregar una nucleasa y, por lo tanto, sin romper la hebra de ADN. Imagínese una cirugía sin bisturí o a un sastre sin tijeras.
Parece imposible pero, de hecho, el primero en demostrar el fenómeno fue el propio Russell en 1998. Si una cadena de ADN introducida por un virus coincide en gran medida con la de un gen concreto (esta semejanza se denomina "homología"), a veces puede intercambiarse por ella cuando una célula se divide. Por lo tanto, una mutación de ADN se puede reemplazar por una secuencia correcta, o editada.
El problema es que estas reparaciones provocadas por virus son muy poco frecuentes, y el proceso es fortuito y aún incomprendido.En algunos tipos de células, sólo una de cada 1.000 células se edita, una cantidad insuficiente para pensar en tratar la mayoría de las enfermedades con este método. Por eso, la edición de virus nunca ha sido ampliamente adoptada por los desarrolladores de fármacos.
Pero Homology afirma que ha encontrado una manera de hacerlo mucho mejor. En mayo de este año, en la reunión anual de expertos en terapia génica y celular, investigadores del laboratorio de la científica fundadora de la compañía, Saswati Chatterjee, del Centro Médico Nacional de la Ciudad de la Esperanza (California), proclamaron haber encontrado virus capaces de editar hasta el 50% de las células en un tubo de ensayo con un gen que las hace brillar.
"El santo grial siempre fue conseguir editar genes con un vector viral sencillo y sin nucleasa. No hay corte del ADN, la toxicidad es mínima, y no hay problemas con la entrega. Si se llega al 50%, sería la mejor técnica de edición de genes creada jamás", afirma Russell. Pero también está seguro de que ese resultado es demasiado bueno para ser verdad. Otros científicos se mostraron también escépticos. El especialista en edición genética de la Universidad de Stanford (EEUU) Matthew Porteus, que asistió a la charla y trabaja en CRISPR, coincide: "Muchos de nosotros no estábamos convencidos de que los resultados presentados estuvieran respaldados por los datos que presentaban".
Nuevos virus
La compañía dio el pistoletazo de salida después de que Chatterjee comenzara a extraer muestras de médula ósea para detectar rastros de virus, llamados AAV (virus adeno-asociados en español), que se usan en la terapia génica convencional.
Este nuevo tipo de virus es valioso por sí mismo porque cada uno puede ayudar a los científicos a contagiar órganos específicos, como el cerebro y el hígado. La creciente variedad de nuevos virus es una de las razones por las que la terapia génica es cada vez más eficaz, permitiendo que los genes se añadan a ciertas células, pero no a otras. Chatterjee encontró 17 nuevos tipos de virus y expidió patentes de ellos.
El director asociado del Instituto Altius de Ciencias Biomédicas en Seattle (EEUU), Fyodor Urnov, se lamenta: "Es uno de esos experimentos en los que te fustigas y dices: '¿Por qué no pensé yo en eso?'"
Pero Chatterjee añadió otra afirmación que dejó a los inversores boquiabiertos. Dijo que sus virus eran también editores de genes de primera división. "Eso prendió el comienzo de la compañía", cuenta el CEO de Homology y ejecutivo de biotecnología, Arthur Tzianabos.
Si la edición eficiente puede ser llevada a cabo con sólo un virus, ésta combinaría el poder de CRISPR con la simplicidad de los métodos de terapia génica. "Esto implicaría que sólo se necesitarían inyecciones para hacer la corrección genética en el cuerpo, y esto sería un gran salto", dice Tzianabos, y añade: "Creemos que es más fácil de desarrollar, menos complicado y más preciso".
Los inversores que perdieron el tren de CRISPR estaban especialmente interesados en pasar a la acción. Algunos de los nombres detrás de la inversión de Homology Medicines son 5AM Ventures y ARCH Venture Partners, ambos grupos de capital de riesgo bien conocidos. Los esfuerzos realizados por MIT Technology Review para hablar con los socios de ambos fondos no tuvieron éxito.
El especialista de la Universidad de Harvard (EEUU) en reparación del ADN Stephen Elledge fue contratado por Homology como asesor científico y está de acuerdo en que aún hay preguntas abiertas. "No está claro qué es lo que han encontrado que lo hace mejor; podrían estar recibiendo más ADN, o podría ser algo relacionado con el virus. Eso no está resuelto totalmente", explica. Pero asegura que los datos que ha visto hasta la fecha le parecen "impresionantes".
Tzianabos explica que Homology todavía está llevando a cabo la investigación en el laboratorio para confirmar y ampliar sus resultados. El CEO admite: "Siempre hay escepticismo cuando aparece algo nuevo, y lo nuestro es muy novedoso. Reconozco que es una tecnología bastante precoz y que sale de un laboratorio académico. Nuestro trabajo consiste en industrializar el proceso".
Por su parte, Chatterjee adelanta que los datos detallados de su laboratorio, que ha presentado para que sean publicados, deberían calmar los ánimos de los que dudan de sus afirmaciones. La investigadora afirma. "No hay fundamentos para sostener que nuestras conclusiones no son posibles".
Otras empresas emergentes también están persiguiendo la edición de virus, aunque ninguna afirma hacerlo de forma tan eficiente. Russell dirige una compañía llamada Universal Cells que está tratando de hacer suministros personalizados de células para trasplantes. Otra empresa, LogicBio, ha recaudado alrededor algo más de 42 millones de euros y quiere utilizar la edición con virus para tratar a los niños que sufren enfermedades hepáticas hereditarias.
Tzianabos explica que, a la larga, Homology Medicines quiere utilizar su método de edición genética viral para tratar la anemia de células falciformes, un problema sanguíneo causada por un pequeño error genético y que también es un objetivo de científicos de CRISPR como Porteus.
Por su parte, Porteus sostiene que de momento sigue apostando por CRISPR. El experto concluye: "Ya hay bastante trabajo duro que hacer como para estar preocupándonos por una ratonera mejor.Mejorar en CRISPR requerirá algo muy especial".
Una 'start-up' afirma tener una técnica de edición genética aún mejor que CRISPR
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