News from October 2019
If it were tried on a person, it might mean awakening in the ultimate sensory deprivation chamber.
In a step that could change the definition of death, researchers have restored circulation to the brains of decapitated pigs and kept the reanimated organs alive for as long as 36 hours.
The feat offers scientists a new way to study intact brains in the lab in stunning detail. But it also inaugurates a bizarre new possibility in life extension, should human brains ever be kept on life support outside the body.
The work was described on March 28 at a meeting held at the National Institutes of Health to investigate ethical issues arising as US neuroscience centers explore the limits of brain science.
During the event, Yale University neuroscientist Nenad Sestan disclosed that a team he leads had experimented on between 100 and 200 pig brains obtained from a slaughterhouse, restoring their circulation using a system of pumps, heaters, and bags of artificial blood warmed to body temperature.
There was no evidence that the disembodied pig brains regained consciousness. However, in what Sestan termed a “mind-boggling” and “unexpected” result, billions of individual cells in the brains were found to be healthy and capable of normal activity.
Reached by telephone yesterday, Sestan declined to elaborate, saying he had submitted the results for publication in a scholarly journal and had not intended for his remarks to become public.
Since last spring, however, a widening circle of scientists and bioethicists have been buzzing about the Yale research, which involves a breakthrough in restoring micro-circulation—the flow of oxygen to small blood vessels, including those deep in the brain.
“These brains may be damaged, but if the cells are alive, it’s a living organ,” says Steve Hyman, director of psychiatric research at the Broad Institute in Cambridge, Massachusetts, who was among those briefed on the work. “It’s at the extreme of technical know-how, but not that different from preserving a kidney.”
Hyman says the similarity to techniques for preserving organs like hearts or lungs for transplant could cause some to mistakenly view the technology as a way to avoid death. “It may come to the point that instead of people saying ‘Freeze my brain,’ they say ‘Hook me up and find me a body,’” says Hyman.
Such hopes are misplaced, at least for now. Transplanting a brain into a new body “is not remotely possible,” according to Hyman.
Brain in a bucket
The Yale system, called BrainEx, involves connecting a brain to a closed loop of tubes and reservoirs that circulate a red perfusion fluid, which is able to carry oxygen to the brain stem, the cerebellar artery, and areas deep in the center of the brain.
In his presentation to the NIH officials and ethics experts, Sestan said the technique was likely to work in any species, including primates. “This is probably not unique to pigs,” he said.
The Yale researchers, who began work on the technique about four years ago and are seeking NIH funding for it, acted out of a desire to construct a comprehensive atlas of connections between human brain cells.
Some of these connections probably span large regions of the brain and would thus be traced more easily in a complete, intact organ.
Sestan acknowledged that surgeons at Yale had already asked him if the brain-preserving technology could have medical uses. Disembodied human brains, he said, could become guinea pigs for testing exotic cancer cures and speculative Alzheimer’s treatments too dangerous to try on the living.
The setup, jokingly dubbed the “brain in a bucket,” would quickly raise serious ethical and legal questions if it were tried on a human.
For instance, if a person’s brain were reanimated outside the body, would that person awake in what would amount to the ultimate sensory deprivation chamber, without ears, eyes, or a way to communicate? Would someone retain memories, an identity, or legal rights? Could researchers ethically dissect or dispose of such a brain?
Also, because federal safety regulations apply to people, not “dead” tissues, it is uncertain whether the US Food and Drug Administration would have any say over whether scientists could attempt such a reanimation procedure.
“There are going to be a lot of weird questions even if it isn’t a brain in a box,” said an advisor to the NIH who didn’t wish to speak on the record. “I think a lot of people are going to start going to slaughterhouses to get heads and figure it out.”
Sestan said he was concerned about how the technology would be received by the public and by his peers. “People are fascinated. We have to be careful how fascinated,” he said.
It’s well known that a comatose brain can be kept alive for at least decades. That is the case with brain-dead people whose families elect to keep them attached to ventilating machines.
Less well explored are artificial means of maintaining a brain wholly separated from its body. There have been previous attempts, including a 1993 report involving rodents, but Sestan’s team is the first to achieve it with a large mammal, without using cold temperatures, and with such promising results.
At first, the Yale group was uncertain if an “ex vivo” brain to which circulation was restored would regain consciousness. To answer that question, the scientists checked for signs of complex activity in the pig brains using a version of EEG, or electrodes placed on the brain’s surface. These can pick up electrical waves reflecting broad brain activity indicating thoughts and sensations.
Initially, Sestan said, they believed they had found such signals, generating both alarm and excitement in the lab, but they later determined that those signals were artifacts created by nearby equipment.
Sestan now says the organs produce a flat brain wave equivalent to a comatose state, although the tissue itself “looks surprisingly great” and, once it’s dissected, the cells produce normal-seeming patterns.
The lack of wider electrical activity could be irreversible if it is due to damage and cell death. The pigs’ brains were attached to the BrainEx device roughly four hours after the animals were decapitated.
However, it could also be due to chemicals the Yale team added to the blood replacement to prevent swelling, which also severely dampen the activity of neurons. “You have to understand that we have so many channel blockers in our solution,” Sestan told the NIH. “This is probably the explanation why we don’t get [any] signal.”
Sestan told the NIH it is conceivable that the brains could be kept alive indefinitely and that steps could be attempted to restore awareness. He said his team had elected not to attempt either because “this is uncharted territory.”
“That animal brain is not aware of anything, I am very confident of that,” Sestan said, although he expressed concern over how the technique might be used by others in the future. “Hypothetically, somebody takes this technology, makes it better, and restores someone’s [brain] activity. That is restoring a human being. If that person has memory, I would be freaking out completely.”
Consciousness isn’t necessary for the type of experiments on brain connections that scientists hope to carry out on living ex vivo brains. “The EEG brain activity is a flat line, but a lot of other things keep on ticking,” says Anna Devor, a neuroscientist at the University of California, San Diego, who is familiar with the Yale project.
Devor thinks the ability to work on intact, living brains would be “very nice” for scientists working to build a brain atlas. “The whole question of death is a gray zone,” she says. “But we need to remember the isolated brain is not the same as other organs, and we need to treat it with the same level of respect that we give to an animal.”
Today in the journal Nature, 17 neuroscientists and bioethicists, including Sestan, published an editorial arguing that experiments on human brain tissue may require special protections and rules.
They identified three categories of “brain surrogates” that provoke new concerns. These include brain organoids (blobs of nerve tissue the size of a rice grain), human-animal chimeras (mice with human brain tissue added), and ex vivo human brain tissue (such as chunks of brain removed during surgery).
They went on to suggest a variety of ethical safety measures, such as drugging animals that possess human brain cells so they stay in a “comatose-like brain state.”
Hyman, who also signed the letter, says he did so reluctantly, because he thinks most of the scenarios are exaggerated or unlikely. It’s hardly possible a tiny brain organoid will feel or think anything, he says.
The one type of research he thinks may call for quick action to set up rules of the road is Sestan’s unpublished brain preservation technique (which the Nature editorial did not discuss). “If people want to keep human brains alive post mortem, that is a more pressing and realistic problem,” says Hyman. “Given that it is possible with a pig brain, there should be guidelines for human tissue.”
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UC Santa Barbara/Google researchers demonstrate the power of 53 entangled qubits
- October 23, 2019
- UC Santa Barbara
- Researchers have made good on their claim to quantum supremacy. Using 53 entangled quantum bits ('qubits'), their Sycamore computer has taken on -- and solved -- a problem considered intractable for classical computers.
Researchers in UC Santa Barbara/Google scientist John Martinis' group have made good on their claim to quantum supremacy. Using 53 entangled quantum bits ("qubits"), their Sycamore computer has taken on -- and solved -- a problem considered intractable for classical computers.
"A computation that would take 10,000 years on a classical supercomputer took 200 seconds on our quantum computer," said Brooks Foxen, a graduate student researcher in the Martinis Group. "It is likely that the classical simulation time, currently estimated at 10,000 years, will be reduced by improved classical hardware and algorithms, but, since we are currently 1.5 trillion times faster, we feel comfortable laying claim to this achievement."
The feat is outlined in a paper in the journal Nature.
The milestone comes after roughly two decades of quantum computing research conducted by Martinis and his group, from the development of a single superconducting qubit to systems including architectures of 72 and, with Sycamore, 54 qubits (one didn't perform) that take advantage of the both awe-inspiring and bizarre properties of quantum mechanics.
"The algorithm was chosen to emphasize the strengths of the quantum computer by leveraging the natural dynamics of the device," said Ben Chiaro, another graduate student researcher in the Martinis Group. That is, the researchers wanted to test the computer's ability to hold and rapidly manipulate a vast amount of complex, unstructured data.
"We basically wanted to produce an entangled state involving all of our qubits as quickly as we can," Foxen said, "and so we settled on a sequence of operations that produced a complicated superposition state that, when measured, returns bitstring with a probability determined by the specific sequence of operations used to prepare that particular superposition. The exercise, which was to verify that the circuit's output correspond to the equence used to prepare the state, sampled the quantum circuit a million times in just a few minutes, exploring all possibilities -- before the system could lose its quantum coherence.
'A complex superposition state'
"We performed a fixed set of operations that entangles 53 qubits into a complex superposition state," Chiaro explained. "This superposition state encodes the probability distribution. For the quantum computer, preparing this superposition state is accomplished by applying a sequence of tens of control pulses to each qubit in a matter of microseconds. We can prepare and then sample from this distribution by measuring the qubits a million times in 200 seconds."
"For classical computers, it is much more difficult to compute the outcome of these operations because it requires computing the probability of being in any one of the 2^53 possible states, where the 53 comes from the number of qubits -- the exponential scaling is why people are interested in quantum computing to begin with," Foxen said. "This is done by matrix multiplication, which is expensive for classical computers as the matrices become large."
According to the new paper, the researchers used a method called cross-entropy benchmarking to compare the quantum circuit's output (a "bitstring") to its "corresponding ideal probability computed via simulation on a classical computer" to ascertain that the quantum computer was working correctly.
"We made a lot of design choices in the development of our processor that are really advantageous," said Chiaro. Among these advantages, he said, are the ability to experimentally tune the parameters of the individual qubits as well as their interactions.
While the experiment was chosen as a proof-of-concept for the computer, the research has resulted in a very real and valuable tool: a certified random number generator. Useful in a variety of fields, random numbers can ensure that encrypted keys can't be guessed, or that a sample from a larger population is truly representative, leading to optimal solutions for complex problems and more robust machine learning applications. The speed with which the quantum circuit can produce its randomized bit string is so great that there is no time to analyze and "cheat" the system.
"Quantum mechanical states do things that go beyond our day-to-day experience and so have the potential to provide capabilities and application that would otherwise be unattainable," commented Joe Incandela, UC Santa Barbara's vice chancellor for research. "The team has demonstrated the ability to reliably create and repeatedly sample complicated quantum states involving 53 entangled elements to carry out an exercise that would take millennia to do with a classical supercomputer. This is a major accomplishment. We are at the threshold of a new era of knowledge acquisition."
With an achievement like "quantum supremacy," it's tempting to think that the UC Santa Barbara/Google researchers will plant their flag and rest easy. But for Foxen, Chiaro, Martinis and the rest of the UCSB/Google AI Quantum group, this is just the beginning.
"It's kind of a continuous improvement mindset," Foxen said. "There are always projects in the works." In the near term, further improvements to these "noisy" qubits may enable the simulation of interesting phenomena in quantum mechanics, such as thermalization, or the vast amount of possibility in the realms of materials and chemistry.
In the long term, however, the scientists are always looking to improve coherence times, or, at the other end, to detect and fix errors, which would take many additional qubits per qubit being checked. These efforts have been running parallel to the design and build of the quantum computer itself, and ensure the researchers have a lot of work before hitting their next milestone.
"It's been an honor and a pleasure to be associated with this team," Chiaro said. "It's a great collection of strong technical contributors with great leadership and the whole team really synergizes well."
- Frank Arute, Kunal Arya, Ryan Babbush, Dave Bacon, Joseph C. Bardin, Rami Barends, Rupak Biswas, Sergio Boixo, Fernando G. S. L. Brandao, David A. Buell, Brian Burkett, Yu Chen, Zijun Chen, Ben Chiaro, Roberto Collins, William Courtney, Andrew Dunsworth, Edward Farhi, Brooks Foxen, Austin Fowler, Craig Gidney, Marissa Giustina, Rob Graff, Keith Guerin, Steve Habegger, Matthew P. Harrigan, Michael J. Hartmann, Alan Ho, Markus Hoffmann, Trent Huang, Travis S. Humble, Sergei V. Isakov, Evan Jeffrey, Zhang Jiang, Dvir Kafri, Kostyantyn Kechedzhi, Julian Kelly, Paul V. Klimov, Sergey Knysh, Alexander Korotkov, Fedor Kostritsa, David Landhuis, Mike Lindmark, Erik Lucero, Dmitry Lyakh, Salvatore Mandrà, Jarrod R. McClean, Matthew McEwen, Anthony Megrant, Xiao Mi, Kristel Michielsen, Masoud Mohseni, Josh Mutus, Ofer Naaman, Matthew Neeley, Charles Neill, Murphy Yuezhen Niu, Eric Ostby, Andre Petukhov, John C. Platt, Chris Quintana, Eleanor G. Rieffel, Pedram Roushan, Nicholas C. Rubin, Daniel Sank, Kevin J. Satzinger, Vadim Smelyanskiy, Kevin J. Sung, Matthew D. Trevithick, Amit Vainsencher, Benjamin Villalonga, Theodore White, Z. Jamie Yao, Ping Yeh, Adam Zalcman, Hartmut Neven, John M. Martinis. Quantum supremacy using a programmable superconducting processor. Nature, 2019; 574 (7779): 505 DOI: 10.1038/s41586-019-1666-5
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Study reveals crucial role of alpha-synuclein protein in DNA repair
- July 29, 2019
- Oregon Health & Science University
- A small protein previously associated with cellular dysfunction and death in fact serves a critical function in repairing breaks in DNA, according to new research. The study is the first to demonstrate the role that alpha-synuclein plays in forestalling the demise of neurons in brain diseases such as Parkinson's. The findings suggest that it may be possible to design new therapies to replace alpha-synuclein's function or boost it in people with Parkinson's disease and other neurodegenerative disorders.
A small protein previously associated with cell dysfunction and death in fact serves a critical function in repairing breaks in DNA, according to new research led by scientists at Oregon Health & Science University.
The discovery, published today in the journal Scientific Reports, marks the first demonstration of the role that alpha-synuclein plays in preventing the death of neurons in brain diseases such as Parkinson's, which affects 1.5 million people in the United States alone.
The findings suggest that it may be possible to design new therapies to replace alpha-synuclein's function or boost it in people with Parkinson's disease and other neurodegenerative disorders.
Aggregates of alpha-synuclein, known as Lewy bodies, have long been connected to Parkinson's and other forms of dementia.
The study published today casts a new light on that process.
The findings suggest that Lewy bodies are problematic because they pull alpha-synuclein protein out of the nucleus of brain cells. The study, which examined the cells of living mice and postmortem brain tissue in humans, reveals that these proteins perform a crucial function by repairing breaks that occur along the vast strands of DNA present in the nucleus of every cell of the body.
Alpha-synuclein's role in DNA repair may be crucial in preventing cell death. This function may be lost in brain diseases such as Parkinson's, leading to the widespread death of neurons.
"It may be the loss of that function that's killing that cell," said senior author Vivek Unni, M.D., Ph.D., an associate professor of neurology in the OHSU School of Medicine.
Researchers found that the alpha-synuclein protein rapidly recruited to the site of DNA damage in the neurons of mice. In addition, they found increased double-strand breaks in the DNA of human tissue and mice in which the protein was clumped together in the form of Lewy bodies in the cytoplasm surrounding the cell's nucleus. Taken together, the results suggest that alpha-synuclein plays a crucial role in binding broken strands of DNA within the cell's nucleus.
Put another way: If alpha-synuclein are workers in a factory, it's akin to all of them gathering for an extended coffee break and leaving the machinery unattended.
Unni, who also sees patients in the OHSU Parkinson Center and Movement Disorders Program, said he hopes that these findings lead to the development of methods to deliver alpha-synuclein proteins into the nucleus of cells or designing methods to replace its function.
"This is the first time that anyone has discovered one of its functions is DNA repair," Unni said. "That's critical for cell survival, and it appears to be a function that's lost in Parkinson's disease."
The work in this study was supported in part by National Institutes of Health grants NS102227, NS096190, NS069625, NS061800, AG024978, AG008017, and T32AG055378; a National Science Foundation graduate research fellowship, the Kinnie Family Foundation, the Oregon Partnership for Alzheimer's Research, and the American Parkinson Disease Association.
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