New nuclear magnetic resonance technique offers ‘molecular window’ for live disease diagnosis
Could use existing non-invasive MRI technology
May 3, 2017
New nuclear magnetic resonance (NMR) system for molecular diagnosis (credit: University of Toronto Scarborough)
University of Toronto Scarborough researchers have developed a new “molecular window” technology based on nuclear magnetic resonance (NMR) that can look inside a living system to get a high-resolution profile of which specific molecules are present, and extract a full metabolic profile.
“Getting a sense of which molecules are in a tissue sample is important if you want to know if it’s cancerous, or if you want to know if certain environmental contaminants are harming cells inside the body,” says Professor Andre Simpson, who led research in developing the new technique.*
An NMR spectrometer generates a powerful magnetic field that causes atomic nuclei to absorb and re-emit energy in distinct patterns, revealing a unique molecular signature — in this example: the chemical ethanol. (credit: adapted from the Bruker BioSpin “How NMR Works” video at www.theresonance.com/nmr-know-how)
Simpson says there’s great medical potential for this new technique, since it can be adapted to work on existing magnetic resonance imaging (MRI) systems found in hospitals. “It could have implications for disease diagnosis and a deeper understanding of how important biological processes work,” by targeting specific biomarker molecules that are unique to specific diseased tissue.
The new approach could detect these signatures without resorting to surgery and could determine, for example, whether a growth is cancerous or benign directly from the MRI alone.
The technique could also provide highly detailed information on how the brain works, revealing the actual chemicals involved in a particular response. “It could mark an important step in unraveling the biochemistry of the brain,” says Simpson.
Overcoming magnetic distortion
Until now, traditional NMR techniques haven’t been able to provide high-resolution profiles of living organisms because of magnetic distortions from the tissue itself. Simpson and his team were able to overcome this problem by creating tiny communication channels based on “long-range dipole interactions” between molecules.
The next step for the research is to test it on human tissue samples, says Simpson. Since the technique detects all cellular metabolites (substances such as glucose) equally, there’s also potential for non-targeted discovery.
“Since you can see metabolites in a sample that you weren’t able to see before, you can now identify molecules that may indicate there’s a problem,” he explains. “You can then determine whether you need further testing or surgery. So the potential for this technique is truly exciting.”
The research results are published in the journal Angewandte Chemie.
* Simpson has been working on perfecting the technique for more than three years with colleagues at Bruker BioSpin, a scientific instruments company that specializes in developing NMR technology. The technique, called “in-phase intermolecular single quantum coherence” (IP-iSQC), is based on some unexpected scientific concepts that were discovered in 1995, which at the time were described as impossible and “crazed” by many researchers. The technique developed by Simpson and his team builds upon these early discoveries. The work was supported by Mark Krembil of the Krembil Foundation and the Natural Sciences Engineering Research Council of Canada (NSERC).
Abstract of In-Phase Ultra High-Resolution In Vivo NMR
Although current NMR techniques allow organisms to be studied in vivo, magnetic susceptibility distortions, which arise from inhomogeneous distributions of chemical moieties, prevent the acquisition of high-resolution NMR spectra. Intermolecular single quantum coherence (iSQC) is a technique that breaks the sample’s spatial isotropy to form long range dipolar couplings, which can be exploited to extract chemical shift information free of perturbations. While this approach holds vast potential, present practical limitations include radiation damping, relaxation losses, and non-phase sensitive data. Herein, these drawbacks are addressed, and a new technique termed in-phase iSQC (IP-iSQC) is introduced. When applied to a living system, high-resolution NMR spectra, nearly identical to a buffer extract, are obtained. The ability to look inside an organism and extract a high-resolution metabolic profile is profound and should find applications in fields in which metabolism or in vivo processes are of interest.
- Ioana Fugariu, Wolfgang Bermel, Daniel Lane, Ronald Soong, Andre J. Simpson. In-Phase Ultra High-Resolution In Vivo NMR. Angewandte Chemie International Edition, 2017; DOI: 10.1002/anie.201701097
Topics: Biomed/Longevity | Cognitive Science/Neuroscience
Brain gains seen in elderly mice injected with human umbilical cord plasma
Memory protein that declines with aging also identified in mouse study
1:00pm, April 19, 2017
Magazine issue: Vol. 191 No. 9, May 13, 2017, p. 7
Plasma taken from human umbilical cords can rejuvenate old mice’s brains and improve their memories, a new study suggests. The results, published online April 19 in Nature, may ultimately help scientists develop ways to stave off aging.
Earlier studies have turned up youthful effects of young mice’s blood on old mice (SN: 12/27/14, p. 21). Human plasma, the new results suggest, confers similar benefits, says study coauthor Joseph Castellano, a neuroscientist at Stanford University. The study also identifies a protein that’s particularly important for the youthful effects, a detail that “adds a nice piece to the puzzle,” Castellano says.
Identifying the exact components responsible for rejuvenating effects is important, says geroscientist Matt Kaeberlein of the University of Washington in Seattle. That knowledge will bring scientists closer to understanding how old tissues can be rejuvenated. And having the precise compounds in hand means that scientists might have an easier time translating therapies to people.
Kaeberlein cautions that the benefits were in mice, not people. Still, he says, “there is good reason to be optimistic that some of these approaches will have similar effects on health span in people.”
Like people, as mice age, brain performance begins to slip. Compared with younger generations, elderly mice perform worse on some tests of learning and memory, taking longer to remember the location of an escape route out of a maze, for instance. Researchers suspect that these deficits come from age-related trouble in the hippocampus, a brain structure important for learning and memory.
Every fourth day for two weeks, Castellano and colleagues injected old mice with human plasma taken from umbilical cords, young adults and elderly adults. The source of plasma infusion changed the behavior of genes in the hippocampus, the researchers found. Elderly mice that had received umbilical cord or young adult plasma showed gene behavior changes that go along with improved hippocampal functioning. And after infusions of human cord plasma, more hippocampus cells churned out a protein called c-Fos, a marker of a busy brain that’s known to decline with age. Elderly mice that received elderly human plasma showed no such changes.
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An elderly mouse that received plasma infusions derived from human umbilical cords (right) had nerve cells in the hippocampus that produced the protein c-Fos (red dots pointed out by black arrows), a marker of nerve cell activity. Some c-Fos protein was seen in elderly brains that received plasma from young adults (middle right). Very little c-Fos was present when the plasma came from elderly people (middle left) or when no plasma was injected (left).
These brain changes came with behavioral improvements, too. Elderly mice that received umbilical cord plasma were quicker to learn and better at remembering the location of an escape hatch in a maze than elderly mice that didn’t receive the plasma. Mice that received injections were also more adept at learning associations between a room and a painful electric shock, and even better at making nests for babies, a skill that usually suffers with age.
Castellano and colleagues searched for the ingredient responsible for the effects by comparing plasma proteins whose abundance changes with age in mice and people. One candidate seemed particularly promising: Levels of a protein called TIMP2 started out high early in life but then dropped with age, in both mice and people.
Infusions of mouse TIMP2 had positive effects on elderly mice, both in their brains and their behavior, the team found. And when researchers removed TIMP2 from young mice, the animals grew worse at remembering new objects.
The study doesn’t explain how TIMP2 might work in the brain, says Gillian Murphy, a molecular cell biologist at the University of Cambridge who studies TIMP proteins and the proteins that TIMPs interact with. “Before any realistic interpretation of these data can be made,” it’s essential to figure out how TIMP2 affects hippocampal cells, she says.
In the meantime, a clinical trial designed to test whether young human plasma can slow the cognitive decline of people with Alzheimer’s disease is under way. Data have been collected and are being analyzed, says study coauthor Tony Wyss-Coray, an Alzheimer’s researcher at Stanford. Wyss-Coray and Castellano have ties to the company Alkahest, which is involved with the clinical trial and therapies to counter aging.
J.M. Castellano et al. Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature. Published online April 19, 2017. doi:10.1038/nature22067.
L. Sanders. Year in Review: Young blood aids old brains. Science News. Vol. 186, December 27, 2014, p. 21.
AI will upload and access our memories, predicts Siri co-inventor
"Instead of asking how smart we can make our machines, let's ask how smart our machines can make us."
April 26, 2017
“Hey Siri, what’s the name of that person I met yesterday?” (credit: Apple Inc.)
Instead of replacing humans with robots, artificial intelligence should be used more for augmenting human memory and other human weaknesses, Apple Inc. executive Tom Gruber suggested at the TED 2017 conference yesterday (April 25, 2017).
Thanks to the internet and our smartphones, much of our personal data is already being captured, notes Gruber, who was one the inventors of voice-controlled intelligent-assistant Siri. Future AI memory enhancement could be especially life-changing for those with Alzheimer’s or dementia, he suggested.
“Superintelligence should give us super-human abilities,” he said. “As machines get smarter, so do we. Artificial intelligence can enable partnerships where each human on the team is doing what they do best. Instead of asking how smart we can make our machines, let’s ask how smart our machines can make us.
“I can’t say when or what form factors are involved, but I think it is inevitable,” he said. “What if you could have a memory that was as good as computer memory and is about your life? What if you could remember every person you ever met? How to pronounce their name? Their family details? Their favorite sports? The last conversation you had with them?”
Gruber’s ideas mesh with a prediction by Ray Kurzweil: “Once we have achieved complete models of human intelligence, machines will be capable of combining the flexible, subtle human levels of pattern recognition with the natural advantages of machine intelligence, in speed, memory capacity, and, most importantly, the ability to quickly share knowledge and skills.”
Two projects announced last week aim in that direction: Facebook’s plan to develop a non-invasive brain-computer interface that will let you type at 100 words per minute and Elon Musks’ proposal that we become superhuman cyborgs to deal with superintelligent AI.
But trusting machines also raises security concerns, Gruber warned. “We get to choose what is and is not recalled,” he said. “It’s absolutely essential that this be kept very secure.”