Ten year collaboration between Google and Harvard may lead to a deeper understanding of the brain and new clinical laboratory diagnostics
With all our anatomic pathology and clinical laboratory science, we still do not know that much about the structure of the brain. But now, scientists at Harvard University and Google Research studying the emerging field of connectomics have published a highly detailed 3D reconstruction of human brain tissue that allows visualization of neurons and their connections at unprecedented nanoscale resolutions.
Further investigation of the nano-connections within the human brain could lead to novel insights about the role specific proteins and molecules play in the function of the brain. Though it will likely be years down the road, data derived from this study could be used to develop new clinical laboratory diagnostic tests.
The data to generate the model came from Google’s use of artificial intelligence (AI) algorithms to color-code Harvard’s electron microscope imaging of a cubic millimeter of neural tissue—equivalent to a half-grain of rice—that was surgically removed from an epilepsy patient.
“That tiny square contains 57,000 cells, 230 millimeters of blood vessels, and 150 million synapses, all amounting to 1,400 terabytes of data,” according to the Harvard Gazette, which described the project as “the largest-ever dataset of human neural connections.”
“A terabyte is, for most people, gigantic, yet a fragment of a human brain—just a minuscule, teeny-weeny little bit of human brain—is still thousands of terabytes,” said neuroscientist Jeff W. Lichtman, MD, PhD, Jeremy R. Knowles Professor of Molecular and Cellular Biology, whose Lichtman Lab at Harvard University collaborated on the project with researchers from Google. The two labs have been working together for nearly 10 years on this project, the Harvard Gazette reported.
Lichtman’s lab focuses on the emerging field of connectomics, defined “as understanding how individual neurons are connected to one another to form functional networks,” said neurobiologist Wei-Chung Allen Lee, PhD, Assistant Professor of Neurology, Harvard Medical School, in an interview with Harvard Medical News. “The goal is to create connectomes—or detailed structural maps of connectivity—where we can see every neuron and every connection.” Lee was not involved with the Harvard/Google Research study.
“The human brain uses no more power than a dim incandescent light bulb, yet it can accomplish feats still not possible with the largest artificial computing systems,” wrote Google Research scientist Viren Jain, PhD (above), in a blog post. “To understand how requires a level of understanding more profound than knowing what part of the brain is responsible for what function. The field of connectomics aims to achieve this by precisely mapping how each cell is connected to others.” Google’s 10-year collaboration with Harvard University may lead to new clinical laboratory diagnostics. (Photo copyright: Google Research.)
Study Data and Tools Freely Available
Along with the Science paper, the researchers publicly released the data along with analytic and visualization tools. The study noted that the dataset “is large and incompletely scrutinized,” so the scientists are inviting other researchers to assist in improving the model.
“The ability for other researchers to proofread and refine this human brain connectome is one of many ways that we see the release of this paper and the associated tools as not only the culmination of 10 years of work, but the beginning of something new,” wrote Google Research scientist Viren Jain, PhD, in a blog post that included links to the online resources.
One of those tools—Neuroglancer—allows any user with a web browser to view 3D models of neurons, axons, synapses, dendrites, blood vessels, and other objects. Users can rotate the models in xyz dimensions.
Users with the requisite knowledge and skills can proofread and correct the models by signing up for a CAVE (Connectome Annotation Versioning Engine) account.
Researchers Found Several Surprises
To perform their study, Lichtman’s team cut the neural tissue into 5,000 slices, each approximately 30 nanometers thick, Jain explained in the blog post. They then used a multibeam scanning electron microscope to capture high-resolution images, a process that took 326 days.
Jain’s team at Google used AI tools to build the model. They “stitched and aligned the image data, reconstructed the three dimensional structure of each cell, including its axons and dendrites, identified synaptic connections, and classified cell types,” he explained.
Jain pointed to “several surprises” that the reconstruction revealed. For example, he noted that “96.5% of contacts between axons and their target cells have just one synapse.” However, he added, “we found a class of rare but extremely powerful synaptic connections in which a pair of neurons may be connected by more than 50 individual synapses.”
In their Science paper, the researchers suggest that “these powerful connections are not the result of chance, but rather that these pairs had a reason to be more strongly connected than is typical,” Jain wrote in the blog post. “Further study of these connections could reveal their functional role in the brain.”
Mysterious Structures
Another anomaly was the presence of “axon whorls,” as Jain described them, “beautiful but mysterious structures in which an axon wraps itself into complicated knots.”
Because the sample came from an epilepsy patient, Jain noted that the whorls could be connected to the disease or therapies or could be found in all brains.
“Given the scale and complexity of the dataset, we expect that there are many other novel structures and characteristics yet to be discovered,” he wrote. “These findings are the tip of the iceberg of what we expect connectomics will tell us about human brains.”
The researchers have a larger goal to create a comprehensive high-resolution map of a mouse’s brain, Harvard Medical News noted. This would contain approximately 1,000 times the data found in the 1-cubic-millimeter human sample.
Dark Daily has been tracking the different fields of “omics” for years, as research teams announce new findings and coin new areas of science and medicine to which “omics” is appended. Connectomics fits that description.
Though the Harvard/Google research is not likely to lead to diagnostic assays or clinical laboratory tests any time soon, it is an example of how advances in technologies are enabling researchers to investigate smaller and smaller elements within the human body.
New non-invasive test could replace traditional painful spinal taps and clinical laboratory fluid analysis for diagnosis of Parkinson’s disease
Scientists at AXIM Biotechnologies of San Diego have added another specimen that can be collected non-invasively for rapid, point-of-care clinical laboratory testing. This time it is tears, and the diagnostic test is for Parkinson’s disease (PD).
The new assay measures abnormal alpha-synuclein (a-synuclein), a protein that is a biomarker for Parkinson’s, according to an AXIM news release which also said the test is the first rapid test for PD.
“The revolutionary nature of AXIM’s new test is that it is non-invasive, inexpensive, and it can be performed at a point of care. It does not require a lumbar puncture, freezing, or sending samples to a lab. AXIM’s assay uses a tiny tear drop versus a spinal tap to collect the fluid sample and the test can be run at a doctor’s office with quantitative results delivered from a reader in less than 10 minutes,” the news release notes.
“Furthermore, emerging evidence shows that a-synuclein assays have the potential to differentiate people with PD from healthy controls, enabling the potential for early identification of at-risk groups,” the news release continues. “These findings suggest a crucial role for a-synuclein in therapeutic development, both in identifying pathologically defined subgroups of people with Parkinson’s disease and establishing biomarker-defined at-risk cohorts.”
This is just the latest example of a disease biomarker that can be collected noninvasively. Other such biomarkers Dark Daily has covered include:
“With this new assay, AXIM has immediately become a stakeholder in the Parkinson’s disease community, and through this breakthrough, we are making possible new paradigms for better clinical care, including earlier screening and diagnosis, targeted treatments, and faster, cheaper drug development,” said John Huemoeller, CEO, AXIM (above), in a news release. Patients benefit from non-invasive clinical laboratory testing. (Photo copyright: AXIM Biotechnologies.)
Fast POC Test versus Schirmer Strip
AXIM said it moved forward with its novel a-synuclein test propelled by earlier tear-related research that found “a-synuclein in its aggregated form can be detected in tears,” Inside Precision Medicine reported.
But that research used what AXIM called the “outdated” Schirmer Strip method to collect tears. The technique involves freezing tear samples at -80 degrees Celsius (-112 Fahrenheit), then sending them to a clinical laboratory for centrifugation for 30 minutes; quantifying tear protein content with a bicinchoninic acid assay, and detecting a-synuclein using a plate reader, AXIM explained.
Alternatively, AXIM says its new test may be performed in doctors’ offices and offers “quantitative results delivered from a reader in less than 10 minutes.”
“Our proven expertise in developing tear-based diagnostic tests has led to the development of this test in record speed, and I’m extremely proud of our scientific team for their ability to expand our science to focus on such an important focus area as Parkinson’s,” said John Huemoeller, CEO, AXIM in the news release.
“This is just the beginning for AXIM in this arena,” he added. “But I am convinced when pharmaceutical companies, foundations, and neurologists see how our solution can better help diagnose Parkinson’s disease in such an expedited and affordable way, we will be at the forefront of PD research, enabling both researchers and clinicians a brand-new tool in the fight against PD.”
One of those tests was “a lateral flow diagnostic for point-of-care use that measures the level of lactoferrin proteins in tear fluid, which work to protect the surface of the eye. … Axim said that low lactoferrin levels have also been linked to Parkinson’s disease and that the assay can be used alongside its alpha-synuclein test,” Fierce Biotech noted.
“It made sense to try and look at the proteinaceous [consisting of or containing protein] constituents of tear fluid,” Lew told Neurology Live. “Tear fluid is easy to collect. It’s noninvasive, inexpensive. It’s not like when you do a lumbar puncture, which is a much more involved ordeal. There’s risk of contamination with blood (saliva is dirty) issues with blood and collection. [Tear fluid analysis] is much safer and less expensive to do.”
In Biomarkers in Medicine, Lew et al noted why tears make good biomarkers for Parkinson’s disease, including “the interconnections between the ocular [eye] surface system and neurons affected in Parkinson’s disease.”
The researchers also highlighted “recent data on the identification of tear biomarkers including oligomeric α-synuclein, associated with neuronal degeneration in PD, in tears of PD patients” and discussed “possible sources for its release into tears.”
Future Clinical Laboratory Testing for Parkinson’s
Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s. It affects nearly one million people in the US. About 1.2 million people may have it by 2030, according to the Parkinson’s Foundation.
Thus, an accurate, inexpensive, non-invasive diagnostic test that can be performed at the point of care, and which returns clinical laboratory test results in less than 10 minutes, will be a boon to physicians who treat PD patients worldwide.
Clinical laboratory managers and pathologists may want to follow AXIM’s future research to see when the diagnostic test may become available for clinical use.
Scientists participating in the modENCORE study have the goal of understanding the causes of hereditary genetic diseases in humans
New discoveries about the interaction of genes and transcription factors in creating different types of RNA will be of interest to pathologists and clinical chemists performing genetic tests and molecular diagnostic assays in their medical laboratories.
The goal of this research is to better understand hereditary genetic disease in humans. The new knowledge is based on studies of the common fruit fly, or Drosophila melanogaster (D. Melanogaster), and to a lesser extent a tiny worm Caenorhabditis elegans (C. elegans). Both have been used as research models to study the human condition.
Research Could Give Pathologists New Diagnostic Tools(more…)
The human proteome map provides a catalog of proteins expressed in nondiseased issues and organs to use as baseline in understanding changes that occur in disease
Given the growing importance of proteins in medical laboratory testing, pathologists will want to know about a major milestone recently achieved in this field. Researchers have announced that drafts of the complete human proteome have been released to the public.
Experts are comparing this to the first complete map of the human genome that was made public in 2000. Clinical laboratory managers and pathologists know how the availability of this information provided the foundation for rapid advances in understanding different aspects involving DNA and RNA. (more…)
The genetic device holds promise for developing cancer-specific gene therapies and could create new consulting opportunities for pathologists and clinical laboratory scientists
In Israel, researchers are making progress on the futuristic concept of biologic, medically-savvy computers that are so small they can fit inside human cells and roam the body detecting and treating diseases in vivo. This is another example of how new technologies can shift diagnostic testing away from clinical laboratories.
This groundbreaking work is being done at the Weizmann Institute of Science in Rehovot. The research team has designed a genetic device that is inserted into bacteria cells where it operates independently. This device is programmed to identify certain disease parameters and mount an appropriate response, according to a story published by Science Daily. (more…)
