Genetic data captured by this new technology could lead to a new understanding of how different types of cells exchange information and would be a boon to anatomic pathology research worldwide
What if it were possible to map the interior of cells and view their genetic sequences using chemicals instead of light? Might that spark an entirely new way of studying human physiology? That’s what researchers at the Massachusetts Institute of Technology (MIT) believe. They have developed a new approach to visualizing cells and tissues that could enable the development of entirely new anatomic pathology tests that target a broad range of cancers and diseases.
Scientists at MIT’s Broad Institute and McGovern Institute for Brain Research developed this new technique, which they call DNA Microscopy. They published their findings in Cell, titled, “DNA Microscopy: Optics-free Spatio-genetic Imaging by a Stand-Alone Chemical Reaction.”
Joshua Weinstein, PhD, a postdoctoral associate at the Broad Institute and first author of the study, said in a news release that DNA microscopy “is an entirely new way of visualizing cells that captures both spatial and genetic information simultaneously from a single specimen. It will allow us to see how genetically unique cells—those comprising the immune system, cancer, or the gut for instance—interact with one another and give rise to complex multicellular life.”
The news release goes on to state that the new technology “shows
how biomolecules such as DNA and RNA are organized in cells and tissues,
revealing spatial and molecular information that is not easily accessible
through other microscopy methods. DNA microscopy also does not require
specialized equipment, enabling large numbers of samples to be processed
simultaneously.”
The images above, taken from the MIT study, compares optical imaging of a cell population (left) with an inferred visualization of the same cell population based on the information provided by DNA microscopy (right). Scale bar = 100 μm (100 micrometers). This technology has the potential to be useful for anatomic pathologists at some future date. (Photo and caption copyrights: Joshua Weinstein, PhD, et al/Cell.)
New Way to Visualize Cells
The MIT researchers saw an opportunity for DNA microscopy to
find genomic-level cell information. They claim that DNA microscopy images
cells from the inside and enables the capture of more data than with
traditional light microscopy. Their new technique is a chemical-encoded
approach to mapping cells that derives critical genetic insights from the
organization of the DNA and RNA in cells and tissue.
And that type of genetic information could lead to new precision medicine treatments for chronic disease. New Atlas notes that “ Speeding the development of immunotherapy treatments by identifying the immune cells best suited to target a particular cancer cell is but one of the many potential application for DNA microscopy.”
In their published study, the scientists note that “Despite enormous progress in molecular profiling of cellular constituents, spatially mapping [cells] remains a disjointed and specialized machinery-intensive process, relying on either light microscopy or direct physical registration. Here, we demonstrate DNA microscopy, a distinct imaging modality for scalable, optics-free mapping of relative biomolecule positions.”
How DNA Microscopy Works
The New York Times (NYT) notes that the advantage of DNA microscopy is “that it combines spatial details with scientists’ growing interest in—and ability to measure—precise genomic sequences, much as Google Street View integrates restaurant names and reviews into outlines of city blocks.”
And Singularity Hub notes that “ DNA microscopy, uses only a pipette and some liquid reagents. Rather than monitoring photons, here the team relies on ‘bar codes’ that chemically tag onto biomolecules. Like cell phone towers, the tags amplify, broadcasting their signals outward. An algorithm can then piece together the captured location data and transform those GPS-like digits into rainbow-colored photos. The results are absolutely breathtaking. Cells shine like stars in a nebula, each pseudo-colored according to their genomic profiles.”
“We’ve used DNA in a way that’s mathematically similar to photons in light microscopy,” Weinstein said in the Broad Institute news release. “This allows us to visualize biology as cells see it and not as the human eye does.”
In their study, researchers used DNA microscopy to tag RNA
molecules and map locations of individual human cancer cells. Their method is
“surprisingly simple” New Atlas reported. Here’s how it’s done,
according to the MIT news release:
Small synthetic DNA tags (dubbed “barcodes” by the MIT team) are added to biological samples;
The “tags” latch onto molecules of genetic material in the cells;
The tags are then replicated through a chemical reaction;
The tags combine and create more unique DNA labels;
The scientists use a DNA sequencer to decode and reconstruct the biomolecules;
A computer algorithm decodes the data and converts it to images displaying the biomolecules’ positions within the cells.
The visualization above was created from data gathered by DNA microscopy, which peers inside individual cells. It demonstrates how DNA microscopy enables scientists to identify different cells (colored dots) within a sample—with no prior knowledge of what the sample looks like. (Photo and caption copyright: Joshua Weinstein, PhD, et al./Cell.)
“The first time I saw a DNA microscopy image, it blew me away,” said Aviv Regev, PhD, a biologist at the Broad Institute, a Howard Hughes Medical Institute (HHMI) Investigator, and co-author of the MIT study, in an HHMI news release. “It’s an entirely new category of microscopy. It’s not just a technique; it’s a way of doing things that we haven’t ever considered doing before.”
Precision Medicine Potential
“Every cell has a unique make-up of DNA letters or genotype. By capturing information directly from the molecules being studied, DNA microscopy opens up a new way of connecting genotype to phenotype,” said Feng Zhang, PhD, MIT Neuroscience Professor,
Core Institute Member of the Broad Institute, and
Investigator at the McGovern Institute for Brain Research at MIT, in the HHMI
news release.
In other words, DNA microscopy could someday have applications in precision medicine. The MIT researchers, according to Stat, plan to expand the technology further to include immune cells that target cancer.
The Broad Institute has applied for a patent on DNA
microscopy. Clinical laboratory and anatomic pathology group leaders seeking
novel resources for diagnosis and treatment of cancer may want to follow the MIT
scientists’ progress.
Even in its early stages the Human Cell Atlas project is impacting the direction of research and development of RNA sequencing and other genetic tests
No one knows exactly how many cell types exist in the human body. Though traditional texts place numbers in the hundreds, recent studies have found ranges from thousands to tens of thousands. Anatomic pathologists and clinical laboratory scientists know that the discovery of new types of human cells could lead to the creation of new medical laboratory tests.
So, it’s an important development that leaders of the Human Cell Atlas Consortium, a project comparable to the Human Genome Project, have set out to determine the exact numbers of cell types. And their findings could open up an entirely new field of diagnostic testing for clinical laboratories and anatomic pathology and lead to advances in precision medicine.
With the ability to identify cell types and sub-types associated with human disease and health conditions, medical labs could have a useful new way to help physicians make diagnoses and select appropriate therapies.
Begun in 2016, the group’s mission according to the Human Cell Atlas website is “To create comprehensive reference maps of all human cells—the fundamental units of life—as a basis for both understanding human health and diagnosing, monitoring, and treating disease.”
The ambitious project aims to catalog every cell type in the human body and “account for and better understand every cell type and sub-type, and how they interact.”
Striving for Deeper Understanding of the Basics
Cells are the basic building blocks of life, but scientists don’t know exactly how many different types of cells there are.
In an NPR interview, Aviv Regev, PhD, Professor of Biology and a core member at the Broad Institute of MIT and Harvard, investigator at the Howard Hughes Medical Institute, and co-leader of the Human Cell Atlas Consortium, said, “No one really knows how many [cells types] there will be,” adding, “People guess anything from the thousands to the tens of thousands. I’m not guessing. I would rather actually get the measurements done and have a precise answer.”
In an innovative move, Regev and her team improved the method they were already using to sort cells—single-cell RNA sequencing. “All of sudden we moved from something that was very laborious—and we could do maybe a few dozen or a few hundred—to something where we could do many, many thousands in a 15- to 20-minute experiment,” she told NPR.
But the project is massive. A typical human body contains about 37.2 trillion cells. So, the Human Cell Atlas scientists decided to complete preliminary pilot projects to identify the most efficient and effective strategies for sampling and analyzing the various cells to create the full atlas.
“It’s kind of like we’re trying to find out what are all the different colors of Lego building blocks that we have in our bodies,” Sarah Teichmann, PhD, Head of Cellular Genetics and Senior Group Leader at Wellcome Sanger Institute in the UK, and co-leader of the Human Cell Atlas Consortium, told NPR. “We’re trying to find out how those building blocks—how those Lego parts—fit together in three dimensions within each tissue.”
Sarah Teichmann, PhD (left), and Aviv Regev, PhD (right), are co-leaders of the Human Cell Atlas Consortium, an ambitious project of MIT/Harvard Broad Institute that seeks to “create comprehensive reference maps of all human cells—the fundamental units of life—as a basis for both understanding human health and diagnosing, monitoring, and treating disease.” Such an advance could lead to significant advances in clinical laboratory and pathology testing and move healthcare closer to true precision medicine. (Photo copyrights: University of Cambridge and MIT/Broad Institute.
Some of the early pilot projects include a partnership with the Immunological Genome Project (ImmGen) to study and map the cells in the immune system. According to the Human Cell Atlas website, the partnership “will combine:
“deep knowledge of immunological lineages;
“clinical expertise and infrastructure needed to procure and process diverse samples;
“genomic and computational expertise to resolve the hundreds of finely differentiated cell types that compose all facets of the immune system; and,
the genomic signatures that define them.”
Other areas the pilot projects will address include:
the Human Developmental Cell Atlas (HDCS), which will investigate the highly specialized cells involved in human development.
Progress So Far
In the two short years since the Human Cell Atlas project began much work has already been accomplished, according to a news release. In addition to organizing the consortium and obtaining funding, the collaborators have published a white paper describing their goals and a framework for reaching them, as well as launching the pilot projects.
Such an ambitious project, however, is not without barriers and challenges. Regev and Teichmann, along with other collaborators, outlined some of those challenges in an article published in Nature.
The complexity of the human body combined with rapidly changing technology make simply agreeing on the scope of the project challenging. In order to meet that particular challenge, the collaborators plan to work in phases and drafts, which will allow for some flexibility and increasing focus on specifics as they go.
Other challenges include:
keeping the entire project open and fair;
procuring samples with consent and in an appropriate manner; and,
organizing in an efficient and effective manner.
The collaborators have developed and detailed strategies for meeting each of these challenges.
The Human Cell Atlas could impact treatments for every disease that affects humans and bring healthcare closer to accomplishing precision medicine goals. By knowing what cells exist in what parts of the human body—and how they typically behave at their most basic levels—the MIT/Harvard/Broad Institute scientists hope to understand what’s happening when those cells “misbehave” in expected ways. The knowledge garnered from the Human Cell Atlas is likely to be invaluable to anatomic pathologists and clinical laboratories.
Ongoing research at the University of Washington promises new methods for identifying and cataloging large numbers of cells quickly, which could lead to more individualized treatments in support of precision medicine initiatives
Researchers have found a new method for identifying specific cell types by groups, a breakthrough that some experts say could lead to new and more accurate methods for diagnosing and treating disease in individual patients, and new tools for fighting cancer and other chronic diseases. If this happens, both clinical laboratories and anatomic pathology labs would benefit from this technology.
A study published in the journal Science titled, “Comprehensive Single-Cell Transcriptional Profiling of a Multicellular Organism,” describes advances in cataloging cells that are much faster than the traditional method of using a microscope. The research is still in the experimental stage, but it is being hailed as both exciting and promising by experts in the field.
Barcoding Large Numbers of Cells for Viewing Simultaneously
To test their method, researchers from the University of Washington (UW) sequenced each cell of an individual Caenorhabditis elegans (nematode). Nematodes are transparent roundworms that have been extensively studied making them ideal for the UW study, since much information exists about their cellular structure.
“We came up with this scheme that allows us to look at very large numbers of cells at the same time, without ever isolating a single cell,” noted Jay Shendure, PhD, MD, Professor of Genome Sciences at the University of Washington.
The UW researchers used sci-RNA-seq to measure the activity in 42,035 cells at the same time. Once all of the cells were tagged, or barcoded, the researchers broke them open so the sequences of tags could be read simultaneously.
“We defined consensus expression profiles for 27 cell types and recovered rare neuronal cell types corresponding to as few as one or two cells,” wrote the researchers in their published study.
Because such a rich body of research on nematodes exists, the researchers could easily compare the results that got to those procured in previous studies.
Jay Shendure, MD, PhD (above), Professor of Genomic Sciences at the University of Washington, and an Investigator at the Howard Hughes Medical Institute, was just a graduate student when his work with genetics led to the development of today’s next-generation gene sequencing technologies. His new cell-type identification technology could eventually be used by clinical laboratories and anatomic pathology groups to diagnose disease. (Photo copyright: Howard Hughes Medical Institute.)
One Giant Leap for Medical Diagnostics
Identifying cell types has been a challenge to the medical community for at least 150 years. It is important for scientists to understand the most basic unity of life, but it has only been in the last few years that researchers have been able to measure transcriptomes in single cells. Even though the research so far is preliminary, the scientific community is excited about the results because—should the methods be refined—it could mean a great leap forward in the field of cell-typing.
However, the study did not identify all of the cell types known to exist in a nematode. “We don’t consider this a finished project,” stated Shendure in a New YorkTimes article.
Nevertheless, researchers not associated with the study feel confident about the promise of the work. Cori Bargmann, PhD, a neurobiologist and Torsten N. Wiesel Professor at The Rockefeller University, and an Investigator for the Howard Hughes Medical Institute from 1995 to 2016, states that the results “will be valuable for me and for the whole field,” adding, “Of course, there’s more to do, but I am pretty optimistic that this can be solved.”
“The ability to measure the transcriptomes of single cells has only been feasible for a few years, and is becoming an extremely popular assay,” wrote Valentine Svensson, predoctoral fellow et al, of EMBL-EBI in the UK, in a paper titled, “Exponential Scaling of Single-Cell RNA-Seq in the Last Decade.” He added, “Technological developments and protocol improvements have fueled a consistent exponential increase in the numbers of cells studied in single cell RNA-seq analyses.” The UW research represents another such improvement.
Human Cell Atlas—Understanding the Basis of Life Itself
There are approximately 37-trillion cells in the human body and scientists have long believed there are 200 different cell types. Thus, there is an enormous difference between a nematode and a human body. For medical science to benefit from these studies, massive numbers of human cells must be identified and understood. Efforts are now underway to catalog and map them all.
The Human Cell Atlas (HCA) is an effort to catalog all of those disparate cell types. The mission of HCA is “To create comprehensive reference maps of all human cells—the fundamental units of life—as a basis for both understanding human health and diagnosing, monitoring, and treating disease.”
According to HCA’s website, having the atlas completed will impact our understanding of every aspect of human biology, from immunologic diseases to cancer. Aviv Regev, PhD, of the Broad Institute at MIT, who also is an Investigator with the HHMI and is co-chair of the organizing committee at the Human Cell Atlas notes, “The human cell atlas initiative will work through organs, tissues, and systems.”
One of the many complications of creating the atlas is that the locations of cells vary in humans. “The trick,” Regev noted in the New York Times article, “is to relate cells to the place they came from.” This would seem to be at the heart of the UW researchers’ new method for “barcoding” groups of cells.
Just as sequencing the entire human genome has brought about previously unimagined advances in science, so too will the research being conducted at the University of Washington, as well as the completion of the Human Cell Atlas Project. It is possible that pursuing the goal of quickly identifying and cataloging cells will lead to advances in anatomic pathology, and allow medical laboratory scientists to better interpret genetic variants, ultimately bringing healthcare closer to the delivery of true precision medicine.
