By Carol Clark
The National Institutes of Health (NIH) awarded Emory University $5.6 million to establish a national center to advance pioneering technology for cellular mechanics. The center is directed by Khalid Salaita, Emory professor of chemistry, whose lab developed the first sensors for detecting cell-receptor forces at the molecular level.
“We’ve been working on our molecular-force probes for more than a decade,” Salaita says. “We’ve demonstrated that these probes can be used to visualize, measure and map cellular forces down to the level of piconewtons. The center allows us to get this technology into the hands of end users — researchers in the biomedical sciences.”
The Center for Molecular Mechanobiology encompasses labs from seven leading research institutions including: Children’s Hospital of Philadelphia, Dana-Farber Cancer Institute, Emory, Georgia Tech, Memorial Sloan Kettering, University of Utah and Vanderbilt University.
The center members will use the molecular-force probes to investigate the biomechanics of processes such as the clotting of blood cells, the response of immune cells to an infection and the migration of cancer cells. Better understanding these processes may lead to the development of new treatments and therapies for a range of diseases and disorders.
In addition to supplying the technology, the center will train researchers to use the molecular-force probes and help adapt the technology to answer specific biomedical research questions.
“Working directly with the research community will help us to further refine and optimize the technology,” Salaita says. “We envision that measuring cellular forces will soon become part of the standard repertoire of biochemical techniques that scientists use to study living systems.”
The center’s associate directors are Yonggan Ke (associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Emory and Georgia Tech) and Alexa Mattheyses (associate professor in the Department of Cell Developmental and Integrative Biology at the University of Alabama).
The five-year award from the National Institute of General Medical Sciences is part of the NIH Biomedical Technology Optimization and Dissemination Centers program. The goal is to optimize and disseminate state-of-the-art, late-stage biomedical technologies.
The first detailed view of mechanical forces
The Salaita lab works at the intersection of chemistry, biology and the physical sciences. It uses the building blocks of nature — nucleic acids — to create synthetic micro motors and probes for investigating fundamental questions of biology.
The molecular-force probes, developed by the Salaita lab in 2011, provide the first detailed view of the mechanical forces on the surface of a cell. The technology can detect mechanical forces as fleeting as the blink of an eye and as faint as piconewtons — about one billionth the weight of a paperclip.
The probes are made from strands of synthetic DNA tagged with fluorescence so that they function like molecular beacons, shining when they sense force. The technique is noninvasive, does not modify the cell and can be done with a standard fluorescence microscope.
In 2014, the lab used the new method to demonstrate how adherent cells — the kind that form the architecture of all multicellular organisms — mechanically sense their environments, migrate and stick to things.
In 2016, the molecular-force probes provided the first direct evidence for the mechanical forces of T cells, the security guards of the immune system. The lab’s experiments on T cells drawn from mice showed how they use a kind of mechanical “handshake” to test whether a cell they encounter is a friend or a foe.
In 2017, the lab shined its molecular beacons on platelets, the cells in the blood whose job is to stop bleeding by sticking together to form clots and plug up a wound. That work revealed the key molecular forces on platelets that trigger the clotting process.
In 2020, the lab and its collaborators combined advances in optical imaging with the molecular-force probes to capture forces at a resolution of 25 nanometers — far shorter than the length of a light wave. “That resolution is akin to being on the moon and seeing the ripples caused by raindrops hitting the surface of a lake on the Earth,” Salaita said at the time.
Key technological goals
The Center for Molecular Mechanobiology will build on this foundational work of the Salaita lab. It will focus on three key technological development goals:
• Optimizing the highest-resolution technique of the molecular-force probes so that it can be applied to a range of research questions.
• Tagging cells based on their force level in order to use force as a marker to barcode cells and their receptors. The idea is to classify the mechanics of individual cells and then link these classifications to gene-expression levels to study the cause-and-effect relationships.
• Amplifying the molecular-force signals to better understand the role of even the weakest forces involved in cellular mechanics, including those involved in the immune response.
Researchers from throughout the country will come to the Center for Molecular Mechanobiology to receive hands-on training in the molecular-force probes and then return to their home labs to become ambassadors for the technology.
“We’ll be adding a whole other layer of information for researchers working on everything from designing vaccines to cancer immunotherapy agents,” Salaita says.
Decades ago, he points out, complicated techniques such as crystallography, PCR and mass spectrometry were not frequently used but have since become routine workhorses in the biomedical sciences.
“We are catalyzing the process of spreading our technology so that studying biomechanics also becomes common and routine in biology,” Salaita says. “Molecular forces are a missing piece to understanding the way biology works.”
Related:
‘Firefly’ imaging method makes cellular forces visible
Chemists reveal the force within you
T cells use ‘handshakes’ to sort friends from foes
New methods reveal the mechanics of blood clotting
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