They used high-resolution confocal fluorescence imaging to take movies of the process, together with biophysical approaches such as laser ablation, or laser nano-dissection, to measure the forces generated by the mutated myosin II motor proteins in vivo.

Kasza found that, while the mutated myosin II motor proteins actually went to the proper places inside cells and were able to generate force, the fine-scale organization of the myosin proteins and the speed of their movement inside cells were different than for the normal wild-type myosin protein. The team saw slower movements of cells within tissues that brought about abnormalities in embryo shape during development.

“By ‘watching’ how cells move and generate forces inside living tissues, we’ve uncovered new clues as to why mutations in the MYH9 gene cause a broad spectrum of disorders in humans,” Kasza observes. “Our work sheds new light on how motor proteins generate forces inside living tissues and on how genetic factors alter these forces to result in disease. This mechanistic understanding will help us better understand these diseases and could lead to new diagnostic or therapeutic strategies down the road.”

The researchers are now working on new approaches to very precisely manipulate the forces generated by myosin motors inside living cells and tissues. These new tools will help the team to uncover how mechanical forces influence biochemical processes that control cell movements and cell fate. These studies will be essential to better understanding how dysregulation of mechanical forces contributes to disease.

Columbia Engineering

Columbia Engineering, based in New York City, is one of the top engineering schools in the U.S. and one of the oldest in the nation. Also known as The Fu Foundation School of Engineering and Applied Science, the School expands knowledge and advances technology through the pioneering research of its more than 220 faculty, while educating undergraduate and graduate students in a collaborative environment to become leaders informed by a firm foundation in engineering. The School’s faculty are at the center of the University’s cross-disciplinary research, contributing to the Data Science Institute, Earth Institute, Zuckerman Mind Brain Behavior Institute, Precision Medicine Initiative, and the Columbia Nano Initiative. Guided by its strategic vision, “Columbia Engineering for Humanity,” the School aims to translate ideas into innovations that foster a sustainable, healthy, secure, connected, and creative humanity.

Images by Karen Kasza/Columbia Engineering | Photo Credit: Karen Kasza/Columbia Engineering & Sara Supriyatno/Sloan Kettering Institute

About the Study

The study is titled “Cellular defects resulting from disease-related myosin II mutations in Drosophila.”

Authors are: Karen E. Kasza1,2,; Sara Supriyatno1; and Jennifer A. Zallen1.

1Howard Hughes Medical Institute and Developmental Biology Program, Sloan Kettering Institute;

2Department of Mechanical Engineering, Columbia Engineering.

The study was supported by NIH/NIGMS R01 grant GM102803 to JAZ. KEK holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund, a Clare Boothe Luce Professorship, and a Packard Fellowship. JAZ is an investigator of the Howard Hughes Medical Institute.

The authors declare no financial or other conflicts of interest.

The researchers evaluated 142 samples, including patients with early Lyme disease, healthy individuals from areas where Lyme disease is endemic, and those with Lyme arthritis. They first screened a set of known diagnostic Lyme disease biomarkers for their ability to detect Lyme disease infection. They then tested the top three biomarkers using a standard enzyme immunoassay, and then mChip-LD, an advanced microfluidic platform developed by Sam Sia, to test the samples.

When tested against additional samples of serum from people with Lyme disease, the multiplexed set of biomarkers was more sensitive than standard Lyme disease tests, while also exhibiting high specificity. The team found that it was better at picking up signs of Lyme disease infection in early-stage samples—possibly because it was able to detect antibodies that peak in the first weeks after someone is infected with Lyme disease.

When the test was run on Sia’s mChip-LD platform, it worked very well, showing strong potential for the development of a point-of-care test for Lyme disease. “While the assay will require more refinement and testing before it can be approved for widespread use as a test for Lyme disease, our results are very exciting,” says one of the study’s lead authors, Siddarth Arumugam, who is a PhD student in Sia’s lab. “It will help so many people if we can develop a single, rapid, multiplexed diagnostic test to identify Lyme disease stage that can be used in doctors’ offices.”

Sia is the co-founder of Claros Diagnostics, whose underlying microfluidics technology is now being commercialized by OPKO Health and was recently approved by the FDA for testing for prostate cancer. He and Gomes-Solecki are now planning a more thorough clinical validation study to see whether the performance of the Lyme microfluidic platform holds up.

Columbia Engineering

Columbia Engineering, based in New York City, is one of the top engineering schools in the U.S. and one of the oldest in the nation. Also known as The Fu Foundation School of Engineering and Applied Science, the School expands knowledge and advances technology through the pioneering research of its more than 220 faculty, while educating undergraduate and graduate students in a collaborative environment to become leaders informed by a firm foundation in engineering. The School’s faculty are at the center of the University’s cross-disciplinary research, contributing to the Data Science Institute, Earth Institute, Zuckerman Mind Brain Behavior Institute, Precision Medicine Initiative, and the Columbia Nano Initiative. Guided by its strategic vision, “Columbia Engineering for Humanity,” the School aims to translate ideas into innovations that foster a sustainable, healthy, secure, connected, and creative humanity.

About the Study

The study is titled “A Multiplexed Serologic Test for Diagnosis of Lyme Disease for Point-of-Care Use.”

Authors are: Siddarth Arumugam a; Samiksha Nayak a; Taylor Williams b; Francesco Serra di Santa Maria a; Mariana Soares Guedes b,c; Rodrigo Cotrim Chaves a; Vincent Linder d; Adriana R. Marques e; Elisabeth J. Horn f; Susan J. Wong g; Samuel K. Sia a; and Maria Gomes-Solecki b,c.

a Department of Biomedical Engineering, Columbia Engineering

b Immuno Technologies Inc, Memphis, TN

c Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center

d OPKO Diagnostics LLC, Woburn, MA

e Lyme Disease Studies Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health

f Lyme Disease Biobank, Portland, OR

g Wadsworth Center, New York State Department of Health, Axelrod Institute

The study was supported by Public Health Service grant (R44 AI096551), and in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Conflicts of interest: M.G.S. is an employee of Immuno Technologies, Inc, and V.L. was an employee of OPKO Diagnostics, LLC while engaged in the research project. We thank the National Institutes of Health, National Institute of Allergy and Infectious Diseases for funding support (grant R44 AI096551) to M.G.S. via Immuno Technologies, Inc. M.G.S. holds 5% or more financial interest in Immuno Technologies, Inc. M.G.S. and A.R.M. hold relevant patents. V.L. declares a financial interest in OPKO Health. S.A., S.N., F. S. S. M., T.W., R.C.C., M.G., S.J.W. and S.K.S. declare no competing financial interests.

“To the best of my knowledge, Professor Agrawal and his team have investigated, for the first time, the muscle mechanisms in the neck muscles of patients with ALS. Their neck brace is such an important step in helping patients with ALS, a devastating and rapidly progressive terminal disease,” said Hiroshi Mitsumoto, Wesley J. Howe Professor of Neurology at the Eleanor and Lou Gehrig ALS Center at Columbia University Irving Medical Center who, along with Jinsy Andrews, assistant professor of neurology, co-led the study with Agrawal. “We have two medications that have been approved, but they only modestly slow down disease progression. Although we cannot cure the disease at this time, we can improve the patient’s quality of life by easing the difficult symptoms with the robotic neck brace.”

Commonly known as Lou Gehrig’s disease, ALS is a neurodegenerative disease characterized by progressive loss of muscle functions, leading to paralysis of the limbs and respiratory failure. Dropped head, due to declining neck muscle strength, is a defining feature of the disease. Over the course of their illness, which can range from several months to more than 10 years, patients completely lose mobility of the head, settling in to a chin-on-chest posture that impairs speech, breathing, and swallowing. Current static neck braces become increasingly uncomfortable and ineffective as the disease progresses.

To test this new robotic device, the team recruited 11 ALS patients along with 10 healthy, age-matched subjects. The participants in the study were asked to perform single-plane motions of the head-neck that included flexion-extension, lateral bending, and axial rotation. The experiments showed that patients with ALS, even in the very early stages of the disease, use a different strategy of head-neck coordination compared to age-matched healthy subjects. These features are well correlated with clinical ALS scores routinely used by clinicians. The measurements collected by the device can be used clinically to better assess head drop and the ALS disease progression. 

“In the next phase of our research, we will characterize how active assistance from the neck brace will impact ALS subjects with severe head drop to perform activities of daily life,” said Agrawal, who is also a member of Columbia University’s Data Science Institute. “For example, they can use their eyes as a joystick to move the head-neck to look at loved ones or objects around them."

Columbia Engineering

Columbia Engineering, based in New York City, is one of the top engineering schools in the U.S. and one of the oldest in the nation. Also known as The Fu Foundation School of Engineering and Applied Science, the School expands knowledge and advances technology through the pioneering research of its more than 220 faculty, while educating undergraduate and graduate students in a collaborative environment to become leaders informed by a firm foundation in engineering. The School’s faculty are at the center of the University’s cross-disciplinary research, contributing to the Data Science Institute, Earth Institute, Zuckerman Mind Brain Behavior Institute, Precision Medicine Initiative, and the Columbia Nano Initiative. Guided by its strategic vision, “Columbia Engineering for Humanity,” the School aims to translate ideas into innovations that foster a sustainable, healthy, secure, connected, and creative humanity.

About the Study

The study is titled “A Robotic Brace to Characterize Head-Neck Motion and Muscle EMG in Subjects with ALS.”

The authors are Haohan Zhang (Columbia Engineering); Biing-Chwen (Columbia University); Jinsy Andrews (Columbia University College of Physicians and Surgeons, Department of Neurology and ALS center); Hiroshi Mitsumoto (Columbia University, Department of Neurology and ALS center); and Sunil Agrawal (Columbia Engineering, Department of Mechanical Engineering and Rehabilitation Medicine). 
 

The authors declare they have no competing financial interests.

The study was led in collaboration with Nicholas Arpaia, assistant professor of microbiology & immunology at CUIMC, and co-senior author on the publication. The team combined their expertise in synthetic biology and immunology to engineer a strain of bacteria able to grow and multiply in the necrotic core of tumors. When bacteria numbers reach a critical threshold, the non-pathogenic E. coli are then programmed to self-destruct, allowing for effective release of therapeutics and preventing them from wreaking havoc elsewhere in the body. Subsequently, a small fraction of bacteria survive lysis and reseed the population, allowing for repeated rounds of drug delivery inside treated tumors. The proof of concept in programming the bacteria in this way was originally developed a few years ago (Din & Danino et al. Nature 2016). In the current study, the authors chose to release a nanobody that targets a protein called CD47.

CD47, a “don’t-eat-me” signal, protects cancer cells from being eaten by innate immune cells such as macrophages and dendritic cells. It is found in abundance on a majority of human solid tumors and has recently become a popular therapeutic target.

“But CD47 is present elsewhere in the body, and systemic targeting of CD47 results in significant toxicity as evidenced by recent clinical trials. To solve this issue, we engineered bacteria to target CD47 exclusively within the tumor and avoid systemic side-effects of treatment,” adds Sreyan Chowdhury, the paper’s lead author and a PhD student co-mentored by Arpaia and Danino.

The combined effect of bacterially induced local inflammation within the tumor and the blockade of CD47 leads to increased ingestion, or phagocytosis of tumor cells and subsequently to enhanced activation and proliferation of T cells within the treated tumors. The team found that treatment with their engineered bacteria not only cleared the treated tumors but also reduced the incidence of tumor metastasis in multiple models.

“Treatment with engineered bacteria led to priming of tumor-specific T cells in the tumor that then migrated systemically to also treat distant tumors,” Arpaia says. “Without both live bugs lysing in the tumor and the CD47 nanobody payload, we were not able to observe the therapeutic or abscopal effects.”

The team is now performing further proof-of-concept tests, as well as safety and toxicology studies, of their engineered immunotherapeutic bacteria in a range of advanced solid tumor settings in mouse models. Positive results from those tests may lead to a clinical trial in patients. They are also collaborating with Gary Schwartz, CUIMC’s chief of hematology/oncology and deputy director of the Herbert Irving Comprehensive Cancer Center, on clinical translation aspects of their work, and have started a company to translate their promising technology to patients.

Columbia Engineering

Columbia Engineering, based in New York City, is one of the top engineering schools in the U.S. and one of the oldest in the nation. Also known as The Fu Foundation School of Engineering and Applied Science, the School expands knowledge and advances technology through the pioneering research of its more than 220 faculty, while educating undergraduate and graduate students in a collaborative environment to become leaders informed by a firm foundation in engineering. The School’s faculty are at the center of the University’s cross-disciplinary research, contributing to the Data Science Institute, Earth Institute, Zuckerman Mind Brain Behavior Institute, Precision Medicine Initiative, and the Columbia Nano Initiative. Guided by its strategic vision, “Columbia Engineering for Humanity,” the School aims to translate ideas into innovations that foster a sustainable, healthy, secure, connected, and creative humanity.

About the Study

The study is titled “Programmable bacteria induce durable tumor regression and systemic antitumor immunity.”

Authors are: Sreyan Chowdhury1,2; Samuel Castro1; Courtney Coker1; Taylor E. Hinchliffe1; Nicholas Arpaia2,3; Tal Danino1,3,4

1Department of Biomedical Engineering, Columbia University

2Department of Microbiology & Immunology, Vagelos College of Physicians and Surgeons of Columbia University

3Herbert Irving Comprehensive Cancer Center, Columbia University

4Data Science Institute, Columbia University

This work was supported by the NIH Pathway to Independence Award (R00CA197649-02) (T. Danino), DoD Idea Development Award (LC160314) (T. Danino), DoD Era of Hope Scholar Award (BC160541) (T. Danino), NIH NIGMS (R01GM069811) (T. Danino), NIH K22AI127847 (N. Arpaia), Searle Scholars Program SSP-2017-2179 (N. Arpaia), Bonnie J. Addario Lung Cancer Foundation Young Investigators Team Award (N. Arpaia and T. Danino) and the Roy and Diana Vagelos Precision Medicine Pilot Grant (N. Arpaia and T. Danino).

S. Chowdhury, N.A., and T.D. have filed a provisional patent application with the US Patent and Trademark Office (US Patent Application No. 62/747,826) related to this work. T.D. and N.A. 270 have a financial interest in GenCirq, Inc.

New York, NY—May 7, 2019—Lung transplantation, the only life-saving therapy for an increasing population of patients with end-stage lung disease, is severely limited by the number of available donor organs. Currently, up to 80% of donor lungs are rejected for serious but potentially reversible injuries. Since the beginning of transplantation in 1960s, clinicians and scientists have been trying to address the critical shortage of donor organs.

Now, a multidisciplinary team from Columbia Engineering and Vanderbilt University has—for the first time—demonstrated in a clinically relevant model that severely damaged lungs can be regenerated to meet transplantation criteria. In a study published today on Nature Communications’ website, the researchers describe the cross-circulation platform that maintained the viability and function of the donor lung and the stability of the recipient for 36 to 56 hours. As Brandon Guenthart, a lead author of the study, explains “to support lung recovery and to demonstrate cellular regeneration, we had to pursue a radically different approach and develop more minimally invasive diagnostics.” Current methodologies of lung support are limited to only 6 to 8 hours, a time that is too short for therapeutic interventions that could regenerate the injured lung and improve its function.

The team, co-led by Gordana Vunjak-Novakovic, University Professor and The Mikati Foundation Professor of Biomedical Engineering and Medical Sciences at Columbia Engineering, and Matthew Bacchetta, the H. William Scott Professor of Surgery at Vanderbilt University and adjunct professor at Columbia’s department of biomedical engineering, also developed new diagnostic tools for the non-invasive evaluation of the regenerating lung. They expect their advance will lead to an increase in the number of lungs for transplant through the recovery of severely damaged lungs that are currently unsuitable for clinical use. Lungs throughout 36 hours of ex vivo support. 

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The researchers have long been focused on developing processes to recover lungs that are being turned down for transplant because of injury to enable people with end-stage lung disease to live longer and better lives. “We have been fortunate to assemble a highly talented, interdisciplinary team of bioengineers, surgeons, pulmonologists, and pathologists, who have designed a durable physiologic support system for a donor lung outside the body, along with new technologies to achieve and monitor lung recovery,” Bacchetta says.

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A previous study from the team demonstrated a cross-circulation platform that maintained the viability and function of a donor lung for 36 hours. The researchers were able to use their advanced support system to fully recover the functionality of lungs injured by ischemia (restricted blood supply) and make them suitable for transplant.

For this new study, the team decided to test the effectiveness of their platform technology combined with conventional therapies and new diagnostics on lungs afflicted by the most frequent injury leading to donor lung rejection—gastric aspiration. This injury is caused by the entry of gastric material into the respiratory tract, resulting in severe injury to the pulmonary epithelium and thus making the lung unacceptable for transplantation. Currently, severely damaged donor lungs cannot be salvaged using existing devices or methods. This new study suggests that lungs injured by gastric aspiration can be maintained outside the body for several days, are amenable to repeated therapeutic interventions, and display evidence of cellular regeneration and improved function. Lungs regenerated on this platform met all criteria for transplantation.

“For seven years, we have diligently worked to develop new technologies for the maintenance and recovery of donor organs. This paper represents a culmination of fundamental and translational studies of lung bioengineering that have converged into a system capable to recover severely damaged lungs. We now have the team and technology to bring this research to the patients, by making more donor lungs available for transplant,” says Vunjak-Novakovic.

The team plans to conduct further studies to evaluate the functional capacity of the lungs following transplantation and the safety of the method, using a clinically relevant large animal model with immunosuppression.

“We envision that interventional cross-circulation may be used to investigate regeneration of other damaged organs, such as hearts, kidneys, and livers, expanding donor pools by salvaging severely damaged organs and leading to more organ transplants,” Bacchetta adds. 

Columbia Engineering

Columbia Engineering, based in New York City, is one of the top engineering schools in the U.S. and one of the oldest in the nation. Also known as The Fu Foundation School of Engineering and Applied Science, the School expands knowledge and advances technology through the pioneering research of its more than 220 faculty, while educating undergraduate and graduate students in a collaborative environment to become leaders informed by a firm foundation in engineering. The School’s faculty are at the center of the University’s cross-disciplinary research, contributing to the Data Science Institute, Earth Institute, Zuckerman Mind Brain Behavior Institute, Precision Medicine Initiative, and the Columbia Nano Initiative. Guided by its strategic vision, “Columbia Engineering for Humanity,” the School aims to translate ideas into innovations that foster a sustainable, healthy, secure, connected, and creative humanity..

About the Study

The study is titled “Recovery of severely damaged lungs using an interventional cross-circulation platform.”

Authors are: Brandon A Guenthart, John D O’Neill, Jinho Kim, Dawn Queen, Scott Chocotka, Kenmond Fung, Michael Simpson, Rachel Donocoff, Michael Salna, Charles C Marboe, Katherine Cunningham, Susan P Halligan, Holly M Wobma, Ahmed E Hozain, Alexander E Romanov, Hans-Willem Snoeck, Vunjak-Novakovic G, Matthew Bacchetta.

Brandon A. Guenthart 1,2,9; John D. O’Neill 1,9; Jinho Kim 1,3; Dawn Queen 1; Scott Chicotka 2; Kenmond Fung 4; Michael Simpson 2; Rachel Donocoff 5; Michael Salna 2; Charles C. Marboe 6; Katherine Cunningham 1; Susan P. Halligan 1; Holly M. Wobma 1; Ahmed E. Hozain 1,2; Alexander Romanov 5; Gordana Vunjak-Novakovic 1,7; and Matthew Bacchetta 1,8

1 Department of Biomedical Engineering, Columbia University Medical Center (CUMC)
2 Department of Surgery, CUMC
3 Department of Biomedical Engineering, Stevens Institute of Technolog.
4 Department of Clinical Perfusion, CUMC
5 Institute of Comparative Medicine, CUMC
6 Department of Pathology and Cell Biology, CUMC
7 Department of Medicine, CUMC
8 Department of Thoracic and Cardiovascular Surgery, Vanderbilt University

The study was supported by grants from the National Institutes of Health (R01 HL120046, U01 HL134760, P41 EB002520), Blavatnik Foundation, and the Mikati Foundation.  

The authors declare no competing financial interests.

The researchers knew that, while many bacteria can grow inside a tumor because of the reduced immune system there, bacteria are killed outside the tumor where the body’s immune system is active. Inspired by this mechanism, they searched for an antibacterial agent that can mimic the bacteria “killing” effect outside the spheroids.

They developed a protocol that uses the antibiotic gentamicin to grow bacteria inside spheroids that are similar to tumors in the body. Using BSCC, they then rapidly tested a broad range of programmed anticancer bacterial therapies made of various types of bacteria, genetic circuits, and therapeutic payloads.

“We used 3D multicellular spheroids because they recapitulate conditions found in the human body, such as oxygen and nutrient gradients—these can’t be made in a traditional 2D monolayer cell culture,” says the paper’s lead author Tetsuhiro Harimoto, who is a PhD student in Danino’s lab. “In addition, the 3D spheroid provides bacteria with enough space to live in its core, in much the same way that bacteria colonize tumors in the body, also something we can’t do in the 2D monolayer culture. Plus, it’s simple to make large numbers of 3D spheroids and adapt them for high-throughput screening.”

The team used the BSCC’s high-throughput system to rapidly characterize pools of programmed bacteria and then to quickly narrow down the best candidate for therapeutic use. They discovered a potent therapy for colon cancer, using a novel bacterial toxin, theta toxin, combined with an optimal drug delivery genetic circuit in attenuated bacteria Salmonella Typhimurium. They also found new combinations of bacterial therapies that can improve anticancer efficacy even more.

The researchers compared their BSCC results to those found in animal models and found similar behavior of bacteria in those models. They also discovered that their top candidate—theta toxin—is more potent than therapies created in the past, demonstrating the power of BSCC’s high-throughput screening.

While Danino’s group focused on cancer therapy in this study, they hope to expand BSCC to characterize bacteria-based therapeutics for various diseases, including gastrointestinal disease and infections. Their ultimate goal is to use these new bacterial therapies in clinics around the world.

Columbia Engineering

Columbia Engineering, based in New York City, is one of the top engineering schools in the U.S. and one of the oldest in the nation. Also known as The Fu Foundation School of Engineering and Applied Science, the School expands knowledge and advances technology through the pioneering research of its more than 220 faculty, while educating undergraduate and graduate students in a collaborative environment to become leaders informed by a firm foundation in engineering. The School’s faculty are at the center of the University’s cross-disciplinary research, contributing to the Data Science Institute, Earth Institute, Zuckerman Mind Brain Behavior Institute, Precision Medicine Initiative, and the Columbia Nano Initiative. Guided by its strategic vision, “Columbia Engineering for Humanity,” the School aims to translate ideas into innovations that foster a sustainable, healthy, secure, connected, and creative humanity.

About the Study

The study is titled “Rapid screening of engineered microbial therapies in a 3-D multicellular model.”

Authors are: Tetsuhiro Harimoto a, Zakary S. Singer a, Oscar S. Velazquez a, Joanna Zhang a, Samuel Castro a, Taylor E. Hinchliffe a, William Mather b, and Tal Danino a,c,d.

a Department of Biomedical Engineering, Columbia Engineering

b BioCircuits Institute, University of California, San Diego

c Data Science Institute, Columbia University

d Herbert Irving Comprehensive Cancer Center, Columbia University

The study was supported by Honjo International Scholarship Foundation 4160341 (Tetsuhiro Harimoto), National Cancer Institute F32CA225145 (Zakary Singer) R00CA197649-02 & P30CA013696 (Tal Danino), and Department of Defense LC160314 & BC160541 (Tal Danino).

T.H., Z.S.S., and T.D. have filed a provisional patent application with the US Patent and Trademark Office related to this work.