How do you think this will benefit Columbia researchers? 

This is going to infuse lots of energy into our current collaborations. And I think it will spark even more. We have an amazing engineering school and an amazing medical center at Columbia, and we’ve built many long-standing relationships between engineering and medicine. So I think the Biden initiative will give a big boost to the many projects we’re already working on as well as inspire new groundbreaking ones. It's going to rejuvenate the field and encourage the amazing women's health researchers that we already have here to go even bigger. And it will be great for our junior faculty members to come on board and adapt their engineering tools for improving women's health research. 

We have an extraordinary group of researchers working in women’s health here. I’ve been at Columbia Engineering for more than 13 years and have been working very closely with Electrical Engineering Associate Professor Christine Hendon to use imaging to assess the mechanical properties of the cervix in relation to preterm birth. We are also collaborating with Noémie Elhadad, Biomedical Informatics and Department Chair at Columbia’s Vagelos College of Physicians and Surgeons. The core group of engineers and doctors have been working together for many years on women's health, gynecologic health, and pregnancy, using imaging, data, and computational simulations to build a bank of fundamental research that we can draw upon to design new techniques and devices to improve women’s health. Columbia has a community of very dedicated researchers who’ve been around for quite a while, but we've all been plagued by small funding pools. So this initiative will be huge both for us and for all the startups that are looking for funding -- they need fundamental research and financial backing to develop their new products.

How do you see this having an impact on your own work?

We are one of the first groups in the world to take maternal anatomy measurements throughout pregnancy, working with patients in a clinical trial at Columbia University Irving Medical Center (CUIMC) and then creating a digital twin of that individual pregnancy to understand how much mechanical load is on the uterus in the cervix and what might lead to a preterm birth. I'm a mechanical engineer and study design, practice design, and teach design to students, so I’m always looking at materials and wondering about their mechanical properties. When I was pregnant eight years ago, I lay there on the examining table, thinking “Hey, can I just spend five more minutes with this ultrasound and measure key anatomical features of me, the mom?” So that’s what we did. We started a clinical study in 2019 and our last patient in the study delivered last May.

President Biden’s announcement is really bringing awareness to the synergies that we researchers all have in women's health, engineering, research, and innovation. One of the interesting things resulting from this increased awareness of women’s health is the fact that the NIH issued a policy less than 10 years ago that states that sex as a biological variable must be factored into research designs, analyses, and reporting in vertebrate animal and human studies. Now you can't study only male monkeys, rodents, etc., which is a really important direction, especially in gynecologic health. In the past, many women’s symptoms such as uterine pain or heavy menstrual bleeding were dismissed -- people just thought of these as a normal part of life, that they didn’t indicate disease. But if we had more basic research data, we would have a much better idea of what healthy physiological functioning looks like, of what really is “normal.”

So I need more colleagues -- I can’t do it all myself. Everytime I fund a graduate student, I'm creating a new researcher in this field and increasing the pipeline. It’s critical for researchers like me to educate the next generation of engineers to solve these problems. And I'm excited about this announcement because my future trainees, my grad students, will read about this in the news and say, “Hey, I want to be in this field, and I can easily adapt what I'm already doing at the bench and work to improve women's health.

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Tell us about your journey from engineering into women’s health and how you decided to focus on the cervix.

I started off as a traditional mechanical engineer in the automotive industry, where I did research projects on things like exploding tires, thinking about how rubber heats and degrades. Once I got to graduate school as a young woman at MIT, I wanted to differentiate myself. I wanted to work on a project that was meaningful to me as an engineer, and I was introduced to the pregnancy mechanics project. This was an easy jump for me because the great thing about engineering is that we learn tools to solve problems. And in this case, I learned about structural mechanics. I was using the same analysis, tools, and material equations to think about how the cervix changes its material properties when exposed to the hormones of pregnancy. This is the work that my NSF Early Career grant was on, and I won the PECASE award for my research on exploring material mechanics of materials and the cervix, and how the cervix remodels itself. The cervix is analogous to rubber, with elastomers heating, degrading, and potentially breaking and becoming catastrophic. 

Working on the cervix and preterm birth issues with my colleagues at Columbia, we ran clinical studies on pregnant women who were eager to participate. Once we got the data from our studies, we made a digital twin by replicating the uterus virtually on the computer. We then ran simulated experiments on the computer to see what might happen under varying conditions. This is much more complicated than it sounds because the human body is really complex and there are so many things we still don’t know. This work will probably take my whole career because I'll keep improving my models with discoveries I make at the biological level with my collaborators. For instance, I’m working with a molecular biologist at the University of Texas Southwestern Medical Center in Dallas to understand the biology of tissue remodeling and I’m trying to figure out what the environmental triggers for that remodeling are. Over the last five years, I’ve integrated factors into my models such as anatomy shape and size, or structural anatomy and tissue material properties. We’ve actually done the measurements and taken the data of how the uterus and the cervix physically deform -- in fact, we’re the only team in the world with this kind of data.

Where will this data take your research next? What’s in store for the future? 

I now have a new hypothesis that we’ll be presenting at a conference in February. My group is going retrospectively into the imaging database at CUIMC in partnership with Mount Sinai, and we're planning to use AI to read all the ultrasounds of pregnancy to pick out a key anatomical feature that might lead to preterm birth. It’s great because we can test our hypothesis because the imaging database also has clinical outcomes -- this is where the AI and bioinformatics work comes in. Then we hope to create digital twins of phenotypes that are related to preterm birth. If we have a phenotype that's related to preterm birth based on this retrospective database, I can design a new therapeutic or a device to structurally bolster the cervix. 

I hope that in five years we'll have new diagnostic and therapeutic innovations and that our work will be translational. I want to reiterate that I can’t get there without first taking the data. I needed the observational study because nobody's measured these features before -- this is why fundamental research is so critical.

I want to lower the barrier of entry for engineers to work in the women's health and pregnancy space. I feel privileged that I have a longstanding relationship with a top-tiered research ob/gyn department and I want to bring more people into the field. The only way to do that is to open source and release all of our raw data sets, all of our models, and all of our model byproducts. 

Is this a long time coming?

Yes!

Your Trunk Support Trainer (TruST) is a great example of that. It was created to assist those with spinal cord injuries. Later, you demonstrated that it’s also effective in helping children with cerebral palsy. Was this an unexpected development, due to overlap in the nature of these disorders, or do you find that you often translate your work to meet different challenges?

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Poor trunk control is a functional impairment that we see in different medical conditions, including spinal cord injury, cerebral palsy, stroke and many others. The TruST robotic device was designed with the following goal in mind: How to provide active support to the trunk at different levels in the upper body while simultaneously challenging a participant to perform tasks that take them outside their base of support. Through an intensive training of the task and changing the level/magnitude of the support, participants are able to relearn and regain their muscle activity and coordination. A similar procedure could be applied to both participants with SCI and children with cerebral palsy. However, TruST had to be fine tuned for the two different patient groups. We just started a new National Institutes of Health-funded project to perform a clinical trial using TruST with a group of 85 children with cerebral palsy to evaluate the efficacy of TruST relative to typical standard of care. We are optimistic that TruST will be able to restore and retrain trunk control in children with cerebral palsy who absolutely need these to be functional in their daily life.

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.

About the Study

Journal: Nature Medicine

Title: Programmable bacteria induce durable tumor regression and systemic antitumor immunity

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

1. Department of Biomedical Engineering, Columbia University
2. Department of Microbiology & Immunology, Vagelos College of Physicians and Surgeons of Columbia University
3. Herbert Irving Comprehensive Cancer Center, Columbia University
4. Data 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).

COI: 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.

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.