Institute hosted scientists from diverse fields to present transformative solutions to pressing medical needs, and unveiled new Diagnostics Accelerator
By Benjamin Boettner and Lindsay Brownell
(BOSTON) – The Wyss Institute for Biologically Inspired Engineering welcomed attendees from every populated continent to its 10th annual Wyss International Symposium on September 20, 2019 for an inspiring day of presentations about Next Generation Diagnostics. Co-organized by Wyss faculty members Sangeeta Bhatia, M.D., Ph.D., James Collins, Ph.D., Samir Mitragotri, Ph.D., David Walt, Ph.D., and Wyss Founding Director Donald Ingber, M.D., Ph.D., the event hit the maximum registration limit of 960 people, with about half of the audience from academia and the other half from government agencies, foundations, and a variety of industries.
Ingber, who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, and Professor of Bioengineering at Harvard’s John A. Paulson School of Engineering and Applied Sciences, opened the Symposium by welcoming the distinguished speakers and attendees, saying, “The future of diagnostics is not what we’ve seen in the past, and today we’ll get a first glimpse of where this field is rapidly moving.” The event featured three thematically linked groups of presentations, followed by the announcement and description of the Institute’s new Diagnostics Accelerator and a panel discussion chaired by Walt.
In the Symposium’s first session, speakers discussed novel diagnostic approaches for urgent medical problems in low-resource parts of the world. Wyss Institute Core Faculty member James Collins, a pioneer of the field of synthetic biology, reported different strategies by which synthetic gene circuits can be engineered to act as diagnostic platforms within living organisms. Collins is also the Termeer Professor of Medical Engineering & Science at MIT. His team was able to take the quorum-sensing system of the cholera-causing pathogen Vibrio cholerae and introduce it into the bacterium Lactobacillus lactis, enabling it to “eavesdrop” on cholera by reporting the presence and density of the pathogen in the gut with high sensitivity.
Collins’ lab is also freeze-drying and printing synthetic gene circuits onto paper, creating diagnostics that are cheap, easy to make, and do not require a cold chain for storage, making them ideal for use in low-resource settings. Leveraging CRISPR and RNA toehold technology, they have been able to engineer new paper-based diagnostics that can identify different strains of the Ebola and Zika viruses in patient samples within 12 hours, whereas commonly used methods often take days to weeks to produce results. Different paper-based diagnostics can measure the concentrations of Clostridium difficile, a potentially fatal colon-infecting pathogen that often spikes after antibiotic treatment, or the probiotic bacterium Bifidobacterium infantis, which is given to infants to help their microbiomes recover from antibiotics. The team is also exploring embedding synthetic gene circuits into “smart fabrics” that can rapidly report the presence of pathogens, metabolites, and toxins in different work environments.
Rebecca Richards-Kortum, Ph.D., who is the Malcolm Gillis University Professor of Bioengineering and Director of the Rice 360° Institute for Global Health at Rice University, presented a two-pronged strategy to accurately diagnose cervical cancer in women who do not have access to standard preventive care. Cervical cancer is the most preventable form of cancer, yet 250,000 women die from it every year, often because it is not diagnosed early enough. Additionally, while variants of human papilloma virus (HPV) DNA are used as a proxy for cervical cancer risk, 80 to 90% of women with HPV never develop cancer, and can be aggressively overtreated.
One arm of her team’s strategy to tackle this problem consists of a “hybrid capture reaction” that requires minimal energy to detect two high-risk HPV gene products using RNA probes in a portable, multiplexed amplification and detection device. The second arm is the “Colposcope”, a confocal microscope which can be built for less than $5,000 and produces high-resolution images of tissue samples that can be analyzed by a deep learning approach to diagnose cancer automatically and accurately. The test costs only a few dollars and can distinguish HPV-positive women with no signs of cancer from those with low- and high-grade cancer. Richards-Kortum and her co-workers are presently conducting a prospective study in Brazil to further evaluate the approach, and are looking for additional partners.
The third talk of the session, presented by Pardis Sabeti, M.D., D. Phil., Professor at the Center of Systems Biology and Department of Organismic and Evolutionary Biology at Harvard University and the Harvard T. H. Chan School of Public Health, and a member of the Broad Institute, centered on the epidemiology of the most recent Ebola outbreak and the creation of on-site approaches to much more rapidly predict the evolution and spread of the virus. Sabeti’s team has used next-generation sequencing methods to construct a “family tree” of the Ebola virus from thousands of samples obtained in Southern Guinea, Sierra Leone, and Liberia, and found that the virus’ genome acquired new mutations frequently, driving its rapid evolution. This analysis also correlated with the movement of the virus through Africa, including its exceptionally fast spread in Sierra Leone, where human-to-human contacts are more frequent due to infrastructure and trade activities.
Sabeti and a team of collaborators are now working towards a vision in which a network of hospital-connected National Genome Centers strategically placed in vulnerable countries can quickly detect future flare-ups of Ebola (and potentially other viruses such as Lassa) and predict how the virus will spread, to enable the best possible preparation. Her lab is also developing a next-generation diagnostic that, like Collins’ paper-based diagnostics, uses CRISPR technology to create multiple Ebola strain- and variant-specific sensors freeze-dried onto paper.
New Approaches to Clinical Diagnostics
The second session showcased new approaches to diagnosing cancer and birth defects driven by artificial intelligence (AI), sophisticated nucleic acid analysis, and state-of-the-art imaging technology. Regina Barzilay, Ph.D., Professor at the Department of Electrical Engineering and Computer Science at MIT, focused on the problem of assessing a patient’s risk of breast cancer, which is currently calculated based on a model that looks at common risk factors and mammogram images. Differences in interpretation by radiologists can lead to missed diagnoses and unnecessary treatment, and the model itself is not reliably predictive. Barzilay’s team has developed an AI approach that uses computational deep learning to visually identify dense breast tissue – a known but underused risk marker of breast cancer. They trained their algorithm on a large collection of available imaging data, and also integrated risk factors like BRCA gene mutation, family history, prior breast procedures, etc., enabling it to predict the occurrence of breast cancer more accurately than trained radiologists and significantly earlier. Barzilay’s model is also better at predicting breast cancer in ethnic groups where conventional physician-based methods are less reliable. Her group is also developing similar approaches for predicting pancreatic cancer from imaging data.
Dennis Lo, M.D., D. Phil., the Li Ka Shing Professor at The Chinese University of Hong Kong, next enlightened the audience with his account of “plasma DNA fragmentomics.” A tiny fraction of DNA released from dead cells in the body circulates as short fragments in blood plasma, and could potentially be used as diagnostic markers to learn about the presence and state of those cells. Lo’s team is focusing their exploration of plasma DNA in trisomy 21, the cause of Down’s Syndrome, as up to 15% of the DNA in a pregnant woman’s blood plasma comes from the fetus, making it easier to detect. They found that fetal DNA fragments from certain genomic regions are usually shorter than those from the mother, and developed diagnostic assays to test for fetus-specific abnormalities. Building on this capability, Lo and his colleagues are analyzing the enzymatic mechanisms that generate the short DNA fragments, allowing them to trace fragments back to their tissues of origin, which may lead to assays predicting various tissue-specific diseases as well as organ rejection after transplantation.
The session’s last speaker was Garry Nolan, Ph.D., the Rachford and Carlota A. Harris Professor at Stanford University School of Medicine. He is interested in better understanding the 3D organization of tumor cells and their surrounding environments as a means to predict their ability to avoid the body’s immune system – a major unmet need in cancer treatment. His team has developed a CODEX instrument that uses antibody-linked DNA nanotechnology to detect more 120 cell-specific markers simultaneously in cross-sections of colorectal cancers and analyze their microenvironments in a highly multiplexed analysis. The resulting cell maps show the organization of tumor cells, immune cells, and other cells in their “neighborhoods” at very high resolution.
Nolan’s team is building mathematical models with additional bioinformatic enhancements for predicting tumor qualities, prognosis, and effective ways to overcome drug resistances. They are also constructing an atomic microscope to decipher tumor pathologies down to individual atoms of visual detail.
In the third session, a diverse series of forward-looking diagnostic approaches were touched upon that encompassed multi-level monitoring of patients at home, infant care in neonatal intensive care units (NICUs), and non-invasive detection of biomarkers deep inside the human body.
Dina Katabi, the Andrew & Erna Viterbi Professor of Electrical Engineering and Computer Sciences at MIT, demonstrated the impressive diagnostic capabilities of her team’s wireless Emerald device. The device detects and evaluates disruptions of electromagnetic signals caused by humans’ movements, and thus can help monitor patients with Parkinson’s or Huntington’s disease, ataxia, and multiple sclerosis. The device, which resembles a wifi router, is sensitive enough to record heartbeats without requiring a patient to wear any sensing technology, and can monitor multiple people simultaneously, including patients and caregivers.
Applied to people with sleeping problems, Katabi’s approach can predict brain wave changes that correlate with the different stages of sleep with the same accuracy as hospital sleep labs, but without inconvenient cables, time-consuming recalibrations with new patients, or disparities in analysis between different sleep technicians. The Emerald box can also monitor breathing wirelessly with 97% accuracy, comparable to state-of-the-art devices, and has been deployed in more than 200 sites.
Presenting an entirely different kind of cable-free sensor technology, John Rogers, Ph.D. spoke about a new breed of soft electronic sensors that can integrate with various organ systems without the need for connecting cables, focusing on the skin. Rogers is the Louis Simpson and Kimberly Querrey Professor of Materials Science and Engineering at Northwestern University. His soft electronic sensors are inspired by silicon wafer-based electronic microchip technology, but instead of being rigid, he uses ultrathin silicon filaments or ribbons bonded to flexible materials. They are thus able to support large strain deformations without damage, and allow skin contact across their entire surface without interfering with skin stretching and folding. Rogers’ group has integrated small-scale sensor technologies into these flexible bandage-like devices to measure skin hydration, electrocardiographic signals, pressure in blood vessels, and other physiological parameters to enable them to be used as clinical-grade diagnostics.
These soft electronic sensors are now being tested in NICUs, where existing equipment used to monitor the vital signs of premature babies restricts their movement, prevents skin-to-skin contact necessary for bonding with their parents, needs to be cleaned or replaced daily, or uses adhesive pads that often damage fragile infant skin. Rogers’ team tested their sensors on babies as young as 24 weeks, monitoring heart rate, blood pressure, breathing rate, and blood oxygen level through wireless transmission. 50 nurses are currently trained in the use of the devices, and the team plans to deploy 15,000 units to India, Pakistan, Zambia, and other countries over the next 12 months to test them in low-resource settings.
In the session’s final talk, Wyss Associate Faculty member Sangeeta Bhatia asked the audience, “How do you get the body to tell you its secrets from deep inside tissue microenvironments without taking a biopsy?” Bhatia, who also is the John J. and Dorothy Wilson Professor at MIT, dove deep into her team’s development of “synthetic biomarkers” made by attaching up to a thousand fluorescently labeled peptide recognition sequences to a nanoparticle core. They first focused on sequences that match the family of matrix metalloproteases (MMPs), which are secreted by many cell types, including cancers, into their immediate environment. Injected into the bloodstream, the probes travel to target tissues where MMP activity liberates a fluorescently labeled peptide fragment that is filtered out by the kidneys and can be read out with a simple urine test.
Bhatia and her team are now working to make the assay more actionable by integrating it with a microfluidic assay that allows multiplexing and automation, and barcoding the protease recognition sequences with DNA tags so that they can be detected with CRISPR technology and nucleic acid sequencing or amplification systems. They are also investigating paper-based solutions for reading out synthetic biomarkers in urine by simple color changes that could make the tests more easily deployable as point-of-care diagnostics, and “breathalyzer” options that could detect the biomarkers in exhaled air instead of urine.
David Walt, Wyss Core Faculty member, Hansjörg Wyss Professor of Biologically Inspired Engineering at Harvard Medical School and Professor of Pathology at Brigham and Women’s Hospital, next took the stage for a special presentation advocating a paradigm shift in the way that diagnostic technologies are developed, informed by his experiences as co-founder of Illumina and Quanterix. He outlined the typical development path followed by companies looking to develop new diagnostics, in which a technology is applied to diagnostic tasks before involving clinicians, which frequently results in tests that are not useful in clinical settings for a variety of reasons. He then presented a redesigned diagnostics pipeline based on “design thinking,” in which the clinical need is the starting point for all diagnostic tests, and clinicians are involved from the very beginning.
Walt then announced the launch of the Diagnostics Accelerator at the Wyss Institute, an effort to re-frame the development of diagnostic technologies so that they are more effective and reach the clinic faster. At the core of the Accelerator is a deep collaboration between the Wyss Institute and Brigham and Women’s Hospital, in which clinicians will identify critical unmet medical needs and then work alongside Wyss scientists and engineers to develop solutions to those problems. A biomarker discovery lab has been set up at the Wyss Institute to identify biomarkers that are able to meet clinical specifications, and any promising technologies will be evaluated in a CLIA-certified laboratory facility at Brigham and Women’s Hospital, where clinicians will evaluate their effectiveness and enable their iteration. Roughly half of the Wyss Institute’s Core Faculty and many of its Associate Faculty and staff who are already involved in the development of novel sensor technologies and diagnostic development will play key roles in the Accelerator, which is expected to improve the speed with which effective diagnostics are approved and made available to the patients who need them.
Translational Challenges Panel
To conclude the Symposium, Walt moderated a fireside chat that included Christina Bender, Ph.D., MBA, Lead of Exploratory Biomarker Commercial Strategy and Global Commercial Oncology at Bristol-Myers Squibb; Chris Somerville, Ph.D., and Heather Youngs, Ph.D., both Program Officers of Scientific Research at Open Philanthropy Project; and Dan Wattendorf, M.D., Director of Innovative Technology Solutions at the Bill & Melinda Gates Foundation. The panel discussed translational challenges for next-generation diagnostics, including regulatory, technical, and clinical issues in patient populations, from philanthropic, regulatory, industry, and research perspectives. Bender pointed out the long time horizons required to develop new diagnostics as particularly challenging: “By the time a new technology is approved, it’s usually obsolete, and we have to constantly be thinking about how to improve it – complexity itself is the barrier.” Wattendorf conveyed the urgency of re-vamping how diagnostics are developed and used: “We need ground truth for measurements, and for measurements to have utility. Existing diagnostic tests are often used in ways that don’t have meaning for the clinicians.”
Wyss Founding Director Donald Ingber closed the Symposium by thanking the speakers and reflecting on the similarities between translational scientific research and solving a jigsaw puzzle: “Most conventional academic funding supports work focused on uncovering all the puzzle pieces, but that happens naturally over time. The real challenge is investing in efforts to start assembling the pieces together and getting answers, and that is precisely what we do at the Wyss Institute.”