Year: 2023
Type: article
Abstract: The concept of disruptive technology was first introduced in a 1997 Harvard Business Review article, where “disruptive innovation” is described as a process by which a smaller company with fewer resources can successfully challenge and replace a larger established business. Disruptive technologies are further distinguished from sustaining ones with the latter maintaining the status quo by providing incremental improvements. Whereas disruptive technologies at first seem inferior to existing ones, over time they improve upon and replace the sustaining product. In the in vitro diagnostics (IVD) industry, the term “disruption” could mean the introduction of a new biomarker or new method for diagnosis or prediction of disease. Undoubtedly, the introduction of continuous flow analyzers, PCR, and mass spectrometry are prime examples of disruptive innovations in our industry. The story behind the making of these disruptive innovations have 2 common underpinnings: they started as ideas either in research labs or small companies and took years to develop and improve through collaborative efforts of a team of scientists. Eventually these technologies changed the way we deliver laboratory services and diagnose disease. What will be the next disruptive innovation in laboratory medicine? Sequencing technologies, microfluidics, machine learning, and artificial intelligence are a few technologies our profession is watching closely with both hope and skepticism. In 2018, AACC launched the first annual Disruptive Technology Award Competition. Each year the competition has recognized innovative solutions from several IVD startups. Here we invite a few finalists and semifinalists from the 2019 to 2022 competitions to talk about their breakthroughs, challenges, and successes. Jong Lee: Day Zero Diagnostics is developing a rapid infectious disease diagnostic that combines whole-genome sequencing and machine learning to identify both the species and the antibiotic resistance profile of a bacterial pathogen directly from a blood sample—without the need for culture—speeding up diagnosis from days to hours. Vamsee Pamula: Digital Microfluidics (DMF) is the underlying technology engine for our innovation. In a DMF cartridge, discrete droplets are manipulated through modulation of interfacial tension on an electrode array. We demonstrated droplet operations such as transport, merging, splitting, mixing, and dispensing, simply by varying voltage patterns. With no fixed channels in the cartridge, droplets can freely move in any direction, and with no mechanical pumps or valves, the instrument can be greatly miniaturized. With these LEGO-like building blocks of droplet operations, we have demonstrated chemistry, molecular, viscoelastic, microbiology, and immunoassay functionalities—all on the same cartridge and using the same instrument platform. These capabilities pave the way for multifunctional syndromic testing, which is a seamless combination of multiple types of tests that are performed to resolve the signs and symptoms associated with any clinical condition. Ajay Shah: Sepsis is among the most common and costly conditions to impact the Emergency Department (ED). Over 80% of sepsis cases present to the ED and these patients can deteriorate rapidly. Sepsis is fundamentally an overwhelming and life-threatening response to an infection. Since not every instance of infection results in sepsis and many other conditions have a similar initial presentation, it is challenging to rapidly identify septic patients amongst the plethora of patients with a simple infection or other maladies. The recently food and drug administration-cleared IntelliSep test aims to provide new clarity using a first of its kind assessment of innate immune dysfunction that evaluates the activation of leukocytes by interrogating their mechanical properties. Unlike previous approaches that evaluate the downstream consequences of immune activation, our innovation directly assesses tens of thousands of cells and provides a direct indication of the immune dysregulation at the root of sepsis via a simple score from 0.1 to 10.0, split into 3 interpretation bands for easy clinical interpretation. Timothy Sweeney: Inflammatix is building novel IVDs for acute infections and sepsis based on “reading” patterns of the host immune response. We have a disposable cartridge that can quantitate dozens of mRNAs direct from samples in a rapid, point-of-care instrument, MyRNA™, and we have novel machine learning algorithms that can read those mRNA patterns to produce new diagnostic insights. Our first test, TriVerity™, is not yet FDA-cleared, but is designed to help physicians determine next best steps in diagnosis and treatment at ED triage. The test can separate bacterial infections, viral infections, and non-infectious illness, and simultaneously estimate the patient’s need for organ support over the next 7 days. Amogha Tadimety: Nanopath is taking a radically different approach to molecular diagnostics. Molecular diagnostic testing is currently dominated by nucleic acid amplification tests (NAATs), such as PCR. In addition to requiring numerous external reagents, these processes are time-intensive, expensive, and generally require trained laboratory technicians in centralized laboratories. Hundreds of millions of dollars have been invested into trying to shorten required amplification times, and thus, time to result, but are hampered by inherent limitations of the technology. Nanopath’s Platform takes a radically different approach, harnessing advances in bioengineering and nanotechnology to sensitively and specifically detect target nucleic acid sequences without nucleic acid amplification. Jong Lee: High-throughput sequencing has been a looming “disruptive technology” for diagnostic labs now for at least a decade. But for most infectious disease labs, it has mainly been a promising research technology viewed from afar rather than something that impacts their daily patient diagnostic routines. But what if you could combine the capabilities of high-throughput sequencing, with enabling technologies to make it reliable enough and simple enough to use it for everyday clinical decision making? That would be truly disruptive. At Day Zero Diagnostics, we have focused on building capabilities that can enable clinical laboratories to unlock the power of sequencing to provide rapid, agnostic high-resolution organism ID as well as antibiotic susceptibility profiling directly from clinical samples, rather than culture. Our first development effort has focused on bloodstream infections, but the platform can be applied to cerebrospinal fluid, respiratory samples, urine, and a range of other sample types so that scaled, cost-effective sequencing can be the backbone of a molecular diagnostic program for a clinical infectious disease laboratory. A clear example of this disruption is in antibiotic-resistant bacteria. Today, all diagnostics that are capable of providing antibiotic susceptibility profiles are based in culture, which can take days to grow. Even for a rapid molecular diagnostic, waiting for a culture sample means that it loses most of the opportunity to impact patient care decisions. Our solution is sensitive enough to work directly from a complex clinical sample like blood, without the need for culture, and to provide a highly sensitivity and specific organism ID as well as an antibiotic susceptibility profile. By reducing time to diagnosis to “day zero,” meaning the first day a patient is admitted, our technology has the potential to dramatically reduce hospital length of stay, the overuse of expensive or ineffective antibiotics and excess mortality. Vamsee Pamula: Disruptive technology should unleash entirely new ways of healthcare delivery that previously were unthinkable; this generally comes from new entrants to the field whose thinking is not hampered by prevailing dogma. Current technologies need to be cannibalized if disruptive technologies are adopted, which is logically a dilemma for companies with pre-existing technologies. Diagnostic testing draws upon results from different sections of a laboratory using different instrumentation and different sample types. DMF enables multifunctional syndromic testing with different sample types on a single instrument. For example, a single DMF cartridge and instrument can be used to combine chemistry, molecular, and microbiology assays for sepsis, or chemistry, viscoelastic, and immunoassays for thrombophilia. The capability to run any combination of tests from different sample types for rapid diagnosis at the point-of-care can significantly alter the way healthcare is delivered. Diagnostics will be much more accessible when everybody can be tested anywhere using any combination of tests. Ajay Shah: A disruptive technology forever changes the status quo and opens up new opportunities for the advancement of society, or in the case of medicine, patient care. These are commonly first-in-kind innovations that satisfy fundamental needs. The fundamental need we focused on is sepsis. Providers currently rely on a mixture of available measurements, clinical judgment, and non-specific biomarkers to separate sepsis from disease mimickers. Cytovale aims to provide a rapid indicator of immune dysregulation that can answer this critical question in time to act quickly. Given its groundbreaking ability to interrogate thousands of immune cells in seconds and provide a direct measure of immune activation in under 10 min, the IntelliSep test has the potential to revolutionize care for sepsis patients in the ED. Timothy Sweeney: I think the idea is that disruptive technology isn’t incremental—it isn’t merely a decrease in cost or a faster turnaround—it is a technology whose adoption requires (or forces) a fundamental change in the system. In the case of host-response diagnostics, that change is in the workflows of the ordering physicians. The goal is to improve patient outcomes by fundamentally changing the acute infection pathway to get patients more accurate care, more quickly. Amogha Tadimety: Our approach is disruptive on the basis of both its underlying technology and its initial application. Pragmatically, our technology allows us to dramatically shorten time to result. Our current total time to result is 15 min, and there is a clear path down to 5 to 7 min. Our platform also has the ability to identify subtle changes in genetic sequence, enabling access to a granularity of information that has never been previously accessible at the point-of-care. Arguably more disruptive is our intentional focus on underserved populations, starting with women. Women’s health has been a consistently under-innovated space, and inclusive healthcare is foundational to gender equity. Our lead product pipeline looks to address a range of pelvic and gynecologic infections that can be treated within an outpatient setting. While our initial focus is on women, we anticipate broad applicability of our technology across use cases. Jong Lee: Day Zero Diagnostics was launched out of the growing frustration of one of our cofounders, Dr. Doug Kwon, an infectious disease physician at Mass General Hospital, who was tired of having to treat patients with ever more powerful, broad-spectrum antibiotics that he knew could be toxic. But in a world of growing antibiotic resistance, he had no choice but to treat blindly because there was no diagnostic that could provide him with the timely information he needed to guide early treatment. Day Zero Diagnostics was launched to address this significant public health need. Antibiotic resistance is a worldwide health crisis directly responsible for at least 1.2 million deaths per year and is expected to grow. We saw the radical pace of change and reduction in cost that was happening with next-generation sequencing, and we had an idea about how whole-genome sequencing could be employed to deliver organism ID and antibiotic susceptibility profiles in hours rather than days. While many companies focus on a solution in search of a problem, we had an intimate knowledge of the clinical problem we wanted to solve. We combined it with a founding team that had an outstanding track record of solving difficult technical and scientific problems as well—a requirement when you take on a challenge as big as sepsis. In time, the mission grew and we realized the potential of our solution to cross over to solve a bigger problem, and we expanded our mission to revolutionize how many infectious diseases are diagnosed and how, in turn, this could support our fight against the growing global threat of antimicrobial resistance. Vamsee Pamula: DMF uses very small volumes of sample, which is most suited for neonatal and pediatric populations with limited sample volume for testing. In the US, >10% of newborns are admitted to the neonatal intensive care unit, where they are evaluated using tests often intended for adults. These tests require large sample volumes that are hard to acquire, leading to insufficient testing, therapeutic errors, and readmissions. Iatrogenic blood loss from diagnostic testing can be up to 22 mL per week in an extreme low birthweight infant that has only 50 mL of blood. Although we started the company to address low sample volumes in neonatal and pediatric populations, as Baebies grew, we found increasing interest in the multifunctional syndromic testing capabilities of our DMF platform for applications that include adult diseases. We are now developing tests that maximize the diagnostic yield from low sample volumes across the age spectrum. Ajay Shah: It was a bit of both—the technology was originally developed by Drs. Henry Tse and Dino DiCarlo at UCLA, and they demonstrated potential applications in oncology, but also saw some interesting signals in the mechanical properties of immune cells. As we sought to commercialize the platform, the potential to provide a rapid, accurate diagnostic in the sepsis space became clear. Seeing the hand-in-glove fit between the technology’s strengths in assessing immune dysfunction within minutes and the clinical need, we jumped at the challenge. Timothy Sweeney: My personal background was in clinical medicine, in general surgery. So the project began, back in its academic days at Stanford, as an attempt to create a better diagnostic for postop infections. All of these years later, that’s still a goal, but we’re first going to focus on getting ED triage right. Amogha Tadimety: We originally developed underlying components of the technology with application analytes currently measured using high volume analyzers in clinical laboratories. As we began to build the company, we became keenly aware that often diagnostics companies generally fail not because of the technology risk, but because the team cannot validate a clear business model and path to market. To this common we started with a to potential clinical with existing and us to our initial focus in outpatient Jong Lee: Doug out to in in sequencing, machine learning, and microbiology from Harvard and to a research to the idea of using whole-genome sequencing and machine learning to identify and their antimicrobial out to from a to if I could help guide the effort background in technology and We the company from the with as Vamsee Pamula: I started first company based on our DMF laboratory research at and it to With a mission of a to every we Baebies with a technology and team that has in our previous We first our to to our in the DMF We up with at research who identify Ajay Shah: In the early we recognized the clear need to with a team across both the technology and clinical the technical we with both the academic as well as such as an in and the clinical we were to build with across clinical microbiology and critical care. on we were by to take on disruptive the company, we an team of and As we the we have been to our team with some in the few Timothy Sweeney: a story that fit in the of the we every other to further the and when all those we either had to up or make the to a So we Our first big was getting a from research was in a In of was the to background is in and of novel molecular diagnostics. so many other critical have to I would is not support at no to So one was in of having support to something Amogha Tadimety: My and I our at where we developed underlying components of Nanopath’s platform. We realized that there were numerous potential applications of the developed technologies in support of a We that our company is only as as the team our mission and Our business is and a is for us is successfully building a of required for Nanopath include and business and Our technology platform requires across the of and from to molecular As 2 and we that both in background and is one of our Jong Lee: most they have a of what they are in for and that was for sepsis first that we had to out a way to replace culture and to work directly from clinical With blood, this is a challenging problem, as the of to pathogen in a septic patient can be as high as to We how challenging a sample it would be we into the we had a and of on our founding team who were all used to very hard in their academic and So we a of time developing an process that allows us to 10 of taking a sample with a more than pathogen to and up with sequencing that has more pathogen than we had to create a machine model to identify the bacterial species and its susceptibility profile based on its To a model of this we had to one of the that both whole-genome and for We that and over the years one of the of its on that we developed a model that can ID and antimicrobial susceptibility Our next challenge will be to our technologies into a instrument capable of the process and with the to get a small when there has previously never been an infectious disease diagnostic for use in clinical microbiology labs of use tests for Vamsee Pamula: to us to when were not a disruptive technology product from the to a product requires of under different Our first application took from to such can disruptive technologies. Ajay Shah: our were We were to a platform into something that could be in laboratories consistently and with limited Our the of microfluidics, and this to provide the and reliable required by the clinical laboratory took As the and technology our have to be clinical and in Sepsis is a space, with and we required clinical our we will need to work closely with our clinical as they the technology to that they are to the of the IntelliSep test as of their early sepsis Timothy Sweeney: I like to a that when we started Inflammatix it was in and and and out of their and the have been and we had to we were to where had We still have to that have had some but our goal of health through broad adoption is still years our solution has been to technical they we all Amogha Tadimety: of the we from the of diagnostics. described how this to building a but it through all of the work we As we’re and As we the and between these will need to move in is also what it such an Jong Lee: a problem you are about and is big and enough that you are to the next 10 years of trying to solve. are to be where but if you have a that you in about what the world should that can that you who can and and who an can be a and what you is with you who care as and as as you about what you are trying to Vamsee Pamula: the have an innovative but if there is no significant to the or product to the or it not unlock new it will not be and will not be disruptive. it is to early on by building with laboratory and any company is a diagnostics healthcare on results by and effort to be to accurate The with a patient’s is and can through the and of a growing Ajay Shah: a team with and to The path is not as as you think at the but make you the Timothy Sweeney: and be for a of from the and move that it will be an out to if I can be of in any Amogha Tadimety: We often that the of starting a business is to that and been critical that as we are on mission and so be about who you in All they have to the of this and have the significant to the and of or and interpretation of or the for of the and to be for all of the that to the or of any of the are and all the potential of of Day Zero Diagnostics, of Cytovale Nanopath and of Baebies for Day Zero Diagnostics, Cytovale Nanopath and Baebies Day Zero Diagnostics has from and ID support via from Nanopath from and from Cytovale to diagnostics. support for from Cytovale support for from or from to host-response
Source: Clinical Chemistry
Authors: Khushbu Patel, Susan Evans, Jong Lee, Vamsee Pamula, Ajay Shah, Timothy E Sweeney, Amogha Tadimety
Language: English
Subfield: Biomedical Engineering
Field: Engineering
Domain: Physical Sciences
Open Access status: bronze
OpenAlex ID: W4320855198