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On March 28, 2024, ImYoo was featured in a ScienceNews article, “How patient-led research could speed up medical innovation.” The biotech startup was showcased for its collaboration with RemissionBiome, a patient-led research project investigating antibiotics as a way to achieve remission for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). RemissionBiome partnered with ImYoo, which provided their single-cell RNA sequencing (scRNA-seq) discovery platform for an N of 1 study and is now releasing its novel findings.*


*For this N of 1 study, medical and scientific disclaimers are provided at the bottom of this article.


ME/CFS is currently incurable and, by many accounts, “a disease doctors can’t diagnose,” due to its wide-ranging symptoms. In the US, it’s estimated to cost 18 to 24 billion dollars per year in lost productivity and medical costs, and it’s on the rise. For the past year, the National Institutes of Health (NIH) has been designing an ME/CFS research roadmap, which features specialists across eight different medical domains. Doctors, policy makers, and researchers have all been struggling to identify the cause of ME/CFS.


Yet, in this messy disease, ImYoo has spotted a promising signal in one individual. The preliminary results set off a Twitter storm within patient circles, and this model of community-based trials has pharma equally excited.


ImYoo gives patients the tools to painlessly collect their own blood from home. From their patient-centric discovery platform, ImYoo has amassed the largest longitudinal single-cell database from self-collected capillary blood. This fuels their machine learning (ML) models, which enables them to decipher relative changes in gene expression in every immune cell they capture. “It’s like generating a molecular snapshot of your immune system,” says Dr. Tatyana Dobreva, CEO and co-founder of ImYoo. “The more snapshots we capture, the more confident we are in the bigger picture. For this study, we captured 9 snapshots. And from those 9 snapshots, we generated a picture of a dynamic ME/CFS immune system for Tess [Falor], findings that we are eager to share with the community,” she added.


ImYoo x RemissionBiome Collaboration


The RemissionBiome study recruited 50 participants, one of whom is its co-founder, Dr. Tess Falor. A former athlete who had set her sights on becoming an astronaut, Falor developed ME/CFS in 2005 during her time interning at NASA’s Jet Propulsion Labs. She continued with her doctoral degree in Earth and Planetary Sciences, while simultaneously managing her symptoms and immersing herself in the ME/CFS literature. “My husband jokes around that I should have a second PhD in medicine, because of how many research papers I've read,” says Falor.


In 2022, Falor and her co-founder, Tamara Romanuk, began designing and crowdfunding their dual N of 1 study. Falor and Romanuk would take AmoxiClav antibiotics* in the hopes of triggering a “remission event,” what they describe as a sudden elimination of ME/CFS symptoms. In 2007, Falor first experienced one of these events by chance; she called it a “Level 2 remission event.” Falor had taken antibiotics for an unrelated infection and, shortly after, experienced brighter colors and higher energy than she could even recall from her pre-ME/CFS life. “That happened overnight,” Falor recalls. “I went to bed feeling horrible, and when I woke up, I was in that state of remission. It was almost like a switch flipping.”


Falor and Romanuk requested ImYoo’s at-home collection kits to capture molecular snapshots of their immune systems during these remission events. Back in 2007, Falor experienced several of these events at varying durations, from minutes to hours. Flash forward to the RemissionBiome study, and it wasn’t a guarantee that either of them could trigger these events with this intervention. However, with ImYoo’s kits on-hand, they could collect at a moment’s notice.


ImYoo would observe the relative changes in Falor’s and Romanuk’s immune systems, before, during, and after the anticipated remission events. Falor and Romanuk collected their first 3 baseline samples and then commenced their antibiotic intervention. Romanuk did not experience a dramatic remission event. However, Falor did. In fact, she experienced multiple events.


On day 2 of the intervention, Falor experienced a “Level 1 remission event,” characterized by reduced ME/CFS symptoms. She collected a sample for her first event and, on days 5 and 9 of the intervention, she experienced two more remission events and collected samples, respectively. After completing the course of antibiotics, Falor reported the return of milder ME/CFS symptoms compared to her condition before the start of the study. In the approximately two and a half months after stopping the antibiotics, Falor collected 3 more samples at this new baseline.


In total, Falor and Romanuk each captured nine samples. Longitudinal samples, let alone a single ME/CFS sample, are uncommon in the research world. “A lot of people [with ME/CFS] can't leave their house or they're even bed bound,” says Falor. “They can't take part in these research studies where you have to actually travel and go into the clinic,” she adds. To investigate the dramatic shifts in Falor’s symptoms, ImYoo dove deep into the data they generated for her. From these never-before-captured samples, ImYoo conducted its analysis and made a novel finding.


The sample collection schedule from the RemissionBiome N of 1 study. For more details, see the detailed research report.


The Remission Event Results


Supporting existing ME/CFS Research


The results from Falor’s samples, provided in an ImYoo report, coincided with the latest research on ME/CFS and may support some of the existing hypotheses that seek to explain the disease. ImYoo’s analysis flagged CD14 monocytes, also known as classical monocytes, an immune cell type implicated in chronic systemic inflammation. This cell type was also flagged by a Cornell University researcher Dr. Andrew Grimson, whose 2024 study similarly found that this cell type exhibited “the strongest signals of dysregulation” in ME/CFS patients. Together, these findings may provide a specific cell type to strengthen support for the Neuroinflammation Hypothesis of ME/CFS.


On April 11th, Grimson joined the RemissionBiome community for a virtual roundtable discussion. When asked about ImYoo’s findings he commented, “It’s consistent with monocytes being important.”


Grimson was also surprised by how clear ImYoo’s findings were. “There’s really no signal in any other non-monocyte cells?” Grimson asked. “That’s amazing, if that’s true.” To which ImYoo’s CTO, Dr. David Brown responded, “I did the most conservative analysis that we can do… After doing that, there wasn’t anything else that showed up in any of the other cell types.”


ImYoo flags a cell type by the number of gene “hits” it generates in their statistical analysis. The analysis generates a “hit” for every significant shift in a gene’s expression. Gene expression can either go up or down, depending on what functions the cell is executing, and a cell can upregulate or downregulate many genes in parallel. Genes can also interact through these complicated pathways. Despite this complexity, ImYoo’s analysis generated 29 hits, identifying 29 unique genes that changed during Falor’s reported remission event.


“By training machine learning models on our large database of cells, we identify groups of cells that share common features,” explains Brown. “It’s not like we saw genes upregulated everywhere,” he added. “These 29 hits were unique to this cell type. In my opinion, this suggests that there's a specific mechanism at play, rather than broad immune system-wide changes.” It’s possible that, among these 29 hits, lies a novel therapeutic target or biomarker.


Repurposing Existing Drugs and Identifying New Targets


One potential therapeutic target that ImYoo flagged was the gene CCL4. During the remission events, it was downregulated. In accordance with these findings, Grimson’s 2024 paper also correlated ME/CFS symptoms to this gene’s activity. The gene has been studied in animal models, where it was associated with metabolism reprogramming in immune cells. Meanwhile, in human models, Dr. Rob Phair at Stanford University is investigating the Metabolic Trap Hypothesis of ME/CFS. If an antibiotic can target CCL4, then perhaps it can regulate the immune system through these metabolic pathways.


“Your immune system is unique,” says Dobreva. “By measuring it over time, we could one day tailor-make drugs to your biology, or, at the very least, identify or dose existing treatments more appropriately.”


It’s known that antibiotics are a double-edged sword: They can kill bad bacteria, but they can also kill good bacteria. As they fend off infections, these antibiotics can disrupt the immune system. Similar to ImYoo’s observations with the AmoxiClav intervention, various other antibiotics have been shown to slow down monocytes, as well. In healthy individuals, immune disruption is an undesirable effect. But in people with chronic inflammation, it may provide an escape route from vicious feedback loops, like the “metabolic trap.”  The outcome of the RemissionBiome study may suggest that immune disruption through antibiotics is a path to controlling hyperactive immune systems.


A box plot showing the reduction in CCL4 gene expression in CD14 monocytes both during and after remission events. For more figures consult the detailed research report.


Through the lens of the microbiome, ImYoo’s findings may connect the dots between ME/CFS and Long COVID, as well. “This is actually really interesting, because it suggests that the microbiome (or microbial metabolites) can impact immune cell activation in this ME/CFS patient,” commented Dr. Lavanya Visvabharathy, a neuroimmunologist at Northwestern University. "This could have implications for Long COVID as well, considering how both conditions occur after viral infections." Long COVID symptoms are often debilitating, persisting in at least 10% of acute COVID infections. The symptoms are similar to that of ME/CFS, with researchers proposing that the two conditions share pathophysiology and even molecular mechanisms.


Steps to treat chronic fatigue through the microbiome are in their promising infancy. In Gulf War Illness (GWI), a common comorbidity with ME/CFS, Dr. Nancy Klimas is investigating fecal transplants as a treatment to repopulate the beneficial bacteria in these patients. It’s also being explored in autoimmune diseases like inflammatory bowel disease (IBD), an indication that ImYoo is currently investigating in its national decentralized studies.


“With our growing database, we hope to connect the dots across autoimmunity,” says Dobreva. “Surely, there are biomarkers that these diseases share. The immune system is the common link, and mapping it out will reframe how we think about disease.”


Next Steps


The results of this RemissionBiome-ImYoo collaboration have seeded hope for a new way of doing research. After completing this N of 1 study, Falor founded RenegadeResearch, a non-profit organization funding community-based studies like this one. They are fundraising to expand this N of 1 study and are also accepting calls for community-based trials in other diseases.


Meanwhile, ImYoo is expanding its platform to research other debilitating diseases with unpredictable, acute events that otherwise wouldn’t be captured in traditional, clinic-based studies. The company has been conducting an internal study in IBD and rheumatoid arthritis (RA) to analyze autoimmune flare-ups from the moment they occur at home. “Like ME/CFS, both IBD and RA flare-ups often prevent patients from getting to the clinic, so we’re excited to see what else we can uncover with timely sampling,” Dobreva shares. As it scales operations, the company is raising its next round of funding.


 

About


For funding inquiries or research collaborations: contact@imyoo.health


For media inquiries: socialmedia@imyoo.health


Visit imyoo.health to register for ImYoo research studies & subscribe to exciting updates like these.


The full Remission Biome case study report can be accessed at https://imyoo.health/remissionbiomereport. Data from this study can be downloaded for non-commercial use at https://zenodo.org/records/11100300.


Thank you


Sequencing for this study was generously provided by Complete Genomics. In December 2022, ImYoo was a recipient of their G99 Sponsorship Program. Complete Genomics’ mission is to drive genomics forward with complete sequencing solutions that improve lives. By providing high-quality, cost-effective sequencing, they enable scientists to accelerate genomics research for precision medicine, making it more accessible for physicians and patients.


* Disclaimers


Medical Disclaimer: Both ImYoo and RemissionBiome would like to emphasize that this N of 1 study is not intended to be replicated without proper medical supervision. For that reason, this article does not disclose the details of Falor’s antibiotic regimen. This N of 1 case study is not intended to offer any clinical or scientific advice, nor conclusions, about diseases such as ME/CFS, Long COVID, or any other conditions cited in these writings. 


Scientific Disclaimer: ImYoo did not inform the design of this study intervention. Rather, ImYoo’s role was solely to provide observational data and analysis. The observations were made in one individual (i.e. an N of 1 study). Therefore, causality cannot be confirmed from ImYoo’s findings. ImYoo cannot confirm that the observed signals were due to the reported remission event, rather than a typical reaction to antibiotics. To distinguish between disease-specific response and general antibiotic response, ImYoo would suggest an additional study that measures immune response to antibiotic treatment. ImYoo acknowledges that, aside from the RemissionBiome intervention, other factors could have contributed to the results presented in this article. For more resources on how to interpret N of 1 studies, consult this article’s supplementary ImYoo report.


ImYoo’s primary objective of this collaboration was to showcase how at-home sampling can enable patient-led research. From this study, ImYoo demonstrated that longitudinal, molecular data can easily be generated for spontaneous biological events from at-home collections. Consequently, ImYoo generated data to share with their community. As a public benefit corporation, ImYoo’s mission is to engage all stakeholders in the careful process of scientific research and the thrilling prospects of scientific discovery.


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When we started ImYoo, we recognized a need to connect patients in their own pursuit of health with medical researchers and clinicians trying to help them. In our original 2020 Nature Scientific Reports paper we wrote “our platform makes collection and profiling of human immune cells less invasive, less expensive and as such more scalable than traditional methods rooted in large venous blood draws.”


(Image source: Science News)

Today, that idea is now a growing trend as recognized by this month’s feature article in Science News. Here’s an excerpt with a quote from CEO and co-founder Tatyana Dobreva:


“Study designs informed by patient experience often prioritize accommodations for people with different levels of symptoms or access to care, meaning a more diverse group of patients may be able to participate. With a patient led, ‘decentralized’ approach to research, ‘we can reach more people in more diverse areas’ who don’t live near medical facilities in big cities or aren’t able to travel for clinical trials, Dobreva says."


You can read the full article here.


“Patient scientist” is how we refer to our study participants - because they're not subjects, they're the experts of their lived experience, and they have to think critically to actively participate in discovery. Every patient has the goal to shed the patient label and become healthy again. Active participation in the greater scientific knowledge discovery process is one way to do that. And what we’ve learned is that when you remove the requirement of visiting a clinic to draw a blood sample and it’s coupled with high throughput single-cell analysis, we can amass greater knowledge from more diverse populations faster and with higher completion rates.


Last year, the FDA took note: “Decentralized clinical trials and digital health technologies are gaining momentum in medical research, allowing research participants to partake in trials remotely using state-of-the-art digital health technologies.”  The FDA also issued further guidance in support of decentralized trials to spur greater and more diverse patient participation. 


Geography, time and cost are the causes of major blindspots in traditional approaches to medical research. The clinical trial you could be eligible for is either in your area or it’s not. “Location” is one of the major search parameters on clinicaltrials.gov for this precise reason. You either can make time to visit a clinic repeatedly for sample collection, or you can’t. Logistics and proximity matter a lot. And of course clinics are expensive to maintain and operate.  So as a result, we simply do not collect enough data from enough people consistently to generate the data needed to drive insight and accelerate discovery. 


But that’s what we’re changing along with all our patients and partners. By prioritizing patient access, ImYoo removes the variables of location and time while lowering sampling and analysis costs. The future of medicine is at home in the growing numbers of patient scientists who are now driving smarter and faster biomedical research.


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Now that we’ve all lived through the pandemic and gotten remarkably comfortable (or at least familiar) sticking swabs up our noses and swirling chemicals around tubes at home, the benefits of at-home testing are clear. It’s fast, convenient, and we can do it on our own time, when we think it’s important to test.


However, despite the obvious benefits, at-home testing and sampling is still far from the norm in discovery research and clinical trials, which still use lab and clinic visits almost exclusively for blood-based sampling. But we’ve started to change that and wanted to share some insights.


At ImYoo, we’ve heard over and over again, both anecdotally and from industry data, that getting enough, diverse participants matching the right inclusion criteria is one of the biggest costs and bottlenecks of running studies and clinical trials. We’ve experienced this ourselves. In the first phase of ImYoo (late 2021), we were running a local immune baseline study at Illumina Accelerator, where participants came on-site to give their blood. We got great turnout (we were able to get a couple hundred samples banked), but there were two limitations of our study. First, we had a hard time getting diverse participants - the people who have the time and interest to drive to a blood collection event in the middle of the day are a narrow slice of the population. Second, we didn’t see good representation of people with diseases (except for the ME/CFS community, which self-organized and came to give samples, thank you!). Getting samples from lots of people in a specific disease is incredibly challenging when you’re restricted to a single local collection site.




We knew that to reach the scale of samples that is necessary to make novel biological discovery at the timescale of an early-stage startup, we had to transition to a completely at-home, decentralized model. Partnering with clinics and academics was slow and insufficient - any one center wasn’t able to provide the kind of sample flow that we were looking for.


So, we spent our R&D efforts on making sure we could get reliable single-cell gene expression data from an at-home shippable solution, complete with in-transit temperature tracking. In mid-2023, we launched our first fully decentralized study for tracking autoimmune flares. We collaborated with patient advocates and people found us online, either through their patient networks, or through ads on Facebook and Instagram. It was really cool how quickly we could find and connect with people. We were able to find participants with a very specific disease phenotype (active Crohn’s or Ulcerative Colitis, with a certain flare profile). A few months into the study, and we are at a sample velocity that far exceeded what we were able to do with a local study.



In addition to the convenience of at-home, we’re also tapping into the network effects of communities. Patient support communities and the power of social media really can’t be underestimated. In one remarkable example, we decided to expand our study to rheumatoid arthritis in February. We wanted 14 participants. On February 13, Ali DiGiacomo (@anotherdaywithra) thought our study was cool and posted about it. In less than 24 hours, we got over 100 sign-ups. 2 weeks later, participants were recruited and had ImYoo kits on the way to their house. Another week later and we’re banking our first RA samples.


At-home patient sampling is poised to generate data from novel assays at a scale and speed that is unprecedented in the current biomedical research world. As we expand to our next studies - postmarketing surveillance of therapeutic interventions, and pan-autoimmune flares - we’ll showcase the power of novel study designs that leverage the scale and on-demand sampling capability of patient scientists taking action from home.

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