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Decoding disease
We go behind the scenes of start-up company Miroculus to explore the roles of alumna Fay Christodoulou and EMBL’s Genomics Core Facility in the development of a non-invasive test for early-stage disease.
“Everything started with a dream,” says Alejandro Tocigl, an entrepreneur from Chile and CEO of Miroculus, a start-up company aiming to ‘democratise’ molecular diagnostics with a tool that could enable patients to be checked for diseases in a simple and affordable way, using just a millilitre of blood. His goal is clear: “To improve early diagnosis, to monitor diseases on a constant basis, and for this to be available to everyone, wherever they are in the world.” Like Tocigl, most of the other founders of Miroculus are also from emerging economies and they are acutely aware of the lack of purchasing power of these countries, especially when it comes to what they call ‘medicine for the masses’. “We want this tool to be available to all of them,” says Tocigl. “We don’t want to discriminate based on socio-economic status.”
Miroculus’ chief scientific officer is EMBL alumna Fay Christodoulou, an expert on microRNAs, which form the basis of the company’s technology. She first met Tocigl and the rest of Miroculus’ founding team in 2013 during a ten-week graduate studies programme at Singularity University, a California Benefit Corporation located at NASA Research Park in Silicon Valley, which offers programmes and activities that encourage the use of technology for change. Its graduate programme attracts individuals from a broad spectrum of disciplines and encourages them to pursue an ambitious goal: to develop an idea and a viable business plan that harnesses exponential technologies to positively impact one billion people within ten years. Christodoulou teamed up with Tocigl together with Pablo Olivares, a doctor also from Chile; Gilad Gome, a biotechnologist from Israel; Ferrán Galindo, an entrepreneur from Panama; and Jorge Soto, a Mexican electronic engineer. The six of them struck on the idea to develop a simple blood test that utilises the potential of microRNAs in the bloodstream as highly sensitive biomarkers for disease detection.
Bright biomarkers
MicroRNAs are small pieces of RNA that regulate gene expression, the building of proteins from the information encoded in DNA. First discovered in 1993, a relationship between microRNA dysregulation and cancer was reported in 2002. Six years later, researchers found that microRNAs circulate in biological fluids like blood, which makes them promising biomarkers for the early stages of cancer, heart disease and neurological diseases. The detection of specific microRNAs in a sample makes it possible to diagnose a disease, identify its type (each tumour, for example, has its own microRNA signature), and monitor its progression and treatment in minimally invasive ways. However, techniques involving microRNAs are challenging because these molecules are no more than 22 nucleotides long and cannot easily be detected with traditional DNA-based methods. Moreover, they are often very similar: two microRNAs may share all but one nucleotide. Hence, methods for their detection and classification need to be able to tell two microRNAs apart based on very small variances.
Miroculus can potentially offer a disease agnostic screening test which simply interprets the microRNA signatures that are found
Christodoulou’s expert knowledge of microRNAs stems from years of research in the field. She completed her doctoral thesis on ancient animal microRNAs at EMBL in 2010 and investigated the role of microRNAs in thyroid cancer during her postdoctoral research. “I have been following the field since 2005 and I am very familiar with the technologies that are available,” she says. “When I think of what we are doing, something like this is definitely missing.” What they are doing is building – and perfecting – a device that scans for diseases quickly, easily and affordably. Miroculus’ method extracts the microRNAs from a standard blood sample and these are then pipetted into a 96-well plastic plate. Each well is filled with the company’s patented biochemical assay that produces a fluorescent signal in the presence of a specific microRNA. To run the assay, the plate is placed inside the device – called mir.i.am – which can be connected to a smartphone. The phone takes photographs during the reaction and sends them to a cloud where the pattern of illuminated wells is matched against data on which disease is associated with which microRNA pattern. “It is the combination of specific microRNAs found in a sample which can reveal the source of a pathophysiological condition,” explains Christodoulou. “By providing an affordable and easy to use platform that can ‘read’ which microRNAs circulate in a sample, Miroculus can potentially offer a disease agnostic screening test which simply interprets the microRNA signatures that are found.” Thus, whereas other diagnostic tests look for a specific disease, Miroculus’ method could be applied to multiple disease types.
Design to development
Although, as Christodoulou points out, the clinical validity and utility of microRNAs as biomarkers has so far only been established for some cancers and cardiological conditions, Miroculus’ team believe that their various advantages over other biomarkers mean that they have great potential for early disease detection. These advantages include the stability of microRNAs in plasma, which stops them from degrading easily even when stored at room temperature, and their high cell-type specificity. As certain microRNAs are only found in certain cells, the assay reveals which cells are present in a given sample. In tests, the team has been able to identify the microRNA patterns indicative of pancreatic cancer, breast cancer and hepatic cancer.
“We want to provide the enabling technology that can establish their use,” says Christodoulou. Yet for Miroculus, simply providing that technology isn’t enough. “After learning how important design thinking is in product development,” Christodoulou recalls, “we follow a different approach to stereotypical spin-offs that have a very good assay or a very good biotechnological solution and then want to make it available as it is.” Rather than simply providing a solution that can only be used under very specific conditions or by experts, the team wants to make the technology available as cheaply as possible to be used by minimally trained lab technicians in low-resource settings. The first two prototype versions of the mir.i.am, Christodoulou explains, were 3D-printed, using cheap, off-the-shelf components, which would make it possible for the device to be reproduced relatively easily.
GeneCore groundwork
As the development of the project began to take flight, Christodoulou conducted instrumental research at EMBL’s Genomics Core Facility (GeneCore), which has been run by Vladimir Benes, a trained biochemist, since its inception in 2000. Christodoulou worked closely with Benes for many years, and since leaving EMBL she keeps returning as a regular tutor on a small-RNA analysis course he organises. Thus, when the Miroculus team realised that they needed to find a place where they could continue the experiments they had begun at Singularity University, Christodoulou’s mind quickly settled on GeneCore, which she describes as “a paradise with all the toys a molecular biologist could dream of. The lab is fully equipped with everything and runs like a Swiss watch,” she explains. “We literally turned up there with our suitcases and started pipetting.”
EMBL had never hosted a start-up before but Benes explains that Christodoulou’s tenacity, motivation and commitment convinced him that she would be able to sustain the project, even during its challenging phases. “So when she asked me if we could do this research together, my immediate thought was: ‘Let’s do it!’”, he recalls. One such challenge occurred when Christodoulou had to significantly alter her scientific approach on realising that the original design of their isothermal assay had reached its limits: not all microRNAs would perform similarly at the same temperature. She praises the support of the team at GeneCore, with Miroculus staff scientist João Pereira de Lima based at the facility for six months to manage the project. “Working together we were able to deliver detailed analyses of individual parameters and components that provided robust data for Fay to present to investors,” explains Benes.
Setting up shop
When Miroculus advanced from a part-time venture to a stage where the project needed the team’s full attention and additional resources, the data produced at EMBL enabled the start-up to secure the funding for the first prototype, which was introduced at a TED global conference last year. This was followed by 25 days of touring the US, pitching it to almost 100 investors – a particular challenge for a company that did not yet have facilities in the country. Miroculus completed the first round of seed funding this year. The company is now based in San Francisco, focusing on optimising the product’s workflow and user experience, while making the assay more robust so that it can tolerate inexpert handling and still produce accurate results. Silicon Valley, with its infinite, revolutionary ideas, excellence, and easy-access expertise has a lot to offer, says Christodoulou: “It is a very fertile environment for developing solutions that have the potential to make a real difference in the world… to where they could never be found before.” EMBL, she insists, is its European equivalent in the life sciences.
Bold innovation is about bringing forward the change you want to see in the world.
Although the notion of leaving academia to pursue an entrepreneurial dream may seem daunting to some, Christodoulou and the others involved in Miroculus are an example of what interdisciplinary teamwork can achieve. To other researchers who ‘flirt’ with the idea of trying out their entrepreneurial skills, Christodoulou has a clear message: “Go for it and don’t be afraid of failure. Bold innovation is about bringing forward the change you want to see in the world.”
