Episode 12

Two years ago, almost to the day, X-ZELL hit a milestone that many say separates the wheat from the chaff – the equally daunting and exhilarating leap from research to commercialisation.

Under the watchful eye of the market, the cancer detection start-up has since completed the development of a new, fully certified R&D complex in Bangkok, Thailand, and officially joined forces with Singapore’s national Agency for Science, Technology and Research (A*STAR)– a move that will fast-track the company’s ambitious productisation roadmap and add significant bandwidth to future research endeavours.

At the same time, X-ZELL’s landmark research on the isolation and visualisation of some of the most promising cancer biomarkers of our time – tumour-derived Circulating Endothelial Cells (tCEC) – gained significant momentum among the scientific community and earned X-ZELL CEO, Dr Sebastian Bhakdi, international praise for his work on slide-based, multiplexed immunostaining.

Navigating the switch from mind to market, however, hasn’t always come easy.

Swimming against the stream

In an environment dominated by well-funded sequencing businesses aiming to scan whole blood for fragments of circulating tumour DNA, X-ZELL’s cell-based approach to screening – specifically designed to slot into existing pathology infrastructure – seemingly goes against the trend.

Instead of promoting systemic disruption, X-ZELL is making use of existing resources and infrastructure to upgrade the system from within.

Instead of betting on an evolving science, X-ZELL is building on a tradition dating back all the way to the 18^th century.

Instead of being on trend, X-ZELL is being on the ground working with medical professionals to understand real-life workflows and decision-making processes.

Making pathology great again

Banking on tradition may seem less futuristic at first, but it’s easy to see why improving the status quo is a promising alternative to jumping on the DNA bandwagon – especially given that sequencing is yet to demonstrate just how effective it will be for the detection of early stage disease across different ethnicities.

By tapping into pathology’s globally standardised, widely accepted infrastructure, X-ZELL’s approach to early cancer detection – we call it Single Cell Pathology – is instantly scalable and will directly impact clinical routine. After all, 95 per cent of all clinical pathways still rely on pathology, according to Britain’s Royal Collage of Pathology.

Despite that inherent link to clinical routine, however, the vision of radically improved, fully digitised pathology is yet to gain the same momentum as the – equally enticing, yet still evolving – promises made by the DNA-based diagnostics industry.

But change is coming. With early cancer detection back on the political agenda and a collective push towards solutions that provide tangible clinical value now, X-ZELL will help the long and rich history of cytopathology – the art of diagnosing disease by assessing single cells and cell clusters under the microscope – get a new lease on life.    

Cell morphology is key

Pioneered by George Papanicolaou, who invented the eponymous Papanicolaou test – commonly known as the Pap smear – cell-based cancer screening is one of only two early detection methods backed by the World Health Organisation (WHO, the second being the mammogram), and the only population-based screening tool that has led to a significant decrease in both incidence and mortality [1].

Papanicolaou predicted early on that visually differentiating normal from malignant cells isolated from body fluids – especially whole blood – might not be limited to cervical cancer alone.

“Although the exact significance of cancer cells in the circulating blood is not known at present, there is some indication that the presence of these cells (…) is a bad prognostic sign,” he concluded in his magnum opus, 1954’s Atlas of Exfoliative Cytology.

In fact, Papanicolaou even proposeda direct link between cell morphology and point of origin – a hypothesis that, if proven right, would fundamentally change our notion of early cancer detection. “Little effort has been made to identify the specific origin of (…) malignant cells, but if exact criteria can be developed, information of this nature would be of great value.”

Due to the inherent limitations of traditional cell analysis – until today, some 90% of all pathology work is based on sequential one- or two-colour staining of tissue samples – Papanicolaou did not live to see such criteria being developed.

Leveraging Papanicolaou’s legacy

With X-ZELL’s ability to bring traditional isolation and visualisation processes into the 21^stcentury, however, his 55-year-old vision is now coming back to life.

Picking up where Papanicolaou left off, X-ZELL developed a sequence of patented technologies that are capable of isolating even the rarest of cells from a small blood or tissue sample (including highly elusive tCEC), fixing them on standard microscopic slides and staining them with up to nine antibodies at the same time.

That’s 3x more antibodies per slide and 3x the speed of today’s best practice, without any of the side effects that come with traditional cell preparation, such as sample loss, auto-fluorescence, cross-talk or unspecific binding. Best of all, all X-ZELL slides are re-stainable and retain more than 90% of the sample’s RNA and DNA for downstream processing.

The basic principles of slide-based cytology, meanwhile, remain the same – there is no loss of cell morphology like in flow cytometry, and the result is a distinct visual of the malignant cell portrayed live on-screen using a proprietary imaging system developed by X-ZELL [2].

Project Cloud Atlas

Dubbed Cryoimmunostaining™, X-ZELL’s upgraded cell analysis system was first applied to develop a revolutionary new tool to identify clinically significant, early-stage prostate cancer in high-risk patients and is now at the centre of a Papanicolaou-inspired landmark project nicknamed Cloud Atlas [3].

Much like Papanicolaou’s Atlas of Exfoliative Cytology, project Cloud Atlas has the potential to shake up the very foundations of cancer research as we know it. By systematically analysing malignant cells for morphological patterns, it will put Papanicolaou’s hypothesis to the test and – hopefully – allow X-ZELL’s research team to categorise malignant cells by origin.

Once reliable criteria have been established, the resulting dataset will form the foundation of a cloud-based, constantly evolving cell image database. Hosted by an Artificial Intelligence, it will be able to compare cell samples isolated and stained using X-ZELL’s Cryoimmunostaining™ technology with an ever-growing number of reference images and suggest a diagnosis on screen. In a nutshell, it will help us digitise diseases.

By standardising and, ultimately, automating the entire process from sample preparation through to image analysis, X-ZELL is hoping to build on Papanicolaou’s proud legacy and develop a whole range of WHO-approved cancer screening solutions that are as simple as they are accurate.

Unleashing pathology’s true potential

If 2017’s pivot from mind to market managed to take a young organisation from obscurity to being ranked among the most innovative medical technology start-ups on the Asian continent, project Cloud Atlasis set to catapult an entire discipline into the digital age – and at the same demonstrate that backing tradition doesn’t always mean living in the past. 

[1] Note that George Papanicolaou was not the first to show that cancerous cells could be identified under the microscope. According to Tan et al. (2015), that honour goes to British physician Walter Hayle Walshe, who referred to this phenomenon in a book on lung diseases one century before. Nor was Papanicolaou the first to study cervical cytopathology in women. In 1927, a Romanian physician by the name of Aurel Babeş used a platinum loop to collect cells from a woman’s cervix to detect the presence of cancer. However, medical history has sided with Papanicolaou as the originator of the Pap test, as the two methods were viewed to be substantially different. Still, in honour of Babeş, Romania refers to the test as Methode Babeş-Papanicolaou.

[2] X-ZELL’s all new imaging solution – the final building block to the industry’s only fully integrated rare cell detection system – is currently under development. To avoid missing any crucial updates, subscribe to X-ZELL’s digital newsletter here.

[3] Cloud Atlas is a scientific moniker paying homage to the eponymous 2004 novel by British author David Mitchell.