User's Voice

Changing "Incurable" – the Path to Lung Regeneration with iPS Cells

You lead a venture spinoff from Kyoto University, aiming to develop novel treatments for respiratory diseases. What led you to start the company? The respiratory system faces threats from diverse diseases like pneumonia, asthma, and lung cancer. Many are difficult to cure completely, and patients suffer tremendously when their conditions become chronic and progressive. Not only that, emerging infectious diseases that attack the respiratory system, like COVID-19, occur periodically. As a physician, I wanted to help deliver better treatments to patients, which led me to shift from a clinical practice to research. At that time, iPS cells were discovered, and research using various cells and organs began with the goal of regenerative medicine and healthcare as a whole. Yet research on the respiratory system was virtually untouched compared with other areas. After searching both in Japan and abroad, I learned that research had finally begun at the Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University. At last, I was able to begin my lung regeneration research.

Origin of HiLung: Taking on the Challenge of the Lung and Turning Research to Clinical Medicine

Why was the use of iPS cell technology delayed in the research on respiratory organs? One reason is the complexity of the respiratory structure. The lungs, occupying most of the upper body, have a highly complex structure, and each part serves a specific purpose. One of the first – and highest – hurdles to clear is replicating that complex structure. For example, mass-producing cells is not enough to develop a cell therapy; we must, to some extent, replicate the lung's structure to simulate organ regeneration. I achieved the efficient production of human respiratory epithelial cells. But from a clinician's perspective, it was still a long way from achieving what was needed in clinical treatment. My research began from my witnessing patients’ suffering without treatment options. To bring this technological seed to clinical application, I founded HiLung in 2020.

How are the technological seeds from your research being utilized? By mass-producing human respiratory epithelial cells that are nearly identical to those in living organisms, we can create human lung disease models and lung organoids. These models enable, for example, efficient prediction and selection of drug candidates, as well as toxicity assessments.
We were in the midst of the COVID-19 pandemic when we founded HiLung. At that time, mice used in tests were not infected with the virus, hindering the research on therapeutic drugs. This situation triggered increased interest in human lung cell models worldwide. Our cells were adopted for research in and outside Japan, confirming our ability to meet the needs of viral research.
On the other hand, we faced significant challenges in mass-producing organoids through 3D cultures. The process of creating lung cells is extremely complex and time-consuming, and it also produces variability. Because organoids are three-dimensional, they are much more difficult to handle and increase complexity at every stage—from production to management and analysis. This makes it even harder to ensure the reproducibility and stability required for drug discovery and screening. Overcoming these challenges is the key to our business, and we continue to push ourselves to find real-world solutions.

Precision Impossible with Manual Handling: Automation Opens a New Possibility in Cell Culture

HiLung implemented the CELL HANDLER™ to address your challenges. How did you find out about this device? I had been aware of the CELL HANDLER™ since Yamaha Motor released its first-generation model, and I was strongly interested in its cell picking and imaging technologies. At that time, I was exploring how to create organoids by hand, and I was astonished that such an advanced machine had appeared. After establishing HiLung and reaching a point where we could provide relatively stable assay systems, I recognized the limitations of manual cell handling and began considering automation. That’s when I met with a Yamaha Motor representative at a conference and discussed the CELL HANDLER™. I felt there was no alternative to the CELL HANDLER™ for its imaging and analysis capabilities, as well as for its cell picking and placing with the precision impossible with human hands. It was exactly the technology we needed to streamline cell culture and facilitate scaling up. Yamaha Motor has also expressed interest in our technology, so we first decided to try out the technology.

How did you arrive at your decision to use the device? First, Yamaha conducted a demo and showed us how the device created organoids using a specific protocol. Typically, cell line experiments rarely succeed on the first attempt, so I didn’t have high expectations, to tell you the truth. I thought it would be nice to see how the machine operated. But on the very first day, it delivered nearly perfect results, matching our expectations. Both our researchers and I were astounded. Compatibility may vary by cell type, but after seeing firsthand the technology achieve such high precision and speed, I confirmed its potential to overcome our challenges.

How about the device’s usability? Our researchers have been using it without any issues and haven't encountered any particular difficulties with its operation. It's not a simple machine, but once you learn to use it properly, it delivers stable results. The CELL HANDLER™ significantly reduced our challenges in cell culture, which is a crucial outcome for us. Yamaha Motor is also working on various improvements, so the machine will likely become even more updated and user-friendly.

What results have you achieved with the CELL HANDLER™? Pharmaceutical companies are our primary clients for organoids. They have diverse needs, and HiLung has updated its production methods to meet those requests. To achieve more stable assay systems, it is sometimes necessary to strictly control the number of organoids. Furthermore, to support high-throughput analysis for drug discovery screening, we must minimize well-to-well variability. Using the CELL HANDLER™ has enabled us to control the number of organoids per well while minimizing variability, which helped us achieve stable organoid production.

Furthermore, machines – like the CELL HANDLER™ – run on nights and holidays. For a business to maintain staff’s work-life balance while handling constantly changing cells, automating the culture process is imperative, both operationally and scientifically. The results of iPS cell handling are often heavily influenced by the individual performing the task, so it is vital to minimize person-to-person variability. Now that we have established a platform for stable cell mass-production, I believe we have a solid foundation for further business expansion.

Bringing Diverse Expertise Offers New Therapy Options for Respiratory Diseases

What are your visions for the future? As I mentioned earlier, one of our roles is to create products and services that effectively address diverse needs. Currently, organoids hold the most significant position within our business. Our immediate goal is to develop products and services for various applications by way of automation. I also want to contribute to the development of treatments for respiratory disorders. Drug discovery for lung and respiratory diseases has a very high rate of clinical trial failures, partly due to the scarcity of suitable animal models. I believe HiLung’s technologies can help deliver treatments to patients. While not as direct as offering cell therapies, our technologies can be implemented in the real world and make a difference in patients' lives.

What future do you envision as a researcher and clinician? Many respiratory conditions remain incurable, so expanding treatment options is crucial. While a cure would be the best-case scenario, even halting progression offers great benefits to patients.
Pulmonary fibrosis is said to have few treatment options. HiLung cell models are frequently used for drug discovery in this realm, which I find very rewarding.
Also, drug-induced interstitial pneumonia, a side effect of medications, is known to occur more frequently in East-Asian patient populations than European and North American counterparts. So, it is very important to develop safer drugs that reduce side effects or to develop platforms to predict them. Developing such safe therapies using Japanese technology is very significant.

It is not easy to predict what is happening in the human body using small cell models. Addressing unmet medical needs requires diverse knowledge and technologies. I believe solutions will only emerge through the convergence of various technologies, including automation and the use of AI. I would love to see more players with diverse backgrounds enter the biomedical field, much like Yamaha Motor did with its CELL HANDLER™.