Shining a light on the inner workings of cells with biophotonics: An interview with Associate Professor Nicholas Smith of the University of Osaka

The world around us is illuminated by light, which interacts with the matter that makes up our environment in a variety of ways. With the right tools and techniques, even the microscopic world, usually impossible to see with the naked eye, becomes observable. These modern optical techniques include methods such as Raman spectroscopy. Associate Professor Nicholas Smith, principal investigator of the Biophotonics Laboratory at the Immunology Frontier Research Center (IFReC) at the University of Osaka, is putting the world of light to use in his research. He is combining a range of techniques such as label-free and hybrid cell imaging techniques, Raman spectroscopy and quantitative microscopy to investigate the intricate world of immunology.

We sat down with him to discuss the decisions that led to him conducting research in Japan, the field of photonics and its applications in immunology, and how international brain circulation has contributed to his career as a researcher.

A shifting gradient through the world of physics leads to Japan

Smith was born in a small town in Australia and first dipped his toes into the world of science as a child, often dismantling objects around the house. "What sparked my interest in science was probably taking apart old clocks, I didn't even really realize that it was science at the time but just doing things that I thought were interesting led to me to think about things like 'how could I make a candle burn faster'". This childlike curiosity led to an interest in gaining a deeper understanding of the physical world around him, and so he undertook an Undergraduate course in physics at the University of Sydney.

Reflecting on his path at university, Smith commented, "I thought that I would build bridges and things like that. But what I found was that behind these applications, different fields seemed connected by the same scientific principles and I found the ideas behind it, the pure science, more interesting, and so I ended up doing physics and pure mathematics." However, this wasn't the end of the journey, as despite it being "his worst subject in physics," Smith found himself drawn toward the field of optics.

This interest began with hopes of studying astronomy, and all of the optics related to it. Despite his own admission that he "didn't particularly like optics," visits to the optics laboratories exposed Smith to a wide range of remarkable experiments and equipment that opened his eyes to the possibilities available in the field. By chance, he wandered into the lab of renowned optics scientist, Colin Sheppard (Professor at the University of Sydney at the time), who Smith described as someone who "seemed very relaxed but was actually very serious." There, he encountered a range of impressive experiments and equipment related to optics. He credited this experience, as well as Carol Cogswell, the supervisor he had at the time for driving his interest in the field.

As it so happened, a well-known Japanese scientist Professor Satoshi Kawata of the University of Osaka, was undertaking a sabbatical in Dr. Sheppard's lab at the same time. This chance meeting turned out to be a turning point in Smith's life. A suggestion from Kawata to try a research period overseas ended up being a life altering event.

Smith reflected on that time, saying, "He said, 'You should come to Japan.' I had no idea about the country at the time. But it seemed like a great opportunity. I remember talking to my friends who told me all kinds of wild things about the country that I now know were clearly not true. But I took the chance and had the opportunity to come out here for three months as a JSPS scholar, a short term invited researcher, before I did my PhD and had three months here as a guest."

At the end of this period, Smith applied for PhD courses in both Sydney and Osaka, and faced a difficult decision, stay at the familiar University of Sydney or take a chance at a long-term position in Japan. He credited the short term invited researcher period as a grounding force which allowed him to see and experience both the exciting new aspects of a foreign culture as well as the potential challenges, and steeling his courage, made the leap to Japan for his PhD study.

Applying optical technics to immunology

Smith's main focus is on the use of optics in immunology, a field named biophotonics. This is a cross disciplinary field that makes use of the world of physics to find applications of light in the investigation of biological molecules. These investigations primarily make use of microscopy and light-based interrogation of samples, or spectroscopy in which light is directed at a sample and resulting wavelength shifts are measured to determine which molecules are present. Despite the seemingly complex mechanisms involved, the outcomes of this research are visible in many everyday objects; biosensors used in label-based tests such as pregnancy and antigen tests are a common example.

Smith commented on his specific area of expertise, "I am an editor for the Biomedical Optics Express Journal and so am exposed to almost all areas of biophotonics, but what I mostly work on are cells, either donor derived materials or cultured cells, and make use of optical techniques to extract data from them."

This is primarily achieved through two major approaches: label-free imaging based on the Raman scattering process, where color shifts are used to investigate the molecular composition of samples, and phase-sensitive imaging, which employs laser interference to probe cell morphology and their dynamics. Smith has been utilizing both techniques to investigate a range of biological processes, including lipid nanoparticle uptake into cells, the behavior of T-cells in the body, and investigating the presence of microplastics in cells.

The microplastics example allows for the investigation of various effects these particles may have on cells. "Using these techniques, we can know if there are microplastics in the cell. We can also look around the outside of it and investigate if it has the same sort of structure and composition as the rest of the cell. If it does, it means the cell hasn't really reacted to the microplastic and it may just be passively entering. However, if there are a whole bunch of lipids around it or the cell is rearranging itself around the foreign object. It means it's actively uptaken or at least provoking a reaction. We are trying to mine the information from all of our optical measurement techniques to try and tease this out either way, and even if nothing is happening that is an answer in of itself." Smith explained as an example of how these optical techniques can be used to deepen our understanding of how microplastics interact with our cells.

In a particularly topical development, Smith's group has also used these methods to detect populations of regulatory T cells, which have gained recent attention following the Nobel Prize awarded to Japanese scientist Shimon Sakaguchi. These cell populations can be observed through optical interrogation processes.

Smith is also keenly interested in artificial intelligence and its potential to have a profound impact on the field. He highlighted both the ways in which science is already changing as a result of AI and how its influence is likely to grow in the future. "In a field like photonics we've got these challenging techniques that are noisy or are difficult to track, and then there is also inherent diversity in biology. On top of this, the impact of batch effects is massive. AI is already being used to help us tease out the information from noisy data sets. The ability to rapidly find information will be a massive game changer, but the big caveat will be that it will always be the responsibility of the researchers, which means us, to determine whether the findings are valid, meaningful, and repeatable".

Beyond the use of AI, Smith hopes that the techniques that he uses in the lab will lead to new, novel discoveries and become one of the gold standards for biophotonics research. However, he also mentioned that there is still value in using these techniques to find and/or prove the existence of cell populations that have been theorized in the past, noting that the "the joy of discovery is not necessarily related to the novelty of the concept."

On the impact of international brain circulation and overseas collaborations

Over his career in Japan, Smith has been an active contributor to international brain circulation, both as a principal investigator in Japan and through various overseas collaborations. When asked about the differences between Japanese and Australian research institutions, he said "Actually, the biggest point is that they are similar. Any place doing high-level research that is successful is more or less doing the same things. In terms of what it is like to 'be there' then there are some big differences."

He has recently been collaborating with several researchers based in Australia, and, just as when he first visited Colin Sheppard's lab back as an undergraduate, he is always struck by how relaxed the environment seems. Despite the laid-back atmosphere, the publications being released by these labs are of the highest caliber, and even the lecturers he had as a first-year student have ties to high level papers and researchers. In Australia, there is a strong emphasis put on being both a skilled researcher and an effective teacher. Inspired by the classes he attended as a student; Smith has brought a number of the ideas he was exposed to in Australian university classes and applied them to his classes (sometimes to the confused looks from his students!) and believes it's a great example of the benefits of international brain circulation.

When discussing the differences between the two environments, Smith highlighted the ease of collaboration. "In Australia people can be more relaxed or less concerned about forming collaborations. They seem a bit more open to sharing ideas and data, but that comes with limits. Here it is very important to do your due diligence and often collaborations can depend on your level. I am a Principal Investigator so I can reach out to other PIs, but even then, I only do so if I am confident it's a good idea." Smith did note that scientists in Australia still treat their time as a precious commodity, but that it can be a little easier to approach different groups.

Smith also pointed to some advantages of doing research in Japan, including the availability of funding, and the public attitudes towards blue sky research. "People in Japan might not know exactly what I'm talking about in terms of science, if you've just got a really interesting idea, it's probably easier to get traction here where someone thinks it's a good idea'" This openness is reflected in the many Ig Nobel Prizes awarded to Japanese scientists over the years.

Smith credited the fortunate timing of his appointment at IFReC as a major factor in his success in Japan. "It was a case of right place right time, I benefited massively from the WPI program as it was a huge influx of funding, this allowed me to start collaborations as soon as possible. My lab is a bit of an outlier in terms of IFReC, as most of the researchers are working on immunology, in collaboration with other immunologist, whereas I am more focused on the tools that support that, and hopefully helping them to find the next new finding in the field."

It was this funding that allowed for further overseas collaborations. The synergy of working through IFReC led to connections with universities back home in Australia, with a few grants with Universities in Melbourne being recent highlights. He looked back on the experience fondly, "I have been well supported and that has allowed me to build my own network, and I hope to expand it further in the future." Smith is also working hard at finding further collaborations across the Asia-Pacific region, a wonderful example of the benefits that international brain circulation can bring to both the Japanese research environment, and the various partners that collaborate with it.

Smith also shared some of his experiences of first moving to Japan, and some sage advice on navigating the early period of a new life in a different culture. "Coming into a new environment, you will have the feeling of being a bit lost, I think everyone has that to some degree, and it's a whole series of micro battles and you will unfortunately lose some of them. What you need to do is win enough of the battles and be able to take the hits. There are some issues that you can't really solve, but it is important to be able to roll with the punches as best you can."

"I think learning to observe people and not take things personally is important and you'll make mistakes. There's always a reason for things here that are slightly different than at home, so you have to just keep an open mind. Don't have too many expectations about how things will be, and you will be OK." This advice applies to all aspects of adapting to a new culture, from learning the language and customs to adjusting to differences between labs and work environments.

Peeking through the microscope of the future

With 25 years of research experience in Japan, Smith plans to continue his work in his adoptive country. However, he also hopes to take advantage of opportunities for research abroad through sabbaticals or other initiatives. He offered some advice for researchers aspiring to follow in his footsteps in biophotonics or conduct research in an international environment.

"Biophotonics is a wonderful playground that you should try to explore. Optics in general involves a lot of complicated concepts, including quantum mechanics and so on, so it's important to keep your scientific curiosity engaged. That's true in science overall, but particularly in this field."

"For Japan specifically, anyone interested in working here could benefit from a short-term visit first. Visiting as a tourist doesn't give you a realistic sense of what it's like to live and work here, so attend meetings and get a firsthand experience of what it is like to conduct research in this environment."

As Smith continues to illuminate the often-unseen world of biophotonics, he also envisions the potential to explore future technologies. Ideas such as growing cells on the lens of a camera for observation, and direct imaging of the brain using interfaces were both touched upon as potential applications in the future. Whichever direction the light bends into the future, Science Japan looks forward to following Smith and the discoveries emerging from the IFReC Biophotonics Laboratory.

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