Creepy-crawlies are creatures that most people don’t want to be anywhere near. But research results from Japan may be about to change that perception. Common spiders, worms, and insect larvae have unique features that are potentially useful to humans. Some, in fact, may be sources of lifesaving treatments.
Scientists at Hirotsu Bio Science have zeroed in on the surprising behavior of a particular nematode, Caenorhabditis elegans, when it comes in contact with human urine. Curiously, C. elegans is drawn to the urine of people with cancer, but it crawls away from urine secreted by healthy individuals. Hirotsu Bio has designed a cancer diagnostic kit making use of the nematodes’ olfactory system that will hit the market in a few months.
“Even stage 0 of colon cancer is detectable,” CEO Takaaki Hirotsu says.
Nematodes aren’t the only creatures generating business ideas in Japan. Silkworms, spiders, and insect larvae are also sources of inspiration for companies large and small. One start-up raised $200 million after demonstrating that it could produce a polymer that shares many attributes of spider silk. Japan, a country well known for its obsession with cleanliness, is proving surprisingly adept at exploiting creatures that many stay away from.
One reason that Japanese researchers are drawn to worms and other simple creatures is their low cost. For example, Genome Pharmaceuticals Institute (GPI), a venture from the University of Tokyo, is developing silkworms as animal models to study human disease.
“The big advantages of using silkworms as animal models are cost and time,” says Sigeaki Toyama, managing director of the company. “Cost-wise, they are 1% the cost of rats, and time-wise, they use 10% of the time.” In addition, Toyama says, companies in industries such as cosmetics want to avoid using rats and other mammals to test products because of ethical concerns.
The basic research underpinning GPI comes from the lab of Kazuhisa Sekimizu, formerly of the University of Tokyo and now at Teikyo University.
Using silkworms as animal models of human diseases, GPI discovered a compound in soil bacteria that could be used to treat ailments caused by Staphylococcus aureus, a bacterium commonly found in humans’ upper respiratory tracts that can also cause skin infection.
GPI is also using silkworms as animal models to screen for functional food ingredients. For example, with support from Japan’s Ministry of Economy, Trade, and Industry, GPI used its silkworm-model system to discover lactic acid bacteria that can be added to food to boost the immune system. The dairy food company Tohoku Kyodo Nyugyo now sells a yogurt using such bacteria.
Silkworms have attracted the attention of another Japanese start-up, AI Silk. An offshoot of Tohoku University, AI Silk is adding a conductive sensor to natural silk made from genetically modified silkworms. The sensor is poly(3,4-ethylenedioxythiophene):p-toluenesulfonate, often called PEDOT:PTS. AI Silk’s material retains the properties of natural silk, such as its smooth texture and water-absorbing capacity.
Partly supported by cash injections from the sports-shoe manufacturer Asics, AI Silk has developed prototypes of clothing that can monitor the wearer’s vital statistics. For example, the company says clothing made with the fiber can be configured to interface with a vehicle’s computer to monitor the driver’s health in real time. A car with self-driving capabilities, for example, could be programmed to take over if the driver falls asleep or becomes incapacitated, according to AI Silk CEO Hideo Okano.
One of the challenges that AI Silk had to overcome early on was keeping the conductive coating attached to the silk during repeated washings, Okano recalls. The company resolved the issue through a research collaboration with Japan’s National Agriculture and Food Research Organization, which helped it design a genetically modified silkworm to complement its natural silkworms. “Silk from genetically modified silkworm and the conductive polymer coating can covalently combine,” Okano says. “This doubles wash resistance.”
After overcoming the washing issue, AI Silk is now focusing on scaling up production. So far, the company can produce up to 100 m2 of its material per month at Tohoku University. “We currently need 100 times as much,” Okano says. AI Silk is sharing its technology with a manufacturing partner that is slated to produce the material in commercial quantities by the end of the year.
Also working with silk—spider silk in its case—Spiber is further on the path to commercialization. Over several years, the Japanese firm has raised $200 million from multinational companies that have become shareholders in the firm.
Well known for its light weight and unusual tensile strength, spider silk has, until now, not been produced commercially. It has been tried, but spiders aren’t like cows that can be bred for their milk. No one has yet come up with an efficient way to collect spider silk, a challenge made harder by the spiders themselves, each of which produces as many as seven types of silk.
Spiber’s solution was to analyze the amino acid sequence in spider silk. It optimized the sequence and incorporated the necessary genes into microorganisms that were then fermented to yield proteins containing components for synthesized spider silk. It is a process that Spiber performs entirely in-house. According to the company, the results are remarkable.
“Our structural proteins provide performance that goes far beyond spider silk,” Director Kazuhide Sekiyama says. “And by using our proprietary protein design technology, we can optimize the amino acid sequences at the molecular level to provide a customized material that meets the quality and performance expectations of various customers.”
This may sound like the brave sales pitch of an entrepreneur looking for customers and investors, but the company’s actions speak for themselves. Investors in the firm include Toyota and the outdoor-clothing company the North Face.
And Spiber is spending $50 million to build a plant on the northeastern coast of Thailand. Scheduled to start production in 2021, it is set to be the world’s largest structured-protein fermentationfacility. The resulting fiber will sell for $40 to $200 per kilogram, depending on the grade. For example, a fiber with a cashmere feel will command premium pricing.
Spiber’s development partners hope to use its fiber in a variety of applications. Sumitomo Mitsui Construction, for example, wants to incorporate it in construction materials. At the North Face, the first product using Spiber’s synthetic spider silk will likely be a T-shirt that retails for over $200.
The North Face had earlier hoped to launch another product, a parka, in 2016 but discovered that the strain of silk it used unexpectedly contracted in the rain. The North Face and Spiber both say the problem has been resolved by using a different protein. The parka is now planned for launch soon after the T-shirt.
At Hirotsu Bio, January 2020 is the month targeted for the Japanese launch of its nematode-based cancer diagnostic kit—branded N–Nose—at a price of around $50. Health professionals in Japan will have access to the kit before then, CEO Hirotsu says, because some of the country’s health insurers plan to include it in their customers’ recommended checkup routines.
The olfactory system of nematodes is surprisingly sensitive. Whereas humans have about 400 olfactory sensors and dogs 800, nematodes boast 1,200.
It is not clear why nematodes are attracted to the urine of people with cancer, but the sensitiveness of their response is remarkable. According to Hirotsu, standard tests are less than 20% accurate in detecting stage 1 colon cancer. The N–Nose kit, in contrast, touts an accuracy of 93.3%. N–Nose has so far been tested on 18 types of cancer, including major ones such as lung and stomach, Hirotsu says.
Support from larger firms has helped Hirotsu Bio’s N–Nose technology move forward. For instance, it has attracted $13 million from Miraca Holdings, a clinical research firm. Other companies, including the information management company Toppan Forms, also funded Hirotsu Bio’s R&D.
Besides nematodes, silkworms, and spiders, Japanese researchers have turned their attention to other creepy-crawlies, though the work seems to be at earlier stages. Two Japanese trading firms, Itochu and Marubeni, each invested about $10 million in a Japanese venture called Musca seeking to use fly larvae to convert the excreta of livestock into fertilizer and animal feed. The two trading houses expect that it will be some time before the technology reaches the commercial stage.
The commercialization of research ideas typically takes a long time, and ones involving insects are no exception. It was nearly 20 years ago that the journal Nature published a paper by Hirotsuon nematodes and their unusual sense of smell (2000, DOI: 10.1038/35005101). After the publication, Hirotsu and his team spent most of their time on academic research and didn’t form Hirotsu Bio until 2016.
“Until August of last year we only did R&D,” Hirotsu says. He and his team became more commercially focused once private companies got involved as funders and advisers.
Dogged perseverance has its rewards. After a long time, this Japanese researcher’s somewhat fanciful focus on creepy-crawlies is finally bearing fruit.
Katsumori Matsuoka is a freelance writer based in Japan.