Nagoya University chemist creates molecules to boost the world’s food supply

Increasing food production to feed a growing population is one of the world’s greatest challenges. And Kenichiro Itami is on a mission to bring chemistry to the fight. Itami is the director of the Institute of Transformative Bio-Molecules (ITbM) at Nagoya University, where chemists and biologists work side by side to develop molecules that could help solve pressing problems in agriculture. Mark Peplow spoke to Itami about the institute’s research and its approach to inter­disciplinary collaboration.

Why is food such a major focus of ITbM’s work?

There are a lot of problems on this planet, and I believe that molecules have the power to solve many of them. More people on this planet suffer from food-related problems than medical issues, yet those of us living in rich countries like the US or Japan often don’t fully realize the problems with food supply.

Our focus on food is a unique way to mobilize the synthetic chemistry community. We’re applying the same principles used in pharmaceutical research to plant and animal biology. We design and synthesize molecules that treat the diseases of plants and animals or that help with their growth, development, and reproduction.

At our institute, research groups don’t work in isolated spaces. We simply let researchers from different fields and groups work together in one big lab so that people can chat. Our building was specially designed to promote these kinds of interactions. So once the biologists have found some small molecules of interest, they can immediately talk to the chemist next to them. This “mixed lab” strategy is how exciting collaborations start at ITbM.

Can you give me an example of your research?

We are interested in developing small molecules that control biological clocks. Over 95% of living things have a biological clock, including plants and animals, and these clocks regulate metabolism, growth, reproduction, and many other functions.

Animal clocks are mainly regulated by four clock proteins. Two of the proteins are accelerators, and two are inhibitors. Together, they create a feedback loop that regulates their own rate of production. So a small molecule that can directly attach to a clock protein can potentially increase or decrease the pace of an animal’s 24-hour rhythm or its seasonal rhythm.

We created more than 50 derivatives of a carbazole molecule called KL001 that binds to one of the inhibitor proteins known as CRY. Some of the derivatives speed up the clock, and others slow it down (Angew. Chem., Int. Ed. 2015, DOI: 10.1002/anie.201502942). We’re starting to understand how their structure affects their activity, and it may be possible to use such compounds to control reproduction in livestock so that they breed more often throughout the year, generating more food. Some animals do not breed during winter when there are few daylight hours, but changing their circadian clock could counter­act that.

ITbM researchers are also developing molecules that can control a plant’s 24-hour clock—for example, to change its flowering time. That could help to accelerate breeding programs or increase the yield of a crop.

What other strategies are you using to improve crop production?

Stomata are essential to plant respiration, allowing the plant to take in carbon dioxide. If we develop small molecules that can control the number of stomata on a plant or regulate how they open, they could affect the efficiency of plant growth, photosynthesis, biomass production, root growth, and more.

In projects like this, we initially rely on chemical screening to find “hit” compounds. Then we make derivatives of the molecules to increase their activity or to make a probe to help us identify the target protein that the molecule acts on.

Using this approach, we developed a pyrazole derivative [ZA144] that increased the number of stomata on flowering plants without stunting their growth (Chem. Commun. 2017, DOI: 10.1039/C7CC04526C). We hope this research could eventually be used to improve a plant’s carbon dioxide uptake or allow it to use water more efficiently.

How do you generate these derivatives for testing?

In a conventional synthesis, if you want to change or add a functional group to a molecule, you have to go back to the starting material. You buy new chemicals with different substituents and redo the same series of synthetic steps all over again, just to make one derivative.

But we often use carbon-hydrogen (C-H) activation chemistry, because it’s a very efficient tool to make lots of different molecules. We can use all kinds of metal-based activation catalysts—containing palladium, nickel, rhodium, ruthenium, or iron—which can activate different types of C-H bonds. That allows us to directly functionalize many different positions in a small molecule to make derivatives that have a higher activity.

C-H activation chemistry can directly functionalize a hit compound, so you only need one chemical step for each new derivative.

What’s your biggest goal for the next few years?

ITbM researchers are developing small molecules to combat Striga, a parasitic plant that infests its host’s roots and deprives it of water and nutrients. Two-thirds of sub-Saharan Africa’s cropland is affected by Striga, damaging crops like maize and sorghum. It’s a huge problem, and there’s no effective solution.

The researchers have just published a paper in Science describing a small molecule called sphynolactone-7 that is very effective against Striga (Science 2018, DOI: 10.1126/science.aau5445). It induces germination of Striga seeds in soil, but they cannot survive in the absence of a host plant—it’s called suicide germination. So if we treat soil that is infested with the seeds before planting a crop, it kills off the seeds and reduces the emergence of Striga.

We can synthesize sphynolactone-7 in three steps from commercially available compounds, and it’s active at femtomolar concentrations. I’ve never heard of such an active biomolecule before, and we’re extremely excited. We went to Kenya this summer to discuss field trials, and we hope to run those tests in 2019.

Mark Peplow is a freelance writer. A version of this story first appeared in ACS Central Science: cenm.ag/itami. This interview was edited for length and clarity.