In 1990, He Hongwu, the member of the Institute for Pesticide Chemistry of CCNU, returned after studying abroad in Japanese. In the following years, targeting pyruvate dehydrogenase, she led her research group to conduct design & synthesis project, hoping to find a pyruvate dehydrogenase inhibitor with herbicidal activity. Luckily, 7 years later, they found HW02 (clacyfos, experimental code) with active hit from nearly one thousand chemical compounds.
“Maybe, this new compound can be developed as a new herbicide.” After many trials, their assumptions were gradually proved to be true. In 2009, having gone through a 12-year long journey , the research group led by He Hongwu reached a breakthrough and then “the Research and Development of Herbicide HW02” won Hubei Technological Invention Award and Wuhan Technology Progress Major Award.
Since then, the creation of clacyfos was sequentially included by The Pesticide Manual 16th edition (2012) and the latest edition The Pesticide Manual the 17th (2015). By the end of 2017, HW02 was the only herbicide created by China, in which case it received quite a bit of attention. Clacyfos is highly selective, secure for Gramineae crops and effective to prevent broad-leaved weed. Besides, it’s has low toxicity, low residue and it is environmentally friendly. Pundits commented that achievement has groped a new way for creating new pesticides in China.
To grab one thousandth of luck
Throughout the ages, 97% pesticides used in China have been the old varieties. Although there are hundreds of pesticides popular on the market, 75% of them are limited to 6 kinds of targets. "Repeated applications of limited targets lead to serious resistance", which is another problem. He Hongwu realized this is a leading edge research subject in the field of pesticide research around the world when she came back from Japan. Then she recruited the first master graduate students and led her group to set about exploring new types of pesticides.
Tan Xiaosong, one of the members in the old Institute for Pesticide Chemistry of our school, has been working with He Hongwu for several years. As the research subject required, talents were needed to worked on the analysis of pesticide components, so he joined He Hongwu’s group. Another teacher in the group is Peng Hao, the graduate student mentored by He Hongwu in 2000. While in graduate school, he participated to carry on this subject research. By the time when Peng Hao graduated, the project hadn’t concluded. Under the circumstances, he decided to stay and continue his study. One session after another, piles of master students and doctoral students constantly contributed to the development of the Herbicide. Although they graduated and left after briefly working on the project, they all contributed to the progress of the project more or less.
The 7th floor of Yifu Chemistry Building is the base camp of He Hongwu's research project - several laboratories which are not so large, with rotating evaporator, glass reactor and other experimental conventional instruments displayed in them. Team members go in and out every day, concentrating on their work.
“Discoveries are achieved through trial and error methods.” They used structured derivative of the substrate, pyruvic acid, to design and synthesized nearly one thousand phosphorous compounds and screened the compounds by active tests. In turn, they used the "culture dish method" and "potted method" to test the inhibitory activity of the compound on the growth and development of multiple single and dicotyledons. To test the selectivity of single and dicotyledonous plants, many experiments should be conducted in field trials to accurately screen the compounds with high activity and plant safety. After a batch of tests, clasyfos, which has inhibitory activity in PDHc, stood out.
The "birth" of this new active compound laid the foundation for the development of "herbicide" and made the appearance of clasyfos possible. He Hongwu conveyed her deep gratitude to the predecessor of the Institute for Pesticide Chemistry of CCNU. She said, the seniors’ guidance and foundation they made is of great help to us juniors. As an expert working on scientific research for more than 40 years, He Hongwu thinks they are lucky, because even for foreign pesticide companies, the successful development of a new pesticide often requires hundreds of millions of dollars to synthesize more than 100,000 compounds. She concluded, invention is created when the reasonable pursuit and opportunity overlap with each other.
Step-by-step experiments are the most abrasive
Because of the high cost, long cycle, high risk, slow return and market demand, many domestic pesticide companies are reluctant to invest in the research, but prefer to copy the old varieties abroad. Compared with foreign countries'demutualization and integration of research and development of pesticide, pesticide research and development in China are mainly concentrated in universities and research institutes. The research links are scattered, funds of research and development are little, and fixed investments are lacking, so creating new pesticide varieties is more difficult.
At that time, the various funds from the government were the only reliance for the team of He Hongwu, and the research had no choice but to pause when there was no subsidy. “We started off with $15,000 in provincial funding” said He Hongwu. Applying for several times constantly, they successively won the funds from the Ministry of Education and the national natural science fund and gained the subsidies of more than ten projects, such as 973 project, national science and technology support plan, up to "scrolling" to the national key research and development plan. It was the tight budget for such a small amount of money that made the research of clasyfos, starting from molecular design, going through several links including chemical synthesis, activity test, structural optimization and mechanism research, head to the stage of application development in fields step by step.
In order to achieve the dream of "creating an herbicide with Chinese intellectual property", it is the a norm for team members to do experiments. Their schedules are repetitive: it’s routine for them to enter the lab at 7 or 8 a.m. and leave at around 10 p.m.; they nearly have no context for holidays. In order to evaluate the performance of clasyfos, the team needs to provide a large sample of kilograms. Hence, They used five-liter containers in the lab to take the place of 200 milliliters of the reaction bottles to improve efficiency, but it also made it harder to operate. Sometimes, in order to catch up with the season of applying agricultural medicine, they work overtime even at a temperature of more than 40 degrees in Wuhan.
In Peng Hao’s opinion, diligence and persistence were the most important qualities the institute needed. He said, “the development of pesticides was a long and uneventful journey of. The promotion of the experimental process required a reasonable design, and also required the researchers to work according to the laws of pesticide science.”
"The result of the design for the molecular properties of pesticides can only be tested by experiment." The safety evaluation of the herbicide includes four stages, including toxicity and environmental behavior evaluation, among which the chronic toxicity test will last 104 weeks. Waiting is also agonizing for the team, because the failure of one indicator means the end of the whole project. “Knowing the result, I could finally breathe a sigh of relief,” said Tan Xiaosong, “we successfully passed a barrier again.”
“No one can make a quick buck, a circle over a decade was normal and we were very lucky” said He Hongwu, “according to the statistics new-developing products of many international pesticide companies, under normal conditions, it takes at least ten years between the birth of the new compound and the launch of the product, let alone we are in such poor conditions.” In the past ten years, Tan Xiaosong’s hair has gone from black to white, he said with smile, “it’s fairly appropriate to use the word abrasive to describe our research and development work.”
Marketization is still on the way
“I think we have good luck.” Tan Xiaosong said positively. Up to now, all the indexes of the experimental evaluation were consistent with the safety standards of pesticide, and proved that clasyfos was safe for the animals and the environment, and the whole development process was successful.
It was a great consolation to He that clasyfos could be included by the latest Pesticide Manual. She thought this is in recognition of their work. Besides, supported by the national science and technology academic works publication fund, Prof. He’s research group summarized the related results of pyruvate dehydrogenase inhibitor as herbicide into English monograph, Environmentally Friendly Alkylphosphonate Herbicides, which has been published around the world in 2015.
He said that they had cooperated with a company in Shandong province and had obtained the "temporary registration certificate" for the production and marketing of pesticides in the decade after the invention. But the company collapsed because of poor management, and the process of commercialization was put on hold. "If the company hadn't gone out of business, our herbicide might have gone into the market,” He Hongwu thought it was a pity.
Given the herbicide's high efficiency, low cost and environmentally friendly feature, He Hongwu predicted that "HW02" should have a promising market outlook. But as for how to promote its commercialization, the group still need to make further efforts.
At present, the team has carried out the design and research of new fungicides based on microbial pyruvate decarboxylase, hoping to inhibit bacteria and fungi and apply their research results to agriculture, Peng said. “This project is still in the stage of 'synthesis and selection of compounds'. Up to now, we have found a lot of high - activity hits. If a new candidate is found at this stage, we will greet the onset of a new decade.” Peng added.
