You may feel unfamiliar when it comes to PHA.
But if I tell you that PHA has begun to be used in many fields such as tableware, food packaging, 3D printing, textile fibers, medical devices, etc., you will feel that it is not far from our lives.
"PHA is a family of polyhydroxyalkanoate materials, which is a new material grown from cells. It is completely degradable in nature and is non-toxic and harmless." Chen Guoqiang, professor of the School of Life Sciences at Tsinghua University and director of the Center for Synthetic and Systems Biology, introduced it in this way when he was interviewed by a reporter from Science and Technology Daily.
As early as 30 years ago, Chen Guoqiang determined that PHA was the direction of future green materials and embarked on the research and development of biomanufacturing PHA without hesitation. "This is a process of continuous trial and error. We hit the wall again and again, and broke through again and again." He said.
Solve the pain of "bacterial contamination"
In order to reduce the use of petroleum-based plastics and avoid causing more white pollution, researchers have been looking for degradable alternative materials. Biomanufacturing is one of the recognized production paths of alternative materials.
"Biomanufacturing, as the name suggests, is to redesign and transform organisms to obtain chassis cells with excellent performance, and then use these cells as factories to produce various materials needed by humans." Chen Guoqiang told reporters.
Among many biomaterials, PHA has the advantages of biocompatibility, thermoplasticity, and degradability. Based on the exploration and practice of the previous few years, in 1994, Chen Guoqiang, who had completed postdoctoral research abroad, came to Tsinghua University to form a team and concentrate on studying how to achieve mass production of PHA.
"In the laboratory, many problems are not easy to expose. In the factory, once the scale is enlarged, all the problems will come." Chen Guoqiang found that the first problem was "contamination" - in the process of cultivating microbial cells, other fungi and microorganisms will grow with them.
Once the microbial cells are "contaminated", the entire fermentation process has to start all over again, with huge losses. In order to prevent the cells from being infected, strict aseptic operation must be carried out, which is demanding on equipment and personnel, and has high energy consumption.
"We tried many kinds of microorganisms, but we couldn't solve this problem." Chen Guoqiang recalled that by chance, he thought of extreme microorganisms.
Extreme microorganisms generally grow in extreme environments where ordinary microorganisms find it difficult to survive, and are not easily infected by other microorganisms. With it, the PHA production process can be relatively open, without the need for complex and cumbersome sterilization operations.
So Chen Guoqiang turned his attention to halophilic microorganisms that are difficult to "contaminate".
Unfortunately, the team members searched in many places, but all returned in vain. It was not until 2006 that they finally isolated a strain with both salt tolerance and rapid growth characteristics from a soil sample retrieved from a salt lake with a low latitude, large temperature difference between day and night, and higher salinity than seawater. This is the halophilic bacteria.
Constructing the foundation of the "chassis"
With the right strain, constructing chassis cells has become the key to achieving biomanufacturing.
"Chassis cells can convert renewable biomass such as glucose, starch, and vegetable oil into PHA during the fermentation process." Chen Guoqiang said, "They are like machines in a factory, which can continuously produce the polymer materials we need."
To obtain chassis cells, the genes of halophilic bacteria must be disassembled and assembled. New problems followed - halophiles are too special and lack ready-made molecular manipulation tools.
"'Molecular scalpels', 'molecular suture needles' and 'molecular transporters' are all necessary tools." Chen Guoqiang explained, "They are responsible for cutting, recombining and transporting microbial genes respectively."
Without tools, halophiles are like a "black box" that can be seen but not used.
Plasmid vectors are commonly used "molecular transporters" that are responsible for introducing recombined genes into recipient cells. "This tool alone has consumed a lot of our energy." Chen Guoqiang told reporters that the team has tried hundreds of existing plasmids, but none of them were successful.
What to do? Only expand the scope and find new plasmids. After unremitting efforts, everyone screened out more than 200 plasmids with potential, tested them one by one, and finally ushered in a turning point - 3 of them can be used!
With plasmids, the "black box" of microbial genetic modification has been opened.
On this basis, the team has developed a series of tools for gene editing, metabolic regulation, and network optimization, which can modify and regulate the performance of chassis cells from different levels.
It took the R&D team a full ten years to develop molecular manipulation tools. "This process is very painful." Chen Guoqiang admitted that the secret of success is faith and persistence.
Finally, the chassis cells were constructed by the team.
"The next step is production verification. We spent another seven or eight years to overcome the difficulties of fermentation process improvement, bacterial morphology transformation, material separation and extraction, and crossed the industrial amplification "death valley." Wu Fuqing, a team member and associate researcher at the School of Life Sciences of Tsinghua University, introduced.
Stepping on the road of "transformation"
During the industrial amplification, in 2018, Chen Guoqiang first proposed "next-generation industrial biotechnology" internationally, and it was verified in "small-scale trials", "pilot trials" and large-scale production.
But this does not mean that this technology can be recognized by enterprises. The team faces a new level-transformation of results.
"'Next-generation industrial biotechnology' uses a continuous fermentation system that does not require sterilization for production. It has the advantages of open, high efficiency, low energy consumption and water conservation. It is a 2.0 upgraded version of traditional biomanufacturing technology." Wu Fuqing said that these subversive characteristics have made traditional fermentation companies worried.
"It has always been strictly sealed and sterilized at high temperature. You said you don't need it, so you don't need it?" Some companies even think that the R&D team is "fooling".
After several twists and turns, the team finally found a large fermentation company willing to try. In order to dispel the other party's concerns, the fermentation test was carried out on site.
200 cubic fermentation tank, the first test, success!
The other party's engineer suspected: Is there a "luck" factor? Then try again, it will still succeed! The cooperation was successfully reached.
In 2021, the achievement transformation enterprise-Beijing Weiguochang Biotechnology Co., Ltd. (hereinafter referred to as "Weiguochang") was established, and industrialization entered the fast lane.
"After the establishment of the company, under the guidance of the market, the progress of laboratory scientific research has been accelerated." Ouyang Pengfei, vice president of Weiguochang, said, "In the past, the strains had three generations in 9 years; in recent years, they have been iterated three generations in one year; this year, it is expected to be iterated 4 to 5 generations."
Iteration has given the strains better performance and laid a more solid foundation for industrialization.
An intelligent production demonstration line with an annual output of 1,000 tons has been built in Shunyi, Beijing, and a production base with an annual output of 30,000 tons has been established in Yichang, Hubei... "We have also joined hands with Chuan Ning Biotechnology to promote the application of medical-grade PHA industry and build a 'lighthouse factory' in Hefei, Anhui to explore various application scenarios." Ouyang Pengfei introduced.
In 2023, based on the development and utilization of halophilic bacteria and the contribution of "next-generation industrial biotechnology" to the industry, the International Society for Metabolic Engineering awarded Chen Guoqiang the "International Metabolic Engineering Award". Today, related technologies have been widely used in open production of biomanufacturing.
At the recently held National Science and Technology Conference, the National Science and Technology Awards Conference, and the Conference of Academicians of the Two Academies, General Secretary Xi Jinping emphasized that we must aim at the commanding heights of future science and technology and industrial development, accelerate scientific and technological innovation in the fields of new generation information technology, artificial intelligence, quantum technology, biotechnology, new energy, and new materials, and cultivate and develop emerging industries and future industries.
Looking to the future, Chen Guoqiang is full of confidence: "We will solidly promote the deep integration of scientific and technological innovation and industrial innovation, continue to improve the level of PHA industrialization, and contribute to my country's realization of the "dual carbon" goal and green development!"