Written by | Liu Runan

At the beginning of 2015, Cai Tao, who was still visiting and communicating abroad, received a call from Ma Yanhe: “In the future, the institute plans to do a synthetic starch project and manufacture it out of thin air.” ”

“Made out of thin air? Is this possible? He was a little surprised.

Six years later, they turned the impossible into reality. The Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences (hereinafter referred to as the Tianjin Institute of Industrial Biology, Chinese Academy of Sciences) has realized the de novo synthesis of starch by electricity/hydrogen energy driven carbon dioxide for the first time in the world through the de novo design and precise regulation of complex metabolic pathways.

The findings were published online in Science on September 24.

The experimenter is doing the starch color development test in iodine. Photo by Ni Sijie

From 0 to 1 From nothing

As an important class of polymer carbohydrates, starch provides the calories needed for human survival. For more than 10,000 years, agricultural cultivation has been the only way to produce starch.

In order to cope with food security, scientists have explored hybrid breeding, modular breeding, molecular breeding and other methods, and also established artificial photosynthetic systems.

“But none of this detaches from the carbon sequestration patterns of the plants themselves.” It’s like running fast, but you essentially rely on your feet. Can you jump out of this mode and build a car? Ma Yanhe, director of the Tianjin Institute of Industrial Biology of the Chinese Academy of Sciences and chief scientist of the synthetic starch project, said.

At the same time, China’s carbon dioxide emission reduction pressure is huge, and the synthesis of carbon dioxide as raw material is a difficult problem in front of all scientists.

“Using carbon dioxide to synthesize starch”, as soon as they heard about this project, even well-known experts in the field shook their heads, “The photosynthesis of plants has existed for more than a billion years, and the system mechanism has not been fully understood, you can synthesize it from scratch”?

Everyone’s doubts are not unreasonable, this is something that no one has ever done, and I have searched through all the literature repositories and cannot find any clues about the synthetic path and research methods.

On the afternoon of July 24, 2018, Cai Tao, associate researcher of Tianjin Institute of Industrial Biology of the Chinese Academy of Sciences and project manager of synthetic starch, was in the conference room upstairs of the laboratory, preparing to participate in the review meeting of key projects of the Chinese Academy of Sciences.

Since the project was established, he and his colleagues have experimented for more than two years, tried countless times, but failed, and seeing that the three-year project is about to end, their pressure has accumulated to the maximum.

At 3 o’clock, Cai Tao received a photo from Qiao Jing, a laboratory technician. In the photo, the three reagent tubes side by side, the iodine solution in the middle is a faint blue-purple, which contrasts significantly with the colorless and dark blue states on the left and right sides.

“On both sides is the control group, and in the middle is the latest test result, which turns blue when it reacts with the iodine solution.” Qiao Jing said.

Cai Tao immediately called to confirm, and after getting an affirmative reply, he was still not at ease, trotting all the way to the laboratory, until he saw the reagent tube with his own eyes, he couldn’t help shouting, “Great!” That’s great! When I reported back, I could finally say, ‘The manufacturing path is open’. ”

Technician Sun Hongbing remembers that everyone was very happy that day, and Mr. Cai changed his usual seriousness with a smile on his face.

“It is equivalent to the Zunyi Conference on the Long March Road.” “It’s the most beautiful color I’ve ever seen.” Cai Tao told the “China Science News” reporter.

At this point, synthetic starch has officially taken a step of “from 0 to 1”, and the cognitive boundaries of human life science have been broadened a little.

Labyrinth Quest From there to excellent

The joy of success erased all previous regrets, so that when they told the research process, they would subconsciously brush aside the early difficulties.

But when they first received this project, even they didn’t believe they could make it.

In natural reactions, starch synthesis and accumulation involve about 60 steps of metabolic reactions and organelle transport, which must be simplified in industrial production and ensure the adequacy and precision of all reactions.

Therefore, how to simplify the complex synthetic pathways in agriculture into the simple synthetic pathways required for industrial production is the biggest challenge for synthetic starch.

After computer algorithm mining and screening, the researchers finally locked 30 possible paths between the starting carbon dioxide and the end starch, each containing 9~12 important reactions.

Every possible path is a labyrinth.

They are at the entrance to each maze that is connected end to end, nested in layers. Each maze has several “levels”, that is, biochemical reactions, and if you want to pass the level, you must find the corresponding “key”, that is, a specific enzyme that can catalyze the reaction.

When it is difficult to clear customs, you often can’t see starch. After all, there are 30 possible paths, and only if you take the only one right, you can be considered successful.

“These enzymes, which are seen as ‘keys’, may or may not exist in nature and need to be redesigned.” The most difficult thing is that, unlike ‘one key opens one lock’, the same enzyme can catalyze multiple reactions, but it will bring ‘side effects’. Cai Tao said.

For 6 years, nearly half of the time, they were stuck in these different pathways, sometimes unable to find enzymes that catalyze reactions efficiently; Sometimes enzymes preferentially react with the preceding substrate, while the latter substrate has no enzyme available; Sometimes only one part can be walked through.

In order to pass the layers of levels in the maze, Cai Tao and others cooperated with more than a dozen research groups.

“A team has limited strength, and I hope to find the most professional people in the niche field to work with.” He said.

At that time, Sun Hongbing and Qiao Jing became extremely sensitive, and they doubted every step they made.

“It may be that the solution is added incorrectly, the dosage is not accurate, and I made a low-level mistake.”

But after each repetition, they have to face the fact that there are no mistakes in the operation, and this path will not work.

“Unlike the research group that works on multiple projects at the same time, we are project-based management, and there is only one project in 6 years, so we will not give up no matter what we encounter.” Cai Tao said, “The worst result is failure, failure in scientific research is normal, big deal to start all over again.” ”

Once, Cai Tao went out to communicate, and a scientist proposed “using carbon dioxide electric/hydrogen reduction to synthesize methanol”.

“The moment I heard this train of thought, I was shocked, and my brain felt like electricity. Can we learn from this and convert carbon dioxide into methanol first, and then convert methanol into starch? He said.

Later, there was a picture of the iodine solution in a light blue color.

On September 15, the reporter of “China Science News” saw in the Tianjin Institute of Industrial Biology of the Chinese Academy of Sciences that Cai Tao was holding a 15 ml centrifuge tube containing a large half tube of white powder, he introduced, “This is the first tube of starch synthesized by using carbon dioxide, which is exactly the same as the starch extracted from plants.” ”

If in 2018 they completed “from scratch”, then from 2018 to now, they have achieved “from something to excellent”.

Step out of the labyrinth and explore the unknown

In the experiment of synthetic starch, Cai Tao wants to find the “easiest path”, and in life, he is the same. From home to the institute, he usually chooses the road with the fewest turns and the fewest traffic lights and walks slowly. “This road is the straightest and there are fewer pedestrians, so it’s easy to concentrate on things.” He said.

In Sun Hongbing’s opinion, Mr. Cai wants to do it too much, his mind is full of projects, as long as he discusses the experiment, his eyes will immediately light up, and his voice will become rich.

“What touched me the most was that in order for us to concentrate on the experiment, he would pave all the roads, from experimental design, communicating with other collaborators about experimental technology, to buying triangular bottles and reagent tubes, every day for 6 years, he did not want to delay for a moment.” Sun Hongbing told China Science News.

It is precisely in this way that they were able to complete the directional modification of key enzymes in a relatively short time, coupling the chemical process from carbon dioxide to methanol and compatibility with the reaction conditions of the biological process from methanol to starch, and ultimately increasing the synthesis efficiency by a factor of 130.

Compared with the natural generation of plants, its carbon conversion rate is increased by 20~40 times.

The small conference room in the lab witnessed every discussion and dispute, as well as 55 revisions to the 71-page manuscript.

“How familiar is Teacher Cai with the manuscript? The other day we needed to look up two words, the number of pages and location of the words, and he blurted out. Sun Hongbing said.

Once, Cai Tao was tired and lying on the bed to rest, received a link from Jiang Huifeng, a researcher at the Tianjin Institute of Industrial Biology of the Chinese Academy of Sciences, in the title, he vaguely glimpsed the words carbon dioxide and starch, and immediately bounced up from the bed, sleepy, heartbeating, “No one will have already made it”, he stared at the mobile phone loading strip, until he read the summary before he breathed a long sigh of relief, “It turned out to be a different study, a false alarm.”

This is what makes scientific research fascinating and cruel, as researchers struggle through a maze of hurdles and hurdles through the hurdles, often not knowing how many “competitors” there are in the field, let alone knowing each other’s progress.

They can only push themselves to be faster, faster, because the laurels of the pioneers belong only to those who arrive first.

In August 2021, the review of Science was approved, and no additional tests were required. Reviewers described the work as “a landmark breakthrough that will have a transformative impact on the next generation of biomanufacturing and agriculture.”

After 6 years, Cai Tao and others finally got out of the maze and came to a broader world, and he was the first person in the world to come here.

He was proud, and more importantly, he wanted to keep going, to pursue bigger and more unknowns.

China Science News (2021-09-27 2nd Edition Highlights Original title is “Synthetic Starch: 2000 Days of Labyrinth Search”)

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