Wen | Zhao Guangli, a reporter for China Science Daily
From the age of 23 to 29, Zhao Zhilei was almost entirely obsessed with studying biting mosquitoes.
"I've been thinking about the problems I'm working on and doing everything I can to make new progress, and I've dreamed more than once about the topic I'm working on."
In an interview with China Science News, the Doctor of Princeton University in the United States admitted that he prefers that unique research: starting from a creature with a certain magical ability, revealing a more universal law.
Mosquitoes are one of them, "they have a very keen sense of smell." Finally, in May 2022, 30-year-old Zhao Zhilei, as the first author and corresponding author, published a paper in Nature on the brain activity of mosquitoes in search of a host (human).
This study scientifically answered the question of "why do mosquitoes bite me?" that made many people scratch their heads.
Today, Zhao Zhilei has gone to Cornell University for postdoctoral research in neurobiology. His postdoctoral project was no longer a mosquito, but turned to parrots.
It was a bit risky, but he was determined at heart.
"If I continue to study mosquitoes, I can find a teaching position faster." But I'm very interested in the parrot, and the new technology means that we can now delve deeper into its brain, and there are some important scientific questions that may be answered by studying the parrot. ”
Zhao Zhilei
Be sure to seize this opportunity
Zhao Zhilei was very curious about mosquitoes in his childhood.
In his hometown of Yunnan, mosquitoes are particularly abundant.
Every night was awful as summer began, and he woke up with a bag — but miraculously, his father.
"The family watched TV together and mosquitoes even bypassed him to bite us." Zhao Zhilei was puzzled by this.
Mischievous, he specially caught mosquitoes and placed them on his father's arm, but the mosquitoes fled in fear.
Mosquitoes suck blood or pick people? If there is also a "selection criterion" for biting, then what is this criterion? This question has always remained in Zhao Zhilei's mind.
In 2015, after graduating from Peking University, Zhao Zhilei wanted to apply to the United States to pursue a doctorate.
In the selection, he found that a laboratory at Princeton University specialized in the study of a tropical and subtropical mosquito, the Aedes aegypti mosquito.
This small mosquito, which originated in Africa, miraculously flew around the world in less than ten thousand years. Moreover, they are becoming more and more fond of biting, as if they are "biting professionals".
During the interview, Lindy McBride, an assistant professor at the lab, showed him an experiment: asking a hundred hungry mosquitoes to choose whether to bite or an animal, and almost all of the mosquitoes quickly chose the human side.
She told Zhao Zhilei that although everyone has known about this phenomenon for a long time, it has always been a mystery what mechanism mosquitoes rely on to distinguish between humans and animals.
The mosquito-like operation made Zhao Zhilei very excited, and he decided to join this laboratory to solve the puzzle on the spot.
With the deepening of his understanding of mosquitoes, Zhao Zhilei, in addition to curiosity, "gradually has a sense of mission."
Mosquitoes are not only annoying, but also very dangerous, and they can efficiently transmit deadly viruses in humans.
When reading the literature, Zhao Zhilei saw a set of figures: according to the World Health Organization, about 720,000 people die each year from mosquito-borne diseases such as malaria and dengue fever.
It's an astronomical number, he thought, "If I can figure out how these mosquitoes accurately distinguish between humans and animals, it will be possible to develop efficient mosquito repellent methods that reduce the harm caused by mosquitoes to people." ”
In fact, this problem has been studied for decades and has not been broken. The reason for this is the limited number of techniques that scientists can use in mosquitoes.
However, it's different now.
Zhao Zhilei thought he was lucky. "At this point in time when I joined the mosquito research, there was a number of powerful technologies, such as gene editing technology and calcium imaging technology. We realized at the time that applying these latest technologies to the study of mosquitoes could lead to breakthroughs. ”
This was a golden age for studying mosquitoes. Zhao Zhilei is lucky enough and "desperate" enough, and he must seize this opportunity.
Do you want to feed blood to raise mosquitoes? Give, arm!
Raising mosquitoes is the first hurdle.
Collecting mosquito eggs in the wild and bringing them back to the laboratory for incubation are all well said, but how to raise them? Or how do you feed them blood?
Aedes aegypti mosquitoes do not like the blood of animals, and the method commonly used in the laboratory to "wrap rabbit blood with a thin plastic film simulating skin" did not work very well; The easiest and most efficient way is to put your arm directly into the mosquito cage.
Is this dangerous? Zhao Zhilei explained to China Science Daily that this method of feeding mosquitoes was approved by the ethics committee on the basis of understanding the biology of mosquitoes.
This, of course, follows the principle of complete voluntariness.
Moreover, this method does not cause the spread of the disease.
He explained that mosquitoes are only vectors for pathogen transmission, not the source of their production, and they will not be transmitted from generation to generation, so mosquitoes hatching from eggs in the laboratory are very "clean" and do not carry pathogens.
At the same time, the laboratory has clear regulations that the same batch of mosquitoes can only be "raised" by the same person, so it will not cause a situation of human-to-human transmission.
In Lindy McBride's lab, a "ruthless" colleague set a record for feeding 3,000 mosquitoes in a single day.
Zhao Zhilei, who is slightly thin, has a record of 1500.
The first time he fed the mosquito, his arm was swollen and itchy for a long time.
Later, Lindy McBride asked him to rinse continuously with hot water (which speeds up blood circulation in the skin), and then slowly reduced the swelling.
After a few months, Zhao Zhilei could not feel the itch by feeding the mosquitoes with his hands, he said, because "the immune system has adapted."
After raising mosquitoes, you can then collect "human smell" and various animal odors, look for differences in odors, and then verify what smells they are interested in through mosquitoes.
Zhao Zhilei told China Science Daily that the way they collect "human smell" is also very absolute, requiring the whole person to lie down in a clean plastic bag after stripping off, and then into the plastic bag into clean air, so that the exhaust air has a "human smell".
However, the process is slightly longer, and people have to lie in plastic bags for two hours.
Through comparison, the research team found that compared with animals, human odor is not unique to any chemical molecule, but there are several molecules in particular, such as decanal and methagenone.
These two molecules are the products of oxidative decomposition of certain oily substances secreted by human sebaceous glands after contact with air.
These oily substances, animal sebum is hardly secreted, which also explains why "human taste" is so special.
The next step is to figure out why mosquitoes like "human taste" so much.
Failure is also an important part of evaluating contributions
To explore this question, their experimental protocol was groundbreaking: give a mosquito a "craniotomy" to see what was "thinking" in its head.
If they can know which part of the brain is activated when mosquitoes smell "human odor", they can further investigate whether the mosquito brain has a fondness for certain molecules ( such as decanal or methylheptenone ) .
Cracking this problem can not only decipher the criteria for mosquito selection in one fell swoop, but also be able to "catch mosquitoes" - compared with the "human taste" composed of hundreds of molecules, specific chemical molecules are easier to manufacture and store, which is more convenient to make new types of mosquito traps.
The mystery is indeed within the scope of this hypothesis. Their subsequent research has found that mosquitoes prefer people with moderate levels of decanalaldehyde in their body odor.
Zhao Zhilei explained that one potential reason is that there are very few or many people in the population with decylaldehyde, and if mosquitoes tend to like such people, then its probability of finding the right person will be reduced, which is not conducive to reproduction.
But in the study, the mosquito's "craniotomy" was not so easy to do — they had to let the mosquitos be opened and still alive.
Genetically modified mosquito larvae that did not survive were provided by respondents
Gene-editing technology makes this bold experiment feasible. By editing mosquito genes, nerve cells in the mosquito brain are specifically labeled to express fluorescent proteins, and when nerve cells in a certain brain area of the mosquito are activated, the fluorescence is enhanced, so that you can know which brain region is activated.
However, the success rate of gene-editing mosquitoes is too low, not even 0.1%.
Zhao Zhilei did gene editing for the first time, and worked hard for nearly 6 months before screening several fluorescent larvae.
He was so excited that he thought he was about to succeed, but within a few days, the fluorescent larvae were "completely annihilated.".
"It was a bad mood. But when we calm down and analyze it carefully, the negative results also lay the foundation for our later success. ”
Zhao Zhilei said that a good experimental design, whether the results meet the initial expectations or not, provides very useful information that can be used to continuously revise and refine our understanding of nature, "which is also an important part of evaluating our contribution to this field."
In this way, it took 5 years for the research team to create genetically modified mosquitoes that could be tested.
Through experiments, they found that although there are nearly a hundred chemical molecules in human odor, only two areas are activated in the primary olfactory brain region of mosquitoes.
They matched a mixture containing only two chemical molecules to activate both brain regions and found that it had a strong attraction to mosquitoes, just like the smell of real people.
"We patented this mixture to be applied to mosquito traps to attract trapped mosquitoes." Zhao Zhilei revealed that there are already several companies developing mosquito control products negotiating with them about the transfer and cooperation of patents.
In addition, Zhao Zhilei said, his colleagues are exploring another idea: If a compound can be screened out that can specifically inhibit the two brain regions that are activated by "human taste", then the compound may be used as a mosquito repellent — it will interfere with the mosquito's sniffing of people.
Adventurous choice
After graduating from Princeton University with a Ph.D., zhao turned to study parrots, and Zhao Zhilei made a risky choice.
Before that, Zhao Zhilei had a "hanging" life: a science graduate in Dali, Yunnan, and was admitted to Peking University to study bioengineering; After graduating from Peking University, he went to Princeton University to study mosquitoes; He now studies neurobiology at Cornell University.
He has his reasons. Zhao Zhilei told reporters that like mosquitoes, parrots also have a magical ability: in the wild they can quickly imitate the sounds of their surroundings, and when they are kept as pets, they will imitate human speech.
"They have very interesting social sexual behavior and cognitive abilities, and this powerful ability to learn and imitate is rare in nature." Zhao Zhilei said that there is a school of view in the academic community that the reason why humans are so successful in evolution is because people can quickly learn to imitate.
Therefore, he felt that to study the brain mechanism of learning to imitate, "the parrot is a very good model."
Zhao Zhilei revealed that his current research focuses on the role of dopamine in the brain in this process.
The road ahead is full of unknowns and even great challenges, but Zhao Zhilei claims to be "more determined in his heart".
He told China Science Daily that he has a wide range of interests and likes to read the history of science and biographies.
"This usual accumulation can be quite useful when making choices. Because there is a general picture of the development of the discipline in the mind, it can have its own understanding of what are the more important problems and what kind of breakthroughs the new technical means can bring. ”
He also attributed his past achievements to his own luck. "I think it should be choice, hard work and some luck." On a personal level, I was fortunate to be born into a family that valued education, and I was supported and helped by many teachers and friends along the way. In a big way, I am very fortunate to live in an era of advocating science and rapid development of science and technology. ”
Related paper information:
https://doi.org/10.1038/s41586-022-04675-4