From the age of 23 to 29, Zhao Zhilei was obsessed with studying biting mosquitoes.
"I have been thinking about the problem I am researching and making every effort to make new progress. I have dreamed about the topic I am researching more than once."
In an exclusive interview with " Chinese Science Journal ", this Princeton scholar from the United States The doctor from the university admitted that he prefers unique research: starting from a creature with a certain magical ability and revealing more universal laws.
Mosquitoes are one of them. "They have a very keen sense of smell." Finally in May 2022, 30-year-old Zhao Zhilei published a paper in Nature as the first author and corresponding author, describing the brain activity of mosquitoes when searching for a host (human).
This study scientifically answers the question "Why do mosquitoes bite me so much?" that has left many people scratching their heads.
Now, Zhao Zhilei has gone to Cornell University to conduct postdoctoral research in neurobiology. His postdoctoral research topic was no longer mosquitoes, but parrots.
It was a bit risky, but he was determined.
"If I had continued studying mosquitoes, I would have found a teaching position faster. But I'm very interested in parrots. New technology means we can now look deeply into its brain, and there are some important scientific questions that may be answered by studying parrots." Get the answer."
Zhao Zhilei
Zhao Zhilei's instructor stretched out his arm to feed the mosquitoes.
The genetically modified mosquito larvae that did not survive. Picture provided by the interviewee.
We must seize this opportunity.
Zhao Zhilei was very curious about mosquitoes when he was a child.
In his hometown of Yunnan, there are a lot of mosquitoes.
As soon as summer comes, every night is unbearable, and he wakes up all wrapped up - but the amazing thing is, except for his father.
"When the family watches TV together, mosquitoes even bypass him to bite us." Zhao Zhilei was puzzled by this.
Being naughty, he specially caught mosquitoes and put them on his father's arm, but the mosquitoes were afraid to avoid them and fled away.
Mosquitoes suck blood and still pick on people? If there are "selection criteria" for biting people, what are these criteria? This question has always remained in Zhao Zhilei's mind.
In 2015, after graduating from Peking University , Zhao Zhilei wanted to apply to study for a doctorate in the United States.
During the selection, he discovered that Princeton University had a laboratory that specialized in studying a tropical and subtropical mosquito - Aedes aegypti .
This small mosquito, which first originated in Africa, miraculously flew to all parts of the world in less than 10,000 years. Moreover, they are becoming more and more fond of biting people, becoming "professional biters". During
's interview, Lindy McBride, an assistant professor in the laboratory, showed him an experiment: Let a hundred hungry mosquitoes choose to bite humans or animals. As a result, almost all mosquitoes quickly chose the human side.
She told Zhao Zhilei that although everyone has known about this phenomenon for a long time, the mechanism by which mosquitoes distinguish between humans and animals has always been a mystery.
Mosquito's mysterious operation made Zhao Zhilei very excited, and he decided to join the laboratory to solve the mystery on the spot.
As Zhao Zhilei’s understanding of mosquitoes deepened, in addition to curiosity, Zhao Zhilei “gradually gained a sense of mission.”
Mosquitoes are not only annoying, but also extremely dangerous. They can efficiently transmit deadly viruses to humans.
While reading the literature, Zhao Zhilei saw a set of numbers: The World Health Organization statistics show that about 720,000 people die from malaria , dengue fever and other mosquito-borne diseases every year.
This is simply an astronomical number. He thought to himself: "If I can figure out how these mosquitoes accurately distinguish between humans and animals, it will be possible to develop efficient methods of catching and repelling mosquitoes, thereby reducing the risk of mosquitoes to humans." "
In fact, this problem has been studied for decades, and there has been no breakthrough. The reason is that scientists are limited in the technical methods they can use on mosquitoes.
However, things are different now.
Zhao Zhilei considers himself very lucky."At the time when I joined mosquito research, a number of powerful technologies happened to be emerging, such as gene editing technology and calcium imaging technology. We realized at that time that applying these latest technologies to mosquito research would lead to breakthroughs . ”
This is a golden period for studying mosquitoes. Zhao Zhilei is lucky enough and "desperate" enough. He must seize this opportunity.
Do you need to feed blood to mosquitoes? Here, arms!
Raising mosquitoes is the first hurdle.
It’s easy to collect mosquito eggs from the wild and bring them back to the laboratory to hatch them, but how to raise them? In other words, how to feed them blood?
Aedes aegypti does not like animal blood. The method commonly used in laboratories of "wrapping rabbit blood with a thin plastic film to simulate skin" is not very effective; the simplest and most efficient way is to directly extend your arm into the mosquito cage. . Is
so dangerous? Zhao Zhilei explained to China Science News that this method of feeding mosquitoes was approved by the ethics committee based on an understanding of mosquito biology.
Of course, this is completely voluntary.
Moreover, this method does not cause the spread of disease.
He explained that mosquitoes are only the medium for the transmission of pathogens, not the source of their generation, and will not be transmitted from generation to generation. Therefore, mosquitoes hatched 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 "fostered" by the same person, so there will be no human-to-human transmission.
In Lindy McBride's laboratory, a "ruthless" colleague set a record of feeding 3,000 mosquitoes in one day.
Zhao Zhilei, who is slightly thinner, has a record of 1,500.
The first time he fed mosquitoes, his entire arm swelled up and he felt itchy for a long time.
Later, Lindy McBride asked him to rinse with hot water continuously (which can speed up blood circulation in the skin), and the swelling gradually subsided.
A few months later, Zhao Zhilei no longer felt itchy when feeding mosquitoes with his hands. He said this was because "the immune system has adapted."
After raising mosquitoes, you can then collect "human odor" and various animal odors to find the differences in odors, and then use mosquitoes to verify what odors they are interested in.
Zhao Zhilei told China Science News that their method of collecting "human scent" is also very unique. They need to take off their clothes and lie down in a clean plastic bag, and then pass clean air into the plastic bag, so that the exhausted air is With a "human touch".
However, this process is a bit long, and the person has to lie in the plastic bag for two hours. Through comparison, the
research team found that compared to animals, human odor does not have any unique chemical molecules, but there are a few molecules that are particularly abundant, such as decanal and methylheptenone.
These two molecules are the products of oxidation and decomposition of certain oily substances secreted by human sebaceous glands after exposure to air.
Animal sebum hardly secretes these oily substances, which also explains why the "human smell" is so special.
The next step is to figure out why mosquitoes like "human smell" so much.
Failure is also an important part of the evaluation contribution.
In order to explore this problem, their experimental plan was groundbreaking: perform a "craniotomy" on the mosquito to see what it was "thinking" in its mind.
If they can know which parts of the mosquito's brain are activated when they smell "human odor", they can further investigate whether the mosquito brain is particularly fond of certain molecules (such as decanal or methylheptenone). .
cracked this problem, not only deciphering the criteria for mosquito selection in one fell swoop, but also being able to "catching mosquitoes" - compared to "human odor" composed of hundreds of molecules, specific chemical molecules are easier to manufacture and store, which is more Convenient for making new mosquito traps. The answer to
is indeed within the scope of this hypothesis. Their subsequent research found that mosquitoes prefer people with moderate levels of decanal in their body odor.
Zhao Zhilei explained that one potential reason is that there are a small number of people with little or a lot of decanal in the crowd. If mosquitoes tend to like such people, then the probability of it finding the right person will be reduced, which is not conducive to reproduction.
But in the study, the "craniotomy" of the mosquito was not that easy to do - they had to keep the mosquito alive after the craniotomy.
gene editing technology makes this bold experiment feasible. By editing the mosquito gene, the nerve cells in the mosquito brain are specifically marked to express the fluorescent protein . When the nerve cells in a certain brain area of the mosquito are activated, the fluorescence will be enhanced, so that we can know which brain area is activated. activated.
However, the success rate of gene editing mosquitoes is too low, less than 0.1%.
Zhao Zhilei did gene editing for the first time. He worked hard for nearly 6 months before screening a few fluorescent larvae.
He was very excited at the time and thought he was about to succeed, but within a few days, these fluorescent larvae were "annihilated".
"I was in a bad mood at the time. But after calming down and analyzing it carefully, I found that the negative results actually laid the foundation for our subsequent success."
Zhao Zhilei said that a good experimental design, regardless of whether the results meet the initial expectations, provides very important information. Useful information can be used to continuously revise and improve our understanding of nature, "which is also an important part of evaluating our contribution to this field."
Just like that, it took 5 years for the research team to gradually create genetically modified mosquitoes that could be used for experiments.
They found through experiments that although there are nearly a hundred chemical molecules in human odor, only two areas are activated in the mosquito's primary olfactory brain area.
They mixed a mixture of just two chemical molecules to activate these two brain areas and found that it was highly attractive to mosquitoes, just like real human odor.
"We have applied for a patent and hope to apply this mixture to mosquito traps to attract and kill mosquitoes." Zhao Zhilei revealed that several companies that develop mosquito control products are currently negotiating with them about the transfer of patents and cooperation.
In addition, Zhao Zhilei said that his colleagues are exploring another idea: if a compound can be screened out that can specifically inhibit the two brain areas activated by "human smell", then this compound may be used as a repellent. Use mosquito repellent - it interferes with mosquitoes' ability to sniff people.
A risky choice
After graduating from Princeton University with a Ph.D., he turned to studying parrots. Zhao Zhilei made a risky choice.
Before that, Zhao Zhilei had a "cheating" life: He was the number one scholar in Dali Prefecture, Yunnan, and was admitted to Peking University to major in bioengineering. After graduating from Peking University, he went to Princeton University to study mosquitoes; now he is studying at Peking University. studied neurobiology at Cornell University.
He has his reasons. Zhao Zhilei told reporters that, similar to mosquitoes, parrots also have a magical ability: in the wild, they can quickly imitate the sounds of the same kind around them, and when kept as pets, they can imitate human speech.
"They have very interesting social behaviors and cognitive abilities. This kind of powerful learning and imitation ability is rare in nature." Zhao Zhilei said that there is a school of thought in the academic community that believes that the reason why humans are so successful in evolution is Because people can also learn to imitate quickly.
Therefore, he believes that "parrots are a very good model" to study the brain mechanism of learning and imitation.
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 "relatively determined".
He told China Science News that he has a wide range of interests and likes to read the history of science and biographies.
"These daily accumulations may be quite useful when making choices. Because I have a general picture of the development of the subject in my mind, I can have my own ideas about what are the more important issues and what kind of breakthroughs new technical means can bring. Understood.”
He also attributed his past achievements to his luck. "I think it should be choice, hard work and some luck. From a personal level, I was lucky to be born in a family that values education, and I have received support and help from many teachers and friends along the way.From a large perspective, I am very lucky to live in an era where science is advocated and technology is developing rapidly. ”
Related paper information:
https://doi.org/10.1038/s41586-022-04675-4
"Chinese Science Journal" (2022-06-30 The original title of the second page character is "Sacrifice one's life to feed mosquitoes for six years just to get rid of it") Clear a mystery》)
