Chapter 8 Section VII

On Monday morning, the researchers extracted the synthesized compound through column chromatography.The reagent mixture was dissolved in chloroform in a long thin glass tube and separated into distinct layers.In addition, he added 0.2% methanol.Turns out he was right.After studying for a master's degree for almost two years, his experimental skills have indeed improved a lot. Let's take a lunch break, Yanren thought as he walked towards the storage room.Putting the laptop left behind by his father into his backpack, the researcher left the laboratory. The day before, when he came back from his father's private laboratory, he approached the real estate agent to find out the situation.The intermediary told him that the old house had been decided to be demolished, and the residents were moving out one after another. "If you live in now, the rent will be very cheap, but you will be evicted in two months." The intermediary said.From this point of view, that place should be seldom visited.The reason why my father rented a house there must be to avoid the eyes of others.For some reason, the mysterious research my father entrusted to the researchers had to be done in secret.

After returning to the dormitory, the researchers searched the "Heisman Report" on the Internet, but found nothing.Then he tried searching for "Heisman Report," but still nothing.Entering a sentence on the Internet today rarely results in no search results.It seems that to understand the details of the "Heisman Report", you have to go to the newspaper reporter named Sugai. The researcher left the building of the School of Pharmacy, passed the concrete bridge over the canal, and walked towards the student cafeteria of the liberal arts campus.This is a habit he has developed all year round.As he was walking, he looked at the windows of the student cafeteria to see if the girl who joined the English club with him in his undergraduate days was there, when suddenly someone greeted him from the side: "Koga-kun."

Turning his head, he saw that it was Kawai Maricai who came.It's been a while since I saw her. Her short hair has reached her shoulders, but her big smiling eyes are still the same as before. "Long time no see." Maricai raised her head slightly, looking at the short Yanren.The backpack full of books weighed heavily on her shoulders. "is it going well?" "Well, it's okay." Yanren replied reflexively.Marina probably didn't know the news of Kento's father's death yet.The researcher didn't want to spoil the current atmosphere, so he followed the conversation and said, "Where's Hehe?"

"Still fighting Carol." "Carol?" "Lewis Carroll." "Oh." Yanren realized that it should be the author.Unexpectedly, fairy tales have also become the research object of English literature. "What are you studying about Carol?" "What I'm researching is—" Maricai showed a mischievous expression, and said with a beautiful English pronunciation, "Perhaps looking—glass milk isn't good to drink..." "Hey?" the researcher asked, "What kind of milk can't you drink?" "Milk in the mirror. I was reading a verse just now."

"The milk in the mirror is not drinkable." Researcher was startled.The world of English literature and the world of chemistry are directly linked. "Is Lewis Carroll a chemist?" "Looks like a mathematician. Why do you ask?" The researcher immediately seized the opportunity to provide suggestions for her research. "The sentence just now refers to enantiomers. A compound with a chiral center can form two structures that have exactly the same shape but cannot overlap, just like the right hand and the left hand. In other words, they are like a pair of Mirror image. Only right-handed substances can be used as drugs, and left-handed substances are toxic, such as acetidine, which can cause fetal deformities. 'The milk in the mirror cannot be drunk', that's what it says."

Marina listened blankly, then hesitated, "Yes", and then asked, "What is Koga-kun studying now?" "How should I put it..." The researcher pushed his glasses and explained as simply as possible, "I am adding various 'side chains', such as amino and nitro groups, to the 'mother core' structure left by my senior." "That's it. It's hard work." "Ok." "Then I'm going to the library." Maricai put on the smiling face when they first met and walked away. Yanren watched her leave, feeling a little regretful.It might be easier to understand if we say "development of new drugs for the treatment of rheumatism".

Yanren walked into the cafeteria sullenly and bought a set meal ticket.In the cafeteria, there are many liberal arts and science students.Students generally agree that the food in the liberal arts department cafeteria is better. After taking the set meal from the side dish window, just a few steps away, the researcher saw a student sitting by the window waving at him. It was Akihiro Doi whom he had known in his undergraduate days.He is now assigned to the clinical department, where he recombines the genes of E. coli bacteria in the laboratory to produce specific proteins. "haven't seen you for a long time."

Yanren sat across from Doi, and Doi smiled knowingly: "I've seen everything here." "What did you see?" Yan Ren asked puzzled. "Is that a liberal arts girl? Are you dating?" This was originally an opportunity to brag, but the researcher still said truthfully: "Let's be close, like two molecules connected by van der Waals force." "Oh..." Doi moaned, "It's so pitiful." "There's a nice girl in the lab, but we're all metal atoms, held together by strong metal bonds, so we can't move." "I really want to be covalently bonded."

"Yes." The two ate their meatloaf set meals in silence for a while. "But," Doi gulped down the miso soup, "girls like boys who can talk, but we are trained to be clumsy." "Have we received such training?" "Your lab also has seminars?" "certainly." The researcher's laboratory will hold a weekly "thesis seminar".Interpretation of the latest thesis by pre-designated students in front of everyone.Any unproved conclusion or logical error will be severely criticized, so the speaker must choose his words carefully.If you don't go through this training, you can't be a qualified scientist.My father often complained during his lifetime: "In the field of liberal arts, people who are good at rhetoric and deceit may also be successful, but in the field of science, there must be no falsehood."

However, this training also has side effects: overly deliberate in social situations, and habitually expressing scientific opinions.For example, a group of people are happily talking about delicious cakes, but they are thinking about the mechanism of taste receptors. "I know what you want to say, Doi." "If you don't dare to say the wrong thing, you will not dare to speak." Doi went on to say, "Besides, a girl in the liberal arts will not find a three-K boyfriend." The researcher was poked in the sore spot.The so-called "three K's" refer to "hard work", "dirty" and "dangerous", and the basic science research department can find the best example of the three K's.The researchers work 14 hours a day, deal with pungent reagents, and must wear sports shoes so that they can escape in the event of an accident. It is inevitable that they are called the "Three K's".

"Girls don't like 'three K', like 'three high'." "What is 'three highs'?" "Highly educated, tall, high income." At best, I can only meet the requirement of "high education", Yanren thought. Doi lamented, "Women are really pathetic." "Really?" said the researcher. Doi asked in surprise: "Do you agree with the selection criteria for women?" "If you think about it, females will always choose stronger males as mates. This is a biological law, and humans are no exception. If women in the world do not want to marry and reproduce with men who are not 'three high', then civilization must will decline." "Having said that, there is something called love in this world." Doi seemed more romantic than Yanren, "Your distorted values ​​will only make you more unpopular with girls." "Are my values ​​skewed?" "Yeah." Doi nodded and said, "It's a bit lonely." Researchers have realized this before.Although he doesn't want to admit it, he has indeed completely inherited his father's eccentric character. "Be a brighter youth, so that you can find liberal arts girls." Yanren cast a resentful look at Doi, but he suddenly realized that this person in front of him was exactly the talent he was looking for. "By the way, I have something to ask you." The researcher said as he took out a copy of his father's experimental records, "I want to make GPCR agonists, is it feasible to operate in the following order?" Doi carefully read the copy handed over and said, "Is this making an agonist? Isn't it looking for a lead compound?" "Yes, I'm not looking for a candidate substance, but the final form." "I understand only the last two items..." Doi refers to "in vitro binding assay" and "in vivo activity evaluation".The researcher asked: "The purpose of these two operations is to confirm whether the synthesized compound can bind to the receptor?" "Well. First create cells with the target receptor, and confirm whether the agonist can bind to it in a test tube. Next, use experimental animals for in vivo evaluation, such as genetically modifying mice to create individuals with the receptor, and then feed the compound , to evaluate the actual effect." The researcher remembered the forty white mice raised in that broken building. "So, there is nothing wrong with this method?" "It's not..." Doi shook his head and said, "No matter how you look at it, it's too simple. Moreover, clinical trials and subsequent steps are all omitted. To put it bluntly, it's too unprofessional." "Yes." Yanren agreed.My father is a scholar of viruses, and it is not an exaggeration to say that he is not professional in pharmaceuticals. "What about this one?" The researcher took out an A4-sized white laptop from his backpack, started it up and said, "Do you know Linux?" "A little bit." Doi replied, operating the computer for a while and said, "I have never seen the software installed in it. Have you heard of 'GIFT'?" "No." Doi started the "GIFT" software.The screen that emerged a few seconds later caused both of them to exclaim at the same time. The panes are divided into three columns, and in the large pane that occupies the right half, a strange CG image appears.On the slightly undulating plane, there are thick petal-like protrusions, with a pocket-shaped hollow in the center.The images are delicate and eerie, making one suspect they were taken by a camera. After watching for a while, the researchers realized that this might be an enlarged image of the surface of the cell membrane.The extremely small world less than one micron is displayed on a fifteen-inch screen. "It looks a bit weird." Doi moved the mouse, pointing to the two panes on the left and said, "Here is the relevant information. This CG picture is 'variant GPR769'." It turns out that the researcher finally realized that this is the problem receptor.What the father wanted was something that would fit into the center depression. "The lower pane contains the base sequence of the gene that makes this receptor. But..." Doi crossed his arms, "Do you know how many GPCRs there are?" "Seven or eight hundred kinds?" "Yes, only one of the forms has been truly grasped, and that is the receptor on the omentum cell of the bovine. For other GPCRs, its structure can only be deduced. That is, based on the similarity of the base sequence of the gene, it is speculated that its The finished product. It's likely that this model was generated that way too, but I'm not entirely sure." "Is there any other use for this software?" "Well..." Doi paused, then picked up the copy of the experiment record, "Maybe this software was used in the first two projects." The researcher poked his head over to check. Stereostructure Analysis of Variant GPR769 Computer Aided Design and Drafting It seems that the function of the "GIFT" software is to predict what kind of protein can be produced based on genetic information, describe its actual shape, and design the chemical structure of the substance that binds to the protein. "That is to say, just follow the instructions of this software to make medicine?" "It always feels a bit fake." Doi said, "I'm not good at computer-assisted pharmacy, you'd better ask someone else." "Do you have any friends who understand this?" "In this regard..." Doi looked at the void, "Ah! Yes! There is a powerful character in the Pharmaceutical Physical Chemistry Laboratory, who is an overseas student from Korea." "Oh?" Yan Ren asked curiously, "Korean Wave?" "I asked him about molecular dynamics simulation before, and he understood me in a few words." "So he has no problem with language?" "I'm fluent in Japanese, and I can speak English." "Can you introduce me?" "Okay. I'll ask if the other party is free." Doi readily agreed and looked at his watch.It's time for him to go back to his lab.Doi stood up with the plate of the finished meal and said, "See you next time." "please." "Let's work together to covalently bond with the girl as soon as possible." Doi walked towards the tableware return port. Yanren watched Doi leave with a smile, and put the laptop back into his backpack.The research that my father entrusted to me can only be discussed after the appearance of Korean students. The researcher picked up the phone and started to do the rest of the work.Last night, he inquired about the newspaper reporter's contact information from his mother in his hometown.But when he was about to make a direct call to the Science Department of Dong-A Shimbun, he suddenly remembered his father's warning. In the future, all communication tools such as telephones, mobile phones, emails, and faxes you use may be monitored. Although the researcher felt that this was purely a fantasy, he still faintly felt a little uneasy.He looked around the cafeteria and found no suspicious person, so he calmed down and dialed a number recorded in his mobile phone. The ringer rang a few times, and a young man's voice came: "Hi, this is the Science Department of Dong-A Shimbun." "Excuse me, my name is Koga, may I ask if Mr. Sugai is here?" "Please wait." At his father's funeral, he treated Sugai with a curt attitude, presumably Sugai didn't like Kento too.But the information can only be obtained from Sugai. "Hello? Excuse me, who is it?" Sugai answered the phone. "I'm Koga. Thank you very much for coming to my late father's funeral not long ago." "Ah, it's Kento-kun." Sugai said kindly. The researcher breathed a sigh of relief, and continued: "I have something to ask you. At the funeral, you mentioned the "Heisman Report" to me. What happened?" "Ah, that matter. The Heisman Report... yes." Sugai was silent for a moment, "Are you free tonight?" "Tonight? I'm going to be in the lab until twelve o'clock." "Can you sneak out halfway? If we meet at the station in Kinshicho at eight o'clock, I can still treat you to dinner." "Okay." Although I feel that this is a bit troublesome, I can feel the care of Sugai's parents.The researcher calculated how long the experiment could be postponed, and said, "At nine o'clock, I might be able to figure out a way." "Okay, see you at the south exit of the station at nine o'clock. You must come with an empty stomach." Kinshicho is a commercial district located at the junction of Tokyo and Chiba Prefecture.However, this place is different from the commercial districts of Shinjuku and Shibuya. Because it is very close to the residential area, it has the functions of a downtown and a commercial street. There are rows of old taverns, as well as supermarkets selling daily necessities, including supermarkets and movie theaters. A modern shopping plaza, in addition to a concert hall that provides first-class symphony performances.In short, almost all the shops and facilities in terms of culture and folk customs can be found here. Kento braved the bitter cold wind and waited for Sugai in front of the JR line station.As soon as he thought of the newspaper reporter's face, memories about his father flooded into his mind, and most of his thoughts were about his father complaining again and again. When I had an evening drink with my father at Atsugi's home, my father said a lot to himself.He told the researchers that the average salary of science students is 50 million yen less than that of liberal arts students.Calculated based on the total working time of 40 years, science students will lose more than one million yen a year. "The salary is pitifully low, what are you talking about to build a country with science? You bastard." The drunk father scolded the politician, "Those liberal arts bastards live by stealing our achievements. Telephones, televisions, cars, computers, all invented by scientists Yes. What does a clever liberal arts bastard contribute to the development of civilization?" At that time, Yanren was only a teenager, and he was quite tired of his father's complaints.However, one thing he encountered later made him realize that his father's complaints were justified, and that was the judgment on the development of blue light-emitting diodes. Blue light-emitting diodes were once considered impossible to develop, but a technician completed the pioneering work, and then a protracted legal battle broke out between the technician and the company to which he belonged.The company believed that the invention could bring in 120 billion yen in revenue, but the court awarded the technician a measly 600 million yen in compensation.Although the judgment of 20 billion was awarded in the first instance, the judgment of the first instance was overturned in the second instance.This can only be understood as the judiciary no longer exercises its powers independently, but acts according to the face of entrepreneurs. The tech world was disappointed by the verdict.These great inventors have spawned trillions in markets around the world while being paid as much as the annual salary of a Major League Baseball player.Many scientists speculate that after the verdict, Japan's international competitiveness will decline sharply.In an era when scientific and technological strength directly determines national strength, how can a country develop if scientific and technical personnel are treated so coldly?It won't be long before Japan is overtaken by China, South Korea and India. "It would be great if human civilization was destroyed." Yanren's father sneered, "Only the sciences can revive scientific civilization. Those guys in the liberal arts will always just talk about it." After the researcher grew up, he gradually understood the truth in his father's words.During the four years of undergraduate study, the researcher was so busy that he finally found time to join the English club.On the contrary, liberal arts students don't even go to class, and eat, drink and have fun all day long, at least the researchers think so.But after graduating, these guys can actually earn 50 million yen in annual salary. Such a contrast is unacceptable to the researchers.This society seems to have turned black and white upside down. People who sweat and work do not earn as much as those who eat, drink and have fun.However, this thought made the researcher very uncomfortable - he found that he had inherited his father's eccentric personality, just like the genes he was born with, and he wanted to get rid of it, but he couldn't get rid of it no matter what. In front of the station in Kinshicho, Yanren put his frozen hands into the pockets of his down jacket, and suddenly remembered a mystery about his father's life. "Since you hate your job so much, why don't you just quit?" Yan Ren once said to his father who was nagging after drinking. The father replied, "But I can't stop researching." "why?" "When you do research, you'll understand," said the father, with a rare happy smile on his face. What's with that smile?How does it reflect the heart of the late father?Although the researcher himself started research work, he still couldn't find the answer.Years of research life only made him understand one thing: it is not easy for science students to survive. People poured out of the gates of the station.The researcher put aside all the thoughts just now, and searched for that familiar face among the passengers getting on and off the train in the station hall.Before long, a man came towards him and raised his hand to him. Kento passed through the crowd and walked towards Sugai. "I'm sorry to ask you to make a special trip." Newspaper reporters in their prime wear no ties, jackets and coats over sweaters.He looked at Yanren from behind his glasses, and said with a smile, "You live alone, so you seldom eat a good meal! Meat, fish, Chinese food, Southeast Asian food, which one do you like?" The researcher never paid attention to eating, he chose the simplest food. "Let's eat meat." "Okay." Sugai looked at the buildings around the roundabout in front of the station, "Then let's eat roast lamb." He said, and he took a step. The researchers were led to a bistro-style restaurant.There are compartments in the restaurant, and each compartment can only accommodate a few people sitting around a table.The two sat opposite each other and ordered the roast lamb buffet. They drank mugs of beer, ate mutton, and chatted for a while about their late father, Seiji, who was a researcher. Finally, Sugai took the initiative to touch on the topic. "Last time you mentioned the Heisman Report..." "Yes." The researcher leaned forward, "I saw "Heisman Report" written in English in my father's experimental notes, and I wanted to figure out what it was." "Experimental notes? Only this is written in it?" "And 'Section Five,' the fifth section of the Heisman Report." "Hmm. I also only vaguely remember that the report has five sections." Sugai rolled his eyes and thought, "I said before, this is a report submitted by an American think tank, right?" "I said it. I think it may have something to do with my father's professional virology." "It's also related to virology." Sugai's gaze fell back on Yanren, "Simply put, the "Heisman Report" is a study on the possibility of human extinction." The researcher couldn't help staring at the newspaper reporter with wide eyes: "Human beings... extinct?" "That's right. Your generation may not have experienced it personally. This report was made about thirty years ago. At that time, the United States and the Soviet Union were in conflict. Both sides possessed a large number of nuclear weapons. The war was imminent. The whole world was worried that once a nuclear war broke out, human beings would will become extinct." "Are you really so worried?" "Well, it was the Cold War era. The Cuban Missile Crisis brought the world to the brink of nuclear war." The researchers were horrified. It sounded like science fiction. "Physicists who developed nuclear weapons predicted the danger of a full-scale nuclear war and set the 'Doomsday Clock', the countdown to the extinction of humanity. When the hydrogen bomb test was successful, the minute hand of the clock was set close to midnight, the moment of human extinction Two minutes ago. Fortunately, the Soviet Union disintegrated, and the minute hand was moved away." The waiter came to clear the plate, Sugai ordered another glass of beer, and continued: "Under such circumstances, the White House of the United States has begun to conduct research on the issue of human extinction, in order to find out the reasons and take corresponding countermeasures to prevent it. Scholars in the think tank Joseph Heisman listed the possible causes of human extinction in the future, summarized in the report. This is the "Heisman Report." "Why would father be interested in such a thing?" "Just now, when the researcher mentioned it, I also remembered that the report may be related to your father's major. Is there something like virus infection in the report?" "You mean, the extinction of humanity by a deadly virus?" "right." Could it be that the father is going to deal with the crisis of human extinction?Just rely on an unknown university professor like his father who is struggling with research funding?Thinking of his father's thin and haggard appearance, Yanren couldn't help laughing.The image of the father and the savior of mankind is too different. Seeing Sugai looking at him in surprise, Kento suppressed his smile. "Do you know the details of the Heisman Report?" "After accepting your father's commission, I checked the news scrapbook repeatedly, but found nothing. However, when the report was published, the magazine published a special report." Having said that, it was a magazine from about thirty years ago and is hard to find. "However," Sugai continued, "I work for a newspaper, so I have a way to get it. Your father said he wanted to know the details anyway, so I found a young colleague from the Washington bureau and asked him to go to the National Archives of the United States to look up the original report. " "Can I see it too?" "Well, we should hear back soon. I'll let you know when I get the report." "please." After enjoying the roast mutton feast and saying goodbye to Sugai in Kinshicho, Kento returned to his rental house. The two concentrated on talking and didn't drink much. Yanren is still sober.Turn on the light in the room, turn on the air conditioner, sit at the small table next to the bed, and take out the two laptops left by his father from his backpack. Press the switch of the black A5 size notebook, but there is still no sign of starting.Had to force shutdown, and turned to fiddling with a larger notebook. The laptop booted up without a hitch. The "GIFT" software interface fills the screen, and the 3D image of orphan receptors in the cell membrane is also the same as before. The researchers worked hard with unfamiliar software and operating systems, copied the base sequence of the "variant GPR769" input into "GIFT" to a USB flash drive, and then connected their usual computers to the Internet. He opened the base sequence search website.As long as you enter a specific base sequence, you can find genes with similar sequences. Paste the base sequence of "variant GPR769" into the search window, set the search object as "human", and conduct a BLAST search.Although this is not a major in human research, he has learned it in his undergraduate days, and it is not difficult for him to do this kind of search.If the receptor in question was a protein involved in viral infection, it would not be surprising that my father's research would involve the Heisman Report. The search results came out, and the researcher stared at the screen.The one with the highest similarity to "variant GPR769" is of course "GPR769".Of the more than nine hundred bases, only one is different.This results in the replacement of one of the amino acids that make up the receptor with something else. The researcher followed the link on the webpage and inquired about the information of "GPR769".Although the English, which contained medical jargon, was a headache to read, he somehow got the gist. The name of this disease is very unfamiliar, and the researchers continued to search for the condition of this disease. This is not the information that researchers expect to see.This disease has nothing to do with viral infection, it is related to genetic mutation of parents. I thought there would be a major breakthrough, but it turned out to be nothing.My own judgment is completely wrong, which is not uncommon in experiments.At this time, the supervisor Sonoda would repeat the same sentence: Put aside preconceived ideas and think carefully about what happened. This sentence is to hope that they will think about why there is a phenomenon beyond expectations.The researcher left the table and began to ponder what his father was going to do.The purpose of the father is obvious. What you do is design and synthesize an agonist for an orphan receptor. The researcher realized a major problem: he had been ignoring the most important part of his father's research.Since it involves knowledge outside of the profession, the researcher has to think twice to ensure that his conclusion is correct. Although it is not clear what function "GPR769" is responsible for, it is undoubtedly a "receptor" in the cell membrane of alveolar epithelial cells.In the sense that it kills if it is incomplete, it must perform some function indispensable to normal breathing.And if this "receptor" is to function, it must have a corresponding "ligand". After the human body secretes the "ligand", it will be transported to the location of the "receptor" with the help of blood.Once the "ligand" and the "receptor" exposed on the outer surface of the cell membrane "recognize" each other and enter the groove of the "receptor", the two will combine with each other due to physical and chemical reactions between molecules. The groove on the "receptor" will shrink inward, driving the entire "receptor" to start shrinking.Because the receptor penetrates the cell membrane, the change also affects the inside of the cell. The movement of the terminal part of the "receptor" will have an effect on other proteins in the cell, and these proteins will activate and start a series of other physical and chemical changes. In this way, the chemical signal is transmitted in the cell and finally to the nucleus, making a certain protein Specific genes exert effects.In other words, the binding of the receptor and the ligand acts like a switch that turns on the cell. As far as the "mutant GPR769" is concerned, the concave part is mutated and cannot be combined with the ligand. This switch cannot be turned on, and the lungs cannot work normally, so the disease occurs.To restore cells to normal functions, they can only produce drugs, that is, artificially create a substance that replaces the original ligand, and only bind to the "variant GPR769" to play the role of a switch.This is the agonist Yanren's father wanted to create. An agonist that activates "variant GPR769". Yanren stood in front of the table, opened his mouth wide, and continued to think. There was no doubt that this agonist was the cure-all for the terminal disease that claimed the child's life: alveolar epithelial sclerosis. The researcher's breathing quickened.He stared at the information on the computer screen, calculating in his mind.He quickly figured out the answer.There are about 100,000 patients with alveolar epithelial sclerosis on this earth.In other words, if this agonist is successfully developed, 100,000 children around the world could be saved. "One hundred thousand people?" Yanren couldn't help shouting, scanning the small rental house.Can I, a graduate student who lives in a six-fold room in Jinsi Town, save 100,000 people? Is this what fathers do?The father spared no personal wealth just to save those sick children? One day, an American will visit.You are going to hand over the synthetic compound to this American. Could it be that the American had a child with alveolar epithelial sclerosis?He came to Yanren with a strong expectation of saving his beloved son? But... Yan Ren turned to worry again.To be honest, the difficulty of developing this drug is too high.Even bringing together all the forces of the pharmaceutical industry does not guarantee a successful development.The development method given by his father was dismissed by Doi as "naive".Even if a drug is synthesized, its safety cannot be guaranteed without clinical trials. Why does my father, who is a virologist, do non-professional research?What are the odds of such research? The researcher decided to keep trying for a while longer, but he couldn't help beating drums in his heart: This is like fishing a big fish with spider silk, will it work? Anyone know from medical school?Thinking this way, the researcher began to search the network of his undergraduate days.