It is now well established that developmental decisions can be overridden by artificial induction of combinations of “core” TFs that yield induced pluripotent stem (iPS) cells or direct lineage conversion (Hanna et al., 2010, Morris and Daley, 2013, Orkin and Hochedlinger, 2011, Takahashi and Yamanaka, 2006, Vierbuchen and Wernig, 2011). https://www.cell.com/cell/fulltext/S0092-8674(14)00229-3
While most of the studies have focused on the biology of virus-specific CD8 TRM cells, basic questions regarding CD4 TRM still remain unanswered. For example: Where do these cells come from; What is the cellular origin of CD4 TRM cells; Which environmental signals maintain them into the tissue; and finally, Are CD4 TRM cells able to rapidly respond to a second challenge? 引用元：https://www.cell.com/cell/fulltext/S0092-8674(19)30831-1
In contrast, mechanistic understanding of dietary modulation of small intestine (SI) physiology, where the majority of dietary exposures and interactions take place remains elusive. 引用元：https://www.cell.com/cell/fulltext/S0092-8674(20)31069-2
Which of the numerous cell subsets in a tumor contribute to the response, how their interactions are regulated, and how they are spatially organized within tumors remain poorly understood (Cardenas et al., 2021; Saltz et al., 2018). 引用元：https://www.cell.com/cell/fulltext/S0092-8674(21)00945-4
In the nervous system, although multiple families of guidance cues have been found in the last decade, our understanding of intracellular signal transduction mechanisms leading from the cell membrane to the cytoskeleton remains limited (Mueller 1999). 引用元：https://www.cell.com/cell/fulltext/S0092-8674(01)00530-X
Nevertheless, the true extent of TCR cross-reactivity, and its role in T cell immunity, remains a speculative issue, largely due to the absence of quantitative experimental approaches that could definitively address this question (Mason, 1998, Morris and Allen, 2012, Shih and Allen, 2004, Wilson et al., 2004, Wucherpfennig et al., 2007). 引用元：https://www.cell.com/cell/fulltext/S0092-8674(14)00476-0
However, understanding the precise molecular mechanisms influencing progenitor cells is precluded by limited knowledge of stromal cell identities in the lung. 引用元：https://www.cell.com/cell/fulltext/S0092-8674(17)30864-4#%20
Mutations that cause TSC are spread over the entire sequences of both TSC1 and TSC2 (26,–29), but mechanistic understanding of the functional consequences is precluded by the lack of biochemical and structural information. 引用元：https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025687/
only a subset of such genes is activated in response to a given signal. Thus, a central problem in signal transduction is how this specificity is achieved. 中略 An excellent model for studying this problem is provided by the virus-inducible enhancer of the human interferon-p (IFND) gene (reviewed by Maniatis et al., 1992; Thanos et al., 1993; Tjian and Maniatis, 1994). https://www.cell.com/action/showPdf?pii=0092-8674%2895%2990136-1
Drosophila provides an attractive system to understand the logic of olfactory perception because flies exhibit complex behaviors controlled by an olfactory system that is anatomically and genetically simpler than that of vertebrates. 引用元：https://www.cell.com/cell/fulltext/S0092-8674(03)00004-7
Odor-evoked memory or the “Proust phenomenon” from the eponymous literary anecdote where Marcel Proust took a bite of madeleine biscuit that had been dipped in Linden tea and was suddenly transported to a long forgotten moment in his childhood, occurs when an odor triggers the recollection of a meaningful past personal episode. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039451/
I raised to my lips a spoonful of the tea in which I had soaked a morsel of the cake. No sooner had the warm liquid, and the crumbs with it, touched my palate than a shudder ran through my whole body, and I stopped, intent upon the extraordinary changes that were taking place. An exquisite pleasure had invaded my senses, but individual, detached, with no suggestion of its origin. 中略 I was conscious that it was connected with the taste of tea and cake, but that it infinitely transcended those savours, could not, indeed, be of the same nature as theirs. 中略 And suddenly the memory returns. The taste was that of the little crumb of madeleine which on Sunday mornings at Combray (because on those mornings I did not go out before church-time), when I went to say good day to her in her bedroom, my aunt Léonie used to give me, dipping it first in her own cup of real or of lime-flower tea. (SWANN’S WAY Remembrance Of Things Past, Volume One 『失われた時を求めて』第1篇『スワン家のほうへ』By Marcel Proust フランス語の原書の英訳)
例文 Several studies have shown important roles for immune cells in tissue homeostasis. Tissue-resident innate immune cells can play a role in regeneration of the gut (Lindemans et al., 2015, Saha et al., 2016) and other tissues (Aurora and Olson, 2014, Stappenbeck and Miyoshi, 2009). （例文の引用元：https://www.cell.com/cell/fulltext/S0092-8674(18)31316-3）
この例文では、一つ目の文では一般的な事柄、抽象的な事柄が述べられていて、次の文ではそれを具体化した内容が書かれています。For example, など具体例を出すためのつなぎ言葉は使われていませんが、意味的に明らかなので文のつながりはスムーズに感じられます。
tissue homeostasis（一般）→regeneration of the gut（具体）
例文 How does the anatomic map translate into a functional map? Previous imaging studies in large insects and vertebrates demonstrate that different odors elicit defined spatial patterns of glomerular activation, revealing a functional representation of anatomic map (文献).（例文の引用元：https://www.cell.com/cell/fulltext/S0092-8674(03)00004-7）
（13:13～）OK. So I find that this program is great. OK, I mean, we’ll see how it goes. But I think, I joke, but I think the department of biology is really getting humanized and culturalized and this is the part of that direction and I’m very pleased to be here. I don’t exactly know what I’m supposed to do but I have never had the chance to attend the previous ones. [INAUDIBLE] So I am guessing. We have about 45 minutes and my understanding is it will good if we save some time for questions and answers because it’s supposed to be a conversation, right? In any case I give you a little bit of a sort of a lead for conversations.
（14:10～） First of all, many years before most of you were born except Herman Eisen, [LAUGHING] I was a student at University of Kyoto, you know, Kyoto in Japan. I was in chemistry major. But toward the end of the four year schooling, I wasn’t sure whether I want to stay in the field of chemistry. And of course, chemistry turned out to be it’s still very exciting field but I did not know enough of it. And I was looking for something new to do for graduate school. And someone told me that– this is 1962. So many, many years ago. Someone told me that the new biology emerging in America, primarily in the United States and partly in Europe, that it’s called the molecular biology. And I had no idea what it was but he introduced me to a couple of papers he recommended to me to read. And those adored paper were by Jacob and Monod, from Pasteur institute, and I hope biology student know these names. And so I read all those papers in the Journal called Journal of Molecular Biology, which was the cell of today at that time. And a long paper. It opened on theory, and I was so impressed by this. And I immediately, instantaneously decided I’m going to be trained as a molecular biologist.
But in Japan there was no molecular biology lab at all. My professor was kind enough to arrange me to study abroad and I ended up one of the most beautiful town in the United States, which is the La Jolla, UCSD was just starting. They had only one more year above me in a graduate school at UCSD. The second year in the history of the UCSD. There were no undergraduate student at the time. So it started as a graduate school university. I was trained as a molecular geneticist, molecular biology, molecular genetics. At that time unlike now, major thrust in molecular biology was not in eukaryotic systems but in the prokaryotic system. Bacteria and viruses which infect the phages. Molecular Genetics I worked on phage lambda, transcriptional control with some genetic components into it at my PhD thesis. This is all OK, but not something I’m particularly proud of.
Then in the ’60, late ’60s 1968, I was going to go do postdoc. Now, among at that time, among the students, my fellow students there was some concern about the future when molecular biology because it looked like the major fundamental problem in molecular biology, molecular genetics all being solved. Genetic code, protein synthesis, messenger RNA, all of those things were discovered and we are wondering is there a future for us when we become independent after several years of postdoc training. Among us, I mean, my close surrounding thought we should go to a more complex system. So the animal cells or plants, something like that, to study at development. Differentiation, cell growth, control, and things like that. But at that time there was no really good technology to do that in order to do rigorous research, and it was down in prokaryotic system. It was a difficult decision to make as to where to go for the postdoc.
And I had of this institute called the Salk Institute, which is right across the street from North Torrey Pine road from UCSD and there was a lab which is run by someone called Renato Dulbecco. Now, amazing thing is among younger people here I don’t know how many percent of you know who Dulbecco is. Those who know please raise hands. You see it’s only older people. [LAUGHING] We don’t use Dulbecco medium anymore in tissue culture, we still use that. People know by the medium was named after him but that’s not his major contribution to research science. And he is a virologist actually. But he comes from this old School of molecular genetics– molecular biology, which was started in Caltech and a few other places. [INAUDIBLE] was a leader and Dulbecco was already there and a younger faculty member. He was the M.D. He was a virologist, but he was already exposed to what used to be called the molecular biology. He had a big lab and he’s main interest was tumor virology, to study load of viruses in tumorigenesis. Tumor Biology There you use the tissue culture from animal cells, and then you have a virus. They were at that time focusing on small genome virus, simian 40 virus, polyoma virus. They had no more than four or five genes in there, you can purify DNA, viral genome, and then you can infect in a culture in a condition where– lytic cycle where the cell host will die or you’ve done in a different type of cell that you can sort of transform them to make actual control for growth. So it sounded to me these are sort of a hybrid between the molecular genetics of prokaryotic system which we are used to, and at the same time you can learn something about the animal cell, the regulation in animal cells. I chose to apply that place and fortunately Renato took me and afterwards I found out several of the postdoc who joined the lab around the time I joined they had exactly the same consideration. They worried about their future and they wanted to have– they wanted [INAUDIBLE] work on the eukaryotic system but not purely animal system or plants or something like that. Postdocs That’s how I was exposed to the eukaryotic system, same eukaryotic system. And I also learned a lot in that lab although I was there only 20 months. And I tell you why I was there only 20 months in a minute. But lab was fantastic. They were very good postdocs, senior postdoc. The big lab, like 30 people. And Renato doesn’t, when you go there Renato doesn’t tell you what to do. He will say, oh, why don’t you just talk to people and try to find something interesting to you. And then he said he is happy to discuss it if I bring up some project ideas. But he will tell you what to do. And I learned a lot from these postdoctoral people, very good people, [INAUDIBLE]. And those people who later became very good senior scientist. Anyway, so I learned something there Trade Practical Training but it was relatively short as I said, less than 20 months.
And the reason why it was less than 20 months is because I came to UCSD with a visa called J1 visa, exchange visitor visa. And nowadays there is some way to get around a little bit but at that time it was very strict. So actually 18 months after you finished PhD, which is called– this period it’s called trade practical training, you have to leave the country. You don’t have to go back to your native country but you have to go out of United States for at least two years, two years to come back. I had to leave the US. Leaving the US I was very happy with what was going on in Renato’s lab but I had to leave. Renato was concerned, very nice to me and he talked to some people in Canada, but Canada is close to US. And then if I stay at the shelter they are for a few years I may be able to come back. [LAUGHING] No, you may laugh this but a lot of people did that at that time.
But my postdoc work was not so spectacular. So I could not expect to have best [INAUDIBLE] petitions Offer Assistant Professor but I ended up having offer assistant professorship in a small town about two or three hours east of Montreal in a town called Shellbrook. It’s a small town with a large hospital. And there were some research division there. I got an offer, I wrote a grant, MRC grant, Canadian MRC grant, and I got it.
And I was supposed to go in about three months when I received a letter, short letter from Renato who was traveling– he’s Italian-American, so he often goes to Europe. He was traveling in Europe and I still have that letter, I could have brought the copy, but I didn’t do it. [LAUGHING] It’s written in a small stationery with the logo of a very famous hotel in Rome, it’s called the hotel Hassler. Hotel Hassler is just above Spanish steps, it’s still there. He wrote this handwritten letter and to me, only 1 and 1/2 pages, small ones. And he said something like I don’t know what you decided about the place you have to go after you leave my lab. But if you have not completely decided here’s I want to suggest an alternative, that’s what he said. And he said something like, he believes. This is 1968. No, 1969 he said, he believes time is ripe for young scientists with good molecular biology training to go into immunology, that’s what he said. And if you are interested, he said, right to doctor– director [INAUDIBLE] 487 [INAUDIBLE] C84058 [INAUDIBLE],, Switzerland. [LAUGHING] And when I saw that email– Jim Watson the letter I took it downstairs in the Salk Institute, where [INAUDIBLE],, you know [INAUDIBLE] is supposed to be an immunologist, but also come from molecular biology. I went there and I showed this letter to a postdoc whose name was Jim Watson. But not the one you know but another one. [LAUGHING] And because I knew him and he come from molecular biology, so I had some affinity to him. So I asked him, is there anything I can do in immunology which could be significant. And as I said he had some molecular biology background. He said, immediately said, no, they had nothing. I went back and put it in my– the letter in my drawer and I forgot it.
And then about a month later, and it was almost two months before I was supposed to be deported unless I voluntarily leave. Renato came back and he came to tell me– he asked me whether I wrote the letter to [INAUDIBLE].. I explained to him that I did not, and I told him I don’t know anything about immunology, and I don’t even know Basel is, I didn’t know who [INAUDIBLE] is. I didn’t think that this is a good idea I told him. But now, I want to tell you something, it is really important. Renato as I told you doesn’t tell you what to do usually. Even do not recommend strongly to do anything but this case some way and it struck me because he said to me Susumu, this is really interesting direction you should really think about it or something like that. Montreal Then about 10 days later I visited Montreal which was the end of December. [LAUGHING] And I was supposed to start in April but, I mean, and it was damn cold. [LAUGHING] I came back and I just–my mind flipped. I said, OK, I’m going to trust Renato and I’m going to go to Basel.
Basel Actually in February I left and went to Basel. And my intention was again, just stay there for two years and continue to work– I was making some polyoma virus mutant, temperature sensitive mutants, which will be defective in transformation, cellular transformation. I wanted to continue that research. Fortunately, [INAUDIBLE] allowed me to do that although when he saw me a week after I arrived he asked me whether this had anything to do with immunology. So I said no, I can’t think of any connection. And the second thing he asked me is do I know the difference between T cell and B cells, and I had never heard of that. So I said no. And but he did not fire me, he let me do.
Horizontal Structure And in Basel institute actually they had this what is called horizontal structure, which means if you have a PhD or a PhD equivalent you’re independent. It doesn’t matter whether you haven’t had any postdoc period or not. And you can corroborate that with anybody but you are given one technician and a half of a room, half of a lab, and a half of a office, and you can do whatever you want to. And you are supposed to do something relevant for immunology but I was ignoring that. [LAUGHING] Cellular Cellular Immunology
But in about two years I suffered actually, because I didn’t understand what they are talking about. There were a lot of seminars. Apparently there were very good immunologists who assemble there but there was no molecular biologist or biochemist or anything like that. It’s pure immunology. At that time dominant area, dominant approach of immunology well it’s called cellular immunology. There are seminars and I mean, I try Research to go but I didn’t really understand. But then gradually my thinking sort of changed. I thought if I’m going to stay here surrounded by apparently very good immunologist I should learn something in immunology and I should try to do some research which interest them. Otherwise I don’t have opportunity to talk with them science.
I fished around and I ran into this problem of genetic origin Antibody Diversity of antibody diversity. When I was exposed to this problem. I actually honestly speaking I didn’t understand why they don’t study antibody genes rather than antibody molecules themselves because the only thing that people are doing at that time, as Lisa said but a lot of other people like [INAUDIBLE] and other people are [INAUDIBLE].. They were sequencing myeloma proteins which is monoclonal immunoglobin proteins. And they are hoping that if you sequence enough of them from that pattern you may be able to answer the genetic origin of antibody diversity and I thought that this is crazy. I mean, how can you do that when you have to look at the gene and compare the genes with the proteins, not just on one side it’s not going to solve the problem. Unfortunately, when I was in Basel– I mean Renato’s lab I already knew about restriction enzyme and also almost gene cloning, it almost becoming coming. That was the great thing about Renat’s lab. Renato’s in tumor biology was the Meca in tumor biology field. So a lot of people actually sent pre-prints to Renato’s lab to I guess to get some opinions or something like that. I already knew they are this in I think 1968, first paper with Smith and what is the other guy? Restriction enzyme applied to– AUDIENCE: Dan Nathan. SUSUMU TONEGAWA: Yeah, Nathan. Smith and Nathan. So I thought– when I heard that I immediately thought Radar the idea that I executed later.
That if you cut up genomic genesantibody producing gene versus no antibody producing genes, if there is any DNA rearrangement, if we cut them up, and if we have a probe by the way, hybridization probe, run the gel and the probe patent. Basically Southern blot, but Southern blot didn’t exist at that time. So that was a technical issue of how to do Southern blot equivalent because it didn’t exist. But theoretically, if you can do something like that one should be able to tell whether gene is rearranging or not automatically. Restriction I started by getting my myeloma cell line to grow them [INAUDIBLE] but at the same time I was always thinking about how to spread out restricted the genomic DNA. And we did something really not elegant because Southern blot it’s very elegant. But we run– people who works on the serum on the separate Electrophoresis proteins in the serum they use electrophoresis, horizontal electro– other electrophoresis. And we owned the preparative thing, they used very large one like 50 centimeter long and maybe 40 centimeter wide, or something like that. You have to run long time because it is a very large gel. And I saw that in the cold room the immunologist were using, so I thought, oh, maybe I can use this one put the DNA, restricted DNA and develop it electrophoretically. And there were a lot of trial and error but it turned out you have to do it very slowly because otherwise if you rush [INAUDIBLE] get constricted and distorted. It takes about 3 and 1/2 days to run. But and then you cut it up, and then extract DNA from each fraction, like 60 fractions. It’s not the Southern blot. And then they do the hybridization with probe, immunoglobulin gene probe, which itself there were no cDNA then. What we did is we purified as much as possible from myeloma cell line, the specific immunoglobulin lichen mRNA. I don’t think it went any more than 97%, 98% pure even if we did the many steps of purification. But then you iodinate. To label you iodinate and then use that as the probe. Iodine That’s how it went. I don’t tell you all of the detail.
But we have only 20 minutes left so maybe I should stop here. And only message I will give to young people is I’m so– of course, I’m so grateful to Dulbecco. And I think that he is a most sophisticated mentor without any intentional planning. He had this, in my view, he had this vision, where the science is going, where the exciting things are going to develop in five years 10 years, maybe 30 years. Immune RNA And he was not immunologist but someway he knew enough to suggest to I guess ambitious young student postdoc, to try. And I think as a matter of fact I’ll tell you a little bit more because he actually in the letter– I abbreviated– but he suggested something very specific it’s called immune RNA.
Now, there was a claim was made around that, just before that one group in Harvard and one group in NYU or something. Independent. If you take a rabbit immunize with antigen Two papers and then afterwards extract RNA from spring, and they inject that RNA to a naive rabbit, that rabbit to become immune to that antigen and that RNA is called immune RNA. But it’s very crude. I mean you just take RNA and inject it. And there was a paper, there were two papers. And Renato happened to see those papers and he was– one thing he was thinking about is that. He was thinking, well, maybe one should study this more carefully and tried to characterize RNA and find out what’s going on. And that probably he mentioned that in this small letter I was wrong as an example of what I might consider doing. It turned out those two papers are fraud, so it was wrong. And some of you may know who the professor at Harvard. But in any case, it is already quite well-known, young professor and most of them are wrong– fraud. They’re made up.
He was completely wrong when he suggested something very specific to me but he was right in suggesting big picture, general direction. And I think this is a very important thing mentors should keep in mind. Mentor should not be just a coach, mentor should be a some [INAUDIBLE] giving person. This is the way I feel and– There are a lot of other things but I’ll stop stopped hereand then I’ll let you ask questions.
AUDIENCE: So when your professor from Kyoto sent you to US, didn’t he expect you to go back? SUSUMU TONEGAWA: Yeah. So when my visa is going to expire I did write to him of course. But I could not– he could not come up with attractive position for me. So oh, you mean, do I have a moral obligation to go back? [LAUGHING] No. I never feel that way. [LAUGHING] No, he was not unhappy that I didn’t come back. He was not unhappy. It was OK. People, one of the message I have is young people should go abroad. I mean, see the world and interact with the different people, and learn from them. I study memory, brain. Brain is so easily shaped by environment. You only think about with information you have in the head. You have to expand it by going to a new place interacting, with new people and exploring new things. But anyway so. Nobel laureates
43:04 AUDIENCE: Renato’s lab produced many other people. Where people– SUSUMU TONEGAWA: Renato’s lab, yes. AUDIENCE: [INAUDIBLE] SUSUMU TONEGAWA: Yeah, yeah, it’s amazing. [INAUDIBLE] AUDIENCE: [INAUDIBLE] is out there, right? SUSUMU TONEGAWA: [INAUDIBLE] is amazing, OK. 43:17 Now, you help me to tell you a little story again. You know Renato’s lab, Renato himself is a Nobel laureate 43:25 and you know. And his mentor is a Nobel laureate who is Salvador Luria. 43:31 And Salvador Luria graduate student who overlapped with Renato’s postdoc period [INAUDIBLE].. 43:39 And then in Renato’s lab. So David Baltimore, Howard Temin, Lee Hartwell, 43:45 and myself. I mean at a different time. Lee Hartwell was when he was a Cal Tech professor graduate 43:52 student. He had four Nobel laureate from his lab. AUDIENCE: And I think I remember Paul Berg. 43:59 SUSUMU TONEGAWA: Yes, Paul Berg when he changed from protein synthesis, molecular genetics 44:07 to eukaryotic system, which led to this recombinant DNA 44:12 technology he spend the one year in Renato’s lab for a sabbatical. 44:18 So he was exposed to eukaryotic system in Renato’s lab. This is quite amazing. How did he do it 44:24 I mean, we asked him how you do it? How he does it? And of course, he doesn’t answer. 44:31 He doesn’t have any answer. That it just happened, he says. 44:38 The only thing is he does his own research, his own experiments. We had no idea what he was doing. And it was every six months or so, he send out notice– not the email. No email then— that he’s going to give a talk in the lab. So he gives a talk, and we don’t understand what he’s talking about when he is so far ahead. You know, 1960– just in the late ’60s, he was already thinking, talking about growth factor in a cell, which would regulate the growth of cells. And he was working under the assumption there was a receptor for the specific growth factor on the cell surface and then did a signal transduction for changing a transcriptional or replicational state. And he was thinking about that. But this is very ahead for everybody else. So we thought, oh, this is– I don’t know. This doesn’t look like hard science. 45:53 But later, we realized that he was just very ahead of everybody else, I think.
Telephone call AUDIENCE: Can you describe the telephone call you got from Sweden? I mean, where you were?
SUSUMU TONEGAWA: I was in bed. It’s early morning. So Boston time is a very early morning. So I was sleeping. But also, call was not from Stockholm. Call was from Tokyo because a reporter called earlier than Stockholm.
Anyway, yes, please?
AUDIENCE: So if you had to make a suggestion Future of brain research to your student or the postdoc, what would be some exciting area– 46:47 SUSUMU TONEGAWA: For the future? AUDIENCE: Five, 10 years or [INAUDIBLE].. 46:53
SUSUMU TONEGAWA: Brain, brain. Well, you should know that everybody– there’s no such a thing as objective visionary. 47:05 So each one has their– is based on their– actually, based on the memory they have in their head 47:13 and what is called a taste. And well, I consider brain is a tremendous future. 47:24 And brain research can be done in many different ways. It’s totally interdisciplinary research. 47:30 You can do biologically. You can do physiologically. You can do behaviors. And a lot of new technology is needed, also. 47:38 More technology has to be invented, particularly if eventually, if we want to study human brain, rather than animals. 47:45 We need a real revolution in a non-invasive technology 47:50 to look at what’s going on in the human brain. So this is yet to come. 47:56 MRI– it’s good now, but it’s not good enough 48:03 for real understanding of human mind. So engineering is definitely there. 48:09 And I think that that’s all I can say. Interdisciplinarity I mean, a lot of people say the same thing. But the more I get involved in brain research, 48:24 the more I’m convinced. And important thing is you are very aware of that interdisciplinarity of brain research. So one should try to learn– train– trained in not in one level of analysis, 48:50 but at least two, maybe three levels, multiple levels, so that you can make a connection between processes, events happening in the different level of complexity– cellular, cellular interactions and physiology behavior, 49:05 and so on. But I also say that since this is a biology department, molecular biology will be powerful– continue to be powerful. There’s no doubt about it. You know this, right? Molecular biology is applicable for any area of life science. So it’s good to be trained as a good molecular biologist, by the way, when you are young. But then, you want to think about exploring new problems.
AUDIENCE: Can you say something about early influences in your life going into the scientific direction? I mean, did you have family members? Did you have a chemistry set? Did you tinker around in the basement?
SUSUMU TONEGAWA: Well, just again, I’m confirming what I already said. Human brain is easily shaped by environment. So the doctors’ children often become a doctor. Lawyers’ children often become a lawyer. Scientists’ or engineers’ children often become scientists or engineers, and so on. So I am not an exception to that. So in my bigger family, and the uncles, grandfather, they are mostly in science or engineering, including my father and my brother. My elder brother became a physicist, and so on. So that’s only world I knew when I was younger– you know, 50:39 teenagers. And it was very natural for me to go into some kind of science. 50:46 Then why chemistry? That’s a difficult question. I guess in high school, my grade in chemistry was good. So that’s why I thought I may have some talent in there. 51:00 But that’s not– yeah, they was just [INAUDIBLE].. How to become a scientist 51:06
AUDIENCE: Can you say a few words about your transition to neurobiology and how you prepared for it? SUSUMU TONEGAWA: How? 51:12 Transfer? Transition? AUDIENCE: Transition from– SUSUMU TONEGAWA: Yeah, transition– so that’s another thing. 51:17 That question is often asked. 51:24 You are young, but not so young. And I’m talking to younger people. You’ll excuse me for that. 51:35 You know, I think as a scientist, if we want to become a scientist, 51:41 I think the most important thing is your, as you say, 51:46 curiosity or your interest, scientific interest. 51:52 So as you do some research in some areas, of course, 52:00 there are other interesting things there. And you can never really finish it. 52:06 The question is, is it really interesting for you? 52:13 I mean, I think people should always think about, every few weeks, am I really doing– what I’m doing here, research, is it really worthwhile doing it compared to something else? And in other words, you should always assess what is called “importance,” which is also very subjective judgment. But that’s OK. Everything is subjective in this world. So you should assess whether you’re really looking at, seeking, something really– what is called “important” for you, important. So in immunology, I worked in so-called immunology. By the way, I never felt I’d been an immunologist, OK? I always felt that I’m a molecular biologist. I just use the molecular biology to study immunological problems. So I did that for, what, 15 years or so? 53:14 Maybe a bit more. And of course, there are still a lot of problems. But I started feeling I really explore something new. 53:24 I said explore something new. And there’s more subtle thinking on this.
In science, as you know, if we want to have a really impact to that field that you are working on, I think you need a few things. One is keen interest. And the second thing is some kind of approaches, expertise, or techniques, or something, which you like, and that you think that you are pretty good at, but other people are not using to study certain problems in the field. So it’s almost like what is called interdisciplinary approach. Otherwise, I think it’s impossible to be able to contribute significantly to a field as a latecomer. You understand that? Because there are thousands of, maybe tens of thousands of bright people who have been thinking about the problems for many, many years. And then all of a sudden, you go in there. 5And if you use the same approach as they are using, or their same thought, applying the same thoughts, I think the chances are very small that you can contribute. So you have to run into something that nobody has done. 55:05 So when I went to Immunology Institute, nobody was doing the molecular biology of nucleic acids. Nobody in the world interested in the immunological problem was doing that. And I happened to be trained in that field in other areas. And all I did is combine the problem with the approach I had. Now, fortunately, nobody else was doing. And I did have competition later, by the way. César Milstein, [INAUDIBLE],, they also came into that.
But in any case, so the same thing in immunology, so I felt immunology is coming to the point where the people who have more medical training, medical, as well as PhD training, will probably have a better– more fun– to continue to study some of the remaining problem in the immunology, like tolerance and so on, or the immunity, or things like that. And I don’t have any medical training, and I didn’t want to let– how do I say? I didn’t feel that I’m the one who should be studying all those things.
So I wanted to have something new. So there is a push and a pull. The push is what I just said. Pull is I was interested in the brain. I was interested in mind. 56:44 But I didn’t know for several years, I didn’t know how to study. In other words, I didn’t have this approach, which is unique, 56:51 or “almost unique,” to me or to my lab. But fortunately, toward the end of immunological research, we are using this transgenic gene knockout system to study immune system as a system. And then one day, [INAUDIBLE],, who is now professor at UCLA, came as a postdoc. When I was talking with him, we realized nobody has applied the transgenic or knockout mouse technology to study the mechanism underlying mousebehavior. Now, there are Drosophila people are already doing that– 57:38 been the study of that several years before that. But it was now possible also to do with mouse, but nobody was doing that. Never had anybody is starting doing that. So I thought this may be– 57:56 and that was a break with which I went in. We went in. It took about seven years to phase out immunology and go up 58:05 neuroscience. But it was a great change because my students are now postdocs. 58:11 Many of them also switched, and we learned together. 58:16 And then some of them know better than me. You know, like an MD postdoc, they know the anatomy of the brain already. 58:23 They tell me all these foreign names to me. And I learn from them. 58:31 And they’re not just anatomy, but many things. So it was OK. Really, I had– the luck I had is had Howard Hughes. 58:41 So we had stable funding. But actually, Max Cohen– I was on Howard Hughes’s own immunology program. 58:49 So when Max Cohen heard that I’m switching, he– 58:55 I don’t know what he did. He wrote to me or he called me, and he expressed his displeasure for my changing it. 59:04 He goes, hey, Susumu, you are in the immunology program. AUDIENCE: I can tell you what he said. 59:10 SUSUMU TONEGAWA: Huh? AUDIENCE: I can tell you what he said because– SUSUMU TONEGAWA: Well, what did he say? AUDIENCE: Yeah, because I was director of the Cancer Center Electrophysiology 59:15 at the time when you were making the switch. And you wanted a room to do electrophysiology. 59:21 And if you remember, I gave you one. And Max called me up and said, we’re not paying for that room. 59:30 We tried [INAUDIBLE]. And we got one to [INAUDIBLE]. SUSUMU TONEGAWA: Right, right. AUDIENCE: And I said, well, I don’t care what we pay for it. 59:38 He’s got the room, and he’s going to do neurobiology. SUSUMU TONEGAWA: Good. AUDIENCE: And he came around later. SUSUMU TONEGAWA: Later. 59:43 Yeah, came around. He came around. As soon the first paper was coming out, we agreed– change. 59:51 And he said, oh, it’s great. 59:58 So in that sense, Howard Hughes people are very good, very nice to us.
Yes, please? 1:00:04 AUDIENCE: What keeps you motivated? I mean– SUSUMU TONEGAWA: I can’t hear you. AUDIENCE: What keeps you motivated to continue 1:00:09 the work that you’re doing? Is it just the interest in what you’re doing? I mean, just what keeps you motivated to keep 1:00:16 going, to keep pushing forward in science? Because some people might have said that you have attained the peak of scientific achievement. So what keeps you going beyond that point?
SUSUMU TONEGAWA: I never thought that I was at the peak. What do you mean? You still have to live. 1:00:39 So you want to do something interesting, right? You want to have fun in your life, as long as you are living. So you have to find something which you get excited about. Right?
So it’s great if you change your field late, late, like I did, because you go back. You become student. You become a student. So you learn a lot of things very fast. It’s a lot like studying in a class and reading a book, textbooks, or things like that. [INAUDIBLE] that’s too slow if we are changing a field. Because tomorrow, I have to talk to a very well-known neuroscientist for collaboration. So by tomorrow, I have to know the basics of what we are going to talk about. So I just ask around, the people, and by ears we learn things. I mean, it’s probably information is not very accurate this way. But at least you get the sound. That’s the way I think the sciences should be done. I mean, the science– it’s up to you.
I mean, if you’re interested, you do it.We have no other choice. Otherwise, you are bored to death– die. I hope it’s useful. I’m not sure. It’s OK? I want to emphasize molecular biology is important, although future is in brain neuroscience.
I have one question. How long do you think it’s going to take to actually model 1:02:32 the human brain with robots? SUSUMU TONEGAWA: Oh. 1:02:38 How long it’s going to take? I’m sure you can ask that question to somebody else. 1:02:45 You will get a better answer. But it’s tough. 1:02:51 You’re talking about a robot who behave, think, like human beings. That– I don’t think it will happen very soon, OK? 1:03:05 AUDIENCE: It could. SUSUMU TONEGAWA: I mean, actually– actually, it’s quite dangerous to do that because if a robot doesn’t like you, they could have much more power than you have, and a different order of magnitude of power. So they may attack you. So we have to– I don’t think– in that way, I don’t think a robot will be ever be like a human being because human being will not allow that, right? But the question is, can robot– without given software– can this machine proactively not only respond to the stimulation, but have a thought? Planning of the behavior? I don’t think people have agreed to do that. So I think it will advance. Technology like that will advance [INAUDIBLE].. But to what extent we can do that, I don’t know. And when? It depends on what robot you’re talking about, what stage of robot. I mean, robot can now take care of patients, for instance– give the pills in the right time and say something soothing to you, to the patients. But that’s all software is there. I mean, the human is giving them to do that. So they have to create their own– I mean, if you look at the human brain, the human brain’s hardware changes in response to environment. Hardware– it’s a network itself– changes to adapt to the environment. We incorporate information from environment. It’s a totally interactive machine with environment. So please ask someone in the– artificial intelligence people at MIT. You know, it’s very interesting because people who are really hardcore thinking-machine people, plus it’s people who are think about robotics, but also at the same time, a neuroscientist, they are viewed completely different.
So I remember someone– yes, I tell you one little thing. I’m going to finish it, OK? Terry Sejnowski is a very good, respected neuroscientist at the Salk Institute who has a very broad understanding– biology to robotics to computational– everything. I really respect him. So he was telling me the other day that some years ago, when the thinking machine at MIT– people who are at the height of productivity– he was invited to give a seminar. And on the way to the lecture room, the host professor warned him not to criticize their robotics or their computers, supercomputers. So he thought about it. And then he said he started– just about he was try to start the lecture, fly, little fly, flew here. And immediately, he thought, you know, you just saw this fly flying here. You know, this little guy can find out where the food is. He knows how to reach there. He knows how to even store it. He can even reproduce himself. Now, I just saw this huge supercomputer in the basement yesterday in here. They can’t even move. They certainly cannot reproduce by themselves. So this was, as I said, many years, 10 years ago. So that’s the difference of a little, simple, relatively simple brain and a huge supercomputer. OK? [APPLAUSE] Thank you.
Hong Kong Newspaper : The husband of the family sprayed alcohol at home to disinfect, his wife went to the kitchen turned on the gas, the home was burned out, alcohol disinfected, be sure to pay attention to safety! Please tell your family that 75% alcohol is flammable . pic.twitter.com/yFJW5qzQ6T
では、複数の意味を持ちうる語句にはどのようなものがあるでしょうか。そのような語句の一つにandがあります。gene A and gene Bのように単語２つを結びつけるandには曖昧さはありませんが、節A and 節B. のように、２つの文構造を結ぶandの場合に、いったいこのandは何を意味するのかという多義性の問題が出てきます。まずA、次にＢという時間的な順序を表すandなのか、理由Ａ、だから結果Ｂという因果関係を表すandなのか、ＡすなわちＢという言い換えのためのandなのか、いろいろな意味がありえることでしょう。接続詞andが持つこのような曖昧さは、科学英語と相容れません。だから、科学英語においては、何も予備知識を持たない読者であっても意味が一意に定まらない限りandは使わないほうがよいと言えます。
andの使用例文①：Similar to the REGEN-COV combination, the COV2-2130 and COV2-2196 cocktail was also resistant to rapid escape and full escape was associated with acquiring multiple mutations within the same virus.
andの使用例文②：All VIR-7831 escape residues mapped to the published epitope of the antibody and the resultant escape virus maintained its ability to replicate, indicating that these mutations were not deleterious to the virus (data not shown).
andの使用例文③：We have previously described a triple antibody combination against Zaire ebolavirus (Pascal et al., 2018) and we similarly decided to assess potential advantages of combining three non-competing neutralizing mAbs targeting the RBD of SARS-CoV2:REGN10933+REGN10987+REGN10985.
andの使用例文④：Of note, in all patients, the three variants were identified at baseline or earliest time points (<5 days after REGEN-COV treatment) and no significant increase in their frequencies between early and late time points were observed indicating absence of treatment related selection.
andの使用例文⑤：However, the question regarding the relevance of these in vitro escape studies remains, and it is important to examine viral dynamics under therapeutic antibody pressure in more relevant settings, including in in vivo efficacy models and in treated patients.
andの使用例文⑥：Our approach allowed us to observe minor variants and our data indicate the vast majority of infected individuals are already harboring spike protein variants at baseline, prior to use of any antiviral agent and before natural immunity is established, as half of the study participants had not yet mounted an antiviral immune response at baseline (Weinreich et al., 2020).
andの使用例文⑦：This clearly demonstrates that the SARS-CoV-2 circulating population is highly heterogeneous in infected patients and the large reservoir of existing (or future) minor variants could be readily selected under the right selective pressure conditions.
andの使用例文①：However, the mechanisms by which cDC1s acquire tumor antigens for cross-presentation remain unclear, and it is not known whether interference with this process can constitute a means of cancer immune evasion.
andの使用例文②：The total amount of fluorescent rhodamine-actin on beads was unchanged by sGSN incubation (Figure 1D), and binding of anti-actin antibody was unaffected or even slightly increased, perhaps due to increased exposure of epitopes (Figure 1D).
andの使用例文③：Many cells can synthesize sGSN in addition to cytoplasmic gelsolin (cGSN), and sGSN can account for more than half of total gelsolin transcript expression in some tissues (Figures S3F–S3H).
andの使用例文④：In contrast, the intersection of CLEC9A expression with expression of cytoplasmic cGSN did not correlate with survival (Figure S6I), and a cDC1 gene signature did not substitute for CLEC9A (Figures S6J and S6K).
andの使用例文①：In addition, HSF1 binding motifs are enriched in the promoters of anhydrobiosis-related genes and we demonstrate binding of HSF1 to these promoters by ChIP-qPCR.
Pv11 is the only animal cell line capable of entering anhydrobiosis [14,15], and the cells can be preserved in the dry state at room temperature for up to 372 days .
To successfully induce anhydrobiosis in Pv11 cells, treatment with a high concentration of trehalose is necessary prior to a desiccation step , and during this treatment, several genes are strongly upregulated, such as the genes encoding late embryogenesis abundant (LEA) proteins [16,19], thioredoxins (TRXs) [16,20], protein-L-isoaspartate (D-aspartate) O-methyltransferases (PIMTs) [16,21] and Lea-island-located (LIL) proteins .
説明 Two independent clauses are often connected with a coordinating conjunction such as and, but, so, or, yet, nor, for.
例文 There are no true coral reefs in Gabon, and most of the largely unmapped reefs are rocky.