Lecture 01. Introduction/What is Chemical Biology?
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00:00
MagmaChemikerFilterMolekülSchubspannungProteineKorngrenzeErdrutschMeeresspiegelZunderbeständigkeitLactitolIonenbindungOrdnungszahlSammler <Technik>Fülle <Speise>Chemische ForschungBiochemikerinChemische BiologieGezeitenstromInlandeisWursthülleAktives ZentrumSingle electron transferMolekülbibliothekBukett <Wein>PferdefleischElektronische Zigarette
09:40
Chemische ForschungVerstümmelungProlinExplosionsgrenzeAuftauenGalactoseKalisalzeAmalgamMolekülOrganische ChemieWasserstoffbrückenbindungProteineKohlenstofffaserSchelfeisAzokupplungBetäubungsmittelDNS-SyntheseEtomidatHydrocarboxylierungReaktionsmechanismusSetzen <Verfahrenstechnik>SchönenFaserplattePentapeptideIonenbindungSignaltransduktionFülle <Speise>ZellkontaktMolekülbibliothekAlphaspektroskopieQuellgebietTopizitätNahrungsergänzungsmittelKohlenhydratchemieChemische ForschungChemische BiologieElektronische ZigaretteChemikerHochwasserKosmetikumLandwirtschaftKorngrenzeChemischer ProzessEukaryontische ZelleFließgrenzeHärteOrangensaftSchussverletzungStratotypWursthülleWeiche MaterieGen notchMultiproteinkomplexInteruniversitäres Forschungsinstitut für Agrarbiotechnologie
19:20
Hydroxybuttersäure <gamma->Chemische ForschungPCTGalactoseMagmaGärungstechnologieMethyliodidBiskalcitratumNicotinsäureArzneimittelGenortBodenChemikerExplosionOrganische ChemieBaseDeformationsverhaltenErdrutschFlussbettMeeresspiegelSetzen <Verfahrenstechnik>KonvertierungGradingFruchtmarkChromosomenkondensationChemische ForschungChemische BiologieElektronische ZigaretteBiogasanlageStahlWasserAnomalie <Medizin>MeeresströmungWassertropfenBetäubungsmittelPeriodateReaktionsmechanismusBrandsilberWursthülleFaserplatteSingulettzustandUnterdrückung <Homöopathie>Vorlesung/Konferenz
28:59
MethyliodidSandMagmaChemische ForschungSeltenerdmineralienKaratKalisalzeGalactoseDavy, HumphryBiosyntheseChemikerChemische ReaktionElektrolyseMolekülMolekularbiologieOrganische ChemieGesundheitsstörungMineralChemische VerbindungenAmmoniumchloridAmmoniumverbindungenAzokupplungCobaltoxideGasphaseHarnstoffMeeresspiegelMonomolekulare ReaktionRadikalfängerSilberchloridTrockenmilchGangart <Erzlagerstätte>BrandsilberRoyal Society of ChemistryStereoselektivitätWursthülleLactitolIonenbindungOrdnungszahlFülle <Speise>Chemische EigenschaftMolekülbibliothekQuellgebietTopizitätPedosphäreChemische ForschungBiochemikerinFalle <Kohlenwasserstofflagerstätte>Chemische BiologieFeuerKochsalzSauerstoffversorgungVerbrennungEukaryontische ZellePeriodateDiallyldisulfidSammler <Technik>CupcakeVorlesung/Konferenz
38:39
MolekülMagnetometerChemische ForschungProteineAmpicillinRNSHalbedelsteinHydroxybuttersäure <gamma->GenSonnenschutzmittelTafelweinMagmaFrischfleischBiopolymereBiosyntheseChemikerChemische ReaktionChemische StrukturEnzymInhibitorMolekülNaturstoffOrganische ChemieGesundheitsstörungProteineRNSChemieanlageOberflächenchemieRibosomKohlenstofffaserGenTiermodellDNS-abhängige-DNS-PolymerasenDNS-SyntheseErdrutschEukaryontische ZelleReplikationFunktionelle GruppeMessenger-RNSReaktionsmechanismusSenseTranslation <Genetik>TriterpeneÜbergangszustandWerkzeugstahlGolgi-ApparatNucleolusPulverReverse TranskriptaseKonvertierungWursthülleTransformation <Genetik>PentapeptideSpanbarkeitSekundärstrukturIonenbindungDiazotypieTranskriptionsfaktorProteinfaltungSeitenketteRNS-SyntheseProteinogene AminosäurenNahrungsergänzungsmittelStammzelleScaffold <Biologie>Chemische ForschungBiochemikerinChemische BiologieKatalysatorEukaryotenOligosaccharideKomplikationDoppelhelixBindungsenergieEtomidatMischanlageLokalantibiotikumPolyketideHelicität <Chemie>Single electron transferFülle <Speise>AlphaspektroskopieComputeranimation
48:19
Hydroxybuttersäure <gamma->Chemische ForschungEnzymCalcinierenMagmaGenomExplosionsgrenzeSpezies <Chemie>EukaryotenChemikerEnzymInhibitorMolekülOrganellOrganische ChemieTransportProteineToxizitätToxinGenQuerprofilChemische VerbindungenTiermodellChemischer ProzessDNS-SyntheseErdrutschEukaryontische ZelleFunktionelle GruppeGenomMeeresspiegelMessenger-RNSMolekulardynamikAmine <primär->RingspannungSenseTranslation <Genetik>WerkzeugstahlLokalantibiotikumWursthüllePentapeptideSpanbarkeitSekundärstrukturLactitolSpezies <Chemie>TranskriptionsfaktorSammler <Technik>f-ElementFülle <Speise>RNS-SyntheseProteinogene AminosäurenBukett <Wein>QuellgebietTopizitätChemische BiologieSäureRNSInselSchlag <Landwirtschaft>PeriodateProlinWasserscheideAtomsondeUntereinheitMultiproteinkomplexProteintoxinAdenomatous-polyposis-coli-ProteinElektronische ZigaretteVorlesung/Konferenz
57:59
GenomChemische ForschungPhysikalische ChemieMagmaRNS-SyntheseDNS-SyntheseRNSHalbedelsteinProteomPosttranslationale ÄnderungÜbergangsmetallTranslation <Genetik>CalcinierenChemischer ProzessProteineOligosaccharideChemische ReaktionEnzymTriterpeneChemische ReaktionChemische StrukturEnzymOrganische ChemieOxidschichtStoffwechselEukaryotenProteineRNSSonnenschutzmittelGenPolymorphismusAzokupplungBaseChemischer ProzessDNS-SyntheseErdrutschEukaryontische ZelleFunktionelle GruppeGenomImidazolIntronMeeresspiegelMessenger-RNSTranslation <Genetik>TriterpeneRNS-SpleißenExonPosttranslationale ÄnderungPolyketideTranskriptionsfaktorSammler <Technik>DiphtherietoxinHelix <alpha->RNS-SyntheseAlphaspektroskopieElongationMicroarrayTranskriptomanalyseMultiproteinkomplexKrankengeschichteMolekülOberflächenchemieToxinElektronentransferFunktionsmorphologiePeriodateWursthüllePentapeptideAtomsondeOktanzahlMolekülbibliothekQuellgebietEmerinElektronische Zigarette
01:07:39
EnzymChemische ReaktionChemischer ProzessChemische ForschungPolyketideSelbstzündungSeltenerdmineralienOrnithinProteineOligosaccharideKohlenhydratchemieHalbedelsteinRNSGenAssemblyChemische BindungMineralMagnetometerGalactoseHexamereMagmaDNS-SyntheseImmunglobulin GBiosyntheseChemikerChemische ReaktionChemische StrukturChemisches ElementEnzymMolekülOxidschichtRadioaktiver StoffRauschgiftProteineTumorBuchtOberflächenchemieKohlenstofffaserGenChemische SyntheseFaserverbundwerkstoffChemischer ProzessDNS-SyntheseErdrutschEukaryontische ZelleGenomMeeresspiegelMessenger-RNSSenseWerkzeugstahlPosttranslationale ÄnderungSetzen <Verfahrenstechnik>WursthüllePentapeptideLactitolIonenbindungChemische FormelSammler <Technik>f-ElementUntereinheitOktanzahlPotenz <Homöopathie>MolekülbibliothekTiefseebeckenModul <Membranverfahren>StickstoffatomMolekulare EvolutionBindungstheorie <Chemie>Chemische BiologieElektronische ZigaretteBenzodiazepineOligosaccharidePentamidinMilSeitenketteAlphaspektroskopieBukett <Wein>HexamereKohlenhydratchemie
01:17:18
Vorlesung/KonferenzBesprechung/Interview
Transkript: Englisch(automatisch erzeugt)
00:00
I'm going to run the class as follows. I'll have the most important announcements at the very beginning of the class. So, I'll be talking about stuff like what's covered on the midterm, what's expected from your proposal assignment, et cetera at the very beginning. So, you definitely want to show up on time, show up early, get a seat, be prepared because the most important stuff
00:21
is going to be in that first five minutes, OK? Oh, and by the way, feel free to interrupt if you have any questions, OK? So, don't hesitate to interrupt if anything comes up. OK. So, some announcements today. And again, the announcements will come out at the very beginning of each class. Our reading assignments this week,
00:41
I'd like you to obtain the textbook. It's available in the bookstore. There are a big stack of them when I visited last week. They ran out? Oh, well, that's good. OK. If they ran out, amazon.com has them on sale and you can get them delivered very quickly, OK?
01:01
And I know for a while Amazon was selling them at some ridiculous discount. So, I know because as one of the co-authors, I'm very interested in how they're selling. Along those lines, as one of the co-authors, I'm planning to donate the profits from the book to anyone in this classroom back to UCI for to support research
01:21
and chemistry, OK? So, I'm requiring a book that I wrote. I'm obviously aware that I'm going to profit from that. The profits will go back to UC Irvine. OK. So, if you have a copy of the course reader from previous years, please throw it away, OK? It's not going to be any good. I mean, it's good but I've changed the material quite a bit
01:44
and the textbook is significantly improved. The problems are slightly different. I think it's the figures are much better, et cetera. And of course, it was edited. So, the course reader for previous years is not going to carry you. You need to buy a copy of the textbook. So, Natalie, how does the sound sound?
02:32
Thank you, Natalie. Yeah. So, yes, they will be posted online for you so you can enjoy them and study from them, et cetera.
02:43
The goal here is that UC Irvine is one of the very first universities to have both a lecture class and a laboratory class in chemical biology. We started this back in 2000 when I was an assistant professor. And since that time, we've obviously built up quite a bit in terms of our sophistication of presenting the subject.
03:01
And so, my goal is to really bring that level to other universities around the world and around the country. So, anyway, that's why we're doing this but it also has some benefits to you as well. OK. So, reading assignment for the first week, read chapter one. I'm going to be covering all the material in chapter one
03:22
so there's nothing for you to skim through or anything like that. On future chapters, there will be stuff that I won't be covering and I'll tell you when that happens, OK? And you'll notice when it happens. OK. If you want to get ahead, start reading chapter two. Chapter one is pretty basic. Chapter two then starts getting more advanced.
03:42
Homework, do the problems in chapter one, all of the odd problems and also all of the asterisk problems. And let me add that to this. So, all the problems that have an asterisk are avail the answers to all the problems of an asterisk are available online.
04:00
So, I'd like you to do those as well. OK. And then in addition, we'll be posting a worksheet, number one, on the website. It's not there yet but it will be posted very soon. Oh, it is there? It will be posted afterwards. OK. So, we'll be posting that. That will form the basis for the discussion sections.
04:22
Please work the worksheet as well. OK. So, before I get started, before I go through very much more, I want to tell you what you should be paying attention towards. The first thing are these announcements that I'm giving you. What's discussed in lecture? The discussions that I give you in lecture are your guide
04:42
to what I think is important, OK? So, right before the midterm, you're going to want to know, what do I need to know on the midterm to get an A in this class? And my answer is always the same, which is what did I talk about in lecture? What I talk about in lecture is what I think is important. I have a limited amount of time for these lectures.
05:01
I'll be doing two lectures per chapter of an hour and 20 minutes each. And so, if I talk about it in lecture, I'm telling you, I think this is important. This is something you need to know for the midterm, OK? So, what's discussed in lecture is super important. This includes both slides
05:20
and anything else that's posted to the website. This discussion worksheets and then the discussion in discussion as well. If you're sitting on the left side of the classroom, can I ask you to sort of scooch in if you have an empty chair on your right? So, just to create some more extra chairs because we have people that are arriving late. So, just sort of scooch over please. Thank you.
05:43
OK. The next most important thing is the sign reading. But, filter the sign reading through the filter, through the lens of what I talk about in class. If I talk about it in class, that's telling you it's important, if I don't talk about it, less important. And then finally, the problems in the textbook as least important.
06:04
Good news, there's a few things that you don't have to worry about. The first of these are references on the slides. I find it almost impossible to do stuff without having some referral back to the literature. That's sort of the nature of scholarship. And it totally impossible to get me to stop doing this.
06:24
When we, when Dave and I wrote the textbook for example, we had a list of references that's like 10 times longer than the one that's posted to the website. And we found it totally impossible that the publisher told us to stop doing it to leave out those references. And so, references are basically the currency
06:42
that underpins what I'm telling you. But on the other hand, this is an introductory class, so don't get worried about those, OK? If you take a graduate class and they have references on slides, you'll want to look up those references. But in an undergraduate level, don't get worked up about it, OK, so don't stress about those. In addition, don't stress about stuff that's covered
07:02
in the textbook that we don't discuss in class, OK? So if I, you know, I've said this before, if I don't discuss it in class and it's in the textbook, don't worry about it, OK? So the text is written at sort of an advanced undergraduate early graduate level and there's material in there that's frankly graduate level. But I don't want you to get stressed out about it, OK?
07:20
So if I don't talk about it in class, that's my signal that I don't think it's so important for you to learn, OK? Any questions about what I'm telling you? Hey. Are there any textbooks reserved in the library? Oh, that's a good question. What is your name? David. David. Miriam, could you look into that for David? No, they're not yet, but there should be with them
07:42
in the next two weeks. OK. So there'll be a, eventually they'll appear there, but not yet. Thank you. OK, thanks for asking. Other question? What is your name? You said it won't be collected, it will just be working. No, so we will not be collecting the problem sets. We'll have plenty of other chances to learn about your intelligence and creativity. So, another question?
08:01
Will the slides be posted? That's a good question. I'll try, but I'm usually frantically getting ready the day of, so I'll do my best. Certainly, the Thursday lecture will be, but maybe not the Tuesday. I'll do my very best though. Other questions?
08:22
OK. More background. Course instructors, Professor Weiss, I've been teaching this class for about 12 years. And I absolutely love chemical biology, it's what makes me run to work. It is my sole passion in life.
08:42
That's a little bit of an exaggeration, but close. OK. So, what else would you like to know about me? Here's your chance. For the next five minutes, you can ask me anything you want. Personal, not so personal. Go ahead in the back first. So, my laboratory is at the interface of chemistry and biology. And we're trying to develop new ways of looking
09:00
at individual molecules and dissecting how membrane proteins work. Thanks for asking. And a question over here? It was. I'm a kind of a competitive guy. I like driving fast. I like racing. So, yeah. Question over here? Chemical biology emphasize, so this is a great question.
09:22
So, the question was, what is the difference between biochemistry and chemical biology? Chemical biology emphasizes what's happening at the level of atoms and bonds. And biochemistry emphasizes what's happening at a larger scale. So, in biochemistry, my colleagues are content to look
09:41
at proteins as sort of large molecules without getting too worked up about hydrogen bond here and hydrogen bond there. Sometimes, they get worked up about those things. But most of the time, on the diagram, signal transduction diagrams and things like that are just large blobs. And in this class, we'll be zooming in and looking at the actual atoms and bonds. OK. Good question.
10:01
OK. Anything else personal? This is your last chance. Ask me anything personal. Ask me about my pets, my hobbies. Oh, go ahead. No, I wish I did. I only get to go out once a year. It's kind of a limitation. So, thanks for asking.
10:22
OK. Well, I should also let you know I have two cats. I'm married. And that's it for the personal information. OK. OK. Last question. Go ahead. I have zero kids. So, I have a two-seater car.
10:41
OK, you guys. That's it on the personal stuff. Enough about me. I'm very pleased that this quarter, we have really the very best TAs in the chemistry department. I've gone through and I've handpicked TAs. Miriam Iftikhar is a great example of this. Miriam and I taught this class last year.
11:00
And she knows everything. There is to know about this topic. Her research is in chemical biology and she's absolutely superb. If she tells you something about the class, you could take that as good as coming from me. OK. In addition, our second TA, Krithika Mohan, isn't here today. She's been tied up in India.
11:20
But she'll be back in the next week or so. And she's also a great source of information. She's also a graduate student in my laboratory. OK. So, we're really lucky to have California's finest natural resource TAing for us, Krithika and Miriam. OK. So, in terms of office hours, I will be having two office hours a week.
11:41
My Thursday office hour is set. My Wednesday office hour, however, will float. OK. So, I will always have office hours Thursday, 11 to noon. The one, this other office hour, the second office hour will float, meaning that my schedule is constantly changing and so I'll have to change this around. OK. So, every week, I will announce when that office hour will take place.
12:02
If, for example, my office hours don't fit your schedule, tell me at the beginning of the week when you'd like my office hour to be and I'll do my best to accommodate as many people as possible each week. OK. So, first office hour fixed, second office hour floating. I will always have the office hours set up in a way that's at the interfaces between classes.
12:22
So, you don't have to attend the whole office hour. If you can attend just the first 15 minutes or so or 10 minutes and then fly off to your class, that's perfectly OK. Show up for five minutes, get your question answered and then disappear, I don't care, I don't mind. But I'll always set them up so they're kind of at the junction between classes, that way then it's less likely that you'll be able
12:41
to tell me that you have a scheduling conflict with every one of my office hours. I've heard that before and I usually ask those people to show me their scheduled classes and I've never seen it actually that way, especially since I have the second office hour floating. So, there's going to be plenty of time for you to meet me this quarter and in fact, I really want to get to know you, OK? I will get to know the names of 95 percent of you
13:02
in this room, I will know something about what your career aspirations are, I will know something about your creativity in terms of your ability to come up with novel ideas, your writing ability and a lot of other characteristics as well. So, at the end of this, I will be able to write a very good letter of recommendation for you.
13:22
OK. This is not apropos of the last topic, but I would like you to shut off your cellphones please, OK? And that also includes text messaging as well. Thank you. OK. So, anyway, come out to my office hours, especially in the first couple of weeks, introduce yourself, tell me why it is you're taking this class, what it is you hope to learn, what it is that you're hoping
13:42
to do once you graduate from UC Irvine and if there's anything I can do to help you in that course, I will do it, OK? That's one of my jobs. And furthermore, even after you graduate from this class, you can still keep in touch with me, you can still get letters of recommendation from me and you can still have my support in your career aspirations, OK?
14:01
That's my promise and commitment to you. OK. And the TAs will also have office hours each week. Their office hours will always be on different days and times than my office hour. And their office hours are much more fixed than my office hour, OK? So, any questions about anything I've said? Any of the announcements so far?
14:23
OK. All right, textbook, I've already mentioned this. Again, it's available on Amazon. I understand it's sold out but you can get it again from Amazon. Supplemental text, I'd like you to have available an organic chemistry supplemental text.
14:41
When I talk about peptides for example and I talk about amide bonds, I'm going to assume that you've read the chapter on amide bonds and peptides in this supplemental text even if it wasn't covered in 51C, OK? I'll just ask you to go back and read that chapter, OK? And so, you need some sort of supplemental text available
15:00
in organic chemistry as basically as reference, OK? And it's nice because this will provide kind of a lower key treatment of a more complex topic. So, for example, if you want to learn the sort of the very fundamentals of DNA or carbohydrate chemistry, the best place to start is whatever textbook you use for 51C.
15:21
Now, I realize many of you sold your textbook right after the class was over. That was a huge mistake but it's not too late to change things. Number one, I can give you or loan you a supplemental text if necessary, come to my office hours. First, five people that show up will get one of those.
15:41
Second, the library, the science library has about three shelves that are like this wide that are filled with organic chemistry text. The exact text does not matter, OK? Basically, if you look at sophomore organic chemistry textbooks, they're all more or less the same, OK? What really matters though is that you have one available to you that you can refer to as reference.
16:02
You need that for this class, OK? Because I'm going to assume that you know the material in there. Now, along those lines, I've gotten a couple of emails from some of you who are concerned. You had trouble in 51C, you had trouble in sophomore organic chemistry and now you're taking this sort of advanced organic chemistry class and you're worried.
16:20
OK. Here's what I want you to do. First, don't panic, OK? I will do my best to get you up to speed on arrow pushing and some other fundamental principles in the next two weeks, OK? So don't panic yet. At the end of that two weeks, if what I'm doing on the board and your ability to keep up a discussion section
16:43
and on the homework are just, you know, apples and oranges, you know, fields apart, OK, you're not even on the same racetrack, then you can start panicking. But for now, no panicking, OK? If you were really, really weak in sophomore organic chemistry,
17:01
I'd like you to open the chapters on carbonyl chemistry. Whatever book it is, reread the chapters on carbonyl chemistry and get up to speed on those. If you understand how carbonyls react, how the alpha carbon is acidic and a few other things,
17:21
you'll be fine in this class, OK? It turns out that's like 60 or 70 percent of the organic chemistry that underlies biology involves carbonyls, OK? So start there first. After you finish with the carbonyls, come see me again and I'll get you up to, I'll give you the next topic which will probably be a means or something like that, OK? Sound good?
17:41
OK. So hopefully I've laid some of your fears. Don't panic yet but get ready to panic in the next week or so. And also get ready to take your game up a notch, OK? So that, you know, even if you had a bad time in 51C, you can do pretty well in this class if you're ready to work pretty hard, you know, do lots of problems,
18:02
come up with creative ideas, et cetera, OK? Discussion sections, these are mandatory. This is especially important if you're weak in organic chemistry. Discussion sections are going to be run in a problem solving format and this is your chance to show that you could do arrow pushing with the best of them.
18:21
So a lot of the problems in this class involve mechanisms. And so in discussion sections, you'll have a chance to demonstrate your ability to do mechanisms, you'll get up to speed on doing these correctly, et cetera. OK, so again, the first worksheet will be posted shortly. The first discussion section will start this Wednesday.
18:40
Miriam will be teaching that one and then after that it will continue. OK, now if you're on a Monday, if you were scheduled for a Monday discussion section, don't panic. What the material that will be covered on Wednesday will then be covered on the next Monday. OK, so we'll have them slightly staggered throughout the class, OK? And it turns out that actually works out fine
19:01
because the midterms are on a Thursday and a Tuesday. OK, so there will be two midterms in this class. And there are no make-up exams available. They will consist of the full hour and 20 minutes. There's going to be an emphasis on arrow pushing and concept problems.
19:22
There will be things like short answer. There will be no multiple choice. There's going to be like short essay type problems. There will be problems where you have to design experiments, things like that, OK? But lots and lots of arrow pushing. So, get ready for arrow pushing. In addition, the other way that I'm going
19:40
to assign your grade is I'll be looking at two written reports that you're going to submit in the class. The first of these is a journal article report due unfortunately on Valentine's Day, happy Valentine's Day from your chemical biology friends. And in this one, in this report, you're basically going to be doing the equivalent
20:00
of a book report but using an article from the primary literature to provide the report. I've already posted to the website an example of this. In addition, instead of a final exam, this class will have a mandatory proposal that's due on the last day of class, March 14th, OK? So that's a mandatory proposal.
20:21
You cannot pass this class without turning in the proposal. But there's no final exam, yay. The proposal will consist of an original idea in chemical biology. Now, I know this is daunting. I've taught this class before. I know this is really intimidating. Don't panic.
20:41
I will have a series of exercises for you this quarter that will get you up to the point where you're ready to come up with creative novel ideas in the cutting edge of chemical biology. So, you will be ready for this. You'll be ready to contribute. And the good news is in chemical biology, there's so much that we don't know that there's lots of room for smart people like yourself to come up with really great new ideas, OK?
21:04
And I see this every year. Every year, I would take the very top proposals from our, from this class and I could present them to the National Institutes of Health and they would get funded, OK? The best ideas, I can put up for faculty ideas anywhere, OK? So I've seen that before. And the other thing is I'm looking for a small idea, OK?
21:23
I'm not looking for, you know, the next Manhattan Project or something like that. I'm just looking for, just give me a base hit, you know, something that will work, that will teach us something new about chemical biology and you're good, OK? Quizzes, I will have a series of quizzes in this class
21:40
that will number between one and five, OK? More likely to be one to two. There will definitely be a quiz sometime in that last week and the reason is our second midterm is in February and the class keeps going till March, OK? So there will be an easy quiz. The quizzes in general are designed to be easy. They're basically, you know, recapitulate something
22:03
that you just saw on the board, OK? So, we'll run these either at the beginning of the class or the end of the class and it'll be something along the lines of you just saw this mechanism, show me again how it works, OK? Something like that. Just basically tells me whether or not you're paying attention and who's showing up for class. And by the way, I'm delighted to see all
22:21
of you happy people out this morning. Welcome. But I know as the class wears on that you guys get very busy. And of course, the lectures will be posted online. There has to be some incentive here to get you rolled out of bed at 930 in the morning, OK? So, we will have some quizzes.
22:41
It won't be too many and they won't be hard, OK? That I promise you. In terms of percent of your grade, those quizzes only count for 5%, the same level of participation. Participation counts in both lecture and discussion and for that matter, even office hours, OK? So, me and Miriam and Krithika getting to know you,
23:00
that's how we determine the quiz scores or the participation scores. Oh, and by the way, I will post all of these slides online, OK? So, they'll be all posted to the website. So, you'll have copies of them. They're not posted now but they'll be posted shortly. OK. Each midterm will count for 22% of your total grade.
23:22
The journal article report will count for 16% and then the proposal which is in place of the final exam, counts for 30% of your grade, OK? So, it's a pretty even distribution. There's lots of opportunities to get for you to get feedback, et cetera. Any questions so far?
23:41
Yeah, in the, what is your name? Anna. It is. I haven't talked about that yet. Thanks for anticipating. I'll get to that in just a moment. OK. Thanks for asking. And Steve, no.
24:00
What is your name? Carl. OK. Carl. Yeah, no problem. Carl's question is, what if I'm assigned to some discussion section that doesn't fit my schedule? Do I, can I go to another one? No problem. And you can even go to one one week and a different one the next week. No problem, OK? And it's posted online or it's posted
24:20
on the syllabus exactly when the discussion sections will take place. Let me show you that. OK. So, this is the course website. OK. Notice over here that there are instructions for the book report. I'll change this very slightly for 2013.
24:41
There are instructions for the proposal. I'll change this very slightly. There are three examples of proposals that got an A and then the syllabus, OK? In the syllabus, I've listed the discussion sections, where they meet, et cetera. Feel free to go to any of these, OK?
25:00
Let me zoom through this. This is online. I'd like you to read this carefully. I'm going to hold you to all of the provisions that are in here, OK? So, anything that's written in here, it's the equivalent to me saying it. All right. I'm not sure exactly why it is as we cut off on the right. A lot of this recapitulates what I just just said.
25:22
OK. Let's get to this Anna's question. Over here, there will be, let's see, one moment. OK. On February 21st, 2013, you will turn in an abstract for your proposal, OK?
25:41
So, an abstract is a short condensate of what your proposal is going to consist of. This tells me whether or not you're on track and I'm going to use this as a way to give you early feedback about your idea and tell you whether or not I think your idea fits the definition of chemical biology, whether or not I think your idea is a
26:02
creative one or not so creative, OK? So, this gives me a chance to give you feedback before you turn in your proposal, OK? And this abstract is worth 10 percent of the points for the proposal assignment, OK? So, in other words, 3 percent of your course grade will be determined by that abstract, OK?
26:22
Note that all assignments are due by 11 a.m. on the due date. There is a late policy, but I hope that doesn't apply to you. Questions so far? All right, yeah? No, just stretching. All right, there's some information here about adds and drops.
26:40
There's a frequently asked question section. Do I need to attend discussion sections? Yes. Discussing paper, turn in the final assignment, oh, if you have not taken all three quarters of Chem 51 or two semesters of sophomore organic chemistry, you should drop the class, OK? You're going to get blown out of the water, OK? So, you must drop the class now.
27:01
It's a prerequisite and then every year someone slips through. Don't take this class if you haven't taken the full sophomore organic chemistry series, OK? OK, there's a whole thing on incompletes over here. Oh, academic honesty. Unfortunately, we're going to talk about this later in the class.
27:20
I do not want it to apply to you. There are the major portion of your grade is going to be writing assignments. And so, academic integrity issues loom large, unfortunately, in this class. Every year, I have to give someone a F grade on the assignment which end up turning into like a C minus D plus kind of deal because they try to plagiarize assignment.
27:41
Don't let that be you. Let's make this the year where I don't have this problem. Along those lines, if this is the year where I don't have any plagiarism problems, I will give an additional 3 percent higher grades. So, I'll assign the grades and then I'll go through and I'll bump up 3 percent of the course grades to the next higher grade, OK?
28:02
So, if everyone in the class avoids having any plagiarism or academic honesty issues, so no cheating on exams, no plagiarism, no academic honesty, I will bump up the grades by 3 percent, OK? That means 4 or 5 of you at each level are going to get a higher grade, OK?
28:20
So that means like four people, three or four people who are going to get a B plus, I'll move them up to A minus. I'll take the top of the three or four top A minuses and move them up to an A, OK? That's the deal, OK? We'll talk some more about this because it's a slippery slope and it's best that we don't have to have this conversation later.
28:40
OK. So anyway, that's the information on the syllabus. I'm holding you entirely to the contents of that syllabus. So I'm expecting you to go home and read the syllabus carefully. I don't have time to talk about every aspect of it now. I'd like you to go home though and read it carefully please. OK. Questions?
29:02
Questions? OK. Skip that. Skip that. OK. Let's get started. So, we already heard the question, what is chemical biology? How does it differ from biochemistry? I gave you kind of a quick answer. I want to delve into this topic a little bit further.
29:21
OK. So, here's the working definition of chemical biology that we'll be using this quarter and it's important that you understand this. This is the definition is using chemistry to advance molecular understanding of biology at the level of atoms and bonds. So the way I know that we're talking at the level of molecular at the molecular level is
29:43
if we're talking about atoms and bonds, OK? And that's what I'm looking for in terms of a definition of chemical biology. There is a second corollary to this definition which is using techniques from biology to advance chemistry. And some examples of this are for example,
30:02
using molecular biology techniques to develop combinatorial libraries of chemicals which is something that is one of the projects that my own laboratory does, OK? So, there are two parts to this, using techniques from chemistry to study biology or using techniques from biology to solve problems in chemistry.
30:21
In both cases, these involve looking at molecules at the level of atoms and bonds and that's where it's distinct from biochemistry. Biochemistry also uses techniques from chemistry but oftentimes, they're content with looking at molecules as sort of amorphous blobs that are represented as, you know, spheres or something like that in textbooks.
30:42
In this class, we'll be down at the level of atoms and bonds and that's how you know we'll be talking about chemical biology. So, later in the class when I ask you to come up with an idea in chemical biology, a proposal idea, then you should be thinking at the level of atoms and bonds and then it tells you whether or not your idea will be acceptable. OK. So, chemical biology advances both chemistry
31:02
and biology and I want to give you a couple of historical examples of this. For my money, the very first chemical biologist was Joseph Priestley, this guy over here. He was a remarkable character. So, he isolated oxygen and other gases.
31:22
OK. So, he was isolating these using electrolysis and other techniques and he would isolate these in bell jars and then he'd use these chemicals to study biology. So, one of the experiments he did for example was subjecting poor mice, mice that he would trap
31:40
from fields to these different chemicals that he was isolating. And he found that the mouse for example could live in oxygen but could not live in many of the other gases that he was isolating. OK. So, that's a really interesting example because it's using the very latest techniques from chemistry to understand better how respiration works,
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how organisms take in oxygen. And at the same time, it's using a technique from biology as a way of solving a problem in chemistry. And the technique in biology is does the mouse live or die? Does the organism, can the organism survive under these conditions to tell me something about those chemicals, right?
32:22
Joseph Priestley didn't have any spectroscopy available to him. So, he's using a technique from biology, a very qualitative technique to be sure but a method nonetheless to tell him something about what's happening at the chemical level. OK. Now, Sir Joseph Priestley had some radical ideas
32:41
about colonists in America and theological descents that were going on in England at the time. And I'd like to say that the very first chemical biologist had his house burned by an angry mob who came rampaging through his village with pitchforks and were out literally to get his head. And we've had a proud tradition ever since
33:02
of iconoclastic thinkers and independent people who are guaranteed to rile up the masses. But of course, he's not getting burned at this or his house is not getting burned because of his chemical virtues. This was then carried on by Sir Humphry Davy who shown here at the Royal Society of Chemistry conducting experiments
33:24
on his colleagues. He's having them inhale bags made out of silk that include gases. And then he's looking at the violent excretions that happened afterwards. And so, this is just a classic woodcut from the period.
33:41
OK. Now, the other, so these are sort of early workers. Perhaps the most historically, the most important experiment in chemical biology was done by the great Frederick Voller in 1828. Here's a picture of him. Notice that these guys are pretty young, OK? These guys, you know, they were doing this stuff in their 20s, OK?
34:01
They're not much older than you. Any of you in this classroom, five years from now, you could also be doing stuff that would change how we think about the universe, OK? That's the way science works. It's one of the great things about science, OK? So, don't think about this as being done only by old people. It's not. It's done, these great ideas are oftentimes done by young iconoclasts who have clever ideas
34:23
and just want to push the bounds. OK. So, here's Frederick Voller, 1828. He's running an experiment in his laboratory where he's running this silver cyanate experiment where he's trying to do what would be like just the most pedestrian of exchanges of salts, OK?
34:41
So, what he's trying to do is synthesize ammonium cyanate using silver chloride which he knows will precipitate out. Recall from Chem 1 that precipitates out in a white powder. And he's doing this by simply mixing silver cyanate together with ammonium chloride. And he's expecting when he heats this up that the silver chloride will precipitate out and he'll be left with ammonium cyanate.
35:03
It turns out that's not what he got, OK? That was not the product that occurred. Instead, what happened was he got out this other product that crystallized out of the reaction flask. And when he smelled this other product, he knew immediately what it was. What he smelled was urea.
35:22
And urea had been isolated from urine, from dogs and humans. And so, it was known that urea is a known compound. And back then, the primary way of characterizing the chemicals was by their smell, by their taste, you know,
35:42
some gross physical properties. And because urea has a distinctive smell, he can readily characterize this. Now, here's the significance of this discovery. What Frederick Wohler recognized was that this urea was identical to the urea that's obtained from dogs and from humans.
36:02
But the difference is this did not come from a living organism. In other words, using just mineral sources, you can make the same chemicals that are found in living organisms. So, there's not some sort of special property that animates the chemistry of living organisms
36:21
that somehow makes it special. Instead, it's going to be governed by the same rules that are found in chemistry that's outside living organisms, OK? And this is really important because at the time, there was this notion that living organisms would have some sort of special spark that in some way would make them alive
36:43
and make them make their chemistry unique and special. And what Wohler is showing us by this experiment is that in fact, there was nothing unique and special about the chemistry inside living organisms. OK. So, these are great examples of using chemistry
37:00
to understand biology at the level of atoms and bonds in the case of urea, let's move on. Another principle that underlies chemical biology is evolution. We're going to be talking a lot about evolution in this class. And so, the reason we're going to be doing this is first, it simplifies knowledge.
37:20
And second, it's going to guide experimental design. And here's two views of the great Charles Darwin. We can't talk about evolution without making reference to Charles Darwin who articulated in, you know, 150 years ago much of, you know, the principles behind evolution.
37:42
There are two steps to evolution. The first step is to diversify, to generate a diverse population of molecules of organisms, of phenotypes really. And then the second step is to select for the fittest from this diverse population.
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I'll explain the word phenotype in a moment. Don't panic if you didn't understand that word. So, there's simply two steps here. Select for generate diversity, select for fittest. These steps are then repeated again and again to evolve organisms that can solve some sort of problem. In terms of chemical biology, we think about generating diverse populations as ways
38:22
of shuffling together, shuffling around bio-oligomers in combinatorial manner, in combinatorial manners. And I'll show you that in a moment. And we often do experiments that involve some selection for fitness. We're going to make a large population of molecules,
38:41
mix them up and pick out the ones that are most that can best fit a criteria or set of conditions. This is a very powerful principle that allows us to make progress very quickly in chemical biology. And this is used as a technique by hundreds of laboratories in the field, OK?
39:02
So, we use evolution not just as some sort of theoretical underpinning, but we also use this as an experimental framework. And I encourage you, when you're thinking about proposal ideas, think about evolution as a tool to help you speed up getting towards molecules that do stuff for you, OK?
39:21
So, this is used extensively. Another way that's used extensively is it's used to organize knowledge. When we talk about say the ribosome which is the machine that translates mRNA into proteins and I'll show you what that looks like in a moment. I don't have to talk to you about some sort of special ribosome that's found exclusively in humans
39:43
or dogs or something like that. Because it turns out that the same mechanism used by ribosomes in humans is also used by bacteria. It's even the same mechanism used by archibacteria, a different stem on the tree of life entirely.
40:00
And so, what this means then is that I don't have to teach you about the special chemistry of humans. I can talk about the chemistry that underlies all organisms on the planet because we all evolved from common ancestors that solve these mechanistic problems in chemical biology. OK? So, this provides the powerful approach
40:22
to evolve molecules which I alluded to on the previous slide. But equally importantly, this helps us to organize knowledge and make it much simpler for us to talk about universal chemical mechanisms that underlie all life on the planet. OK. So, speaking of sort of universal principles
40:45
that underlie all life on the planet, the central dogma of modern biology is going to appear in multiple ways throughout this quarter. In the first way, this is how we've organized the textbook that we'll be using this quarter, OK?
41:02
So, the textbook has different chapters and it's organized according to the central dogma. So, the central dogma describes all biosynthesis that takes place in cells and on the planet, OK? So, everything that you're going to synthesize in your cells is in some way encoded by the central dogma.
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The central dogma tells us that the DNA found in nuclei and eukaryotic cells is the blueprint upon which all biosynthesis is based. This DNA is transcribed into RNA and then translated into proteins, OK?
41:42
So, this is the earliest diagram by the great Francis Kripp who recognized the far reaching implications of this dogma very early on, OK? This is his earliest example of where it was articulated. It looked just like this. We now know, for example, that there is in fact this dash line
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over here is in fact a real line. There is an enzyme reverse transcriptase that can convert RNA into DNA. But this line over here where RNA is used as a template to make new copies of itself, this line never materialized. We have not found it in many years of looking.
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In fact, it would be a great chemical biology proposal to come up with a way of doing that. OK. So, here is a different way of looking at the central dogma of modern biology. So, at the very top, DNA, this biopolymer up here is going to encode messenger RNA and in fact all RNAs.
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This, the conversion of DNA into the complementary RNA takes place using an enzyme called RNA polymerase, OK? This is nice because it's going to be polymerizing RNA, this makes sense. I'm going to be referring to enzymes today
43:02
and in future classes, enzymes are proteins that catalyze chemical transformations, OK? So, these lower the transition state energy for key reactions that take place in the cell. And here's our first example of this, the enzyme RNA polymerase that's responsible for transcription.
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In addition, there's an enzyme DNA polymerase that allows replication of the DNA to make new copies of the DNA when the cell has to divide. OK. Here's the ribosome that I alluded to earlier on a previous slide that is responsible for translation of RNA into proteins.
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This central dogma continues as proteins then can catalyze reactions that lead to other bio-oligomers that are going to be very important in this class. For example, we're going to see a class of bio-oligomers called terpenes that are used in used by plants and microorganisms for signaling,
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polyketides, a class of molecules that's very important as natural products for antibiotics and other pharmaceutical uses. And then oligosaccharides, the glycans that decorate the surfaces of your cells and play key roles in protein folding and key roles in cell-based signaling.
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OK. So, here's my plan for this quarter. We're going to have two lectures about each of the bio-oligomers that's depicted here. OK. So next week, I'll give you all talk two lectures about arrow pushing. The week three, we'll have two lectures about DNA. Week four, two lectures about RNA.
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Week five, two lectures about proteins. Week six, oligosaccharides. Week seven, polyketides. Eight is terpenes. Oh, actually, I'm sorry. I'll have four lectures total about proteins. I can't resist. I'm a protein guy. So, yeah, so I'll have a total of four lectures about proteins but everything else, we'll have two lectures about
45:01
and we'll be covering a chapter a week in the class. OK. So, necessarily, some of the material in the textbook will be left aside. OK. Everyone still with me so far? OK. So I told you that everything that's synthesized in the cell is synthesized in a deterministic way starting with the DNA up here.
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And it turns out that's not strictly, strictly true. And I want to explore a little bit more about what the subtleties of this concept. So, first of all, we need to define what is the unit of synthesis. So, proteins and DNA, sorry, DNA is read
45:42
out in units called genes, OK, where each gene is going to coat a single protein. Genes have two essential parts, an on-off switch and an express sequence. The on-off switch is where transcription factors bind. These are proteins that can encourage RNA polymerase to bind
46:03
to the start of this gene and encourage it to start transcription. OK. Similarly, there's other, if there's promoters, there's also other ways of shutting off the synthesis as well. It gets complicated. This transcribed region then becomes the messenger RNA
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which is then translated by the ribosome into the protein down here. OK. So here's an example for a transcription factor binding to DNA. Notice that the DNA has a structure that can nicely accommodate the structure of this protein.
46:40
I'm going to be talking a lot more about proteins later but I want to tell you about a convention that we're going to be using. OK. So proteins hopefully as you know are composed of amino acids that are strung together by amide bonds. OK. If what I told you totally doesn't make sense, we'd go back and read the reference supplemental organic chemistry text.
47:01
OK. So when we look at these amino acids and we just look at the amide bonds and the carbon that's alpha to that amide bond, we can trace out that backbone using these ribbon structures. So these ribbon structures do not look at the side chain
47:20
of the amino acid rather they simply trace out the sort of the scaffolding backbone of the protein. OK. So that's what these ribbon diagrams will look like. And then here's a structure of DNA down here. Notice that this alpha helical ribbon, this curly Q ribbon fits neatly into the DNA's major groove.
47:40
We'll talk much more about that later. OK. Let's take a look at the world's smallest gene. This is the Guinness Book of World Records for smallest gene. In this case, this gene encodes for microsyn C7 or the gene will, the protein it will encode for is called microsyn. Microsyn is a translation inhibitor.
48:03
It's a protein, it's, well, it's a peptide, a short piece of protein called the peptide that's used by microorganisms to kill off their neighbors. OK. So the microorganisms that grow on your skin, that grow in the, you know, far recesses of this,
48:20
of the walls, you know, that grow all around you are constantly fighting chemical warfare with each other. OK. Their goals are to kill off their neighbors and then give themselves more resources that allow them to grow better, OK, to grow faster and to be more populous. OK. And microsyn is a good example of one
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of those antibiotics or compounds that kill other organisms, OK. And this is actually a very complicated binary toxin. On the one hand, there's this peptide over here that allows the microsyn to be transported
49:00
into the competing bacteria. OK. So the bacteria look at this complicated thing, they sniff at the peptide region and think, oh, that peptide looks yummy. And if I eat that, I'll get amino acids as a source of building blocks for my own proteins, OK.
49:20
That's kind of like the bait, OK. So, the competitor picks up the bait, transports microsyn C7 into it, into itself and in which case enzymes in the competitor then break apart this peptide
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and then unveil the translation inhibitor down here that shuts down translation by the ribosome. This is very bad news for the competitor, right? If the competitor organism, microorganism cannot translate mRNA into proteins, it cannot live, it cannot divide.
50:01
It will die very quickly, OK. And so, in the end, what we're seeing is that the smallest gene is rather complex. Its toxic fragment is highlighted over here and the rest of it also plays a key role as well. OK. So, this to make something as complicated
50:22
as this requires a large number of genes that are lined up over here where each one of these arrows represents a sequence of DNA. OK. We'll talk more about the directionality of the arrows. Later, week three, for now, don't get too worked up about it, notice though that it takes several genes
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to compose this toxin, OK. So, some of these genes are doing things like adding on this non-peptide like toxic fragment, OK. So, some of these genes up here are encoding various enzymes, OK. So, that's this microsyn, this MCCB, MCCD, MCCE enzymes.
51:03
So, these enzymes are adding on stuff and modifying the peptide that was otherwise encoded by MCCC in the center over here, OK, or sorry, MCCA that was encoded up here. Now, at the end of this,
51:20
even though this is the world's smallest, you know, the smallest gene delivering a tiny little peptide, the result in peptide is still fiendishly complex, OK. This thing includes a large number of different stereocenters indicated by the dashes and the wedges. And furthermore, this isn't the half of it, right.
51:42
This is just a very simple example. The proteins we'll be talking about, the proteins I've been showing you today, for example, a transcription factor consists of hundreds of subunits, hundreds of amino acids, each one likely with its own stereocenter. And so, the chemical biology considerations become enormous
52:05
when we start looking at this in greater detail, OK. All right, so we've looked at a gene. Let's talk next about the collection of genes. All of the genes together that are found in an organism are referred to as a genome.
52:20
Here's one representation of the genome of the bacteria model system, bacteria called E. coli. We'll be talking a lot about E. coli. I'll have another slide about it in a moment. This is used extensively in chemical biology laboratories including mine. And its genome looks like this.
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We're in this representation, it's shown as a circle. And each one of these colored bars tells us something about the size of the gene, whether or not it's GC, whether it's GC richnesses, et cetera, OK. So, reading out the information here, not so important. Suffice it to say that the human genome has
53:02
around 24,000 or so genes. And when you compare that against almost any other machine that we have around us, this number sounds ridiculously small. One of the challenges however is even though we have this complete parts list for simple organisms like E. coli,
53:21
it's not clear what each one of these parts is doing. And so, a goal of functional genomics and a goal for that matter of chemical biology is to try to make better sense of these parts list, OK. And let me show you what I mean on the next slide. OK. Let's imagine that you had a transmission from a car, OK.
53:44
And imagine that you had parts list of all the different gears found in that transmission, OK. I can tell you from some experience that just staring at those different gears, even, you know, staring as hard as you possibly can and using your best, you know, sort of logical reasoning, you're going to have a really,
54:02
really hard time trying to put together each one of those little gears, OK. I don't care how smart you are. It's really a hard problem. And so, we have that same problem when we look at genomes. When we look at genomes, it's not clear what each one of these parts are doing. And one of the roles of chemical biology is
54:22
to help us annotate genomes and teach us about what each one of those parts is doing in terms of the larger machine. We'll talk some more about that. That will be a topic called functional genomics. OK. So, chemical biology helps us fill in the dynamics of the process and how these pieces fit together, OK.
54:42
So, one way that it fills in dynamics, dynamics means change over time is an important area of chemical biology develops new tools that allow us to see molecules at the single molecule level and understand how they change over time, how they dynamically interconverted to different speeds and things like that.
55:01
And Miriam is one of the world's experts at this. She can tell you more about this. Now, another big challenge that we have is that oftentimes we have big differences in genomes that lead to the same species. Here for example are three different strains of the model bacteria E. coli.
55:23
OK. So, here's three different strains and only 40 percent of proteins are shared between these three. Notice that they look identical. They're all the same species because they can mate, they can exchange DNA with each other which in terms
55:41
of bacteria turns out is not necessarily the same as being same species. But in any case, these are named, all named E. coli yet they have vast differences in what DNA they've picked up from their environment and from other microorganisms. So, simply knowing the parts list is not going to be enough
56:02
for us to explain what's similar and different between these organisms, OK? And for that matter, when we start looking at different, when we start looking at different organisms from the same population, we see a similar sort of diversity despite having very, very, very similar genomes.
56:21
OK. So, I've been talking to you both about humans and also bacteria. I need to hopefully just very briefly review for you that the differences in those organisms are vast, OK? I'm hopefully not telling you anything you don't already know.
56:41
Bacteria are classified as prokaryotes, humans and other multicelled organisms or organisms even that are single cell that have multiple compartments in them are classified as eukaryotes. I'd like you to or I'll tell you that in a moment. The big difference here is that the prokaryotes don't have any compartments
57:02
for the most part. The DNA is kind of organized into nucleolid but for the most part, there are no compartments inside of the cell of a prokaryote whereas when we look at eukaryotes under the microscope, we find something totally different. What we find is a bunch of organelles which are these little compartments in here, OK?
57:21
And these organelles have different functions for the cell rather than being just the big bag that has all of the functions being carried out kind of randomly within that bag. OK. Now, getting back to this idea of genomes, nearly identical genomes can lead to very different people.
57:41
So, even though our genomes are 99.9 percent identical, we see vast differences. So, this is a challenging concept but what's happening here is vast differences in transcription underlie these different phenotypes that are observed where phenotype is the physical outcome of the gene, OK?
58:01
So, all of us have roughly the same genomes yet the phenotypes that come out differ at the cellular level by different transcription levels that program our cells into having different functions. So, even though each one of these cells has the same genome, the cells end up having different functions
58:22
by having different transcription levels of different sections of the gene, different genes within the genome. And furthermore, at the organismal level, this plays out in other ways as well. OK? Also at the level of transcription. OK. So, here's six different human cells
58:41
and you can see vast differences in their morphologies, their shapes, et cetera. And for that matter, I don't think I have to work hard to convince you that these have very different functions inside the organism, in this case humans. OK. So, I showed you briefly a prokaryotic cell over here.
59:01
I'd like you to memorize all the structures, everything that's labeled here and labeled in the book, the textbook. OK. You should memorize those structures. And along the same lines, I'd like you to memorize all the parts that are labeled in the textbook for a eukaryotic cell. OK. So, you should know basically that the simple anatomy of a cell.
59:22
OK. The basic functions, if it's in the book, yeah, I'd like you to know. OK. So, we've looked at DNA. DNA gives us genes which gives us genomes. Next section down on the central dogma is RNA.
59:41
So, from RNA, the complete collection of RNA transcripts in a cell tissue organism is called the transcriptome. OK. So, here's the DNA, the genome of the organism. Here's a bunch of RNA transcripts. And the number of copies of each one of these transcripts,
01:00:00
is controlled by transcription factors that I showed you earlier, OK? That was the alpha helix fitting into the DNA. If that transcription factor is very effective at grabbing on to RNA polymerase, then you'll get more copies of the mRNA transcript being produced, OK?
01:00:20
So, these more copies of the transcript being produced can give rise to very different phenotypes of the organism. So, ultimately, a lot of the phenotypes that are observed are being driven by differences in transcription in addition to differences in the encoding DNA.
01:00:41
Everyone still with me? OK. Things are going to get a little bizarre next. It turns out that the RNA that's encoded by DNA is further diversified by a process called RNA splicing, OK? So, RNA splicing takes the RNA that's encoded by the DNA
01:01:03
and then sort of shuffles it around very subtly, OK? And the result are a bunch of different mRNAs encoding potentially different proteins down here, OK? And the results sometimes are dramatically differences in the result in proteins.
01:01:21
So, these proteins, the consequences of this can be proteins that have very different function from the starting mRNAs. So, you can end up with two different proteins splice variants of each other that are encoded by the same DNA that have different results inside the cell
01:01:40
in different phenotypes, OK? Now, there's going to be further diversity but just to organize things. So, we've seen at the DNA level, the collection of all genes is called the genome. We've seen at the RNA level, the collection of all RNA transcripts is called the transcriptome.
01:02:00
And then at the level of proteins, the collection of all proteins is called the proteome, OK? This is sort of a neat organization to all of this, OK? Now, what I'm showing you, I've already showed you this representation of the genome for E. coli. This is a way of representing the transcriptome using a
01:02:23
technique called RNA microarrays. We'll talk about this more in week four. And then you can do a similar thing, make a big collection of all the different proteins found in the cell or organism or tissue and array these on microscopic slides as well, OK? So, all these techniques are ones that we'll talk
01:02:42
about later in the class. OK. So, we've talked about how you can start with an RNA transcript. Oh, question over here. Yes.
01:03:01
OK. So, what is your name? Ashley. OK. So, Ashley's question is, what actually gets translated on the messenger RNA? And there's what? Yes. What actually gets translated into proteins from the messenger RNA?
01:03:22
OK. That's your question, right? No. Yes. So, we only keep the exons. The exons? So, I wonder if there are any introns in the mRNA, the final product. Oh, OK. So, your question is more subtle than that.
01:03:41
OK. So, could I defer that until we get to week four which is the RNA? Oh, OK. Yeah. OK. Good question. It will get an answer. Other questions? OK. So, we've seen how splicing can start with transcripts and then add additional diversity. It turns out that proteins are also subject
01:04:01
to diversification as well. So, after the proteins are synthesized by the ribosome during translation, these are subject to further diversity in a couple of different ways. OK. The first way is for the proteins to be modified chemically on their surface. And so, one example of this is an elongation factor 2.
01:04:26
So, this is post-translationally modified to produce this functionality up here called diphthamide. OK. So, the protein is enzymatically converted from having this imidazole functionality up here
01:04:44
into having a diphthamide functionality. This is absolutely required for translation by this organism, organism being humans. OK. So, elongation factor 2 that's been post-translationally modified is required for translation to take place.
01:05:03
However, the diphtheria toxin has a way of cleaving off this diphthamide. OK. When that happens, that prevents protein translation from taking place. OK. Diphtheria toxin, fascinating. It's an effective way of killing cells.
01:05:22
What's important here though is this notion that even after the proteins are synthesized, they're further diversified by chemical reactions that take place on their surface. Because this takes place after translation, these are referred to as post-translational modifications.
01:05:41
OK. Post meaning after, translation, modifications, translational modifications. And this is really important. This means that we can start with say 24,000 or so genes in the genome, get, you know, say 50,000 or 60,000 different splice variants,
01:06:02
get say 60,000 different proteins and then further diversify those 60,000 different proteins into 200 or even more thousand different proteins. So in the end, although our genomes look relatively on complex at the level of 24,000 or so different parts,
01:06:21
the true number, this vastly understates the true number of parts which is much, much larger due to reactions like this one. OK. Furthermore, these proteins go off and catalyze other functions within the cell leading to further diversity.
01:06:40
OK. Everyone still with me on the post-translational modification? Let me show you what I mean. I refer to this as post-translational processes. So, this is the process by which proteins catalyze as enzymes the production of other molecules, oligosaccharides,
01:07:01
glycans, polyketides and terpenes. OK. So, once the enzyme is made, it's just the start. After that, all kinds of other things take place, OK? And this is proteins can be covalently altered by enzymes. OK. That's the modified proteins
01:07:21
that I showed you on the previous slide. In addition, there are spontaneous processes that alter the surfaces of proteins. OK. So for example, oxidation of proteins is sort of an unavoidable consequence of having a metabolism that's dependent upon oxidation, right, and producing oxidation products.
01:07:41
So, there are some strong oxidants that are produced by your cells and those oxidants will come along and modify the surfaces of proteins spontaneously, OK, using thermodynamically accessible reactions. And so, these are examples of post-translational modifications. In addition, proteins themselves will catalyze reactions
01:08:04
that will synthesize these molecules down here, which again are part of the central dogma. They're bio-oligomers. Now, one thing I have to tell you is that while I told you that the central dogma in a deterministic way determines everything that's being
01:08:22
synthesized by the cell, while it determines everything synthesized by the cell, it's not purely deterministic, OK? And there's an element of randomness to all of this, OK? And that's what I want to show on the next slide, OK? This is, we're going to have randomness in the sense
01:08:41
that the central dogma will dictate the identity of enzymes and then these enzymes are going to go off and catalyze reactions that will not be determined by the DNA, that will be at some level a little bit randomized, OK? So, one good example of this is the process of appending oligosaccharides to the surfaces of proteins, OK?
01:09:05
So, R over here is meant to represent a protein and each one of these shapes is meant to represent a different carbohydrate glycan that's being, that's going to be attached to the surface of the protein, OK? Now, the way this works is that each one
01:09:23
of the enzymes that's going to do this attachment is encoded by some gene up here, encoded by the DNA, translated, transcribed into messenger RNA which in turn makes the protein, the enzyme that's going to catalyze bond formation to add this glycan
01:09:41
onto the oligosaccharide, OK? What's less clear though is, you know, small variations in the resulting glycans down here. So, for example, enzyme 2 makes this bond. If there's enough enzyme 2 around, maybe it makes another bond.
01:10:01
Enzyme 11 makes this bond but maybe if there's enough enzyme 11 around, maybe it makes another bond over here. So, there's diversity in the resultant structures that are biosynthesized by the enzymes, OK? Furthermore, even though I'm lining up the enzymes
01:10:20
in this order, the order of the genes in the genome is unrelated to the final product that results in this glycan on the surface of the protein which eventually appears on the surface of the cell. So, there is considerable heterogeneity in these post-translational processes both in terms
01:10:41
of modifications in the sense that some of these modifications are occurring spontaneously just through thermodynamically accessible reactions. And furthermore, when these post-translational processes are catalyzed by enzymes, there is considerable stochasm,
01:11:03
randomness in terms of what the resultant structures will be, OK? So, this is one of these kind of mind-blowing concepts that we have to get comfortable with, OK, that we can't in a deterministic way know every single molecule in the cell to a precise level, OK? Everyone comfortable with that concept?
01:11:22
OK. Don't look so mopey-eyed and downcast. At the end of this class, hopefully, you'll at least have a framework to understand it, OK? OK. So, I want to switch gears now and talk about some other principles, different types of techniques that you need to know that are going to make our lives
01:11:43
so much easier in understanding the experiments behind chemical biology. OK. So, earlier, I told you that an important principle in chemical biology or an important technique used extensively in chemical biology is to make large diversity, a large diversity of molecules
01:12:04
and then sift through this diversity to find a few molecules that do something special, OK? This is a technique of molecular evolution. It's used extensively in chemical biology. So, there's going to be one equation in today's lecture that I need you to know and this is the equation
01:12:21
that determines the diversity of a collection of molecules. That diversity, the number of oligomers that results is the number of subunits raised to the power of the length of the oligomer, OK? And let me try to show you this in action. OK. So, let me turn on some lights here.
01:12:48
OK. So, let's start with DNA. Let's make a big collection of DNA. So, DNA consists of four bases, OK, A, C, G, and T. Again,
01:13:01
we'll talk some more about their chemical structure in a moment. Let's try to imagine then that we're going to make a collection of all possible tetramers, OK? OK. So, number of possible DNA.
01:13:22
Oh, let's make it pentamers, OK? OK. So, the number of possible pentamers is going to be equal to the number of subunits raised to the length
01:13:46
of the bioeligomer, OK? So, this is the number of subunits is four, that's the number of bases, the raised to the power of five, that's because we're making pentamers, OK?
01:14:02
If we wanted to make, OK, so this is example of fivemers, if we wanted to do 10mers, again, we'd have four raised to the 10th power, OK? OK. So, this is a very simple equation, very, very useful. It can tell you very rapidly whether or not the experiment you've proposed is reasonable, right?
01:14:24
If you propose something that's going to fill this room with DNA, probably not so reasonable, right? That's not practical. But if you propose something that you could fit in say a one mil test tube, totally reasonable or one mil tube, epiNORF tube, that would work, right?
01:14:42
OK. Any questions about this formula? You ready to apply it? OK. Good. OK. One of the great failings of teaching a class like this one is that the example problems that I'll do for you where we apply an equation or whatever inevitably are a lot easier than the ones that appear on the exam. And I apologize about that.
01:15:01
That's kind of, that's part of pedagogy, I guess. OK. Now, it turns out that chemical biologists apply this to DNA but they also apply it to much more complicated molecules. So, for example, we can do a combinatorial synthesis
01:15:22
of a series of molecules that look like this, OK? So we can do, we can set up a modular architecture to allow combinatorial synthesis that in a way similar to composing bioligomers will result in molecules
01:15:41
that have modules that have been tethered together, OK? So, for example, this is a framework called a peptoid, OK? And so instead of a peptide where the peptide would have a side chain coming
01:16:01
out on the alpha carbon over here, instead this has side chains coming out on the nitrogens, you can very readily make a large combinatorial library of these peptoids and make a great diversity of number of structures using exactly the same formula that I showed on the previous slide to calculate the result
01:16:20
in diversity, OK? And let me show you how that would work. If you have 20 subunits, so you have 20 different possible building blocks and you're going to make three MERS, then you would have 20 to the 3, the power of 3, 20 raised to the third power would be the result in diversity of that library, OK?
01:16:41
Where a library is a collection of diverse molecules, OK? So, this idea of combinatorial diversity applies both at the level of shuffling around bioligomers and is applied in biology. But equally importantly, it's used as a principle that underlies chemical synthesis in chemical biology
01:17:02
as well including the chemical synthesis that you learned about back in 51C, OK? And we can get much more complicated and make libraries of benzodiazepines which are shown here and this is an important class of small molecules that's very commonly used in many different drugs. OK, why don't we stop here.
01:17:20
When we come back next time, we'll be talking about diversity in biology.
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