| [{"text": "The following\ncontent is provided", "start": 0.61, "duration": 1.83}, {"text": "by MIT OpenCourseWare under\na Creative Commons license.", "start": 2.44, "duration": 3.9}, {"text": "Additional information about our\nlicense and MIT OpenCourseWare,", "start": 6.34, "duration": 3.78}, {"text": "in general, is available\nat OCW.MIT.edu.", "start": 10.12, "duration": 2.61}, {"text": "GEORGE CHURCH: OK,\nso welcome tonight,", "start": 22.51, "duration": 3.36}, {"text": "a very special lecture for\nme tonight in more ways", "start": 25.87, "duration": 4.18}, {"text": "than I can express.", "start": 30.05, "duration": 1.49}, {"text": "This is the last of my\nlectures, but I look forward", "start": 31.54, "duration": 2.22}, {"text": "to your lectures coming up.", "start": 33.76, "duration": 2.73}, {"text": "I really do.", "start": 36.49, "duration": 0.7}, {"text": "I've heard from the\nTFs, and from what", "start": 37.19, "duration": 1.82}, {"text": "I've seen from talking\nto many of you,", "start": 39.01, "duration": 2.14}, {"text": "this is going to be a really\namazing set of projects", "start": 41.15, "duration": 3.38}, {"text": "this year, more\nthan any other year.", "start": 44.53, "duration": 3.06}, {"text": "Anyway, last week, we asked what\ncan biology do for computing?", "start": 47.59, "duration": 7.77}, {"text": "And this week is going to be\na little less nuts and bolts", "start": 55.36, "duration": 3.93}, {"text": "than usual.", "start": 59.29, "duration": 0.69}, {"text": "The entire course--\nas you all understand,", "start": 59.98, "duration": 1.89}, {"text": "you're all self-selected\nto life survey", "start": 61.87, "duration": 2.399}, {"text": "courses, at least this one,\nbecause you're still here.", "start": 64.269, "duration": 3.781}, {"text": "And tonight's going to be more\nof a survey than ever before,", "start": 68.05, "duration": 3.856}, {"text": "and it's going to be talking\nabout topics for which we don't", "start": 71.906, "duration": 2.954}, {"text": "have answers for the most part.", "start": 74.86, "duration": 4.59}, {"text": "There'll be some interesting\ndetails along the way.", "start": 79.45, "duration": 3.63}, {"text": "But anyway, instead of what\nbiology can do for computing,", "start": 83.08, "duration": 3.96}, {"text": "this is more about what\nbiology and computing can", "start": 87.04, "duration": 2.52}, {"text": "do for the world.", "start": 89.56, "duration": 1.11}, {"text": "That's really what\nwe want to do,", "start": 90.67, "duration": 2.13}, {"text": "and also, the\nhigher level network", "start": 92.8, "duration": 2.61}, {"text": "models that we can build since\nthis is network number three.", "start": 95.41, "duration": 3.84}, {"text": "So we'll start out--", "start": 99.25, "duration": 1.46}, {"text": "we've been talking mainly about\ncellular models as our highest", "start": 100.71, "duration": 3.73}, {"text": "level of networking,\nand so we'll", "start": 104.44, "duration": 1.5}, {"text": "talk about multicellular\nmodels, in particular,", "start": 105.94, "duration": 3.22}, {"text": "the sort of multicellular\nmodels that you get that involve", "start": 109.16, "duration": 3.02}, {"text": "sensory integration and\nintegration of higher levels,", "start": 112.18, "duration": 6.93}, {"text": "and then all the way up to\nmulti-organ systems, where", "start": 119.11, "duration": 4.11}, {"text": "we'll take an example\nfrom the atomic scale,", "start": 123.22, "duration": 3.9}, {"text": "all the way up to\norgan system failure.", "start": 127.12, "duration": 4.77}, {"text": "And then we'll go from there.", "start": 131.89, "duration": 2.85}, {"text": "So let's start with\nmulticellular models.", "start": 134.74, "duration": 2.76}, {"text": "And this is something that I--", "start": 137.5, "duration": 4.38}, {"text": "I'll show you a few slides\nthat will remind you", "start": 141.88, "duration": 2.43}, {"text": "of the first lecture.", "start": 144.31, "duration": 1.282}, {"text": "They either were taken\nfrom the first lecture--", "start": 145.592, "duration": 1.958}, {"text": "in this case, this is a wildly\ndifferent author, and approach,", "start": 147.55, "duration": 3.43}, {"text": "and so forth, but\nit's the same lesson", "start": 150.98, "duration": 1.982}, {"text": "as from the first\nlecture, which is", "start": 152.962, "duration": 1.458}, {"text": "we not only have these\nexponential curves going", "start": 154.42, "duration": 2.19}, {"text": "through the 1900s, but\nthey're super exponential.", "start": 156.61, "duration": 2.19}, {"text": "They go up, and the\ntrend lines you get", "start": 158.8, "duration": 1.68}, {"text": "depend on which set of points\nyou use, the steepest one being", "start": 160.48, "duration": 3.21}, {"text": "the most recent one, 1995.", "start": 163.69, "duration": 2.31}, {"text": "And this basically\nis part of when", "start": 166.0, "duration": 1.74}, {"text": "it is that we will\nhave computing power", "start": 167.74, "duration": 2.85}, {"text": "that might be on the order of\nan integrated human neural net.", "start": 170.59, "duration": 5.67}, {"text": "We talked about neural nets\nlast time as a metaphor,", "start": 176.26, "duration": 2.76}, {"text": "or as an algorithm,\nbut when will", "start": 179.02, "duration": 3.24}, {"text": "we actually have a\ncomputer that has", "start": 182.26, "duration": 3.27}, {"text": "the capability of the\nhuman cerebral cortex,", "start": 185.53, "duration": 5.4}, {"text": "or entire integrated\nnervous system?", "start": 190.93, "duration": 2.19}, {"text": "And the basis of\nthose calculations", "start": 193.12, "duration": 2.4}, {"text": "that Moravec made,\nand in lecture one", "start": 195.52, "duration": 3.96}, {"text": "Kurzweil was the\nsuper exponential", "start": 199.48, "duration": 2.55}, {"text": "curve that I showed.", "start": 202.03, "duration": 1.35}, {"text": "Moravec made them\nbased on his studies", "start": 203.38, "duration": 3.33}, {"text": "on how the retina works.", "start": 206.71, "duration": 2.83}, {"text": "And I think those\nof you who have", "start": 209.54, "duration": 4.16}, {"text": "done a lot of\ncomputer programming,", "start": 213.7, "duration": 2.82}, {"text": "that understanding\nhow the retina works", "start": 216.52, "duration": 4.23}, {"text": "is probably one of\nthe more intuitive", "start": 220.75, "duration": 2.13}, {"text": "of our various human senses, in\nthe sense that you can program", "start": 222.88, "duration": 5.19}, {"text": "an algorithm that might do in\nthe lower right of slide four", "start": 228.07, "duration": 3.85}, {"text": "here, edge or motion detection.", "start": 231.92, "duration": 2.45}, {"text": "When a frog sees a fly, black\nand white, high contrast,", "start": 234.37, "duration": 4.77}, {"text": "zoom across its visual\nfield, something goes off.", "start": 239.14, "duration": 4.2}, {"text": "And you could write an\nalgorithm that could do that,", "start": 243.34, "duration": 2.49}, {"text": "given a few frames\nof any kind of form.", "start": 245.83, "duration": 4.3}, {"text": "So anyway, but there's been\nliterature on the subject.", "start": 250.13, "duration": 3.75}, {"text": "And when you go through even\nthe best algorithms right now", "start": 253.88, "duration": 3.11}, {"text": "for doing these\nkind of calculations", "start": 256.99, "duration": 2.43}, {"text": "and you figure out how\nlong it takes to do--", "start": 259.42, "duration": 5.04}, {"text": "the retina is doing about 10\nmillion detections per second.", "start": 264.46, "duration": 4.62}, {"text": "And then you scale up from\nthat 0.02 gram chunk of retina", "start": 269.08, "duration": 5.94}, {"text": "up to the 1,500\ngram human brain,", "start": 275.02, "duration": 4.05}, {"text": "then you get the extrapolation\nthat was in the previous slide.", "start": 279.07, "duration": 3.61}, {"text": "I think this is interesting\nboth as an introduction", "start": 282.68, "duration": 2.283}, {"text": "to the kind of algorithms we'd\nlike to think about when we", "start": 284.963, "duration": 2.417}, {"text": "think about integrating\na multicellular system,", "start": 287.38, "duration": 3.57}, {"text": "but also in terms of\nwhere the compute power", "start": 290.95, "duration": 4.5}, {"text": "both biological and\ncomputational is going.", "start": 295.45, "duration": 3.06}, {"text": "Do we want to engineer\nbiological systems", "start": 298.51, "duration": 3.99}, {"text": "to keep up with these silicon\nor whatever other computational", "start": 302.5, "duration": 4.77}, {"text": "system we're using a\ndecade or so from now.", "start": 307.27, "duration": 5.77}, {"text": "Now, so I said that\nthe visual system", "start": 313.04, "duration": 4.25}, {"text": "is a relatively intuitive\ncomputational system", "start": 317.29, "duration": 2.94}, {"text": "to program.", "start": 320.23, "duration": 1.36}, {"text": "In contrast, I would say\nthe olfactory system is less", "start": 321.59, "duration": 3.78}, {"text": "intuitive, at least for me.", "start": 325.37, "duration": 2.61}, {"text": "We know now quite a bit\nabout the molecular biology", "start": 327.98, "duration": 3.36}, {"text": "of the system.", "start": 331.34, "duration": 0.6}, {"text": "There are 1,000 receptors.", "start": 331.94, "duration": 1.47}, {"text": "It's probably one of the largest\nclasses of genomic repeated", "start": 333.41, "duration": 5.04}, {"text": "proteins.", "start": 338.45, "duration": 1.71}, {"text": "And these receptors\nare in the same family", "start": 340.16, "duration": 2.94}, {"text": "as the receptors that are\nthe major class of drug", "start": 343.1, "duration": 2.7}, {"text": "receptors, the G protein\ncoupled receptors.", "start": 345.8, "duration": 3.57}, {"text": "And there is\nbasically one receptor", "start": 349.37, "duration": 2.73}, {"text": "per cell, which is\nquite a trick, right?", "start": 352.1, "duration": 1.98}, {"text": "Because you got one receptor\nfrom mom and one from dad.", "start": 354.08, "duration": 2.88}, {"text": "And you've got\nthousands of receptors.", "start": 356.96, "duration": 2.28}, {"text": "But there's basically\none per cell.", "start": 359.24, "duration": 3.3}, {"text": "And they detect olfactory\nmolecule concentrations", "start": 362.54, "duration": 7.8}, {"text": "over about seven logs, where\nthey can detect a concentration", "start": 370.34, "duration": 11.16}, {"text": "threshold with a particular\nstandard deviation.", "start": 381.5, "duration": 4.74}, {"text": "Now this is the\nbeginnings of the model,", "start": 386.24, "duration": 1.8}, {"text": "just stating the fact\nthat you know about it.", "start": 388.04, "duration": 2.61}, {"text": "When you look at the\nneuroanatomy, you've got this--", "start": 390.65, "duration": 4.575}, {"text": "the odorant molecules\ndown at the very bottom", "start": 395.225, "duration": 1.875}, {"text": "of this figure, cilia\nolfactory neurons, which is", "start": 397.1, "duration": 4.8}, {"text": "a primary signal transduction.", "start": 401.9, "duration": 2.73}, {"text": "This thing goes up where it's\nintegrated in the glomeruli.", "start": 404.63, "duration": 4.11}, {"text": "And you can think of\nthis like the neural nets", "start": 408.74, "duration": 2.24}, {"text": "that we're talking\nabout last time, where", "start": 410.98, "duration": 1.708}, {"text": "you had these interneurons.", "start": 412.688, "duration": 1.512}, {"text": "You had the extra layer that\nwe showed was so important.", "start": 414.2, "duration": 7.08}, {"text": "And the thing that's\namazing about this system", "start": 421.28, "duration": 2.07}, {"text": "are lodged in these\nfour basic olfactory", "start": 423.35, "duration": 5.94}, {"text": "facts, which I take from\nHopfield's work, which", "start": 429.29, "duration": 3.81}, {"text": "is really just like this is the\nsame Hopfield that introduced", "start": 433.1, "duration": 3.63}, {"text": "us to or really championed\nthe concept of neural nets", "start": 436.73, "duration": 3.81}, {"text": "as a computational\nalgorithmic metaphor.", "start": 440.54, "duration": 3.36}, {"text": "And here, the idea is you have\nodor and memory recognition.", "start": 443.9, "duration": 6.51}, {"text": "You have background\nelimination, just", "start": 450.41, "duration": 2.7}, {"text": "like how your eyes adapt\nto a mostly red room,", "start": 453.11, "duration": 5.43}, {"text": "your nose is great, or\nwhole olfactory system", "start": 458.54, "duration": 3.87}, {"text": "is great at adapting\nto background odorants.", "start": 462.41, "duration": 4.8}, {"text": "So you have one known and\none unknown thoroughly mixed.", "start": 467.21, "duration": 4.62}, {"text": "Number three, you can\nhave component separation.", "start": 471.83, "duration": 2.73}, {"text": "You can have a few\ndifferent odors at once.", "start": 474.56, "duration": 3.12}, {"text": "You have odor separation\nwhere you have unknowns.", "start": 477.68, "duration": 5.535}, {"text": "I mean, the combination of\nthese is quite remarkable.", "start": 486.53, "duration": 4.24}, {"text": "So the basis of the model that\nHopfield has proposed is this.", "start": 490.77, "duration": 7.82}, {"text": "You have a coverage for\neach of the i receptors,", "start": 498.59, "duration": 4.38}, {"text": "where i goes from 1 to 1,000.", "start": 502.97, "duration": 2.1}, {"text": "This will vary depending\non the organism.", "start": 505.07, "duration": 2.01}, {"text": "Mice have twice as many as\nwe do, probably, and so on.", "start": 507.08, "duration": 3.31}, {"text": "But the coverage of\neach of those receptors", "start": 510.39, "duration": 6.14}, {"text": "is equal to the minimum\ncoverage for the concentration", "start": 516.53, "duration": 8.52}, {"text": "of the target, where let's\nsay the target is the target", "start": 525.05, "duration": 2.49}, {"text": "odorant that you're looking for\nover the concentration that's", "start": 527.54, "duration": 4.47}, {"text": "the threshold for firing\nthat neuron for that target,", "start": 532.01, "duration": 3.87}, {"text": "threshold of t.", "start": 535.88, "duration": 1.62}, {"text": "And you multiply that times\neither one or some fraction.", "start": 537.5, "duration": 3.72}, {"text": "It's 1 if you really\nhit the target.", "start": 541.22, "duration": 3.93}, {"text": "And it's this fraction for\nthat particular receptor", "start": 545.15, "duration": 4.47}, {"text": "and that particular target.", "start": 549.62, "duration": 1.53}, {"text": "You've got some crosstalk.", "start": 551.15, "duration": 1.47}, {"text": "And the amount of\ncrosstalk you can", "start": 552.62, "duration": 2.64}, {"text": "think of this as a field\nof receptors, which", "start": 555.26, "duration": 5.77}, {"text": "all have variable binding.", "start": 561.03, "duration": 2.06}, {"text": "And that binding is over\nthe six or seven logs here.", "start": 563.09, "duration": 4.12}, {"text": "And this just reflects\nthat same thing", "start": 567.21, "duration": 1.925}, {"text": "that we were talking about.", "start": 569.135, "duration": 1.125}, {"text": "So the total number\nof inputs going", "start": 572.96, "duration": 4.26}, {"text": "to the next layer in the\nneural net, the coverage here,", "start": 577.22, "duration": 2.97}, {"text": "is the sum of this target signal\nplus the background signal.", "start": 580.19, "duration": 7.33}, {"text": "So the first term is target.", "start": 587.52, "duration": 1.25}, {"text": "And the right hand\nterm is the background.", "start": 588.77, "duration": 1.99}, {"text": "And so you can see they have the\nsame form, the same threshold,", "start": 590.76, "duration": 2.96}, {"text": "and concentration. c sub b is\nconcentration of background.", "start": 593.72, "duration": 3.705}, {"text": "Now, so let's see\nhow this plays out", "start": 603.63, "duration": 3.66}, {"text": "when you actually try this\nout in an olfactory processing", "start": 607.29, "duration": 6.51}, {"text": "problem.", "start": 613.8, "duration": 0.66}, {"text": "Here you have an odor space.", "start": 614.46, "duration": 3.03}, {"text": "And what you have here\nis 80 different neurons", "start": 617.49, "duration": 5.67}, {"text": "is the y-axis at the\ntop of slide seven.", "start": 623.16, "duration": 3.63}, {"text": "And then across the x-axis\nis time in milliseconds going", "start": 626.79, "duration": 6.93}, {"text": "from 0 to 800 milliseconds.", "start": 633.72, "duration": 1.65}, {"text": "And this is all modeled on\nfairly realistic parameters", "start": 635.37, "duration": 5.67}, {"text": "based on experiments.", "start": 641.04, "duration": 2.7}, {"text": "And so what you have here\nis 80 adapting neurons.", "start": 643.74, "duration": 2.85}, {"text": "And what you're doing is\ntwo sniffs of a mixed odor.", "start": 646.59, "duration": 2.67}, {"text": "That's what this\nis modeling, OK?", "start": 649.26, "duration": 3.66}, {"text": "First, you have a 100 to 500\nmilliseconds, the range from--", "start": 652.92, "duration": 6.57}, {"text": "so you can see that something's\nhappening at 100 milliseconds.", "start": 659.49, "duration": 3.33}, {"text": "And up to 500 you\nhave a mixed odor,", "start": 662.82, "duration": 2.34}, {"text": "which is 50 parts of x\nplus 1,000 parts of y,", "start": 665.16, "duration": 4.17}, {"text": "or 1,000 times y.", "start": 669.33, "duration": 5.22}, {"text": "And then 500 milliseconds\nyou change this ratio very", "start": 674.55, "duration": 3.63}, {"text": "slightly, you see?", "start": 678.18, "duration": 0.96}, {"text": "You just up x by 75 and\ny up from 1,000 to 1,100.", "start": 679.14, "duration": 8.21}, {"text": "OK, so that's the paradigm,\n50 and 1,000 to 75 and 1,100.", "start": 687.35, "duration": 6.06}, {"text": "And the sniff at 100\nmilliseconds, that first one,", "start": 693.41, "duration": 3.93}, {"text": "that mixed odorant, it activates\nmore than half the neurons.", "start": 697.34, "duration": 5.35}, {"text": "So this is not like\nyour retina, where", "start": 702.69, "duration": 2.48}, {"text": "if you have a\nsingle point source", "start": 705.17, "duration": 2.01}, {"text": "it will activate that one\nbroad cell, or maybe a center", "start": 707.18, "duration": 4.89}, {"text": "surround effect.", "start": 712.07, "duration": 2.31}, {"text": "But it's really activating\nhalf of the neurons, OK?", "start": 714.38, "duration": 3.45}, {"text": "And then the changed sniff at\n500 milliseconds-- remember,", "start": 717.83, "duration": 3.09}, {"text": "just these two small changes--", "start": 720.92, "duration": 2.07}, {"text": "is almost invisible, right?", "start": 722.99, "duration": 3.36}, {"text": "So that's what you're\nseeing right here,", "start": 726.35, "duration": 5.37}, {"text": "OK, is this huge,\nswamping amount.", "start": 731.72, "duration": 4.68}, {"text": "But then in B-- so that's\nwhat happened in A. B,", "start": 736.4, "duration": 5.55}, {"text": "you've now plotting instead\nof individual neurons,", "start": 741.95, "duration": 4.71}, {"text": "you're doing the instantaneous\nrate in hertz, OK?", "start": 746.66, "duration": 3.81}, {"text": "And now, you can see\nthe second sniff here", "start": 750.47, "duration": 7.74}, {"text": "at the 500 milliseconds,\nwhich even though you really", "start": 758.21, "duration": 2.85}, {"text": "can't see it in the\ncorresponding point", "start": 761.06, "duration": 1.782}, {"text": "where you're looking at all\nthese individual neurons.", "start": 762.842, "duration": 2.208}, {"text": "And so you can see that\neven a 20% spread in one", "start": 765.05, "duration": 6.27}, {"text": "of these parameters is enough\nto get this kind of easily", "start": 771.32, "duration": 5.55}, {"text": "detectable signal.", "start": 776.87, "duration": 2.4}, {"text": "Now, that's an example\nof a simulation.", "start": 779.27, "duration": 2.46}, {"text": "That's not a simulation of\na particular experimental", "start": 781.73, "duration": 3.12}, {"text": "dataset, but it's based\non experimental datasets.", "start": 784.85, "duration": 3.06}, {"text": "And the code, this\nis not Mathematica,", "start": 787.91, "duration": 1.92}, {"text": "this is Matlab,\nwhich we all wish", "start": 789.83, "duration": 2.22}, {"text": "we could have interchangeably\ntaught in this course.", "start": 792.05, "duration": 2.88}, {"text": "And you can see here in\ngreen are the comments.", "start": 794.93, "duration": 2.28}, {"text": "And you can see\nsome of the things", "start": 797.21, "duration": 1.47}, {"text": "that we've been\ntalking about here.", "start": 798.68, "duration": 1.458}, {"text": "The number of receptor\ntypes is actually", "start": 803.673, "duration": 1.667}, {"text": "here 2,000 instead of 1,000.", "start": 805.34, "duration": 2.04}, {"text": "You see the target,\nremember, I said", "start": 807.38, "duration": 2.34}, {"text": "could be some random number\nthat goes over six logarithms.", "start": 809.72, "duration": 3.995}, {"text": "Well, the way\nthat's done here is", "start": 813.715, "duration": 1.375}, {"text": "here's a random number\ngenerated and you generate", "start": 815.09, "duration": 4.628}, {"text": "as the log of the target.", "start": 819.718, "duration": 1.042}, {"text": "And then, you get the target\nby taking the exponential.", "start": 820.76, "duration": 2.292}, {"text": "It's very straightforward and\nthe code goes on from there.", "start": 823.052, "duration": 4.828}, {"text": "OK, now this brings us to\na very interesting point.", "start": 827.88, "duration": 4.88}, {"text": "Since these three\nlectures on networks,", "start": 832.76, "duration": 2.622}, {"text": "and in a certain sense,\nthe whole course,", "start": 835.382, "duration": 1.708}, {"text": "is building towards systems\nbiology network models.", "start": 837.09, "duration": 4.16}, {"text": "And for these\nmodels to be useful,", "start": 841.25, "duration": 1.92}, {"text": "in the same sense that\nthe models we have", "start": 843.17, "duration": 1.832}, {"text": "for X-ray crystallography,\nand the models", "start": 845.002, "duration": 1.708}, {"text": "we've had for genome\ninterpretation in terms", "start": 846.71, "duration": 2.61}, {"text": "of homology, and\nsequence folding,", "start": 849.32, "duration": 3.42}, {"text": "and so forth needed\nto be shared.", "start": 852.74, "duration": 3.72}, {"text": "The models, even\nmore than the data,", "start": 856.46, "duration": 1.95}, {"text": "need to be shareable\nbecause in a certain sense,", "start": 858.41, "duration": 4.23}, {"text": "even modest\nmanipulation of the data", "start": 862.64, "duration": 2.94}, {"text": "usually involves some\ngood model behind it.", "start": 865.58, "duration": 2.323}, {"text": "And so these are some\nof the work groups", "start": 867.903, "duration": 1.667}, {"text": "that are working on\ndifferent modeling schemes.", "start": 869.57, "duration": 3.27}, {"text": "In particular, I\nshould point out", "start": 872.84, "duration": 2.535}, {"text": "that BioSpice is\nnow DARPA BioSpice,", "start": 875.375, "duration": 3.195}, {"text": "and SBML is kind of a\ngrowing part of that.", "start": 878.57, "duration": 3.0}, {"text": "System Biology Markup Language\nis a way of sharing this data.", "start": 881.57, "duration": 3.66}, {"text": "And as yet, there's not\nthe kind of convention", "start": 885.23, "duration": 3.6}, {"text": "that we have in\ncrystallography and DNA", "start": 888.83, "duration": 3.24}, {"text": "sequencing where you submit--", "start": 892.07, "duration": 1.818}, {"text": "at the time that\nyou publish a paper,", "start": 893.888, "duration": 1.542}, {"text": "you submit your data\nand model, data/model,", "start": 895.43, "duration": 4.41}, {"text": "with an accession number\nto the database or else", "start": 899.84, "duration": 2.58}, {"text": "you don't get it published.", "start": 902.42, "duration": 1.14}, {"text": "We're nowhere near that now\nfor the rest of biology.", "start": 903.56, "duration": 2.43}, {"text": "But these kind of\nefforts, probably,", "start": 905.99, "duration": 2.22}, {"text": "are moving in that direction.", "start": 908.21, "duration": 1.27}, {"text": "And you can see that the\nfeatures of each of these", "start": 909.48, "duration": 3.115}, {"text": "are some of the\nthings that we've", "start": 912.595, "duration": 1.375}, {"text": "been talking about before.", "start": 913.97, "duration": 1.083}, {"text": "You've got stochastic\nmodeling, kinetic modeling,", "start": 915.053, "duration": 3.927}, {"text": "enzyme receptor cell geometry,\nneural nets, and so on.", "start": 918.98, "duration": 11.37}, {"text": "This is by no means\ncomprehensive.", "start": 930.35, "duration": 1.96}, {"text": "And there are hypertext\nlinks here if you really", "start": 932.31, "duration": 2.0}, {"text": "want to dig into them.", "start": 934.31, "duration": 1.38}, {"text": "And some of the\nplatforms that they've", "start": 935.69, "duration": 1.83}, {"text": "been thinking about different\nways of making it slightly less", "start": 937.52, "duration": 4.74}, {"text": "system-dependent.", "start": 942.26, "duration": 1.17}, {"text": "Everyone has their attempts.", "start": 943.43, "duration": 2.1}, {"text": "Obviously, Windows is\nnot system-independent.", "start": 945.53, "duration": 4.89}, {"text": "So that's two very\nbrief examples", "start": 950.42, "duration": 3.0}, {"text": "of multicellular models, both\nof them being neural models", "start": 953.42, "duration": 5.55}, {"text": "kind of building from what we\nwere thinking about last time.", "start": 958.97, "duration": 2.67}, {"text": "But now we're going to a\ncompletely different kind", "start": 961.64, "duration": 2.22}, {"text": "of multicellular model, all the\nway up from individual effects", "start": 963.86, "duration": 5.19}, {"text": "that a single nucleotide-- how\nmuch effect a single nucleotide", "start": 969.05, "duration": 3.45}, {"text": "can have on a whole organ\nsystem, which in this case", "start": 972.5, "duration": 3.48}, {"text": "will be cardiovascular.", "start": 975.98, "duration": 1.96}, {"text": "So we go from--.", "start": 977.94, "duration": 2.33}, {"text": "And there are a number of\nphysiome and cardiome projects", "start": 980.27, "duration": 5.79}, {"text": "that are of active interest.", "start": 986.06, "duration": 2.77}, {"text": "Just like the\nprevious slides that I", "start": 992.44, "duration": 1.95}, {"text": "showed showing all the ways\nof sharing system models,", "start": 994.39, "duration": 2.94}, {"text": "many of these efforts are kind\nof loose consortium alliances", "start": 997.33, "duration": 6.12}, {"text": "where people have put together\ndifferent models either to deal", "start": 1003.45, "duration": 4.44}, {"text": "with the anatomy,\nphysiology, or sometimes,", "start": 1007.89, "duration": 4.98}, {"text": "a integration of molecular to\ncellular, cellular to, say,", "start": 1012.87, "duration": 7.71}, {"text": "neural or muscular, and all\nthe way up to fluid dynamics", "start": 1020.58, "duration": 4.71}, {"text": "and so on.", "start": 1025.29, "duration": 3.069}, {"text": "So let's start with a\nsingle base-pair change.", "start": 1028.359, "duration": 3.951}, {"text": "And I start with\nthis one because you", "start": 1032.31, "duration": 2.683}, {"text": "should feel comfortable\nwith it at this point.", "start": 1034.993, "duration": 1.917}, {"text": "We mentioned it briefly before.", "start": 1036.91, "duration": 3.05}, {"text": "We'll talk about it\nin more detail now.", "start": 1039.96, "duration": 2.04}, {"text": "This is the single\nnucleotide polymorphism,", "start": 1042.0, "duration": 2.589}, {"text": "which causes the change of the\nbeta subunit of hemoglobin,", "start": 1044.589, "duration": 5.751}, {"text": "which is a tetramer,\nto go from a glutamate,", "start": 1050.34, "duration": 6.69}, {"text": "normally, in most people at\nposition six of the beta chain,", "start": 1057.03, "duration": 3.42}, {"text": "to a valine.", "start": 1060.45, "duration": 2.52}, {"text": "So that's the purple\nset of tetramers.", "start": 1062.97, "duration": 3.21}, {"text": "Or to tryptophan, and that's\nthe cyan set on the far right.", "start": 1066.18, "duration": 5.22}, {"text": "And this, from combinations\nof X-ray crystallography", "start": 1071.4, "duration": 8.27}, {"text": "and three-dimensional\nmodeling, and this", "start": 1079.67, "duration": 2.19}, {"text": "is not speculation, just based\non primary sequence data,", "start": 1081.86, "duration": 3.09}, {"text": "even though the primary sequence\nhere is very, very close,", "start": 1084.95, "duration": 3.12}, {"text": "just a single nucleotide and\na single amino acid change.", "start": 1088.07, "duration": 4.33}, {"text": "Nevertheless, these\nauthors have been", "start": 1092.4, "duration": 2.21}, {"text": "building this from the\ncrystallographic data", "start": 1094.61, "duration": 4.23}, {"text": "where not only do you care\nabout the tetramer itself,", "start": 1098.84, "duration": 3.36}, {"text": "but how the tetramers\ninteract with one another", "start": 1102.2, "duration": 2.61}, {"text": "to make these long, fibrous\nchains, which are considerably", "start": 1104.81, "duration": 3.69}, {"text": "more stable in the sickle cell.", "start": 1108.5, "duration": 2.82}, {"text": "And what you see here is sort\nof the valine substitution", "start": 1111.32, "duration": 7.86}, {"text": "is locked in one\nkind of conformation", "start": 1119.18, "duration": 2.58}, {"text": "and the tryptophan in another.", "start": 1121.76, "duration": 2.53}, {"text": "And you can see\nhow these authors", "start": 1124.29, "duration": 2.81}, {"text": "have decided how a\npotential fiber can", "start": 1127.1, "duration": 4.02}, {"text": "form in the different cases.", "start": 1131.12, "duration": 2.16}, {"text": "Now those fibers, in\none way or another,", "start": 1137.11, "duration": 2.76}, {"text": "which is not totally\nmapped out, but you", "start": 1139.87, "duration": 5.52}, {"text": "affect the efficiency of\nthe hemoglobin slightly", "start": 1145.39, "duration": 5.35}, {"text": "and the shape of the\ncell much more radically.", "start": 1150.74, "duration": 3.2}, {"text": "And this combination\nresults in the cell,", "start": 1153.94, "duration": 5.26}, {"text": "especially under any kind\nof stress, either oxidative", "start": 1159.2, "duration": 3.89}, {"text": "or other metabolic\nstress, becoming sickled.", "start": 1163.09, "duration": 2.82}, {"text": "So you can have a combination\nof cells which have", "start": 1165.91, "duration": 3.42}, {"text": "varying degrees of sickling.", "start": 1169.33, "duration": 1.68}, {"text": "Here in this microscopic\nslide on the left,", "start": 1171.01, "duration": 6.42}, {"text": "you have both the sickle\ncell and the normal cell side", "start": 1177.43, "duration": 2.7}, {"text": "by side.", "start": 1180.13, "duration": 2.08}, {"text": "I think when we built up the\nred blood cell metabolic model,", "start": 1182.21, "duration": 3.05}, {"text": "we talked about some of the\nnon-metabolic considerations", "start": 1185.26, "duration": 2.79}, {"text": "of that, which were that its\nfunction is to transport oxygen", "start": 1188.05, "duration": 4.23}, {"text": "and so forth.", "start": 1192.28, "duration": 2.4}, {"text": "And what we're talking about now\nis more a cell membrane issue.", "start": 1194.68, "duration": 3.65}, {"text": "This is on slide 13, where the\ninternal environment, which", "start": 1198.33, "duration": 5.35}, {"text": "is the hemoglobin, is\ngreatly affecting now", "start": 1203.68, "duration": 2.37}, {"text": "the external environment,\nwhich is the hemodynamic flow", "start": 1206.05, "duration": 3.12}, {"text": "in the capillaries.", "start": 1209.17, "duration": 3.15}, {"text": "So this falls under\nthe heading now", "start": 1215.68, "duration": 2.16}, {"text": "of how is it that we can go from\nthat single nucleotide change", "start": 1217.84, "duration": 3.72}, {"text": "to a very dramatic\nmorphological change?", "start": 1221.56, "duration": 2.16}, {"text": "In this case, it's\npathological, but you", "start": 1223.72, "duration": 2.25}, {"text": "could imagine that in the hands\nof evolutionary adaptation,", "start": 1225.97, "duration": 4.917}, {"text": "an organism could take\nthis and run with it.", "start": 1230.887, "duration": 1.833}, {"text": "Maybe not sickle cell mutation,\nbut some other one that", "start": 1232.72, "duration": 2.46}, {"text": "causes some other morphological\nchange in some other cell", "start": 1235.18, "duration": 2.88}, {"text": "or complex aggregate of cells.", "start": 1238.06, "duration": 3.06}, {"text": "Because here you can see a whole\nvariety of different shapes", "start": 1241.12, "duration": 6.63}, {"text": "of red blood cells.", "start": 1247.75, "duration": 2.043}, {"text": "And remember, these red\nblood cells are very simple.", "start": 1249.793, "duration": 2.167}, {"text": "They have no macromolecular\n[INAUDIBLE],, no DNA, no RNA,", "start": 1251.96, "duration": 4.94}, {"text": "so we're really just talking\nabout a bag of proteins which", "start": 1256.9, "duration": 2.64}, {"text": "are greatly affected by\nthese different conditions", "start": 1259.54, "duration": 4.05}, {"text": "or enzyme deficiencies.", "start": 1263.59, "duration": 1.87}, {"text": "So the system models\nthat were built up,", "start": 1265.46, "duration": 1.82}, {"text": "where we had the kinetic\nparameters for the enzymes,", "start": 1267.28, "duration": 4.17}, {"text": "here can, in principle, be\nmodeled on the impact it would", "start": 1271.45, "duration": 4.65}, {"text": "have on the osmolarity, or the\nother membrane properties that", "start": 1276.1, "duration": 5.22}, {"text": "were listed in the\nprevious slide,", "start": 1281.32, "duration": 1.59}, {"text": "or the sickling that\nwas in two slides back.", "start": 1282.91, "duration": 2.34}, {"text": "So from a single\nnucleotide polymorphism,", "start": 1296.68, "duration": 5.13}, {"text": "we've gone from this\nthree-dimensional fiber", "start": 1301.81, "duration": 2.43}, {"text": "of hemoglobin to a change in\nthe three-dimensional structure", "start": 1304.24, "duration": 5.76}, {"text": "of this biconcave\ndisk to a sickle disk.", "start": 1310.0, "duration": 7.02}, {"text": "But you can also go,\nsort of in parallel,", "start": 1317.02, "duration": 2.52}, {"text": "the same single-nucleotide\npolymorphism, or some like it,", "start": 1319.54, "duration": 3.42}, {"text": "can take you up to\npathogen resistance.", "start": 1322.96, "duration": 2.79}, {"text": "We've already mentioned that\nsickle cell hemoglobin can take", "start": 1325.75, "duration": 3.75}, {"text": "you to malarial resistance.", "start": 1329.5, "duration": 2.19}, {"text": "But in addition, you\ncan get components", "start": 1331.69, "duration": 7.32}, {"text": "of the enzymatic\nmetabolic pathway,", "start": 1339.01, "duration": 3.85}, {"text": "such as the one that we\nmodeled a few lectures back,", "start": 1342.86, "duration": 6.08}, {"text": "such as glutathione peroxidase.", "start": 1348.94, "duration": 1.69}, {"text": "This is part of the\nredox components.", "start": 1350.63, "duration": 4.52}, {"text": "And here, erythrocytes\nthat are heterozygous", "start": 1355.15, "duration": 3.96}, {"text": "for this particular\nallele should", "start": 1359.11, "duration": 7.12}, {"text": "be more efficient in\nsheltering the cell membrane", "start": 1366.23, "duration": 2.16}, {"text": "from irreversible oxidation\nin binding hemoglobin caused", "start": 1368.39, "duration": 2.7}, {"text": "by the oxidant\nstress that's exerted", "start": 1371.09, "duration": 2.04}, {"text": "by the malarial parasite.", "start": 1373.13, "duration": 4.53}, {"text": "And what they observe\nhere is actually", "start": 1377.66, "duration": 2.25}, {"text": "an interaction between these\ntwo possible haplotypes.", "start": 1379.91, "duration": 7.56}, {"text": "So it's actually, you can think\nof it as a pair of haplotypes.", "start": 1387.47, "duration": 2.61}, {"text": "It's the one is\nthe hemoglobin AS,", "start": 1390.08, "duration": 4.8}, {"text": "the one we've been talking\nabout for sickling,", "start": 1394.88, "duration": 3.12}, {"text": "and then, this\nglutathione peroxidase.", "start": 1398.0, "duration": 2.88}, {"text": "And so you can imagine, that\nsince both of these things", "start": 1400.88, "duration": 2.76}, {"text": "interact with malaria\nparasite, that your genotype", "start": 1403.64, "duration": 3.39}, {"text": "will depend--", "start": 1407.03, "duration": 0.87}, {"text": "I'm sorry, your phenotype\nin respect to malaria", "start": 1407.9, "duration": 2.16}, {"text": "will depend on the alleles\nthat you have at both cases.", "start": 1410.06, "duration": 3.517}, {"text": "So you can-- here, you can\nhave an A over S heterozygote", "start": 1413.577, "duration": 2.333}, {"text": "and a two over one heterozygote.", "start": 1415.91, "duration": 3.337}, {"text": "And so that's something to\ntake into account when you're", "start": 1419.247, "duration": 2.333}, {"text": "trying to do any kind of\npredictive modeling or modeling", "start": 1421.58, "duration": 4.59}, {"text": "to explain the functional\ngenomics that you", "start": 1426.17, "duration": 3.03}, {"text": "have in a patient who's\na compound heterozygote", "start": 1429.2, "duration": 2.64}, {"text": "like that.", "start": 1431.84, "duration": 1.54}, {"text": "So now, the third pathway.", "start": 1433.38, "duration": 2.21}, {"text": "Now, from single-- the same\nset of single nucleotide", "start": 1435.59, "duration": 2.37}, {"text": "polymorphisms that\naffect either hemoglobin", "start": 1437.96, "duration": 1.83}, {"text": "or one of the major enzymes\nin the red blood cell.", "start": 1439.79, "duration": 3.01}, {"text": "Now, on to cell morphology.", "start": 1442.8, "duration": 3.5}, {"text": "On to pathogen interaction.", "start": 1446.3, "duration": 3.39}, {"text": "And finally, to\ninteraction with drugs.", "start": 1449.69, "duration": 1.98}, {"text": "We talked about\npharmacogenomics.", "start": 1451.67, "duration": 1.62}, {"text": "Here's another example where you\nhave the drug-induced oxidative", "start": 1453.29, "duration": 6.36}, {"text": "hemolysis that you occur\nwith certain enzymopathies", "start": 1459.65, "duration": 4.68}, {"text": "like glucose-6-phosphate\ndehydrogenase.", "start": 1464.33, "duration": 4.14}, {"text": "This enzyme, glucose-6-phosphate\ndehydrogenase,", "start": 1468.47, "duration": 4.08}, {"text": "interacts with drugs\nsuch as primaquine.", "start": 1472.55, "duration": 4.11}, {"text": "And it disrupts mitochondrial\nfunction, heme biosynthesis,", "start": 1476.66, "duration": 6.04}, {"text": "and so forth, and so on.", "start": 1482.7, "duration": 3.0}, {"text": "This is a very\nsignificant consideration", "start": 1485.7, "duration": 6.02}, {"text": "with a long list\nof 20-some drugs", "start": 1491.72, "duration": 2.7}, {"text": "that has to be taken\nto account when", "start": 1494.42, "duration": 2.04}, {"text": "you have any of a variety of\nred blood cell enzyme changes.", "start": 1496.46, "duration": 7.03}, {"text": "So we've got these three\neffects of a limited number", "start": 1503.49, "duration": 4.67}, {"text": "of single nucleotide\npolymorphisms.", "start": 1508.16, "duration": 3.15}, {"text": "How do you make this\ntransition from--", "start": 1511.31, "duration": 5.55}, {"text": "and they're all\nsomewhat interconnected.", "start": 1516.86, "duration": 1.71}, {"text": "Part of the reason it's\nresistant to malaria", "start": 1518.57, "duration": 1.833}, {"text": "is because it's less\neffective in its cell", "start": 1520.403, "duration": 1.947}, {"text": "shape, and its ability to\ntransport oxygen, and do", "start": 1522.35, "duration": 5.4}, {"text": "its metabolism.", "start": 1527.75, "duration": 1.7}, {"text": "And same thing with\ndrug sensitivity.", "start": 1529.45, "duration": 3.01}, {"text": "How are these changes\nin the hemoglobin--", "start": 1532.46, "duration": 7.29}, {"text": "might they be reflected in\nthe three-dimensional shape", "start": 1539.75, "duration": 2.94}, {"text": "of the erythrocyte,\nwhich is a kind", "start": 1542.69, "duration": 2.67}, {"text": "of a membrane-bound compartment?", "start": 1545.36, "duration": 2.58}, {"text": "And here's a model that\nstruck me as interesting.", "start": 1547.94, "duration": 2.58}, {"text": "It's not been that\nextensively tested since 1998.", "start": 1550.52, "duration": 5.62}, {"text": "But the idea is that Band3--", "start": 1556.14, "duration": 2.69}, {"text": "this is one of those\nnames that just comes out", "start": 1558.83, "duration": 2.43}, {"text": "of the molecular\nbiologist literature,", "start": 1561.26, "duration": 3.06}, {"text": "that they ran a\ngel, and they count", "start": 1564.32, "duration": 2.01}, {"text": "the bands, and number three.", "start": 1566.33, "duration": 1.77}, {"text": "And it turns out it's about 10%\nof the red blood cell membrane.", "start": 1568.1, "duration": 5.28}, {"text": "It's a very abundant protein.", "start": 1573.38, "duration": 3.27}, {"text": "And it's responsible\nfor the equilibration", "start": 1576.65, "duration": 4.02}, {"text": "of anions such as carbonate and\nchloride across the red blood", "start": 1580.67, "duration": 3.81}, {"text": "cell membrane.", "start": 1584.48, "duration": 1.26}, {"text": "It's not a pump, it just\nkind of allows these anions", "start": 1585.74, "duration": 3.42}, {"text": "to go across because\nthe pump here", "start": 1589.16, "duration": 2.04}, {"text": "is the pumps that are\ninvolved in proton", "start": 1591.2, "duration": 2.97}, {"text": "and there's also\nsodium potassium.", "start": 1594.17, "duration": 3.57}, {"text": "And that's what your ATP in the\nred blood cell is going for.", "start": 1597.74, "duration": 2.58}, {"text": "And these are just kind\nof following along.", "start": 1600.32, "duration": 1.792}, {"text": "The idea here is that if\nyou change the degree--", "start": 1604.46, "duration": 9.73}, {"text": "let's see, I think this\nis covered in more detail.", "start": 1614.19, "duration": 3.248}, {"text": "No, sorry.", "start": 1617.438, "duration": 1.332}, {"text": "The mechanism of\naction here is greatly", "start": 1622.405, "duration": 3.265}, {"text": "affected by its\ndisulfide effects.", "start": 1625.67, "duration": 3.18}, {"text": "And if you change the redox\ncomponents in the red blood", "start": 1628.85, "duration": 4.74}, {"text": "cell, you get just a slight\nchange in conformation", "start": 1633.59, "duration": 3.81}, {"text": "of this molecule.", "start": 1637.4, "duration": 1.44}, {"text": "And then that can result\nin a net difference", "start": 1638.84, "duration": 3.3}, {"text": "between the cross-sectional area\nof this protein on the outside", "start": 1642.14, "duration": 3.9}, {"text": "and the inside, which\ntranslates into a net change--", "start": 1646.04, "duration": 3.78}, {"text": "since the phospholipids\ndon't exchange,", "start": 1649.82, "duration": 4.457}, {"text": "or the rate constant for\nthe phospholipid exchange", "start": 1654.277, "duration": 2.083}, {"text": "is slow and known,\nthen this results", "start": 1656.36, "duration": 2.4}, {"text": "in a conformational change.", "start": 1658.76, "duration": 7.14}, {"text": "Anyway, that's the model.", "start": 1665.9, "duration": 2.94}, {"text": "That connects the\nsingle nucleotide to--", "start": 1668.84, "duration": 3.06}, {"text": "could connect it to the\nthree-dimensional structure", "start": 1671.9, "duration": 3.0}, {"text": "of the cell.", "start": 1674.9, "duration": 0.87}, {"text": "Then you want to connect the\nthree-dimensional structure", "start": 1675.77, "duration": 2.333}, {"text": "of the cell to its ability\nto carry out its function", "start": 1678.103, "duration": 3.457}, {"text": "in the capillaries.", "start": 1681.56, "duration": 1.26}, {"text": "And its function there\nis to allow the fusion", "start": 1682.82, "duration": 3.57}, {"text": "of oxygen and carbon dioxide.", "start": 1686.39, "duration": 6.18}, {"text": "So here, each of these cells is\nshaped by a mechanical process.", "start": 1702.52, "duration": 6.03}, {"text": "A mechanical process\nhere, you can", "start": 1708.55, "duration": 1.8}, {"text": "take the known or the\nmeasurable mechanical properties", "start": 1710.35, "duration": 5.67}, {"text": "of a red blood cell\nand subject them", "start": 1716.02, "duration": 3.21}, {"text": "to a method called finite\nelements analysis where", "start": 1719.23, "duration": 5.94}, {"text": "you're solving these partial\ndifferentiable equations.", "start": 1725.17, "duration": 4.62}, {"text": "And you can calculate the\nexchange of the oxygen--", "start": 1729.79, "duration": 5.71}, {"text": "alveolar just refers to--\nthis would be in the lungs.", "start": 1739.27, "duration": 2.455}, {"text": "This would be a small\ncapillary in the lungs.", "start": 1741.725, "duration": 1.875}, {"text": "And you can see\nthe capillary now,", "start": 1743.6, "duration": 1.417}, {"text": "the endothelial walls are close\nenough so that the red blood", "start": 1745.017, "duration": 2.653}, {"text": "cells are basically\ndeformed in their shape", "start": 1747.67, "duration": 3.158}, {"text": "as they go through there.", "start": 1750.828, "duration": 1.042}, {"text": "And the exact shapes that\nare compatible with this", "start": 1751.87, "duration": 2.82}, {"text": "will determine the rate that\nthese little arrows that", "start": 1754.69, "duration": 2.55}, {"text": "go from the oxygen on the\noutside the lung epithelium", "start": 1757.24, "duration": 4.23}, {"text": "get through to the blood cell.", "start": 1761.47, "duration": 2.89}, {"text": "So that's a reference that\ndeals with that kind of problem.", "start": 1764.36, "duration": 6.77}, {"text": "Now, as we start thinking about\nbuilding up a larger system", "start": 1771.13, "duration": 8.45}, {"text": "model, the other parts of\nthe system, each of them--", "start": 1779.58, "duration": 2.52}, {"text": "so we've got a red\nblood cell model,", "start": 1782.1, "duration": 1.5}, {"text": "it's the metabolic model.", "start": 1783.6, "duration": 1.042}, {"text": "In principle, it could also be\na shape model and a diffusion", "start": 1784.642, "duration": 4.358}, {"text": "model.", "start": 1789.0, "duration": 1.26}, {"text": "But the other\nparts of the system", "start": 1790.26, "duration": 3.1}, {"text": "typically involve muscle cells.", "start": 1793.36, "duration": 4.65}, {"text": "They have the smooth muscles\nthroughout the entire arterial", "start": 1798.01, "duration": 9.82}, {"text": "and venous system, and most\nsignificantly, the heart", "start": 1807.83, "duration": 4.99}, {"text": "muscles.", "start": 1812.82, "duration": 0.93}, {"text": "And so here you have an example\nof action potential in one", "start": 1813.75, "duration": 6.12}, {"text": "of the ventricular\ncells of the dog heart.", "start": 1819.87, "duration": 3.51}, {"text": "And it includes all the\ncomponents that at least we,", "start": 1823.38, "duration": 4.35}, {"text": "since this is not an entire\ncourse on ventricular heart", "start": 1827.73, "duration": 6.73}, {"text": "modeling.", "start": 1834.46, "duration": 2.43}, {"text": "This is the sort of\nparameters, in terms", "start": 1836.89, "duration": 2.34}, {"text": "of all the I to the currents for\neach of the different potassium", "start": 1839.23, "duration": 3.39}, {"text": "channels to K, all of--\neach of the ones at I", "start": 1842.62, "duration": 3.36}, {"text": "sub K was all potassium.", "start": 1845.98, "duration": 2.7}, {"text": "And then there's some in sodium,\nand sodium and calcium, calcium", "start": 1848.68, "duration": 3.87}, {"text": "potassium, sodium alone.", "start": 1852.55, "duration": 2.057}, {"text": "And so each of these things,\nthat internal storage", "start": 1854.607, "duration": 2.083}, {"text": "of calcium [INAUDIBLE] from\none subcellular compartment", "start": 1856.69, "duration": 3.21}, {"text": "to another and so on.", "start": 1859.9, "duration": 3.31}, {"text": "You get the idea.", "start": 1863.21, "duration": 0.71}, {"text": "Each of these things has to\nhave the parameters measured.", "start": 1863.92, "duration": 3.21}, {"text": "And any of that are\nabsent, you have", "start": 1867.13, "duration": 3.03}, {"text": "to have reasonable ways\nof getting surrogates.", "start": 1870.16, "duration": 6.51}, {"text": "And so this is just\nthe sort of data", "start": 1876.67, "duration": 3.66}, {"text": "that would go into the other\nmajor type of cell that", "start": 1880.33, "duration": 4.14}, {"text": "comes into this\ncardiovascular modeling.", "start": 1884.47, "duration": 4.92}, {"text": "And finally, you can\nintegrate this up", "start": 1889.39, "duration": 3.87}, {"text": "to a fairly complete system.", "start": 1893.26, "duration": 2.76}, {"text": "It's obviously not\ncomplete until you", "start": 1896.02, "duration": 1.56}, {"text": "get to the whole organism,\nbut higher level,", "start": 1897.58, "duration": 2.88}, {"text": "and how we're talking about\nwhole body recirculation.", "start": 1900.46, "duration": 3.8}, {"text": "This NSR group, this\nis a hypertext link", "start": 1904.26, "duration": 3.28}, {"text": "for this particular model\nwhich you can download.", "start": 1907.54, "duration": 3.39}, {"text": "And it has a\nfour-chambered heart.", "start": 1910.93, "duration": 1.57}, {"text": "We were just talking\nabout one ventricular", "start": 1912.5, "duration": 2.12}, {"text": "cell on the previous slide.", "start": 1914.62, "duration": 1.68}, {"text": "But that would be--", "start": 1916.3, "duration": 1.8}, {"text": "if we look at the second\nbox from the top here,", "start": 1918.1, "duration": 2.88}, {"text": "this is where the heart and\nlung model would fit in there.", "start": 1920.98, "duration": 4.15}, {"text": "It's got seven different organs,\nwhich include kidney, liver,", "start": 1925.13, "duration": 3.17}, {"text": "lower limbs, and so forth\ndown at the bottom part", "start": 1928.3, "duration": 2.84}, {"text": "of this diagram.", "start": 1931.14, "duration": 1.85}, {"text": "And you get the picture.", "start": 1932.99, "duration": 1.19}, {"text": "Each of these things, you're\nmodeling the volumes and flows,", "start": 1934.18, "duration": 9.51}, {"text": "Now, this is systems biology.", "start": 1943.69, "duration": 2.1}, {"text": "This is really kind of a\nrenaissance of interest", "start": 1945.79, "duration": 3.75}, {"text": "in physiology, which is what it\nwould have been called before.", "start": 1949.54, "duration": 2.79}, {"text": "And there are some really\ninteresting mysteries out there", "start": 1952.33, "duration": 4.47}, {"text": "to be solved that are really\nonly solvable, or possibly only", "start": 1956.8, "duration": 4.77}, {"text": "solvable, at the system level.", "start": 1961.57, "duration": 1.35}, {"text": "You never know,\nsomebody could come up", "start": 1962.92, "duration": 2.22}, {"text": "and say, oh, yeah,\nthis is really", "start": 1965.14, "duration": 1.59}, {"text": "well understood immunology\nand that answers everything.", "start": 1966.73, "duration": 3.61}, {"text": "But even if it's some\nkind of immunology,", "start": 1970.34, "duration": 4.967}, {"text": "you still have to say,\nhow does it play out?", "start": 1975.307, "duration": 1.833}, {"text": "And what happens is we've\nbeen talking about sickle cell", "start": 1977.14, "duration": 2.333}, {"text": "disease, and you can\nhave fairly mild pain", "start": 1979.473, "duration": 3.487}, {"text": "as one of the major symptoms.", "start": 1982.96, "duration": 2.17}, {"text": "But then all of a\nsudden, out of nowhere,", "start": 1985.13, "duration": 1.85}, {"text": "you'll get this\nmulti-organ system failure", "start": 1986.98, "duration": 2.49}, {"text": "where almost every major\norgan in that previous slide,", "start": 1989.47, "duration": 4.38}, {"text": "lungs and so forth,\nfill up with fluid", "start": 1993.85, "duration": 1.74}, {"text": "and you have a very\nhigh chance of dying.", "start": 1995.59, "duration": 3.492}, {"text": "And this could happen to\nevery one of us in this room", "start": 1999.082, "duration": 2.208}, {"text": "because it's not\nrestricted to sickle cell.", "start": 2001.29, "duration": 2.55}, {"text": "If any of you have severe\nburn, or car crash, major bone", "start": 2003.84, "duration": 7.14}, {"text": "injuries, and so forth,\nyou have a very good chance", "start": 2010.98, "duration": 2.61}, {"text": "of getting into\nmulti-organ system failure.", "start": 2013.59, "duration": 2.44}, {"text": "And it really isn't\nknown how that plays out.", "start": 2016.03, "duration": 3.47}, {"text": "I mean, not even that-- not\njust a quantitative model,", "start": 2019.5, "duration": 2.79}, {"text": "but even qualitatively.", "start": 2022.29, "duration": 2.73}, {"text": "So I think this is something--\nthere are projects now", "start": 2025.02, "duration": 4.2}, {"text": "to get genomic data collection,\nboth genetic and expression", "start": 2029.22, "duration": 5.4}, {"text": "data, and time will tell whether\nthat is actually the best", "start": 2034.62, "duration": 5.85}, {"text": "route to solving that mystery.", "start": 2040.47, "duration": 2.3}, {"text": "So that was multi-organ.", "start": 2042.77, "duration": 1.57}, {"text": "Now we're talking\nabout multi-organism.", "start": 2044.34, "duration": 3.09}, {"text": "After you've built up\nan entire organism,", "start": 2047.43, "duration": 4.26}, {"text": "then you want to\nknow how it acts", "start": 2051.69, "duration": 1.98}, {"text": "at the next level of network\nanalysis, which is how does it", "start": 2053.67, "duration": 4.89}, {"text": "fit in with other organisms?", "start": 2058.56, "duration": 3.929}, {"text": "None of us, almost\nno organism, really", "start": 2062.489, "duration": 3.841}, {"text": "belongs in ecological\nniche all by itself.", "start": 2066.33, "duration": 3.36}, {"text": "And some of the modeling we\nare taught in this course", "start": 2069.69, "duration": 5.969}, {"text": "could be called simulation.", "start": 2075.659, "duration": 2.071}, {"text": "And probably one of the\nlongest-lasting computer", "start": 2077.73, "duration": 6.09}, {"text": "games in the world, and\none of the most successful,", "start": 2083.82, "duration": 4.62}, {"text": "I've heard, is The Sims.", "start": 2088.44, "duration": 4.11}, {"text": "It started with SimCity in--", "start": 2092.55, "duration": 1.98}, {"text": "SimCity in '87.", "start": 2097.44, "duration": 1.08}, {"text": "And then this particular\none illustrated here", "start": 2100.995, "duration": 1.875}, {"text": "is SimLife, which is all\nabout ecological modeling.", "start": 2102.87, "duration": 3.6}, {"text": "And it's not entirely\ndifferent from what", "start": 2106.47, "duration": 2.4}, {"text": "a serious ecological-modeling\nprogram would do.", "start": 2108.87, "duration": 3.66}, {"text": "It certainly has a lot of\nthe interesting parameters", "start": 2112.53, "duration": 2.34}, {"text": "such as the lifespan here.", "start": 2114.87, "duration": 3.54}, {"text": "You're doing demographics\nhere so you have the lifespan,", "start": 2118.41, "duration": 3.48}, {"text": "the amount of food needed,\nthe size, kind of vision,", "start": 2121.89, "duration": 6.96}, {"text": "roaming, so forth, of all these\ndifferent kinds of animals.", "start": 2128.85, "duration": 3.45}, {"text": "You can have plants, you\nhave herbivores, carnivores,", "start": 2135.09, "duration": 3.87}, {"text": "and so on.", "start": 2138.96, "duration": 0.97}, {"text": "And then you can set up\nthe population sizes,", "start": 2139.93, "duration": 2.63}, {"text": "and then it will do\nsimulations based", "start": 2142.56, "duration": 3.42}, {"text": "on that, where each individual\nanimal is tracked in terms", "start": 2145.98, "duration": 5.46}, {"text": "of its position and quantity.", "start": 2151.44, "duration": 2.13}, {"text": "And as you would expect,\nas the carnivores build up,", "start": 2153.57, "duration": 5.79}, {"text": "then they knock\ndown the herbivores,", "start": 2159.36, "duration": 1.5}, {"text": "and the plants go\nup, and so forth.", "start": 2160.86, "duration": 3.3}, {"text": "And it goes through\nthese cycles.", "start": 2164.16, "duration": 2.52}, {"text": "And so this is basically\na stochastic model,", "start": 2166.68, "duration": 2.31}, {"text": "just like the stochastic models\nthat we had for molecules,", "start": 2168.99, "duration": 4.74}, {"text": "but here, at the organism level.", "start": 2173.73, "duration": 2.28}, {"text": "And what's happening here in\nthe slower right-hand section", "start": 2176.01, "duration": 3.15}, {"text": "is you've got little\ngreen plants getting", "start": 2179.16, "duration": 3.42}, {"text": "eaten by herbivores, and\nthe herbivores getting", "start": 2182.58, "duration": 2.58}, {"text": "eaten by carnivores.", "start": 2185.16, "duration": 1.2}, {"text": "Now, hopefully, this\ncourse has already", "start": 2189.05, "duration": 6.16}, {"text": "or will inspire you to\nreally think globally.", "start": 2195.21, "duration": 4.89}, {"text": "To think not only\nglobally in terms", "start": 2200.1, "duration": 2.4}, {"text": "of how little pieces\nof molecular tools", "start": 2202.5, "duration": 5.52}, {"text": "fit together into\nsystems and networks,", "start": 2208.02, "duration": 2.73}, {"text": "but how our systems\nand networks we model", "start": 2210.75, "duration": 2.85}, {"text": "fit into the big picture of what\nare really important problems.", "start": 2213.6, "duration": 4.83}, {"text": "Maybe a slightly\nimproved Viagra is not", "start": 2218.43, "duration": 6.12}, {"text": "in the same category as\na new tuberculosis drug", "start": 2224.55, "duration": 3.78}, {"text": "or maybe it is.", "start": 2228.33, "duration": 0.75}, {"text": "I mean, you decide for yourself\nwhat is thinking globally.", "start": 2229.08, "duration": 4.05}, {"text": "But you have to act\nlocally, and that's", "start": 2233.13, "duration": 1.74}, {"text": "what we're doing in this class.", "start": 2234.87, "duration": 1.292}, {"text": "When we're thinking\nglobally, and we're", "start": 2239.07, "duration": 1.71}, {"text": "thinking about\necological systems,", "start": 2240.78, "duration": 2.46}, {"text": "we're thinking about the\nlithosphere, for the most part,", "start": 2243.24, "duration": 5.25}, {"text": "and its interaction\nwith the hydrosphere.", "start": 2248.49, "duration": 3.66}, {"text": "The lithosphere is\nmostly silicon dioxide,", "start": 2252.15, "duration": 7.88}, {"text": "a tiny bit of carbon, and it\ngets very hot, very quickly.", "start": 2260.03, "duration": 4.85}, {"text": "So only the top 0.1%, that's\nthe top four kilometers of it,", "start": 2264.88, "duration": 7.88}, {"text": "is survivable in any type\nof organism we know of.", "start": 2272.76, "duration": 3.75}, {"text": "About 110 degrees centigrade\nis where organisms start", "start": 2276.51, "duration": 3.21}, {"text": "having a great deal of trouble.", "start": 2279.72, "duration": 2.22}, {"text": "You and I would have\ntrouble before that.", "start": 2281.94, "duration": 1.8}, {"text": "The biosphere here\nis about 3 times 10", "start": 2287.57, "duration": 3.44}, {"text": "to the 15th grams, my\nestimate for marine organisms.", "start": 2291.01, "duration": 10.14}, {"text": "And maybe 10 to the 18th grams\nfor all land plants and animals", "start": 2301.15, "duration": 6.06}, {"text": "and microorganisms.", "start": 2307.21, "duration": 2.94}, {"text": "The microbial hydrosphere\nhere is about 10", "start": 2310.15, "duration": 6.275}, {"text": "to the 21st milliliters,\nwhich works out about 10", "start": 2316.425, "duration": 5.155}, {"text": "to the 27th cells.", "start": 2321.58, "duration": 1.38}, {"text": "A phenomenal number of\nthese cells, about 10", "start": 2322.96, "duration": 1.97}, {"text": "to the 26th of those\ncells is a single species,", "start": 2324.93, "duration": 2.71}, {"text": "which is prochlorococcus,\nwhich is responsible for maybe", "start": 2327.64, "duration": 5.07}, {"text": "about 50% of the\nEarth's photosynthesis.", "start": 2332.71, "duration": 3.96}, {"text": "A lot of that photosynthesis\ndoes not end up in fixed carbon", "start": 2336.67, "duration": 3.99}, {"text": "because it is\nimmediately consumed", "start": 2340.66, "duration": 2.91}, {"text": "by one of its other\npredators, basically.", "start": 2343.57, "duration": 7.5}, {"text": "But there's really quite a\nlot of cells out there which,", "start": 2351.07, "duration": 7.027}, {"text": "to the extent that\nthey're well-mixed,", "start": 2358.097, "duration": 1.583}, {"text": "and they're not-- of course,\nit's not perfectly mixed,", "start": 2359.68, "duration": 2.25}, {"text": "all the Pacific and\nAtlantic and so forth.", "start": 2361.93, "duration": 1.84}, {"text": "But it's a considerably\nmore well-mixed,", "start": 2363.77, "duration": 2.09}, {"text": "say, than the\nlithosphere organisms,", "start": 2365.86, "duration": 1.62}, {"text": "where you have organisms down\na kilometer into the ground.", "start": 2367.48, "duration": 3.91}, {"text": "They don't move\naround very rapidly.", "start": 2371.39, "duration": 3.51}, {"text": "So when you have a\npopulation of that size", "start": 2374.9, "duration": 1.75}, {"text": "as you remember from one\nof our first lectures", "start": 2376.65, "duration": 1.96}, {"text": "on population size, the\neffect of population size", "start": 2378.61, "duration": 2.91}, {"text": "determines the rate of drift and\nthe optimality of the organism.", "start": 2381.52, "duration": 8.058}, {"text": "So one of the things\nthat we do, when", "start": 2389.578, "duration": 1.542}, {"text": "we've been talking about\nmining the biosphere, one", "start": 2391.12, "duration": 3.54}, {"text": "of the things that\nwe're looking for", "start": 2394.66, "duration": 1.5}, {"text": "are new tools that we can\nuse for nanoengineering.", "start": 2396.16, "duration": 7.38}, {"text": "And kind of one of my pet ones\nthat I'm becoming interested", "start": 2403.54, "duration": 3.63}, {"text": "in, we don't work\non the same thing,", "start": 2407.17, "duration": 1.5}, {"text": "but it is kind of interesting,\nis a set of-- we mentioned this", "start": 2408.67, "duration": 4.2}, {"text": "briefly in the drug protein\ninteraction lecture where--", "start": 2412.87, "duration": 5.845}, {"text": "but I don't think I mentioned\nthis particular one-- where", "start": 2418.715, "duration": 2.375}, {"text": "you have polyketides\nthat go together.", "start": 2421.09, "duration": 3.21}, {"text": "It's another polymer that\nhas certain similarities", "start": 2424.3, "duration": 3.75}, {"text": "to the basic polymers\nwe talked about,", "start": 2428.05, "duration": 1.62}, {"text": "but each step in it had\nto have a protein enzyme--", "start": 2429.67, "duration": 4.32}, {"text": "an enzymatic domain\nto accomplish that.", "start": 2433.99, "duration": 2.56}, {"text": "And so one of these\nis tetracycline.", "start": 2436.55, "duration": 2.0}, {"text": "And this is one of\nthe more aromatic kind", "start": 2438.55, "duration": 2.49}, {"text": "of coupled-aromatic\ncompounds that's", "start": 2441.04, "duration": 1.86}, {"text": "made because you have\nthese [INAUDIBLE]", "start": 2442.9, "duration": 2.04}, {"text": "and aromatases in addition\nto the polymerization steps.", "start": 2444.94, "duration": 5.31}, {"text": "And so you make this\nthing that looks", "start": 2450.25, "duration": 2.1}, {"text": "kind of like a poly\naromatic hydrocarbon.", "start": 2452.35, "duration": 3.6}, {"text": "And also in nature, you will\nfind, in soot, in forest fires,", "start": 2455.95, "duration": 5.25}, {"text": "in all kinds of\nnatural phenomena,", "start": 2461.2, "duration": 1.77}, {"text": "you will find polycyclic\naromatic hydrocarbons, which", "start": 2462.97, "duration": 4.44}, {"text": "some of you may know about\nas the potent carcinogens,", "start": 2467.41, "duration": 3.3}, {"text": "but they're also just\nnatural components.", "start": 2470.71, "duration": 3.96}, {"text": "But they also-- you\ncan start to see this", "start": 2474.67, "duration": 2.37}, {"text": "looks a little bit like the\nbuckyballs and buckytubes", "start": 2477.04, "duration": 2.61}, {"text": "that we talked\nabout when we were", "start": 2479.65, "duration": 1.375}, {"text": "talking about\nmolecular-type transistors.", "start": 2481.025, "duration": 3.545}, {"text": "So the possibility of mining\nthe biosphere for enzymes", "start": 2484.57, "duration": 5.22}, {"text": "that act to\nsynthesize or degrade", "start": 2489.79, "duration": 2.16}, {"text": "this class of\ncompounds, I think,", "start": 2491.95, "duration": 1.56}, {"text": "would be just an example.", "start": 2493.51, "duration": 1.42}, {"text": "We could list many others.", "start": 2494.93, "duration": 1.2}, {"text": "But the part of it is\njust to dream, to imagine,", "start": 2496.13, "duration": 3.02}, {"text": "what it is would like\nto find out there.", "start": 2499.15, "duration": 2.44}, {"text": "And if there's an\nabundant source of it,", "start": 2501.59, "duration": 5.36}, {"text": "then you should be able to--", "start": 2506.95, "duration": 1.77}, {"text": "abundant source of, say,\nthe compound, in this case,", "start": 2508.72, "duration": 2.29}, {"text": "you need to be able to find\na microorganism and an enzyme", "start": 2511.01, "duration": 4.02}, {"text": "that goes with that\nbecause there's a truly", "start": 2515.03, "duration": 2.03}, {"text": "phenomenal amount of diversity.", "start": 2517.06, "duration": 2.13}, {"text": "Another very important\nglobal consideration,", "start": 2522.37, "duration": 3.21}, {"text": "rather than just mining\nit for new tools,", "start": 2525.58, "duration": 3.03}, {"text": "is thinking about ways that\neither we could engineer", "start": 2528.61, "duration": 2.91}, {"text": "or accidentally mess\nup our entire planet,", "start": 2531.52, "duration": 5.37}, {"text": "as we could be doing with\nglobal warming or could do.", "start": 2536.89, "duration": 5.91}, {"text": "And perhaps it's naive\nto think that we actually", "start": 2542.8, "duration": 3.06}, {"text": "are having such a\nbig effect because we", "start": 2545.86, "duration": 1.83}, {"text": "know that global warming changes\nperiodically over millennia.", "start": 2547.69, "duration": 4.41}, {"text": "But it is very clear\nfrom the record", "start": 2555.11, "duration": 4.92}, {"text": "just exactly how much carbon\ndioxide we are releasing", "start": 2560.03, "duration": 2.38}, {"text": "and it makes sense, that it\nis consistent with the kind", "start": 2562.41, "duration": 3.848}, {"text": "of temperature\nchanges that have been", "start": 2566.258, "duration": 1.542}, {"text": "observed since the\nIndustrial Revolution.", "start": 2567.8, "duration": 2.73}, {"text": "In any case, when you\nlook at, in particular,", "start": 2570.53, "duration": 5.26}, {"text": "the Southern Ocean--", "start": 2575.79, "duration": 2.06}, {"text": "up at the top of slide 27--", "start": 2577.85, "duration": 2.108}, {"text": "you can see there is a\nfew places, in particular,", "start": 2579.958, "duration": 2.042}, {"text": "Southern Ocean seems like\nit's a prime candidate where", "start": 2582.0, "duration": 2.33}, {"text": "you have high nutrients\nbut low chlorophyll.", "start": 2584.33, "duration": 3.18}, {"text": "And you say, well, why would\nyou have high nutrients", "start": 2587.51, "duration": 2.22}, {"text": "but very little of the\nchlorophyll around,", "start": 2589.73, "duration": 5.2}, {"text": "which is a tipoff that you have\nthe photosynthetic bacteria.", "start": 2594.93, "duration": 5.24}, {"text": "And the reason is that\nyou have a limitation", "start": 2600.17, "duration": 3.33}, {"text": "of some micronutrient.", "start": 2603.5, "duration": 1.17}, {"text": "Micronutrient means it's not\nneeded in the vast quantities", "start": 2604.67, "duration": 4.68}, {"text": "that you need nitrogen,\nphosphorus, carbon, oxygen,", "start": 2609.35, "duration": 2.92}, {"text": "and so on.", "start": 2612.27, "duration": 1.2}, {"text": "So iron, typically, is\nthe limiting micronutrient", "start": 2613.47, "duration": 2.6}, {"text": "in the Southern Ocean.", "start": 2616.07, "duration": 1.26}, {"text": "And so there actually have\nbeen little pilot experiments", "start": 2617.33, "duration": 3.48}, {"text": "to drop iron off the\nbacks of huge tankers.", "start": 2620.81, "duration": 4.08}, {"text": "And there are now at\nleast seven patents", "start": 2624.89, "duration": 2.37}, {"text": "that have been filed\non doing this in order", "start": 2627.26, "duration": 2.46}, {"text": "to balance out the carbon\ncredits for different nations.", "start": 2629.72, "duration": 4.02}, {"text": "This is potentially a very big\nbit of terrestrial engineering", "start": 2633.74, "duration": 3.96}, {"text": "that might happen.", "start": 2637.7, "duration": 1.14}, {"text": "It involves trying to\nchange phytoplankton.", "start": 2638.84, "duration": 5.4}, {"text": "And as this line here\nbegins to point out,", "start": 2644.24, "duration": 4.21}, {"text": "even though\nphytoplankton are only 1%", "start": 2648.45, "duration": 2.6}, {"text": "of the total global\nbiomass, it's about 50%", "start": 2651.05, "duration": 2.7}, {"text": "of the carbon fixation.", "start": 2653.75, "duration": 3.19}, {"text": "What is the source of\nthis 50-fold anomaly?", "start": 2656.94, "duration": 2.63}, {"text": "Why is it that even\nthough it's doing--", "start": 2659.57, "duration": 4.96}, {"text": "how is it doing 50% of\nthe carbon fixation?", "start": 2664.53, "duration": 1.88}, {"text": "And what's happening\nis a lot of the carbon", "start": 2666.41, "duration": 2.34}, {"text": "is going right back\nout after being fixed.", "start": 2668.75, "duration": 3.693}, {"text": "Instead of settling to\nthe bottom of the ocean", "start": 2672.443, "duration": 1.917}, {"text": "and never bothering us\nagain, it gets returned.", "start": 2674.36, "duration": 5.67}, {"text": "And the exact modeling\nof that requires", "start": 2680.03, "duration": 2.25}, {"text": "a much deeper knowledge\nof exactly what organisms", "start": 2682.28, "duration": 3.18}, {"text": "are present in the ocean.", "start": 2685.46, "duration": 1.35}, {"text": "One of the problems\nwith this however,", "start": 2686.81, "duration": 1.78}, {"text": "is a genomic problem, in\na certain sense, which", "start": 2688.59, "duration": 4.16}, {"text": "is that very few\nof these organisms", "start": 2692.75, "duration": 3.93}, {"text": "can be cultivated\nin the laboratory.", "start": 2696.68, "duration": 2.16}, {"text": "On the order of 99.9% of the\norganisms that you sample", "start": 2698.84, "duration": 3.39}, {"text": "from the ocean,\nor from the soil,", "start": 2702.23, "duration": 1.95}, {"text": "a number of different\nenvironments,", "start": 2704.18, "duration": 2.91}, {"text": "do not grow well\nin the laboratory.", "start": 2707.09, "duration": 2.26}, {"text": "So if you were to\nstudy them, some people", "start": 2709.35, "duration": 3.77}, {"text": "are feeling that the best\nroute to studying them", "start": 2713.12, "duration": 2.76}, {"text": "is going directly for--", "start": 2715.88, "duration": 3.15}, {"text": "looking at their genomes,\nwithout necessarily", "start": 2719.03, "duration": 2.07}, {"text": "being able to grow\nthem in the laboratory.", "start": 2721.1, "duration": 2.532}, {"text": "Now, when we talk\nabout this problem of--", "start": 2726.41, "duration": 4.44}, {"text": "even if we fertilize\nthe oceans, and we", "start": 2730.85, "duration": 3.93}, {"text": "can model this whole procedure,\nI won't go into details.", "start": 2734.78, "duration": 2.46}, {"text": "But if there are predators\nthere that take the fixed carbon", "start": 2737.24, "duration": 10.15}, {"text": "and turn it back\ninto carbon dioxide,", "start": 2747.39, "duration": 2.43}, {"text": "you want to be able\nto monitor that.", "start": 2749.82, "duration": 2.37}, {"text": "Now, of course, the ocean\nis a large, complex set", "start": 2752.19, "duration": 3.48}, {"text": "of prokaryotic\nautotrophs that are, say,", "start": 2755.67, "duration": 3.87}, {"text": "photosynthetic bacteria, and\neukaryotic photosynthetic", "start": 2759.54, "duration": 2.91}, {"text": "bacteria, and prokaryotic\nand eukaryotic predators", "start": 2762.45, "duration": 5.76}, {"text": "of various sorts.", "start": 2768.21, "duration": 1.36}, {"text": "And this is, I think, one\nof the more interesting", "start": 2769.57, "duration": 2.9}, {"text": "predator-prey differential\nequation models.", "start": 2772.47, "duration": 6.09}, {"text": "It's almost the same as many\nof the other differential", "start": 2778.56, "duration": 2.82}, {"text": "equations that we did from\nthe first lecture on growth.", "start": 2781.38, "duration": 5.5}, {"text": "We did the logistic\nequation, some", "start": 2786.88, "duration": 2.3}, {"text": "of the ones we did on\nrepressor function, and so on.", "start": 2789.18, "duration": 2.838}, {"text": "But the thing that's kind of\ninteresting about this one", "start": 2792.018, "duration": 2.292}, {"text": "is it's not simply a\nsingle-cell bacteria", "start": 2794.31, "duration": 5.85}, {"text": "being eaten by a\nsingle-celled heterotroph,", "start": 2800.16, "duration": 3.15}, {"text": "let's say, a blue-green\nalgae being eaten", "start": 2803.31, "duration": 1.71}, {"text": "by a single-cell heterotroph.", "start": 2805.02, "duration": 1.47}, {"text": "Here, they are\nboth multicellular.", "start": 2806.49, "duration": 2.45}, {"text": "They're sort of the\nminimal multicellular.", "start": 2808.94, "duration": 1.75}, {"text": "But because they\nare-- so Chlorella", "start": 2810.69, "duration": 2.55}, {"text": "is one of the smallest\nplants, multicellular plants.", "start": 2813.24, "duration": 2.79}, {"text": "And Brachionus is a small\nrotifer, a multicellular", "start": 2816.03, "duration": 7.89}, {"text": "animal.", "start": 2823.92, "duration": 0.595}, {"text": "Because they're\nmulti-cellular, though,", "start": 2824.515, "duration": 1.625}, {"text": "now you have the demographic\nmortality and fecundity", "start": 2826.14, "duration": 5.55}, {"text": "of each of these things\nthat has to be modeled in.", "start": 2831.69, "duration": 2.43}, {"text": "That's the m and the\nlambda for Brachionus.", "start": 2834.12, "duration": 4.83}, {"text": "And so this plays into these\nequations where you have here,", "start": 2838.95, "duration": 6.45}, {"text": "in the upper-right\nof slide 28, the rate", "start": 2845.4, "duration": 3.3}, {"text": "of change of nitrogen\nwith respect to time,", "start": 2848.7, "duration": 5.43}, {"text": "and concentration of Chlorella.", "start": 2854.13, "duration": 2.82}, {"text": "So nitrogen is N,\nChlorella is C.", "start": 2856.95, "duration": 3.42}, {"text": "The R is the Brachionus\nthat are reproducing", "start": 2860.37, "duration": 7.59}, {"text": "and B are the Brachionus\nwhich are the total.", "start": 2867.96, "duration": 3.43}, {"text": "And you can see each of these\nequations and how it plays out.", "start": 2871.39, "duration": 3.02}, {"text": "Now this is how--", "start": 2874.41, "duration": 1.53}, {"text": "and the way they play\nit out here is you do it", "start": 2875.94, "duration": 2.7}, {"text": "by dilution rate, delta, here.", "start": 2878.64, "duration": 2.82}, {"text": "And the dilution rate is shown\nalong the horizontal x-axis", "start": 2881.46, "duration": 11.49}, {"text": "for each of these\nthree plots here.", "start": 2892.95, "duration": 2.04}, {"text": "And what they're modeling\nis on the far left,", "start": 2894.99, "duration": 4.44}, {"text": "the nitrogen concentration as\na function of dilution rate.", "start": 2899.43, "duration": 7.36}, {"text": "And you can see you get these\ndifferent sectors of behavior.", "start": 2906.79, "duration": 7.85}, {"text": "When you look at\nthe Chlorella, this", "start": 2914.64, "duration": 1.74}, {"text": "is a green, photosynthetic,\nmulticellular organism,", "start": 2916.38, "duration": 4.59}, {"text": "in units of millions of\ncells per milliliter,", "start": 2920.97, "duration": 2.79}, {"text": "that can take different--", "start": 2923.76, "duration": 3.86}, {"text": "it take different\npathways here where,", "start": 2927.62, "duration": 4.15}, {"text": "as a function of\ndilution rate, you", "start": 2931.77, "duration": 1.65}, {"text": "get this bifurcation\nwhere you get", "start": 2933.42, "duration": 2.19}, {"text": "a huge split in the possible\nconcentrations of Chlorella", "start": 2935.61, "duration": 7.77}, {"text": "is the one curve and the\nBrachionus, the predator,", "start": 2943.38, "duration": 3.84}, {"text": "is the other curve.", "start": 2947.22, "duration": 1.095}, {"text": "This kind of bifurcation\nis the sort of thing", "start": 2948.315, "duration": 1.875}, {"text": "we talked about earlier,\nboth in the logistic equation", "start": 2950.19, "duration": 4.62}, {"text": "and in the\nself-exclusion modeling.", "start": 2954.81, "duration": 10.1}, {"text": "And in the upper-right-hand,\nhere's our friend", "start": 2964.91, "duration": 4.38}, {"text": "the coefficient of\nvariation in percent,", "start": 2969.29, "duration": 2.03}, {"text": "ranging from 0 to 80 or\nso on the vertical axis", "start": 2971.32, "duration": 4.84}, {"text": "and the dilution rate.", "start": 2976.16, "duration": 1.57}, {"text": "And again, you can see that you\nget a peak in the dilution rate", "start": 2977.73, "duration": 4.82}, {"text": "at around 0.75.", "start": 2982.55, "duration": 1.92}, {"text": "The bottom two are models, and\nthe upper right is the data.", "start": 2984.47, "duration": 5.08}, {"text": "You can actually see, when\nyou run real Chlorella", "start": 2989.55, "duration": 2.33}, {"text": "and Brachionus in here, that you\ndo get a peak just as you would", "start": 2991.88, "duration": 3.27}, {"text": "predict in this kind\nof bifurcation analysis", "start": 2995.15, "duration": 2.145}, {"text": "in kinetic modeling.", "start": 2997.295, "duration": 2.385}, {"text": "That's due to-- where you\nget interesting behavior", "start": 2999.68, "duration": 5.28}, {"text": "in this complicated-- or this\nfairly simple model ecosystem", "start": 3004.96, "duration": 4.08}, {"text": "where you just have two species.", "start": 3009.04, "duration": 1.92}, {"text": "In the ocean, of course,\nyou have a lot more.", "start": 3010.96, "duration": 4.11}, {"text": "Now, that's out\nin the wide world", "start": 3015.07, "duration": 2.16}, {"text": "where you have 10\nto the 26 cells.", "start": 3017.23, "duration": 3.66}, {"text": "But inside every one of us\nin this room, no offense,", "start": 3020.89, "duration": 3.42}, {"text": "but there are about 10 times\nas many non-human cells", "start": 3024.31, "duration": 4.86}, {"text": "in each of us as\nare human cells.", "start": 3029.17, "duration": 2.88}, {"text": "And we have our own ecology.", "start": 3032.05, "duration": 2.97}, {"text": "And there is a literature\nwhere certain organisms", "start": 3035.02, "duration": 4.95}, {"text": "we know cause\ndiseases, and they're", "start": 3039.97, "duration": 1.77}, {"text": "put into one category,\ninfectious diseases,", "start": 3041.74, "duration": 3.24}, {"text": "but then there's\nanother set that", "start": 3044.98, "duration": 1.47}, {"text": "takes some time to sort out.", "start": 3046.45, "duration": 1.69}, {"text": "And you can see here\nare candidate diseases", "start": 3048.14, "duration": 1.97}, {"text": "and candidate organisms.", "start": 3050.11, "duration": 1.41}, {"text": "And all these little bars\nthat are going in here", "start": 3051.52, "duration": 2.46}, {"text": "are references that\nyou can look up", "start": 3053.98, "duration": 3.33}, {"text": "where maybe it's not\nan airtight case yet,", "start": 3057.31, "duration": 3.21}, {"text": "or maybe it's not\neven-- maybe there's", "start": 3060.52, "duration": 1.8}, {"text": "controversial or\ndiscredited [INAUDIBLE],,", "start": 3062.32, "duration": 2.79}, {"text": "but these are links where,\neventually, this will be", "start": 3065.11, "duration": 2.88}, {"text": "called an infectious disease.", "start": 3067.99, "duration": 2.01}, {"text": "Helicobacter pylori\ncauses stomach ulcers.", "start": 3070.0, "duration": 2.52}, {"text": "I think that fact's\nbasically already accepted.", "start": 3072.52, "duration": 2.415}, {"text": "Some Australian\ndoctor named Marshall", "start": 3077.98, "duration": 2.28}, {"text": "decided to drink a\nbunch of Helicobacter", "start": 3080.26, "duration": 1.833}, {"text": "to prove to his colleagues,\nwho didn't believe", "start": 3082.093, "duration": 1.917}, {"text": "any stomach ulcers were caused\nby Helicobacter, much less all", "start": 3084.01, "duration": 2.82}, {"text": "of them.", "start": 3086.83, "duration": 0.81}, {"text": "And he drank it, he cured\nhimself, he drank it again.", "start": 3087.64, "duration": 4.32}, {"text": "And he caused stomach\nulcers in himself.", "start": 3091.96, "duration": 5.46}, {"text": "And hopefully, none\nof you will volunteer", "start": 3097.42, "duration": 4.14}, {"text": "to do similar things with\nsome of these other nasty guys", "start": 3101.56, "duration": 3.63}, {"text": "here because I think some\nof the list of things", "start": 3105.19, "duration": 2.7}, {"text": "that they cause are a little\nmore serious than stomach", "start": 3107.89, "duration": 2.43}, {"text": "ulcers, and the cures\nare a little less obvious", "start": 3110.32, "duration": 2.67}, {"text": "than the cures for a\ngram-negative bacterium", "start": 3112.99, "duration": 2.25}, {"text": "like Helicobacter.", "start": 3115.24, "duration": 3.6}, {"text": "There have been\nvarious efforts started", "start": 3118.84, "duration": 2.76}, {"text": "to actually mine what's the\nconnection with genomics", "start": 3121.6, "duration": 4.35}, {"text": "and computational biology?", "start": 3125.95, "duration": 1.26}, {"text": "To mine the transcriptome\nfor evidence of these.", "start": 3127.21, "duration": 5.13}, {"text": "You can look for\nbacteria very easily", "start": 3132.34, "duration": 1.8}, {"text": "because they have ribosomal RNA\ncomponents which you can PCR.", "start": 3134.14, "duration": 5.52}, {"text": "Viruses are more complicated\nbecause they're not conserved,", "start": 3139.66, "duration": 5.94}, {"text": "or they don't have any\nuniversally conserved element", "start": 3145.6, "duration": 2.79}, {"text": "like ribosomal RNA.", "start": 3148.39, "duration": 1.59}, {"text": "But there have been\nefforts to look", "start": 3149.98, "duration": 3.93}, {"text": "for what's present in the\nhuman transcriptome that's not", "start": 3153.91, "duration": 2.613}, {"text": "present in the human genome.", "start": 3156.523, "duration": 1.167}, {"text": "The human genome is something\nhighly purified and cloned", "start": 3157.69, "duration": 4.38}, {"text": "and so forth, while\nthe transcriptome", "start": 3162.07, "duration": 2.1}, {"text": "is whatever cells they\nground up that day and they.", "start": 3164.17, "duration": 4.38}, {"text": "And indeed, lurking in there\nare many of these hepatitis,", "start": 3168.55, "duration": 4.26}, {"text": "papilloma, Epstein-Barr virus,\nretroviral-like elements which", "start": 3172.81, "duration": 4.92}, {"text": "are not present in the\nhuman genome as yet.", "start": 3177.73, "duration": 2.55}, {"text": "Human genome is not\ncompletely finished.", "start": 3180.28, "duration": 2.11}, {"text": "So that's still\nan escape clause.", "start": 3182.39, "duration": 1.94}, {"text": "But basically, these are smoking\nguns for at least commensals.", "start": 3184.33, "duration": 6.33}, {"text": "Microorganisms and viruses that\nare living in tissues, some", "start": 3190.66, "duration": 5.1}, {"text": "of them may be tissue-specific.", "start": 3195.76, "duration": 1.86}, {"text": "Some of them, subset, may\nactually cause disease.", "start": 3197.62, "duration": 2.723}, {"text": "And that's the\nwhole problem then,", "start": 3200.343, "duration": 1.417}, {"text": "is sorting out cause and effect.", "start": 3201.76, "duration": 1.75}, {"text": "We know how it's been\ndone, heroically,", "start": 3203.51, "duration": 3.95}, {"text": "with Helicobacter\npylori, but how do", "start": 3207.46, "duration": 1.5}, {"text": "we do it with the other ones?", "start": 3208.96, "duration": 1.208}, {"text": "Some of them will have\ntissue-culture models.", "start": 3210.168, "duration": 1.957}, {"text": "At the time this slide\nwas done, but so--", "start": 3216.43, "duration": 4.68}, {"text": "this is just illustrating\nkind of the flow", "start": 3221.11, "duration": 4.68}, {"text": "of nucleic acid information\nthat comes in about--", "start": 3225.79, "duration": 6.24}, {"text": "that was capable of being\nmined for new microorganisms,", "start": 3232.03, "duration": 3.39}, {"text": "new viruses that might be\npresent in a tissue-specific", "start": 3235.42, "duration": 3.0}, {"text": "fashion, might be pathogens.", "start": 3238.42, "duration": 2.83}, {"text": "These are some of the\nmost popular sequences", "start": 3241.25, "duration": 2.12}, {"text": "from which we're mining.", "start": 3243.37, "duration": 1.44}, {"text": "Obviously, human was\npopular at times [INAUDIBLE]", "start": 3244.81, "duration": 4.71}, {"text": "the human genome was in place.", "start": 3249.52, "duration": 1.72}, {"text": "Here's Brachionus,\nour friend, which", "start": 3251.24, "duration": 1.76}, {"text": "was pretty high up on this\nlist, considering most of you", "start": 3253.0, "duration": 2.73}, {"text": "probably didn't hear about\nBrachionus before this lecture.", "start": 3255.73, "duration": 2.47}, {"text": "Now you've heard of it twice.", "start": 3258.2, "duration": 1.79}, {"text": "There just was a spurt\nin sequencing interest.", "start": 3259.99, "duration": 3.45}, {"text": "And of course, HIV\nis the winner year", "start": 3263.44, "duration": 2.49}, {"text": "after year because of the\nimportance of resequencing it", "start": 3265.93, "duration": 3.15}, {"text": "for new mutations.", "start": 3269.08, "duration": 2.32}, {"text": "And it really has a record\nnumber of new mutations.", "start": 3271.4, "duration": 4.52}, {"text": "And we've talked about\nHIV from a variety", "start": 3275.92, "duration": 7.2}, {"text": "of different standpoints.", "start": 3283.12, "duration": 2.28}, {"text": "One of them is\npolymerase, is protease,", "start": 3285.4, "duration": 2.88}, {"text": "is drug targets, and as a\nsource of drug resistance.", "start": 3288.28, "duration": 4.44}, {"text": "And that you can follow\nup that model, that sort", "start": 3292.72, "duration": 3.83}, {"text": "of atomic-scale\nprotein modeling,", "start": 3296.55, "duration": 2.92}, {"text": "where you're looking\nfor new drugs", "start": 3299.47, "duration": 4.62}, {"text": "where the polymerase,\nthe mutant polymerase,", "start": 3304.09, "duration": 2.16}, {"text": "will not be resistant\nto the new drug.", "start": 3306.25, "duration": 2.01}, {"text": "But you can also monitor\nat the population scale.", "start": 3308.26, "duration": 2.34}, {"text": "As HIV goes to a\nparticular patient,", "start": 3310.6, "duration": 3.39}, {"text": "or to a population of patients,\nhow does the drug resistance", "start": 3313.99, "duration": 6.54}, {"text": "change as a function of time?", "start": 3320.53, "duration": 1.65}, {"text": "Here, the horizontal axis\nis in days, up to 30 days,", "start": 3322.18, "duration": 3.66}, {"text": "and then the vertical\naxis is the titers", "start": 3325.84, "duration": 9.59}, {"text": "of the viruses [INAUDIBLE]\nas a function of time.", "start": 3335.43, "duration": 4.69}, {"text": "And what you have here is\nrates of exponential increase.", "start": 3340.12, "duration": 8.65}, {"text": "These are all on\nlogarithmic scales.", "start": 3348.77, "duration": 2.73}, {"text": "And where you're\nmodeling such a thing", "start": 3351.5, "duration": 2.52}, {"text": "as the clearance to the\nimmune system and so forth.", "start": 3354.02, "duration": 3.623}, {"text": "Originally, this\nvirus was thought", "start": 3357.643, "duration": 1.417}, {"text": "to be a very slowly replicating\nvirus, almost cryptic.", "start": 3359.06, "duration": 6.96}, {"text": "And then later\nwas found out this", "start": 3366.02, "duration": 1.38}, {"text": "is actually a very rapidly\nreplicating, but immune system", "start": 3367.4, "duration": 3.24}, {"text": "is very rapidly responding.", "start": 3370.64, "duration": 3.177}, {"text": "Just each of these\nmodels we've gone through", "start": 3373.817, "duration": 1.833}, {"text": "has a set of parameters\nthat it goes along with.", "start": 3375.65, "duration": 2.26}, {"text": "In a certain sense,\nthere's quite a bit", "start": 3377.91, "duration": 1.7}, {"text": "you can learn about a model just\nby seeing what parameters are", "start": 3379.61, "duration": 3.06}, {"text": "present or absent, whether\nthey're experimentally", "start": 3382.67, "duration": 3.63}, {"text": "determined, how\naccurately, and so on.", "start": 3386.3, "duration": 2.52}, {"text": "And model parameters here are\nmortality rate of uninfected", "start": 3388.82, "duration": 4.86}, {"text": "CD4+ T-cells, same thing\nfor infected cells,", "start": 3393.68, "duration": 4.235}, {"text": "and they can have different\n[INAUDIBLE] you can see", "start": 3397.915, "duration": 2.125}, {"text": "on the far right that there's a\nhuge difference between a diet", "start": 3400.04, "duration": 4.26}, {"text": "of 1/4 per day versus\n[INAUDIBLE] and so on.", "start": 3404.3, "duration": 5.95}, {"text": "There's rates for getting\ninfected, rates of virus loss,", "start": 3410.25, "duration": 5.0}, {"text": "production, threshold value for\nremission, so on and so forth.", "start": 3415.25, "duration": 10.65}, {"text": "And these are\nimportant parameters", "start": 3425.9, "duration": 3.35}, {"text": "for how the virus\npopulation changes", "start": 3429.25, "duration": 4.29}, {"text": "within a person\nor the population.", "start": 3433.54, "duration": 2.268}, {"text": "How it spreads\nthrough the population", "start": 3435.808, "duration": 1.542}, {"text": "depends on, in many cases, on\nthe herd immunity and so forth.", "start": 3437.35, "duration": 7.21}, {"text": "And we get into issues\nof public health.", "start": 3444.56, "duration": 2.99}, {"text": "It's almost a truism that\nmost of the additional quality", "start": 3450.87, "duration": 9.24}, {"text": "years of life, quality-adjusted\nlife years here,", "start": 3460.11, "duration": 3.66}, {"text": "QALY, that we have in the\nworld the fact that our life", "start": 3463.77, "duration": 5.19}, {"text": "expectancy is so much\nlonger and so forth,", "start": 3468.96, "duration": 1.77}, {"text": "are mainly public health\ndecisions that have been made,", "start": 3470.73, "duration": 4.53}, {"text": "not so much pharmaceutical.", "start": 3475.26, "duration": 1.8}, {"text": "Such things as clean water\nhave made a huge impact.", "start": 3481.04, "duration": 7.06}, {"text": "And so we need to think--", "start": 3488.1, "duration": 1.46}, {"text": "but even when you think about\nthe pharmaceutical aspects,", "start": 3489.56, "duration": 2.895}, {"text": "it needs to be thought of\nin a public health sense.", "start": 3492.455, "duration": 2.125}, {"text": "And a surprising amount\nof public health officials", "start": 3494.58, "duration": 3.47}, {"text": "in even the most developed\nnations, maybe most of them", "start": 3498.05, "duration": 5.25}, {"text": "do not have formal\neducation in public health.", "start": 3503.3, "duration": 2.34}, {"text": "And so I urge you all to get at\nleast some education in this.", "start": 3505.64, "duration": 4.68}, {"text": "Because in this, we have--", "start": 3510.32, "duration": 2.16}, {"text": "here, they're trying\nto build and have", "start": 3512.48, "duration": 3.57}, {"text": "built quantitative models,\nnot only for the kinetics", "start": 3516.05, "duration": 5.17}, {"text": "which a disease will go\nthrough a population or even", "start": 3521.22, "duration": 2.66}, {"text": "through an individual, but the\nway that you make decisions.", "start": 3523.88, "duration": 6.52}, {"text": "And this is having an impact\non the way decisions are--", "start": 3530.4, "duration": 2.66}, {"text": "how these different\nprojects are prioritized.", "start": 3533.06, "duration": 2.52}, {"text": "At any given time,\nyou might have", "start": 3535.58, "duration": 1.74}, {"text": "hundreds of different\ncandidate vaccines, which", "start": 3537.32, "duration": 4.5}, {"text": "is one of the major, very\neffective public health", "start": 3541.82, "duration": 3.99}, {"text": "strategies.", "start": 3545.81, "duration": 2.49}, {"text": "And this is the way\nthey prioritize it.", "start": 3548.3, "duration": 2.05}, {"text": "So the level one, saves\nmoney and it improves life.", "start": 3550.35, "duration": 3.68}, {"text": "So that's almost a no-brainer.", "start": 3554.03, "duration": 3.72}, {"text": "Then you have different levels.", "start": 3557.75, "duration": 1.39}, {"text": "We have it might cost\na $10,000, or $100,000", "start": 3559.14, "duration": 5.21}, {"text": "per quality-adjusted\nlife year saved.", "start": 3564.35, "duration": 2.565}, {"text": "And so the level one\ncandidates are cytomegalovirus,", "start": 3570.2, "duration": 3.66}, {"text": "and therapeutic vaccines.", "start": 3573.86, "duration": 2.4}, {"text": "These are not aimed at\nan infectious disease,", "start": 3576.26, "duration": 2.46}, {"text": "they're for diabetes, rheumatoid\narthritis, multiple sclerosis,", "start": 3578.72, "duration": 3.78}, {"text": "various bacterial ones.", "start": 3582.5, "duration": 1.695}, {"text": "And of course, HIV was\nnot even in this study", "start": 3584.195, "duration": 1.875}, {"text": "because it was such a\nhigh priority already", "start": 3586.07, "duration": 3.96}, {"text": "within the NIH.", "start": 3590.03, "duration": 0.72}, {"text": "So is there a role for genomics\nand computational biology,", "start": 3595.773, "duration": 2.417}, {"text": "the title of this course,\nin this vaccine research", "start": 3598.19, "duration": 3.09}, {"text": "and development?", "start": 3601.28, "duration": 1.56}, {"text": "I think the answer\nis yes, but it", "start": 3602.84, "duration": 2.25}, {"text": "requires a great deal of\ncreativity and resourcefulness", "start": 3605.09, "duration": 2.85}, {"text": "on all of your parts.", "start": 3607.94, "duration": 2.19}, {"text": "There are new opportunities\nwith DNA vaccines where", "start": 3610.13, "duration": 3.6}, {"text": "you can have one or more\nDNAs shot intramuscularly", "start": 3613.73, "duration": 4.29}, {"text": "or a variety of other ways.", "start": 3618.02, "duration": 2.73}, {"text": "What is delivered\nby the DNA vaccine", "start": 3620.75, "duration": 2.25}, {"text": "can be various so-called\nintracellular vaccines,", "start": 3623.0, "duration": 4.74}, {"text": "which can either act through\ncell-mediated immunity", "start": 3627.74, "duration": 2.37}, {"text": "or in some other\nway intracellularly.", "start": 3630.11, "duration": 2.88}, {"text": "RNAi is a rapidly emerging\nway of delivering things", "start": 3632.99, "duration": 8.49}, {"text": "that may not be\nclassically considered", "start": 3641.48, "duration": 2.82}, {"text": "therapeutics or vaccines.", "start": 3644.3, "duration": 2.97}, {"text": "The concept of multiplexing--", "start": 3647.27, "duration": 2.49}, {"text": "many of us have received\nmultiple vaccines at a time.", "start": 3649.76, "duration": 7.68}, {"text": "Typically, every\nyear, your flu vaccine", "start": 3657.44, "duration": 1.89}, {"text": "will have two or\nthree strains in it.", "start": 3659.33, "duration": 1.84}, {"text": "But as you can see from\nthis middle article,", "start": 3661.17, "duration": 4.85}, {"text": "the diversity of\ncertain diseases,", "start": 3666.02, "duration": 1.86}, {"text": "like HIV and influenza, almost\ndemand attention from genomics.", "start": 3667.88, "duration": 5.46}, {"text": "The diversity that can occur,\neither from year to year", "start": 3673.34, "duration": 3.42}, {"text": "or throughout the entire\nglobal set of viruses.", "start": 3676.76, "duration": 8.29}, {"text": "Another opportunity\nis when we have", "start": 3685.05, "duration": 2.69}, {"text": "vectors for, say,\narthropod vectors,", "start": 3687.74, "duration": 4.38}, {"text": "insect vectors like mosquito.", "start": 3692.12, "duration": 1.95}, {"text": "And we have opportunities\nto hit malaria and all", "start": 3694.07, "duration": 6.0}, {"text": "the different life stages.", "start": 3700.07, "duration": 1.347}, {"text": "There are multiple life\nstages within humans", "start": 3701.417, "duration": 1.833}, {"text": "and multiple stages\nwithin the insect vector.", "start": 3703.25, "duration": 5.19}, {"text": "And now, the genomics\nof these two just", "start": 3708.44, "duration": 2.28}, {"text": "came out recently, in the same\nweek, in Nature and Science.", "start": 3710.72, "duration": 6.03}, {"text": "This provides a whole new\nset of inspirations for work", "start": 3716.75, "duration": 4.767}, {"text": "that can be done on these.", "start": 3721.517, "duration": 1.083}, {"text": "I think we should take\na little break now,", "start": 3722.6, "duration": 2.4}, {"text": "and we'll wrap up the\ntalk after that break.", "start": 3725.0, "duration": 4.25}] |