Synthetic and Systems Biology: Reinventing the Code of Life

00:00:00 The Healing Center this is working I'm Ed nessian director of the heing center welcome to this program on synthetic and systemic biology um before uh Rob pener introduces the participants and tells you a word or two about our future programs I'd like to say that the me meeting will last around an hour an hour 15 minutes after that you'll have time to ask questions but please please ask

00:00:31 questions rather than making commentaries uh I think it works better that way thank you so let me tell you first about some upcoming events on Saturday May 18th from 6:30 to 8:30 we're going to have the second annual heavy mental variety show it's a night of mind brain and Magic the amygdaloids led by uh neuroscientist Joseph Leo will'll play several Suites of original songs on mind

00:01:02 brain topics the Mind Body problem memory emotion unconscious processes and mental disorders each Suite will be preceded by a short lecture on the scientific or philosophical foundations of the topic uh also uh internationally acclaimed magician Mark Mitten will Dazzle you with mindbending and brain twisting tricks of his trade doors open at 6:15 admission is $10 without drink tickets and $17 for tickets with two beers or glasses of wine uh Saturday June 8th altruism and

00:01:35 empathy is a program with Stephanie Brown Alan Leslie W Schwarz and others uh then there are some roundtables that are in the works for September but I want to uh make special emphasis on uh a symposium that we'll be holding on October 12th and 13th in co-sponsorship with the algama foundation of Switzerland uh it'll be a two-day Symposium exploring the signific of the work of ab warberg for art science and psychoanalysis we will reexamine his work through the compound

00:02:07 lenses of current knowledge of dynamic memory the Freudian unconscious and historical scholarship it will be an international Gathering of Scholars drawn from the Arts and Sciences uh featuring roundtables uh exploring warberg ideas and their admirations and will'll focus on neurotics memory and unconscious psychosis and creativity and uh biswanger and warberg P Wanger was his psychiatrist at one point and classical and Renaissance art uh also the evening preceding it Friday the 11th

00:02:38 will feature the meloid returning for pre Symposium performance and joining us at the Symposium thus far are historian Christopher Johnson historian and psychoanalyst Peter lonberg art historian David Friedberg philosopher and art historian George DD huban philosopher Andrea pinotti warberg Institute historian franois qu neuroscientists Christina alberini Anan chat and Victorio gesi and Pier magistrati uh and psychoanalysts franois

00:03:09 an and edner Cassian also novelist and essayist Siri husted let me go on now to today's program uh no as as soon as we have uh the definite uh times of the roundtables and the confirmed uh other participants will put it up on the website but keep checking back thanks so let me introduce today's uh participants Andrea califano is the Clyde and Helen woop professor

00:03:40 and chemical and systems biology in the Departments of biochemistry and molecular biophysics and of biomedical informatics at Columbia University he is currently the founding director and chair of the Columbia Initiative for systems biology he also serves as associate director for bioinformatics in the Herbert Irving Comprehensive Cancer Center Dr califano serves on numerous editorial and scientific advisory boards including the board of scientific advisors of St Jude Children's Hospital the Sanford Burnham Institute MD and Anderson genomic medicine department and

00:04:10 the National Cancer Institute Mark Fishman is president of the novaris institutes for biomedical research he leads worldwide Discovery and early clinical activities of nardis which aims to develop novel Therapeutics for diseases prior to joining novaris Dr Fishman was professor of medicine at Harvard Medical School as well as chief of Cardiology at the Mass General Hospital and the founding director of their cardiovascular research center Dr Fishman is a fellow of the American Academy of Arts and Sciences and the Institutes of Medicine of the nationaly Michael HEC is Professor of

00:04:41 chemistry at Princeton and holds Affiliated appointments in the department of molecular biology and The Institute for Integrative genomics his research is at the interface of chemistry and biology specifically his LAB Works in protein design and synthetic biology as well as on the molecular underpinings of Alzheimer's disease in addition to teaching and research Dr HEC is the master of Forbes College one of the six undergraduate colleges at Princeton University Christopher Mason is assistant professor at Wild Cornell Medical College in the department of physiology and biophysics and at The Institute for computational biom

00:05:11 medicine Professor Mason also holds appointments in the tri-institutional program on computational biology and Medicine of Cornell Memorial slung kering and Rockefeller and at the wild Cornell Cancer Center where he's the director of the single molecule lab he is co-founder also of the New York synthetic biology Association s Tavy is a systems biologist who was professor in the department of molecular biology and The Institute for Integrative genomics at Princeton before joining The Faculty at Columbia University in 2011 over the years his

00:05:41 laboratory has addressed fundamental challenges in decoding the regulatory genome and revealing how networks of interacting genes Implement complex phenotypes the long-term goal of his research is to achieve a predictive understanding of biological behavior in terms of the structural and dynamical properties of the underlying molecular Networks and Michael Wald hotz most recently served for six years as managing editor at Bloomberg News business week following his 25-year career as a writer editor and bureau chief at the Wall Street Journal at Bloomberg he was responsible for news coverage related to

00:06:13 healthc care and science including the pharmaceutical and biotechnology Industries health insurance medical services public health and health policy Mr Wald Holz is the author of the book curing cancer and a co-author of genome he was awarded the 1996 Pitzer prize for National reporting for his stories on the Breakthrough in AIDS

00:06:44 medicine Let's uh let's start the conversation who would like to initiate with a question or a remark or maybe say a few words about what the subject is about I think one of the ways to um discuss the the topic I'm a systems biologist but also dabl in synthetic biology but um these new Fields as they emerge they have a definition problem because the

00:07:14 initial the initial Pro um initial investigators who are you know forging the path forward they're all doing somewhat different things and they're in in the process of actually defining the field and so I think one way to uh to to Define system biology is in contrast to the prevailing approaches of of Modern Biology of the last century that have been extremely successful two axis of which are um biochemistry and genetics so I I think if if you if I were to describe this really powerful um

00:07:46 existing methodology that that is responsible for basically everything that we know almost everything that we know right now there are two ways of studying biological systems one is to break it down into its composite components and and intricately study the details of those individual components in attempt to figure out what what they're what they're doing what the whole system is doing that's sort of uh what biochemistry does the other approach is been very successful is even older than biochemistry which is genetics which is to take those individual components break them down

00:08:18 and see the effect that that has on the system see how that perturbation causes a malfunction in the system right and um so it's it's akin to essentially studying for example how a car works by you know slowly destroying little parts of it like taking out the spark plug or the carburetor and seeing what effect that has so it's it's an extremely gross and caveman approach to understanding the system but it has been extremely successful but the real challenge nowadays for for all of us in biology

00:08:50 and I think that's what kind of was the impetus behind systems biology is to attempt to understand what the whole system is all about what is it doing how are the part parts coming together and I think the grand um vision of think I think for us to shoot for is to have an understanding of of biological systems in ways that are more similar to what physicists uh think about systems which is to be able to predict the dynamical trajectory of a system in time know it well enough to understand that right

00:09:20 that's the challenge and I would argue that we're very very far from that still but this is kind of the um this is kind of the goal that we're shooting for to engineer system well I think engineering a system is important because I think one way and that that's sort of What synthetic biology is about but I think in order to really if if you want to prove to someone that you really understand the system you you should be able to re-engineer an instant of it and and and have it and and predict what that thing is going to do and I think that's this this scientific value of synthetic

00:09:52 biology there of course other aspects of synthetic biology that are really important yeah agree I think that's the the true test of our understanding is the ability to forward engineer and then you know discreetly predict exactly what might occur it scares some people though that's the thing when you say synthetic biology there's often uh people uh who are worried that you're going to be creating super bugs or or um you know they think of evil scientists in their lab hackling late at night but the you know most most biohackers or more synthetic biologists are generally just tinkerers they just want to try to

00:10:22 discern what is sort of this test of their understanding of the genetic system and um he's even a laboratory in Brooklyn that's called space which is a Community Laboratory the way you think of buying a gym membership today you could go to Brooklyn on Atlantic Avenue and get a membership to gen space and go and play with Pip pets and if you want to make some of your Sal turn green with gfp you can do that in a couple weekends and uh learn how to do it so there's you know and that's just synthetic biology but when they set up the lab in in Brooklyn they had the FBI come first to make sure that they were legitimate and they invited them to come so really we're just a group of people who want to

00:10:53 Tinker they're really tinkerers and so you go from that impetus of tinkering I think in in larger academic industrial centers to make it on a on a real high throughput scale so it's well I I was just going to say maybe as a as a as the lay person the non-science scientist on the panel it might be good for everyone here if someone could give because I I think that was a really great General picture of of of how systems biology differs from what was being done but I think for many of us synthetic biology needs a

00:11:26 very specific description with examples of what's going on I'll do that um so again I think what what s was defining was systems biology synthetic biology um in a sense I'd like to Define that by saying that biology as we know it be it old biology that was taking things piece at a time or systems biology the modern type of biology those fields are looking at that which is and I think synthetic biology goes a Step Beyond that and asks what might be possible what what might we have not yet

00:11:57 seen but it's still possible okay so in a sense well just just that that synthetic biology is going beyond that which is and explores that which might be possible which really does have a bit of a a you know science fictionally Brave New World tone to it um but it's real so could you let me elaborate on that and I'll tell I think much of what people normally think of as synthetic biology um is where people are taking pre-existing genes proteins or regulatory elements from various different uh cells organisms and mixing

00:12:30 and matching them to make new cells that have particular properties the example you gave a moment was a moment ago where you can take a green fluorescent protein that exists in one particular system and then move it into another system and you know people have made well green fluorescent organisms that are that didn't fluores before so that's one form of of uh synthetic biology um and that's eco like bananas for example right so and and in that in that case there people are taking pre in a sense one can look at it as as an analogy as a toolkit of parts and so the

00:13:04 natural biology that we have is a toolkit of Parts genes and proteins and Regulatory elements and much of what people do in synthetic biology is to take these tools these parts and rearrange them into different machines um that's one form of synthetic biology and that's what most people think of when they discuss synthetic biology I have a different take on synthetic biology which I I don't want to uh well I'll do it now a different take on synthetic biology which is a bit perhaps more synthetic um and that is well you started by saying how do we Define the

00:13:34 basics and maybe we'll define biology before we even get going and um so what does it take to be a living system what does it take to be a cell what are the minimal requirements to be a cell and I think in some respects one can say that a living system a cell has to have molecular Machinery molecular machines that do stuff right so a living system has to have an enzyme that digests food that's a molecular machine or a molecular machine that enables vision um so those are molecular machines and most of the molecular machines in biology are proteins so one thing living systems

00:14:05 need are are defining living systems is a collection of molecular machines that do stuff the second thing I think that living system that we need to Define in terms of living systems are a blueprint or an encoding a way of encoding those molecular machines such that can be passed down from generation to generation so a factory is a is a collection of machines not molecular machines but it's not a it doesn't pass down that collection of machines to the Next Generation biological system cells have a collection of molecular machines

00:14:35 the proteins that do stuff and a genome that encodes those molecular machines and the genome gets passed down along the way so my view of synthetic biology is a bit different from from what I mentioned earlier in the sense that instead of taking molecular machines and genes that pre-exist in nature and recombining them into different systems taking the banana smell and put it into bacteria taking the green fluorescent protein and putting it into C hats or whatever instead of mixing and matching pre-existing Parts I think synthetic biology in it in its most extreme case is now at the point where rather than

00:15:07 take those pre-existing machines and mixing and matching them one can ask is it now possible to come up with new sequences new proteins new genes that can sustain life I would I would challenge a little bit that because um I think there's a much broader sense in which we can think of synthetic biology um for for instance if you go back to what say was saying in terms of sort of creating something that has essentially a new function that has not been previously seen utilizing biological components let's say that for instance

00:15:37 using sa to synthesize alcohol in a bath was probably the oldest form of synthetic bio and and it doesn't necessarily have to do with uh with with a genome or sort of forance there are many ways in which you can even use Natural Evolution um you create environments in which bacteria can multiply and naturally achieve certain type of selective functions and that also can be considered sort of synthetic biology and so I would say there's an entire progression of application of

00:16:09 synthetic biology that go all the way from uh sort of synthesizing molecules using sort of biological forms um all the way to actually synthesizing no forms of biological Life by messing around with the DNA and I think kind of they're almost I say synthetic biology and system biology are almost the two faces of the same coin I think if you exclude reproduction the two strongest pulsions of the human mind is one to try and figure how things work and the second one is to mess around with them as soon as you understand how it work and to some extent it's exactly what the

00:16:41 two fields are doing cist biology is trying to figure out things work and is trying to do so in a way that sort of takes steps back and goes into much more unbiased sort of completely uh neutral approach to understand biology where for instance people say an example in the English language and say the word duck uh depending on how where you say the word duck you know somebody says duck and you're in the street you better just get out of the way but if somebody say dock in in a French restaurant then know it means a completely different thing

00:17:11 and so in biology is exactly the same thing same gene may be doing completely different things in different context yet the old vision of M biology was that this is oppressor this dysfunction this activates theosis these are all true uh observation in a particular context and I think if system biologist thought us something is that context is extraordin important and context is both molecular and phys uh so on the other side I think once we have this recipe for something

00:17:41 that we we think ourselves sort of living in our lab living at the boundary of of systems and synthetic biology some of the things that we use from systems to actually implement the synical biology is reprogramming cells so if you take for instance uh two genes and modulate them using molecule or using genetic approaches and you can now turn a lineage of a cell into another lineage uh that's a form of of biology doesn't necessarily require reprogramming the DNA but certainly reprograms the full

00:18:11 cells into do a complete not function so so these are I would say there's an entire repertoire and this is also a way to ditify a little bit the field because if you start thinking ofy as the way you know beer was down in the first place then it becomes a little bit less threatening if you think about you know it's manipulating DNA making Frankenstein uh so and where you put exactly that threshold you say it goes from being something that is controversial to being something not controversial I that's where you really have to move your ethical slider and try

00:18:42 to figure out where it is but uh it's not a it's not a real breakpoint entire I I I think the break point is that it's now just in the last few years become possible to not just move proteins and genes from one system to another but to actually create new SE sequences that bear no resemblance to anything that ever existed before and to have those enable biological functions I think that's new that's nature that all the time so every day you go on a plane you're you're getting exposed to

00:19:12 ionizing radiation and you know every cell your body accumulates novel changes so I'm just saying you could achieve the same goal by using goal directed functional optimization in a high uh sorry in a high mutational context for instance you remove DNA repair gen from a bacterium you can essentially engineer the same way as if you actually put in new pieces I have a simpler definition M which is any interaction that humans have with biological systems that changes the

00:19:44 behavior of those systems and the implications that come from that run a gamut as a physician I'll start with the medical possibilities are fantastic you can make new medicines in fact any medicine in fact is syn a synthetic biology both in its origin and its impact on the cell and then the second is the scientific question which I think is what's being addressed here too which is

00:20:15 a question of how do you actually influence a cellular system and what's remarkable is how robust systems are they tend not to change so you can push on them in many many ways without them changing and that's where as a geneticist the caveman approach which is what I do um is so remarkable because the that approach the genetic approach finds those few nodes in the whole

00:20:46 system that are critical and causes the system to either collapse or to amplify and those are in many ways where the synthetic biologist will go because most of the the places you interfere turning genes up or down or proteins on or do nothing and so in fact of course it's actually a miracle that any of us survive any drug we're given because these drugs have very

00:21:17 powerful effects somehow the body buffers them in most cells except for the cancer cell or the cell that needs to be attacked so that's the scientific element but for me it's not a comp synthetic biology is not complicates anything you do that changes the system the behavior of that system I think I think something that's really fundamental to that point is you know the the origin of these systems right biological systems come about through this random process of mutation and natural selection over hundreds of

00:21:47 millions billions of years right and the and you know there are there's an organizing principle there a bunch of organizing principles that contribute to its Evolution and function so if you imagine these kind of buffered systems where you perturb lots of different components quite a bit actually and the cell is doing perfectly fine you'd imagine that you would say that the biological systems in general are extremely robust to environmental pation to noise and so on and so forth whereas if you compare them to human engineered

00:22:18 systems like 747 or something right each of the components in these in these machines have been designed to have some tolerance but the tolerances that they have are typically much worse than biological systems and part of that has to do with the fact that these systems have to withstand a certain amount of mutation as they evolve with time they have to they have to have components that are modular because of the mix and matching that goes on and the sharing of genetic information that happens as a function of evolution mostly among the

00:22:49 microbes in horizontal Gene transfer but those kind of contingencies of natural selection are embedded in the way in which the system function functions that are very different different from the kind of things that people think about when they want to design a system from scratch and I think what's really what's really amazing uh and really fascinating I think to to to look forward to in the future is is the adoption of a lot of these evolutionary methods some of which I think Michael has has done in his work and others is to use

00:23:20 utilize rapid evolutionary scenarios to design systems that are robust to variety of different Environmental peration and variations and you know what's interesting about that just as a footnote is that cancer is not robust that's why we can kill it because it didn't evolve to support the rest of the system that's right that's right and to that to that end I think the idea of starting to Design Systems designing life again we would probably not like some of the things that Evolution has designed for example increasing gene

00:23:52 expression noise as a measure of Fitness in some cases or increasing mutation rate to give you a further adaptive advantage for some bacteria we would probably not design a system to start to do those things but they're actually Evolution has has created them I I think as a again as a lay person looking in the thing that interests me about synthetic biology is that it is an extension of of using all the tools of uh molecular biology or genetic engineering that have come about over the last 20 to 50 years to do what

00:24:22 Michael says which is to create new forms of of of life or new versions of existing forms of life by actually in the laboratory creating SE genetic sequences that don't exist often using the same uh laws of of that uh govern how we exist today laws of mutation I think for most people we don't understand that we've evolved to who we are today through some sort of natural selection but that we aren't exactly who

00:24:55 we might have engineered from the first place and you know if we had to choose but that a lot of this tinkering has exactly you know people get very concerned and I'll bet you we get questions from the public that you are playing God or tinkering with with nature in a way that you know how do you have the right and who's governing you but that kind of tinkering of course mankind has been doing and nature has been doing from the get-go I often think of the piece of corn for some reason I I always look at corn when when corn first evolved on in

00:25:29 in this hemisphere in the North or Southern Hemisphere it didn't look anything like what corn looks like today and corn looks like what it does today because of human tinkering with with it same with apple same same with apples dogs dogs are even better example so we've been tinkering all along or horses yeah I would even argue I even push back against people who who critique it and one is the historical context you just mention but I would even argue I guess I'd put forward the thesis that it's actually our duty as a species to embrace the engineering and that that um our survival may very well depend on if

00:25:59 you think in the long long term I I'll posit the sort of thought experiment so you think 100 years from now or a thousand years from now or a million years from now um I actually have this question whenever we interview grad students or faculty for the Department my last question I always ask them is how long do you think the human species Will Survive and it always throws people off because they're not expecting that at a job interview or a student interview but I like it because it gives me a sense of their hope actually for the human species and a lot a lot of times people say a thousand years or a million years and I usually remind them we've been here at least for several years in our current form uh but one person even said 100 years I think well

00:26:31 humans only be here for another 100 years and I said well well good God man why don't I just go to the beach and sell bananas and hang out he said well I want the last 100 years to really count it actually what he said I couldn't imagine it but but I would argue it's our duty because if we probably won't be here on this planet forever and the human genome's not built to live on other planet so we may have to think of a time when we reengineer the species on which we depend or even the human genome uh in order to actually survive in a long long long term I think we we we have the ability as a species to think think that far so we should consider that as a thought experiment so there's there's a precise moment in time I think

00:27:02 if you look at Albert's Nathan's and Smith Nobel Prize right when they restriction enzymes that demarcated very important Milestone because before the only thing you could do to manipulate biology was essenti looked very natural you know like you could graft a plant on top of another plant you know and people have been doing that for tens of thousands of years nobody ever thought that would be you know either an ethical or potentially controversial um people have been breeding dogs Etc but the moment you could actually do it molecularly and and actually infringe on

00:27:32 the domain of the most sacred molecule was DNA then all a sudden things escalate to tremendous proportion I think you know obviously one of the things that actually Mark says I think is extremely important is that you have you know we we live to be a system at ostasis and so actually 90% of our Machinery is to keep the cell doing exactly what it's doing regardless of perturbation but the biggest ostatic system is the actual world you know that if you look go outside you one of the biggest problem you have right now people try to engineer alga to produce

00:28:03 lipids at much higher rates so you for instance get better biofuel production and people have been very successful doing that you know why we're not producing fuels because the moment you actually start bring these things in normal environment they are immediately outco competed by normal algae that don't do that and so that's the way of the of the planet of getting back and basically telling you look yeah you can produce more fuel but for the planet it's not very helpful and so these these species will actually be out computed and will eventually die we become not a dominant species so I think that we have to always come to terms um with with I

00:28:35 think today I read the New York Times that our CO2 levels are the highest in 400 million years that worries me heck a lot more because that can trigger an absolutely irreversible catastrophe in planets no way to react to that um most of the living organisms uh if you think at the number of species that we have and the number of genetic experiments that are happening every day in each one of them just because because of you know rate normal rates of mutations almost everything that you could possibly do in the lab is actually been done out there uh so when you say we're synthesizing new virus for influenza that is lethal

00:29:07 and can transmit man to man that's been done every day out there I have to disagree with that I have to go back to what I said before and disagree with that I think the current and the next stage of synthetic biology profoundly different it's not just ionizing radiation and individual mutations and it's not just sampling sequences that may have been already sampled I think it's it's at the point now one one can design proteins entirely from scratch that are not mut mut uh not mutationally related to anything that's been seen on Earth before and one can sample new sequences both protein

00:29:39 and DNA sequences that are unrelated to anything that's ever been around and I think that's a fundamentally different thing it's not just making mutations Michael can you give has anything been created like that that can a specific example well I that's what my lab does but there there's also um I mean I think you know in terms of of protein design there's there's David Baker in Seattle who's doing computational work to design proteins entirely from scratch with predetermined folds and predetermined activities um that are unrelated to

00:30:09 anything that any sequences that exist on Earth my own work we're making libraries of of Novel sequences unrelated to anything that has ever existed on Earth sequence space is larger than can have ever been sampled over the history of of the universe and so one can now make sequences that have never existed before and then challenge those sequences to provide to to see whether they can provide life sustaining functions so one can actually go into bacterial cells knock out parts of the genome and then see if those parts of the genome can be replaced by sequences

00:30:40 that never existed before so if you do that if you take a bacterial cell that has 4,000 genes and you replace four of them well then it's an ecoli that's a little weird and it has four new genes again these are not mutant genes these are genes unrelated to anything that ever existed so if you do it 4 out of 4,000 it's minor thing but when you start it's I'm not going to do this but one can imagine just around the corner that people can now replace large sections of a genome of let's say a bacterial cell with sequences that never existed before in the history of the

00:31:11 earth and then that I I think one has to sort of come to grips with the fact that those are new forms of life that are not evolutionary variants of existing forms of life they're fundamentally new fundamentally new sequences proteins designed from scratch genomes designed from scratch that I think is around the corner and I think that's you know in terms of philosophical or theological issues that's sort of you know something that one wants to think about another example would be chemotherapy often we use nucleoside analoges we have variations of ACG andt that are just different enough that they kill the

00:31:41 cells and so you can use synthetic biology I would even argue the chemotherapy could be viewed as a form of synthetic biology and the Gen the genetic code there were 20 amino acids for as long as the world's been around but we can now engineer the genetic code to have more than 20 amino acids Why is the I'm trying to understand or grasp what is the fundamental semantic difference between having a protein that is completely different from another one and got to be completely different because through some very complex evolutionary path got there or one that you engineer from scratch parentage the

00:32:13 difference is parentage the difference is lineage the difference is whether it evolved from something that pre-existed out in Darwin swamp or whether it's something that came to be in in a synthetic lab I understand but what I'm saying is it's a different it's a form of mental Evolution like instead of deriving from uh a process where you one mutation at a time you get there by a process by which the mutation the complete set of mutation is is computed by computer by a and be but the but the point is you now have a new protein I'm saying we are creating new proteins all the time we're doing that mutation me

00:32:44 some some cases we're doing by big rearrangements and so other things that are you know you do an inversion for instance that is a really again I think in the Public's mind one is the The evolutionary is natural natural and this is synthetic and I think that is the question that the product is the same you know the protein is the same so for instance again to get you know as as a journalist we try to get down to examples I think there are a couple of examples of synthetic biology that are

00:33:15 out there already that are interesting and it's interesting to see whether the public is bothered by it uh one is create changing the genes of of algae to produce algae produce lipids or Oils or fats and getting algae to produce biofuel of some type or in another instance changing the genome the genetics of yeast to not only uh create alcohol when they interact with sugar but now to create fuel which is already happening not in a commercial level but

00:33:46 it's happening and those are examples of what at least has been described to me as synthetic biology at that level I think the public sort of feels okay you know we're we're s sort of tinkering with yeast in one instance and maybe bacteria in or algae in another instance but what what is it when we start tinkering with humans so you're talking about the fact that there may be medicine in the future do what do you from synthetic biology what do you see let me take it over several different

00:34:17 ranges the first is we can now take uh individual genes in a bacteria and line them up in a way so they will make novel drugs because you can predict from the sequence of the enzymes you put in there all the reactions that the cell will do and then they will excrete that and so you could in principle um make very comp and do can naturally make very complicated molecules naturally in a Cell in fact

00:34:49 these are called natural products even though these of course are unnatural in the sense that way we're thinking about it so from the point of view of new medicines very powerful because the these kinds of natural products are extremely good at being drugs let me take it to the extreme I have uh taking care let's say we're taking care of a a child who has uh inherited disorder well now we can go in with a particular set

00:35:19 of enzymatic Replacements and this has not been done but in principle we certainly have done it in experimental systems take out the bad Gene and put in the good Gene replace it with the normal Gene uh would you deny that to a child you're changing their genome yeah why would you not do that now we're not there we're far from that there's lots of issues about how many cells would have to take it up Etc but if you had uh

00:35:52 a child with let's say with hemophilia uh rather than getting regular injections every day uh or regularly to prevent bleeding would you not take the opportunity to fix uh their uh hemophilia Gene of course you would at least I would as a physician what if it was an embryo it's easier if it's an embryo there's less you can certainly do it as an embryo and that's where it's been done in other animal species but even in uh an adult in Prince or or a child in principle if you could change enough of the uh liver and you get

00:36:25 enough into the liver you could do it so there you have an extreme one you're tinkering with bacteria everyone says you can make a drug the other you're tinkering with humans both cases you will change you will revolutionize medicine for the better there's even the more extreme scenario that's actually being used in in human trials so HIV infects uh T lymphocytes and so there's a small fraction of a Western European population that has a variant of a COR receptor on the surface of the cells that is very ineffective for HIV infection and so what they're doing now

00:36:57 in humans now is going in taking out some of those white white cells in HIV patients and using zinc finger nucleosis to inactivate or modify that that Co receptor in a way that makes that t- cell this patient's t- cell in vitro impermeable to the HIV put it back into the human and have that grow and repopulate and the idea is that eventually this could be a a nice way to to to uh destroy the uh to get rid of it

00:37:27 so these these kind of things because of the example that Mark brought and there going to be many more examples coming up because now because of really amazing fundamental basic Research into understanding the way in which molecules work we now have generated these tools that allow us to go in and engineer human cells or any kind of cells we want and people are going to be wanting these treatments because they're critical Cristiano has engineered his Gene directly into the stem cell compartment of the bone marrow and essentially repopulate the niche this thinki bullosa

00:38:00 and you know basically this one child that was treated was effectively almost completely cure of of pretty bad Disease by essentially doing the the direct transplantation in the bone M these are but I I mean what I was trying to do before was simply to some extent demystifying and when I do this I'm doing I'm kind of doing a more maybe a little bit provocator way because obviously I'm not trying to say that I'm not trying to in fact to pass Judgment at all this entire field I'm just basically saying that there are over

00:38:31 sessionization of of the process and then there are under sensationalization of the process that that are happening in some cases for instance we think that certain things are you know immoral when we have actually been doing some other things that are very very close to them and are not quite substantially different in in theory um but that were considered to be natural and all of a sudden because you're doing this at the molecular level it's no longer natural um and to some understand there always when chemistry gets involved that things get complicated but we have to remember that we all work with chemistry whether

00:39:03 it's natural chemistry or not uh so when you actually graft a plant on another plant and you mixing their genomes to some extent you are doing chemistry you're doing chemistry in a way that doesn't involve pipets but it's still chemistry I think I I I want to bring the conversation a little bit back to systems biology because the degree to which synthetic biology is going to be successful and people are going to rely on and and it's going to actually over longterm produce results that people aren't going to be afraid of relies on a

00:39:34 foundation of understanding of of how cells work right and that's where systems biology and Modern Biology comes in right and um so one of the major challenges for us is to understand these systems well enough to be able to predict exactly what happens if you re-engineer a particular molecule in the cell and what is the what are the what are the consequence of that when you put it back in in a very complex multiscale system which is a human body all these organs interacting with each other where we have just only

00:40:05 begun to scratch the surface of that kind of potential interactions that can happen so so I think um you know I think synthetic biology and system biology are going to be interacting with each other as as they as they co-evolve and and synthetic is going to heavily depend on on on on systems and I think this marks the this marks actually The Divide between what my we're talking about which is using natural selection Evolution to develop variant of existing molecules is a is a is a you know

00:40:36 brainless essentially brainless thing you just set up the selection cause mutations and you you you'll end up finding bacteria that can do a particular thing or or mimon cells but having the knowledge of what are the compositional components the organizing principles by which amino acids come together to form proteins what do those folds do how do the folds interact and how do you make machines out of those folds is a is a is a foundational knowledge that we need to gain and

00:41:07 people are gaining you know Michael's laboratory for example in order to set up a foundation that allows us to build new things based on rational engineering principles and I think that's where the most exciting stuff is happening because that's where it will impact our understanding of biological systems right um um and so so I think that's what I find really and the other way around too I think actually what has been to me R transformation is that we always think that understanding biology informs the ability to engineer it but actually ability to engineer it also

00:41:38 really helps dissect it so for instance Diego de Bernardo who came from uh Jim Collins lab engineered in East a fairly complicated circuit and that circuit was used in this this conference that we ran for the last seven years called dream where we essentially challenge existence biologists to dissect the piece of biology we actually know the problem is that there's really no piece of biology that we actually know literally there's not a single one that we actually know except for Extraordinary simple things so having an actual engineer system and was engineered in a way that could not

00:42:08 interact with the the rest of the environment needs um was incredibly important because now you can get data that basically says if you can reconstruct what the logic of the circuit was now we know that that your method works well before there's really no way whether to know whether it was able to reconstruct you have a gold standard you have a gold standard it's so this was actually I think that there's an entire new um new sort of discipline in synthetic biology that will help uh assistance biology dissect regulatory models i' like to elaborate on elaborate on something s said a

00:42:38 moment ago about making mutations and selecting is is brainless is easy and I agree um versus engineering and and knowing something about the system and I think it it has to do with Darwin on the one hand and engineer on the other hand and having them work together so if you make random collections ofic mutations and you do selection he said it's it's brainless and Mindless we can do that and it works um however if you understand the system then you can make a smart Library so suppose you can make 10 to the 9th a billion different variations of something if you make that

00:43:09 billion variations randomly and you select among them for a desired property you may or may not get a hit of what you want even among a billion however if you know something about the system the system being either the molecule or the entire cell then you can devise a collection same number 10 the 9th AB but now that billion is sampling that region of space that's most likely succeed to succeed and that's incredibly powerful so if you can now make a smart Library um I'm using the word library to indicate a collection right you now make a smart library of 10 to the 9th

00:43:41 variations and you select in a darwinian sense among those then you've combined both the smarts of the engineering and the the dumb selection of Darwin and then you have a much better chance of getting Michael again I I asked the question of specificity you you are making libraries of of proteins or sequences right in a particular re area for what I'll give you an example so so for what purpose I mean ex or give me an example well an example is so I mean for example Jack Shack who's a very

00:44:12 well-known scientist um Nobel Prize winner he did some spectacular work where they made libraries of 10 to the 12th a huge number of sequences and selected among them for particular features and they found them because 10 the 12th is a big number and if you you know you weed through that Library you'll find what you're looking for in our case we try to make designed libraries and we'll make a library of 10 to the six much much much much smaller and it'll be much richer in terms of getting folded proteins or functional proteins because you're you're pre

00:44:43 you're pre- biasing the library to that part of space um you know that where where you're more likely to get something that you want I mean again though are you are you developing proteins of a certain type for a specific purpose or you just doing it to see if you can do it tinkering um in our what we're doing is we're we're trying to see what's possible um what let me give an example from something that happens in in Cancer all the time so with a very precise thing so people do routinely uh know

00:45:13 Steve EG and other people introduce the technique um very large screens where they essentially knock out every single Gene in a particular cell to see what are because cancer as Mark was saying is a little bit less stable in normal cells actually certain vulnerabilities emerge that are not normally in normal cells and so they they knock down every Gene and they say okay which Gene kills the cell um if you do that is an extraordin inefficient way of doing it so one thing that that we've shown for instance is that you can now study the entire regulatory model of the cell so you

00:45:45 reconstruct it from scratch from a large number of observation of the cell and when you interrogate these models with the specific question of how you would want to sort of abrogate the uh the self liability they give you a set of recipes and these recipes have typically a hit rate of about 60% meaning that the best one was 100% the worst one was 30% on average we get 60% across maybe 15 different tumor types that we looked at so now instead of having to shut down 24,000 genes and then maybe you have you

00:46:17 know most of the genes that actually will kill the cell are like shooting on the wheels of a car they'll kill every cells the one that are specific maybe very very small number uh you now end up having a so we go from a percent hit ratio of maybe 1 in a thousand to a hit ratio now of 60% which is a huge which is a huge change and is exactly what Z completely derived by our ability to understand in IR rational way what the cell is doing mechanistically right so we still seem a PR problem I guess I

00:46:47 think all of us are very Pro synthetic biology Pro systems biology but there's still I think a large segment of the public that is is frankly ter terrified I guess but I mean I know what do you think are the ways we could I mean try Dem demystify it somehow make it more palatable I I thought that's how we're going to get bombarded in the question period well yeah I think one of the medical I think one yeah one of the questions you know dance around is some specific examples not just I'll give you one I'll

00:47:18 give you one I mean when you try to find a way to kill a cancer cell with an antibody you have an antibody that carries tox toxin you will screen through artificial libraries that look like antibodies they're made of antibody components but they may not be real until you find one that binds tightly will carry your toxic payload in to kill the cancer cell that's how you do the business so you're always you know these screens can lead to very powerful new drugs and they're new proteins that may

00:47:48 be uh unnatural in the sense of being seen before so the analogy there might be nuclear power that we could use nuclear energy but for a good in that sense I'm I see I'm not troubled by this because I think it's the same issue that you have with nuclear power if if you call everything Atomic then you have the good and the bad if you call everything synthetic biology there will be some places we have to worry about it right so calling if you throw everything into the same bucket instead of saying let's look at each of the kinds of specific

00:48:21 applications and see are there any that actually have problems and the vast majority are either add to fundamental knowledge or will add to a therapeutic arm and I think again the public or at least the people I deal with when I'm answering questions as a as a journalist uh for I think an example you gave or give a similar one would say well there is a drug out there called embro that works very well against rheumatoid arthritis it is a synthetic

00:48:52 antibody in other words it's a man-made antib it's a manmade antibody it was made in a laboratory it takes something that was natural which is an antibody and and scientists figured out a way of of manipulating it or creating it in a form that it works specifically against a in a receptor in the immune system you know in arthritis the immune system is overactive so this inter antibody turns the immune system down most patients

00:49:23 give an enil don't know that it's like me when I get in my car I don't really care how it works I know that when I turn the key and put it in drive it goes all that other stuff I don't care about so when most patients don't care that enil does exactly what I just said so in that place place people don't care that it's synthetic but when we talk about creating new kinds of bacteria or new forms of yeast or taking cells out of the body like you said manipulating it

00:49:54 and then putting it back in the body people I think begin to have issues with that well yeah I know I mean for example the experiments at the University of Pennsylvania where they took lymphocytes out of patients who had terrible cancer and engineered a totally synthetic new receptor on their surface and then those lymphocytes went and killed that cancer cured those patients that's about as and stayed in that patient forever so they're carrying this abnormal sequence forever and my guess is quite happy to

00:50:25 do so so I think it again is important what it's for the other point which needs to be made and was made back at the origin of the molecular biology Revolution when everyone was worried and actually shut down molecular biology as you recall for a few years is that pretty much everything we make is not going to survive in the world because it has not been selected for it has it does it is not robust Evolution has done a wonderful job of selecting out anything

00:50:56 with any weakness so pretty much anything we make and this has been proved time and again whether it's a unusual Mouse which was the original question or these bacteria or Yeast will die in competition so realistically it's going to I think that the the problem is small but it's not non-existent and that's why I think we should say there will be times you should worry about it and times you don't and I wouldn't just put it all under the one one rubric One Umbrella of synthetic biology just mentioned with those

00:51:26 children what happens when those children's children they don't they no longer doesn't affect the germine right but so I would take even a step back so the question is you have to be very pragmatic about these things so the question is is there anything that has ever been possible to do in terms of stopping progression of knowledge and that has never worked out I mean we try no so could you have stopped understanding sort of that you can break the atoms and that creates energy to

00:51:57 some exent we could have prevented it but somebody at some point would have done and so I think that the more important in trying to understand whether knowledge is good or bad I think knowledge is is neutral is is how we use knowledge that we can become good or bad and so I think that this is a matter that is very important for legislation to take a stance what are the things that are you know B that put safely into so they have to be obviously you know a number of safety constraint that have to be satisfied Etc and but um but this is much more of a legislative uh matter

00:52:28 than a matter of of whether the the the knowledge producing exercise that we now that essentially the scientific Enterprise is is undergoing is should be arrested or continued because that that's going to fail no matter what you try never there's never been one single situation where we're being able to uh stop the progression of scientific knowledge so I would step ahead of that and try to figure out what we do with it I think it's important the case where you have malicious intent where you try to create uh you know Warfare agents and you know

00:52:58 in this in this crazy world of ours today that's that's possible the only way to stay ahead of that is to just no more that's the most important thing no more than than the than the guys who are attempting to build uh malicious agents the other thing is that we have to do a better job of educating the public which is pretty dismally scientifically literate about a lot of these issues I see it in the nuclear case for example it is by by attaching a label onto something you demonize it immediately

00:53:29 and you shut down the cortex and nobody nobody looks deeper and the same we we we are in the you know in the realm where that could happen with synthetic biology it's up to us I think as a scientific Community to do better Outreach and to educate the public more uh about the details of exactly what we're doing how is it that how is it that we're generating these things where do they come from what were we doing during dog domestication era how was that different you know why do we love dogs I mean it was a really amazing experiment of of

00:54:00 human selection right and so I think those are the two things that um and I agree with Andrea you can't really stop the pursuit of knowledge and sometimes it'll be used for malicious uh purposes the other aspect of it I think the bad is the inadvertent um problems that we might have with some of these things we engineer we don't know how well they'll function that's where as a community we have to set standards that for example the FDA will have to adopt about these Therapeutics to make sure that that that we don't do harm on average that that we

00:54:32 we apply these methods to extreme cases where there is for example no other alternative at so the standards will evolve these things happen naturally all the time I don't know if you looked at Aspen recently there are no trees anymore because of the of the beetle infestation the the entire Forest is being completely destroyed and I'm just and there was no genetic engineering at place so these these uh these things happen you know an organism or a microorganism getting out uh the other one is like I don't remember no P but

00:55:03 this plant that grows over vegetation if you go in every US highway right now K didn't exist 50 years ago now essentially the entire forests are completely covered in that the ccr5 deletion and the Berlin patient it's called for the native immunity to HIV infection was a that deletion occurred naturally you I had the impression you in discussing these new sequences were trying to get somewhere with it were you leading towards the possible problems

00:55:35 with it or the positive aspect there was something implied in what you I was just I was just putting out putting out there the idea oops putting out there the idea that that the novelty is is at a new scale that it's it's I just I was not going to put any value judgments on at all at all but just to say that the possibility for uh one of the things i' I've talked about with students it's not a question of if new forms of life are possible it's when it's not if it's when many and and so I

00:56:08 think that's something that you know one needs to think about I um I I I sort of agree with what you two were saying before I think transparency right um and you can't stop the progress of science but in an attempt to prevent evil from happening I think transparent is the most important thing and it's certainly better to know than not to know because otherwise somebody else will do it first right but I think you when people do things behind closed doors in secret then then you got to worry I mean we've seen that in societies forever but when people do things out in the open I have

00:56:39 more faith that people will do good things and that's to some degree it occuring the bio bricks Foundation is the foundation of people the idea is you want to build a house with bricks you don't want to build a genome and an organism the same way and all the parts you can order them online are all you can look up at what every piece is every piece D it's all open I wonder if you're also though up against a certain psychological uh orientation of the public who is not steeped in the in the science where there tends to be an idealization followed by a de idealization of new technology you know

00:57:10 it's I think the same thing happened with nanotechnology that like there was the promise of you know all these wonderful things that were going to take place in the world and transforming uh human life and then there's the you know the big bad gray goo that's going to you know the Nanobots that are going to take over but I wonder if there's I think you make a really good point because I think people are essentially scared of what they don't really understand in detail so when you do a graph and you know put a plant on top of another one people understand that intuitively um and

00:57:41 they're not scared of it simply because they feel they have achieved that level of reassurance that is necessary to let that be in the back of their mind uh when you start talking about very complicated operations the manipulations of you know fundament Al molecules of life then people only grasp certain aspects of it and it scares it scares them to no end because simply they don't know exactly what's been done uh and so I think that one of the thing that really should be important about this about de demystifying this process is so actually really have a major effort in

00:58:12 education and in dissemination because some of these things can be explained in relatively simple layman terms in a way that you know if you want to know about it you you can actually do it I think there's the educational aspect and the fear that that you refer to but I also wonder whether you think that there's uh just a tendency that when the the promises especially when these new technologies are kind of hyped and people don't really know what what the hard work is all about to develop the

00:58:42 science that there's a disappointment then when these things aren't forthcoming and so then there's tends to but I think that disappointment currently constantly exists the war the war on cancer you know gee that was 40 years ago uh the sequencing of the human genome where's all the great discoveries well the truth is in the Laboratories the war on cancer has advanced and there have been great breakthroughs but cancer isn't cured and the human genome sequencing has led to

00:59:12 all this synthetic biology but you know we we don't we're not buying anything in the grocery store at least that I know of or the drugstore as a result of it and I think that kind of that's just the nature of Being Human I I would like to make one pitch I think one pitch as a retired working journalist I mean I'm still working as a science writer but not for a publication is that I believe it's in the best interest of the scientific Community the

00:59:43 pharmaceutical industry uh biotechnology industry uh to uh help educate the public listen news people never think we never think of ourselves as educated the public we think of ourselves as seeking the truth but there are very few people who are as skilled as I am in doing what I do and it took me about 30 years to figure out how to do it and um I would argue that as the science gets more complicated as these issues become uh uh

01:00:14 more difficult for the lay public to grasp that a a group of writers who can translate science into understandable easily accessible but an entertaining uh not just writing but you know video and film and whatever and you know someone ought to get together because the field of Journalism in which those writers uh Bubble Up I mean there are schools of of that teach science writing but there aren't places for those people to have jobs I mean that in other words the

01:00:47 world of the media world has changed so dramatically that it isn't a self- poop populating area I would say in the 19 ' 50s and 60s there was an explosion and and in other words the creation of the science writers and it was around the space probe but there was I mean think about it in New York City alone there were six newspapers for those and each one of them had one or two science writers writing about space that's gone science writers are are well it's for what I just told you that's really disturbing and and without and so what's happening again not to stay to the the

01:01:18 new model is a nonprofit model there are a number of nonprofit news organizations and investigative news organizations like propublica that are being funded by non-for-profit organizations sort of like the Gates Foundation the Kaiser Foundation Kaiser health Foundation underwrites um the science news at uh PBS and the Gates Foundation is underwriting Science News at NPR and if those didn't exist there wouldn't be science writing at those two places so

01:01:49 that's my pitch what science well that's the New York Times what about in Seattle I don't know there's no there's no science writer in Seattle I I I think there's a there's even a a bigger issue which is not the I think the scientific literacy issue and our our ability to outreach is very very critical to to um to all these issues we're discussing but I think the fundamental challenge that I see now in in in modern Progressive societies is is

01:02:19 the lack of teaching of the history of science science and techn ology to the to the to the to the population that is supporting it with their taxpayer money the if you ask an average person on the street you know uh what all this money is going for they will tell you well they're there they're they're curing cancer they're they're they're they're using it to develop new nanot technology Nanobots or whatever but actually what they don't appreciate is that the reason why their cell phone

01:02:49 works which is a miraculous technology the reason their laptops work has to do with with a very long viewed investment in basic understanding of nature that came decades decades ago microwaves quantum mechanics attempt to understand the fundamental working principles of the universe that had no application whatsoever these were just crazy passionate individuals who worked on specific problems because of their because of their taste in those problems

01:03:21 because of their passion because of their love of understanding the universe that decades later maybe even a century later accumulated into a level of understanding that allows us to now build whatever the hell we want based on fundamental rational principles this is the history lesson that we that we fail miserably at communicating to people and that's why the budget of the of the NIH which supports all of biomedical research is 130th or 140th of the military budget in this country which is an outrage for modern let me push it

01:03:52 even further because I think this is really important why said there is this perception that you can actually find applied research and that applied research will miraculously generate the microwave and uh and the cell phone etc etc and unfortunately everything that applied research does is to move our fundamental understanding of how matter and and biological matter works or or inert matter Works uh into into something that is then a protic value but if you don't have that knowledge you don't push that knowledge forward the

01:04:23 well will dry up and we won't be able to do any more applied research so the idea that we now everything has to be translational everything has to be applied is is really a major problem because in the long run we'll figure out that all these things now being translated and there's no more basic advancements that can be translated into something to follow up on that what gets hit hardest in times of austerity are exactly the topics we're discussing today systems biology synthetic biology approaches that are out of the box that

01:04:54 are new that that don't have a great track record because what does well is very well defined almost no risk uh proposals that attempt to move science forward incrementally so you have a very well established field of traditional biology and if you send your proposal to the NIH your ability to get that funding for your proposal relates directly to how close you are to existing inertia of knowledge that exists in your field

01:05:24 if you're totally out of the box you get penalized and in times of austerity that's even worse so if our fields are actually suffering this Innovation Challenge partly because of this you know funding uh that that that that I alluded to but partly because what funding limitations do is to then you know then it goes to the Congress and goes to the White House and these guys are saying we need you guys to have deliverables you need to give us deliverables within a year or two what have you done for us in the last 10 20 years you promise all this stuff and you

01:05:55 haven't delivered so we want to make your uh science more applied get solve these specific problems they don't understand that in order to have any chance of solving these complex problems you need a foundation of investment in basic research and that takes a long time part of the problem isn't the education of what you're calling the lay public most of the problem is educating the scientist very few scientists know where their history came from that's true and you know if you take the average graduate student now they will

01:06:27 go back two years uh go back 10 years they're considering it a history lesson and if you look for example if you want to go back to the cures for cancer many of the those discoveries came out of the fundamental work by nine volhard on the fruit fly absolutely right this was to understand how a fruit fly cuticle gets patterned did all the work work worked out all the original Pathways all the stuff that you guys are working on now

01:06:58 all those Pathways were discovered by a set of genetic experiments that then later 30 40 years later led to that uh those cures if you want to look at atherosclerosis cures and the statins prevention you have to go back to 1948 for the first epidemiological scientific studies which were really pretty much curiosity driven about what relates to disease so the the the you can you can draw a trajectory and that arrow in my

01:07:29 experience is about 40 to 50 years if you're lucky if it's going to work minimally minimally so I think the problem though is with the scientists as much as it is with the L public and my cwan old s s was all yeast it was like all those all those all the major Target for for for I want to go back to one thing that you said because um you know this issue we were joking before you guys are right because I arrived a little earlier that we always promise science to solve a problem in 10 years you know to some extent you know nion in

01:08:01 10 years going to solve cancer then Andy uh forgot his name the director of the National Cancer Institute 2000 um we won't go there and the that was promising the cure for cancer probably 15 years Etc and every every once in a while we come up with another 10 year or 15 years but the reality is that actually the only problem is that cancer is not cancer is cancers plural and because a lot of cancers have been solved in the 10 years for instance I was in basil when the day that actually

01:08:32 they announced that that that that uh GLE was in fact approved FDA approved and that actually sold one cancer complete you know essentially you know 30% of the patient will relapse but uh but but uh people that the next day were going to die in chronic lukemia all of a sudden they were saved uh the same thing in secular cancer same things in for instance in her two t breast cancer are one used to be one of the absolutely worst tumors that you could possibly get now they react very very well to transa

01:09:04 uh and and on and on and on so uh I think that we have you know if you count the number of 10 years blocks we've solved more cancers than those number of 10 year blocks it's just that we have discovered that this is such a heterogeneous disease both within the patient and across patients you want to say something with it because I was surprised that you said that every patient's cancer is different from the next so the spectrum of genetic alterations that lead to Mor Genesis and progression are essentially different in every single patient there's no two patient that have the same the same set

01:09:36 of mutation there are some recurrent mutation that occur in multiple patient but those only tell a part of the story so in fact we're now doing a span cancer study where we study literally about 7,000 patient that be fully profiled and you you can see that these patterns of genetic alteration they don't cosegregate on any two patients um and so one I mean a big initiative I was actually part I'm I'm sharing the ne co-sharing the next uh annual meeting of uh uh the ACR the American Association for cancer research and one of the big topics in that meeting and also one that

01:10:06 we had as a forum in this year meeting is is going to be the N of one study that is studies clinical studies that are going to have a single patient and we have three patient right now Colombia and other places that that have done this on a genetic basis we do in on a more syst biology basis where we're trying to solve cancer just for one patient at a time and not that we think that we're actually going to fight cancer one patient at a time but we need to understand cancer one patient at the time before we can understand what are the rules that can be generalized and so this is really so understanding the

01:10:37 genetics under the machine understanding how the genetics collapse into creating certain dependencies that are then much more Universal than the genetics right so the genetics is distributed so for instance Let me Give an example uh many very very bad cancers uh have a mut Gene called K Ras or in other Ras genes uh but if you have a mutation in another Gene called NF1 you will have almost the same phenotype because NF1 actually is the protein that allows kasas to it's called gtps have it GPS function so

01:11:08 whether you mutate one or the other really makes very little difference and you can have very similar phenotype and there's an entire set of protein Downstream from that that will give you like B WP and the V ra that give you exactly the same or very similar phenotype this tend to be mutated differently in different cancer so for instance in melanoma you may have more B mutation in uh uh pancreatic cancer 60 70% of the patient have KRA mutation uh but no b or very few B mutation so so so the question is that if you actually go in and try to figure these things out

01:11:39 one gene at a time you will really never be able to get the full story and we know for Kass is called right now an undruggable Target although many companies assuming King nobody is probably trying to find the drug that will shut down Kos um and so the the what we're left with is trying to figure out if this is the actual mutation what is the node in the cell that becomes the vulnerability because you have that mutation okay which may be another Gene so for instance right now we know that if you use in in in prostate cancer a combination of a gene that inactivates

01:12:10 protein called akt through VI different mechanism and one another protein called Mech that the tumors that have Keras mutation tend to be respond well um but that may be just uh an observation will it working patient we don't know ET so so I think this this is exactly why I think we need to try and understand tumors on an individual basis before we can now generalize because generalized has not really helped us certainly helped us in some cases but we have picked up the low hanging fruits and now we're left with all the other things that we don't really understand

01:12:43 very so individual well I can't speak for any other group than mine uh our approach is what we call a molecular Pathways approach which is basically a systems biology approach because I would agree entirely that it's very difficult to explain biology in general whether it be cancer regenerative biology on the basis of one protein but what we know is that the language of biology the grammar of biology is the

01:13:15 pathway signal the receptor transduction into nuclear uh transcription and those pathways are conserved from fruit fly to man probably only a few dozen of these Pathways so for us we what we've taken upon ourselves to do is to try to dissect these Pathways health and disease and say not only what are the pathways that are perturbed because they can be perturbed as you say in many different

01:13:46 places but what are the vulnerable nodes where we could hit them with a drug and so for us we can play with all turning up turning down all the different parts of the pathway without effect but then we'll find one node that may not have been ever known to be associated with that pathway before and that we can hit and we know we can turn the pathway on or off and then that's the beginning of the process that takes then 10 years after that to make a medicine and it can get more complic I

01:14:17 mean I guess I see similar things in leukemia um as Andre was describing in other cancers is that being like a cancer biologist today is being sort of like a molecular mechanic and someone just comes to you and says I have leukemia which is the same as saying my car doesn't work and you just say well it could be because you have no gas in your car you have no wheels you have no steering wheel you have no headlights it could be be for any number of other all these reasons that may actually intersect the same pathway but just saying I have cancer um can be very very different for a lot of different reasons and it's being a m mechanic U makes it a bit you know you have to figure out

01:14:47 which one it is I'd say what the job is I think the I think the the the way in which systems biology impacts that I think is uh is one way is we were discussing about the molecular pathology and the pathways involved in disease the other side of this I think which is a new Revolution in medicine this a birging revolution medicine which is which is the an attempt to to approach medicine scientifically science medicine has evolved through these really kind of old-fashioned approaches to you know

01:15:17 physical signs and symptoms and I think it has done a terrible job of doing the kind of data mining that we do on large data sets that we get from The genome that have billions of pieces of information so you go to the doctor you you make you make all these measurements they use your CBC you have various physical signs and symptoms written down in paper often not inputed into electronic form in ways that could in retrospect much better Define a subtype of disease so we lump things together

01:15:49 because you know we're lazy because we we've never had a molecular pathy olog molecular molecular basis of the path pathology that's going on now that we have we can have that molecular pathology the other side of medicine which is to characterize and Bin individual patients into pathologic classes in order to then come up with the exact treatment that works for them based on these pathway now so that's going to be really revolutionary and I think in fi in the field that's most I think most in need of that is Psychiatry

01:16:21 where um the you know a lot of the classification of disease states are still very oldfashioned and aifi and I think that's a very exciting area where potentially the kind the kinds of data that we're getting on the systems level and together with existing um uh quantification can can lead to much better molecular Psychiatry what's coming say can I direct that for questions one other pivot point I guess to to comment on the to go back with the mechanic analogy is that we the humans are though difficult and we do have have

01:16:53 many many genetic elements that are not in mice or not in chimps not in reesus maacs uh you know there is evolution uh keeps adding things and moving things around and so one of the big challenges people say well I haven't figured out cancer yet there are we're still discovering how many genes there are in the human genome a lot of people think 25,000 or 40,000 the number is at least 55,000 by current counts and I'm I can promise you it's going to end up higher and so and we're just you know getting even within the scientific Community people to figure out how many genes are there in the human genome is itself you

01:17:24 know it could almost prompt wrestling matches at conferences and I've threatened to tackle people who use the number 25,000 genes and I'll do it again today publicly um but so it's it's complicated and we're still learning that's okay uh so any questions have to come up here uh thank you breathtaking what comes to mind is a question about time

01:17:54 management you gentlemen have great goals limited time how do you want to spend your time and advise other people who might want to do this kind of dissemination and research to divide their time most effectively sleep less um well I I would say it would be fantastic if um if we were supported at

01:18:25 a level that was commensurate with the goals ambitious goals that we have uh and the and the impact the economic and um lifestyle impact that that these this scientific methodology will have in the future so that would be great because that'll free us from not writing grants because right now we're spending 30 40% of our times writing grants to the NIH and that's very very painful and and n and nine out of 10 of those the funding rate now is such that maybe the 10th percentile roughly maybe worse it's

01:18:56 worse okay so maybe the I don't if let's be optimistic and say it was the 10th percentile that means not the number we have here but Suppose there are 10 of us in this room writing grants the NIH nine of them or more go into the shredder and don't get funded then you go back and you spend you know however however many hours or days it takes or weeks it takes you months and you write it again so that's I think it's very hard to make progress when you're spending most of your time writing grants that will go into the shredder and not get funded and

01:19:28 the ones that go into the shredder and don't get funded are not by people who don't know what they're doing theyby hopefully we know what we're doing people like us and so that's so it's very it's very interesting because I spent I did the opposite of what Mark did so I spent 16 years in Industry then I moved to Academia and I realized when I moved to Academia that I had to start writing grants which was a completely foreign notion when you are in in industry and um I realized that if American industry worked on using the same metrics that the nhh works there would not be an American industry

01:19:58 because the idea is that what you actually do in Industry you have a track record and based on that track record you keep getting funded and your track record goes down you stop getting funded and you will shrink your project and then maybe you can grow again at a later stage when you come up with new bride ideas in in um in uh NIH funding uh uh concepts with through the grants your track record really doesn't count very much in fact most of these grants old say exceptional investigators you you'll get top votes for that but in the end what counts is whether somebody says oh

01:20:29 your proposal is too ambitious well you know whether it's ambitious or not it should be based on the fact of whether you accomplish in the past funding cycle and so I think that there's pretty much a general uh understanding that we need to rethink a little bit the ways that so of funds for research are are are managed and distributed because and then maybe we need two two different mechanisms one for establish inest investigators that we should be based mostly on track record unless you propose something completely new and one for Junior Investigator really starting

01:21:00 together their career launch and need maybe some extra boost and help but but the way the system works right now has become really really very very difficult there's from oh 80% and there there's a serious concern I hear this from friends all the time that we're going to lose a generation of scientists that the Next Generation coming along people who are in graduate school and doing postto now they look at us and they see that we spend our time writing grants that don't get funded and get demoralized and they in graduate school and postto say I

01:21:30 don't want my boss's job I want to do something else because because of the you know the tightness of the funding and how time is spent it's very demoralizing we're certainly losing the American scientists because Aman scientists are are essentially is a is a species that should go under protection because right now it's is is is under yeah yeah and there's only so many times you can say failure makes me more determined I guess that's so Dr Fishman had commented that the administration of a particular compound would not affect subsequent Generations um forgive me I missed it

01:22:02 was it the compound related to Emerald the drug that was being discussed no we were talking about the cells that were generated artificially using a construct to Target the te cells of a person to their own cancer I'm curious if other members of the panel would feel confident making that statement that if would not affect subsequent Generations it depends on the therapy there have been publications of gene therapy that has showed up in germline tissue uh I mean I can't speak to this particular uh experiment but I I I think I I know the

01:22:34 literature you're probably thinking that's only T Cell so you can't in this particular case it should not as far as I know but um these aren't these are not replicating viruses so you take out the t- cell you put in something when that t- cell dies eventually can't go the virus the the concern about EP gentic actually yes you're concerned about EP addressing your PR problem yes uh so epigenetic interactions it's been intergenerational epigenetic interactions have been studied pretty well in mice but very scarcely in humans that's changing with

01:23:05 the What's called the epome road map project from the NIH is helping with that but most of that is not intergenerational and in the short answer is I'd say you people probably haven't looked at what the the just for the audience I guess epigenetic just refers to changes that aren't to the DNA of acgt but when you have modifications those uh ACG andt that the letters don't change but their state does and so epigenetic changes um are heritable um but we I don't I don't know if there's any evidence no there is evidence that they are for example there are it's been

01:23:36 proved best in the nematode worm where you can something that happens in a grandfather worm can be passed on through two generations epigenetically without any change in the sequence of DNA there are suggestions from old studies but they epidemiological suggestions s of epidemiological effects of a grandfather's smoking in Scandinavia upon two generations later disease diet wasn't it no the diet was I think the diet you may be right but the smoking in

01:24:08 the grandfather affected the diet of the two gener the obesity rate in two generations but that's that's of course epidemiological there are diseases that are completely transmitted epigenetically so wil Wilm tumors for instance is completely epigenetic disease fragile X syndrome as an epigenetic R syndrome as an epigenetic but but the actual proof of the transmission is has been Dred on in the nematode worm well I asked my question in an attempt to address yours actually um I agree that transparency is Paramount uh as far as PR for your

01:24:39 industry uh but huous and Trust speaking as a member of the public is something will require thank you for this time thank you thanks I I wanted to go back to the the funding issue and ask so forgive me this is a very eastern US Eastern group here and there are companies that are printing DNA you can you can order it online and get

01:25:10 little vials of DNA there are VCS funding this kind of stuff and so I'm curious whether you guys have gone and looked for your funding not with the ni or in Boston but out in Silicon Valley where there is in fact a lot of money and the freedom to do really interesting stuff the the VCS tend to fund I mean especially these days they tend to fund they tend to be essentially Bankers what they want to do is to minimize absolutely every risk possible and assure themselves that they're going

01:25:40 to have a huge return on investment and then jump in and also and there there are three to at most fiveyear um you know Horizon and this is just not the way the science can work not all of them huh not all of them but the V fre to let us know the ones are are you representing one come see me afterwards I don't want to take this over but some of VC problems they're tied to you know very the terms of getting that money are very either honorous in terms of the timeline or what what strings come attached to it

01:26:11 there um as a you know but I've I've done some work with industry you know just grants just well they say we just we're interested in how perfectly you can take a single cell amplify the genome and correctly you know genotype it you know work like that that's industry funded um you know there's definitely a lot of convergence of ideas and passion from industry and academic and government researchers and clinicians but um but they rarely intermingle as much as they should I think is what you're getting at the major issue is the gold directed nature of that transaction and that you can't impose that expectation on scientists

01:26:44 for are attempting to understand the system they don't know much about right you need to support Innovative uh adventurous researchers to follow for you know for 5 10 years down a path that they don't even know ahead of time and that you might not yield anything and if you do enough of that once in a 100 you will have the Breakthrough of a generation that will solve all your problems you just don't know who that person is going to be and that is not the kind of structure that industry or VCS will support they just cannot they

01:27:14 cannot quantify the risk and the and the ROI on that let me let me give you some very practical examples so we are all uh sort of asked by many pharmaceutical companies and biotech uh to work and collaborate with them but the kind of collaboration that they always have in mind are the ones where we they look at something that we've already done and is really ready from PR so two two days ago we just signed a letter of intent to do a clinical trials in breast cancer that was a complete no Con coming from sistens biology so that's now been done that's the kind of thing that they're

01:27:45 looking for they're not looking to find the research that led to that and so I think that the problem is that that that well will dry up and you know there are some companies like for instance novaris that and and others that actually have also take a step back and and have a lot of collaboration the CCL this is the creation of this thing called the cancer cell line encyclopedia has been one thing that novaris has done has been trans it's been transformational for the entire Community um and it's truly a a basic science effort I wish there were even more dissemination of the data that

01:28:16 came back from that into to the open Community but uh what has already been put out there has been really valuable and this has been collaboration with in that casee the broad Institute and and other Institute so there are there are examples like that but I would say 99% of the examples that we have are very very pragmatic um I'll talk to whoever wants to after that's great I love if you have ideas crazy billionaires maybe more than that sounds good um so we're funding a lot of the N of1 for instance using that type of support yeah well I agree with

01:28:47 all the places where blame was placed I think one was not mentioned that is the drug companies themselves I can't remember the exact numbers but if you look at their marketing budgets versus their research budgets you know it's opposite directions and you know just look all the ads on TV um and my question is wouldn't that money be better spent supporting your guys research than marketing and what what caused this why did drug companies go in this direction quot we may have

01:29:19 unbiased I run research so I'm happy have as much of the funding as I can get but the you have to remember that the companies and I'm not defending it by the way I'm just explaining what I think happened historically because I'm not an expert in marketing but these are publicly held companies so these are companies that part of their job is to make money and to have a share price it worked is the answer in other words they were able to make money so here's the history that's an interesting history and I think is quite educational

01:29:51 in terms of thinking how they should go forward historically uh pharmaceutical companies could make a lot of money by making uh minor modifications in a drug that was there so if you look at the history of FDA approvals over years there's only about 20 new drugs approved a year which is very few considering the number of pharmaceutical companies and only five six of those are really new and would change medicine the rest are relatively

01:30:23 minor modifications you say well how can a company do that and they did that because they couldn't it worked it was cheaper to do the experiment because you already knew that it worked when you got into the clinic all you had to do was change the slight absorption see not that they're always unimportant changes but they're relatively minor now also patents because of patents running out they just modify and get a new exactly exactly but here's the problem now or which is I think good in the direction that you're suggesting uh as governments throughout

01:30:56 the world not just the United States become more conscious that the medical budgets are eating up a lot of their uh funding they're pushing for for novelty they're saying I don't really want to approve or not or to fund uh pay back for something that's not really Innovative so the pressures from the outside are now conspiring I believe in a good work way to force companies to do more Innovative work and to have more

01:31:26 breakthroughs the other thing that's changing is I think that the notion of marketing which was driven by just num sheer Mass efforts that's why it was so expensive is not necessarily the future when you have a lot more that can be available online on the web uh Etc so I think there may be a lot of forces conspiring to change that balance over time at least that's my okay can something I mean one thing that we've observed actually over the last

01:31:57 few years is that there has been a shift back towards uh Eng pharmaceutical company and biotech engaging uh academic uh centers at a much earlier stage uh and essentially Outsourcing to some extent part of the research we do it a little differently we have actually markedly expanded my basic science Discovery group so a very large part of what we do is fundamental pathway analysis and fundamental Discovery publishable work we have 100 posts we

01:32:27 also interact a lot with Academia so for my bet which which we don't know if it'll work because this things take so long is that the more we discover fundamentally in the long run the more medicines they'll be hi uh I might be at the wrong place I'm not sure um I need I think we all feel that way actually uh I need a new disc gr is there anything going on out there right now I I broke my lumbar off six years ago and destroyed the

01:32:58 disc I can tell you a little bit about it right now it's early stages in what's called regenerative medicine and I certainly can't promise anything now but there are two directions that you can think about one is that there are some studies that suggest that you have in your so the problem is your the the disc is distorted the bone is distorted so the question is can you regenerate normal tissue and we know we do have cells

01:33:29 sitting in our spine and in our cartilage that can do that but they don't so one set of groups are looking for drugs or to spark that yeah and the other of course are devices and there I'm not an expert at all but uh newer smarter better devices that are are less destructive but you you may have an extreme form of it but I everyone has has uh degenerative disease in their their spine pretty much everyone over uh in middle age or over has starts having

01:34:00 problems with it we're not meant to stand upright but it's a big problem it's 94% of people over 40 that have these issues yeah it's a huge problem and it's been but I think now with our understanding of Developmental biology and where the the the stem cells come from in the I'm not talking about the kind of stem cells you read about in the newspaper but the stem cells that sit in your cart or sit in your bone that could become new carage they're there I can't though promise when uh is anybody working on the cure for greed for what a cure for greed greed I think we'd have

01:34:32 to understand it first that's the uh that was the reference to the Psychiatry I think that's that's that's an important Frank for that thank you um hi first of all thank you for Extraordinary discussion and to ask my question I I have to make a couple of points first if we oversimplify and summarize what was said here it's like we believe in evolution but we don't

01:35:04 like it we like creation and second um point is if we start to play and we create toys we won't stop and at some point it's the question from like your question when Humanity will end it's like at the at some point we will be able to create something from scratch and probably in our

01:35:37 image so would we do this would we give these new creatures absolute Independence and Free Will or we try to control if they're sensient absolutely if they're if they're bacteria it becomes that's a good question I think if they're if they're bacteria that you made I think they should be some statutory responsibility for the thing that you created that has no sensient I think it has to otherwise people will make them and say well I don't know I'm saying about something

01:36:08 bigger like in our image well then you then I mean you know what you children essentially are made in our image and but we wait till they're 18 I guess you know they I don't I don't give my children feel will they take it you don't have to give it they take it I'm not going to give it but this came up to when people talked about cloned or IVF babies you know are they real people or do they have souls or these questions have come up before and I I think without question if they're people uh you know if they have

01:36:39 somewhere between 45 and 48 chromosomes and they look like all of us and they are what we'd call human I think it's I think it's you don't even have to go you don't even have to go that far I mean right now there's always you know we from half of the Sci-Fi literature is about getting sent organism that are actually non biological based you know they they're silicon based and I think that's probably a much earlier uh much earlier things to come because now they starting to achieve some pretty dramatic computational power so and already they're starting to this place some

01:37:11 pretty scary characteristics so and I can't speak for everyone but I'd be happy to give more rights rather than to take them away from entities but uh it's easier to for control purposes I guess to take them away things that you are scared of but we have one last question thanks for uh for for coming here today um my question actually comes around to the point that uh each of you come from kind of different sectors of the industry um private and research and and whatnot um what are you doing or what is

01:37:41 being done in order to have more of a Brain Trust and a collaboration of discoveries um you know I come from the technology sector so we have a lot of crossbreeding in in philosophies around designing and architectures um but it's easy for us because technolog is fundamentally programming is fundamentally free um but your funding it touches the funding issue of where that money comes from and then the private sector of the profitability the business model and then actually the interest in the research right the actual why are we trying to figure out

01:38:12 these protein sequences or what may what it may be so I'm just kind of curious if your opinions on on that area and how you see the future of that moving forward so that's really a great question because because if I've seen something that has been really is being really transformational right now is that the old model of funding this is I'm talking about Academia in this case but the old model funding where that was it's called R1 base R1 is a particular type of grants that funds an individual investigator so you know Chris gets an another one and then his Labs does specific research that they propos in one um but there have been a number of

01:38:44 now sort of we call them networks um of of research centers um one that was forance participating in in the last five years was called cancer Target Discovery and development and it's essentially group of centers we started with five centers then it's been expanded because it was a very successful experiment to 13 centers and we are essentially not not just forced but really encouraged to collaborate with each other and it's been one of the most extraordinary experiences in terms of

01:39:14 having um really valuable incredibly productive collaborations that we really would never have thought of if we had continued to do the research in a more traditional way so I think the NIH is starting to recognize this and I think NSF as well um and so there is a there's a trend I'm not saying that it should be only collaborative research that that needs to be done but finding the right balance between the two is probably going to be really instrumental because most of the especially things like system biology um when we have a system biology paper today it it has anything

01:39:46 from people that did the mathematical model people that actually run the soft infrastructure did the experimental validation people did the mouse work etc and ends up being humongous team efforts not not just things that you can do in one lab and so I think the you hopefully we're going to see more and more of these type of collaborations uh and and they will be very very I mean as productive as we've seen them be thank you thank you very

01:40:17 much for thank you very much wel good to see you