High-throughput genomic analysis and show them a newborn screen. Okay, just to clarify, I did put out hard copy documents for all of you about these two separate RFA's that you should have at your places, just so that we can keep the two different concepts that I'm presenting straight. So I'm going to be presenting two different RFA concepts to you today. The first of these is a U19 Cooperative Research Program Project Award. So this is like a program project, but as a cooperative agreement. And these came out of the newborn sequencing future initiative that we've been working on in collaboration with our colleagues at NICHD. Overall, the goal of this proposal is to explore opportunities to use genomic sequencing information to broaden our understanding of diseases relevant to the newborn period. And to start with, I'm going to talk specifically about the U19 program. As we've mentioned earlier today, and Jeff gave a great setup for this presentation, the cost of genome sequencing has been dramatically dropping over recent time. And because of this, it came to our attention that we might need to re-evaluate as it becomes more technologically feasible and cost-effective to evaluate more variants at once, whether or not this is something that we want to be doing in different screening paradigms. We held a workshop in December of 2010 with the goal to look at newborn screening in the genomic era and to help set a research agenda. This was initiated because it was realized that newborn screening may be one of the first areas to adopt genomic sequencing because they already do do a number of genetic testing, as well as the fact that this could potentially be a way for individuals to realize lifetime personalized medicine due to the near universal inclusion of individuals in the newborn screening paradigm, and it would be useful to start doing some research to determine whether or not having this genomic sequencing information is of additional clinical utility. These would be pilot studies, just a first step along this pathway. This would not be setting a definitive set of disorders or things that should be screened for using sequencing for the newborn screening, but rather just looking at this as a first set of pilot initiatives to determine what could genomic sequencing add to newborn screening. And within the workshop, it was really highlighted that we were talking about this in the characterization of screening of newborns, not specifically as newborn screening the public health program, and that we really wanted to focus on what does the sequencing add. There were a number of recommendations that came out of this workshop for what these pilot programs should contain. The first of these was to focus on what the genomic sequencing was adding to newborn screening and then look at more over what this could add to moving towards integrating genomic analysis into healthcare and start anticipating what some of the challenges might be to adding this sort of information into a healthcare setting and whether or not this information is ready at this point in time or what additional utility you would have by adding this information. They really felt that it was important for these grants to look at exploring ethical, legal, and social implications for individuals as well as their parents and the clinicians as well as really starting to address what the clinical validity and utility was. Not just can we do this technically, but what are we getting out of this? We also thought that it was important to focus on higher risk individuals within the workshop. This was mainly driven by a need to be able to reduce costs that this could fit within a pilot type study and that focusing on individuals that are at higher risk or have a positive newborn screening result would allow you to look at smaller sets of individuals and potentially a set of individuals who are more likely to benefit from the results of the sequence information. Furthermore, along those lines it was felt that incorporating longitudinal data would be very useful for determining how this sequence information could potentially affect treatment down the line. We're well aware of the fact that there's a lot of contention and issues surrounding newborn screening and blood spots and consent most recently within Minnesota and so for this program we would require that all individuals have received informed consent for participating whether that be the parents or the actual individuals themselves depending upon the age of the individual whether they're being recontacted or a newborn who would be screened for the program. Currently, just to give you a feel for how the newborn screening process works in Maryland, there's about 50 conditions that are screened for and the results are given back within about a 10 day period. The parents only receive information if their child tests positive for one of the newborn screen results. And what we're looking to do is see if you look across the whole genome with sequencing or potentially exome targeted sequencing as a first step, what additional information could we add to this marathon. This also fits within NHGRI's strategic plan with the idea of moving once again towards the right. We would be looking at delivering genomic information to patients and particularly exploring the implications related to genomics in society of giving this information back to the patients. For the newborn sequencing U19 RFA in particular, our goals are to stimulate research in three coordinated areas and all the applicants would be required to address each of these areas within their application. The first of these is acquisition and analysis of a genomic dataset along with clinical research and a component on research related to LC implications of possibly implementing this type of broad DNA based screening. Within the first component, we would require individuals to acquire and analyze a genomic dataset, whether that be whole genome, whole exome, or targeted sequencing of a large number of genes greater than 500. This would include projects such as applying existing or developing new technologies to get genomic sequence data from newborns as well as potentially comparing the quality of a blood spot sample versus whole blood. Within the clinical research component, we would look at advancing the understanding of disorders that are identified via newborn screening through this genomic analysis. We would require these individuals to be in order to have a confirmed positive newborn screen in order to participate. Projects in this component could be areas such as correlating the genomic information with phenotypic data to determine more about prognostic factors or identifying and really trying to address what the additional clinical utility is of adding genomic data compared to the current newborn screening results. The last component would focus on LC research and the possible implementation of this type of genomic screening program. This component would include research such as examining how return of results may affect behaviors as well as identifying and addressing the LC challenges of informed consent when dealing with potential newborn participants. For these studies, we expect that they may either do reconsent for the individuals or would have to initially consent individuals for this type of large-scale sequencing, but we require that all individuals have that type of consent. That the sequence would be genome-wide or on a large scale and that they would present a plan for return of results from a clear approved lab. We would not require individuals to return results but that they present a plan as to why they feel that results in their particular circumstance are or are not important to be returned in that particular grant. They would then require that all applicants deposit their sequence in dBGaP if it is not already deposited and would like applicants to follow subjects longitudinally whenever possible. We'd suggest a couple of programmatic priorities looking at multiple diseases or traits to help determine that this is applicable across a wide range of different conditions. Look for grants with a greater return of results, a large ethnic diversity of populations, larger sample sizes, covering a larger portion of the genome. Children study within five years of their newborn screening so that we can cover more of the LC implications related to working with newborn patients as well as applicants that have no data use limitations in order to enhance the reusability of this data. For these U-19s, we would anticipate funding four to five awards. NHGRI and NICHD would each commit roughly 2.5 million per year for five years. And we would encourage participation of other NIHICs in order to fund more applications with a greater range of phenotypes as well as larger sample sizes. Overall, we understand that this is a very complicated issue. However, we feel that with these decreases in cost and the technical reality that this is going to be able to happen soon, that it's worth us starting to take a real first look at this and try and plan out what our first steps could be into this vast wilderness of genomic medicine and how are we going to apply this potentially in a newborn screening context. I'd like to thank all of the individuals here at NHGRI that have helped with the development of this initiative, as well as our colleagues at NICHD. And with that, I'll take any questions. So as you probably know, that every state has very different laws about the retention and use of newborn samples, and I'm assuming data, although I don't know the laws around the use of data as well. So are you going to exclude states where residual research use of the data or samples is not legally permitted? Well, I mean, because the deposition and the requirement that it be deposited into DbGaP and it have no data use limitations, I mean, that seems fairly restrictive in certain states based on differing state laws. So the idea would be that a new sample would be collected for this as a research project. So you wouldn't necessarily be using the initial blood spot that was collected for doing the newborn screening, especially since these individuals would be individuals who had already tested positive for a newborn screening disorder in states that do allow for their samples to be used for research if those individuals had been consented for doing this type of large scale sequencing that would be acceptable or if those individuals could be recontacted by some way so that they could be consented that would be possible. But for the most part we're thinking that these would probably be new sample collection specifically for this research purpose. So, sorry if I missed this, but are you going to be collecting just DNA or are other biospecimens going to be collected, for example, for RNA sequencing or proteomics or methylation or whatever? We have thought about potentially including some other DNA based methylation, epigenetic potentially transcriptomic data within this initiative and the goal is that it's looking more as whole genome genomic type data rather than just focusing on a specific gene. We would require them to do the gene sequencing but if they wanted to do additional tests beyond that, that would be acceptable. But wait, RNA and things that Carlos is saying are genome-wide. There's not one gene at a time. I think that's why you were asking is that could you do those things? There's just a couple of technical points. One is, I didn't see whether you had this but with newborns and severe phenotypes the first thing to do is copy as large DNA changes a copy number because you can account for about 15% of them with, or at least a lot of those have been identified. So you'd want to know that anyway. I think is that included as part of this or are you just exploring what to do in the concept clearance? We're trying to explore what could genomic approaches add to newborn screening. So we would require that they do a genomic sequencing approach and that would need to be either whole genome, whole exome, or a large collection of genes more than 500. After that they could add on if they wanted to look at CNVs, if they wanted to look at methylation beyond that. CNVs first because you're going to immediately know for some large fraction of them at least for developmental disorders. The other thing is that it's going to be harder to get big DNA from blood spots than it will be from whatever else your fresh blood or whatever else you're doing. You want to be sure to deal with those technical. And they wouldn't be required to do this from blood spots especially if they're collecting a second sample. If they were going to collect a sample then it wouldn't necessarily have to be blood spot DNA. It depends on how old the individual is at that point in time but they could use other sample collection methods. So is the proposal limited to only those kids who test positive to then go back and do more somewhere within five years of birth? Yes but not within five years of birth part. That's something that we considered to be a programmatic priority but the initiative would require as proposed that individuals have a positive newborn screen. Okay so I guess one question I have one question and I have a big concern. The question is of those diseases which are currently part of screening if test positive for how many would normally in routine care go on to have more sequencing? Or is this totally researched across the board? I don't know the exact numbers of how many would go on to do sequencing. I know that typically genetic testing is only done on the secondary level for some of these conditions and it's only a few of the conditions that do gene testing as their next step. Right. It would be specific genes. Okay and then my concern is and this is the pediatrician in me is given the lack of genetic literacy in our population, given the anxiety around pregnancy and the birth and having sat through are you going to breastfeed or not breastfeed and seeing people torn apart by that decision. The idea of presenting what I think is one of the things here is that potentially getting consent at the get go if something's positive is it okay if we also do further screening. I think that needs major LC evaluation before it's proposed. My concern is it is just such a vulnerable period not only for the kid for the family and you don't know enough of what to do as an adult if I get some of these things back. I realize you're taking kids who are positive but you might find some other things. You know the whole self-fulfilling prophecy of well my kids positive why bother. I just think there's so many LC issues there. I'm quite squeamish about this. I think the LC issues are very interesting and really should be driven and I support that but I think that whole interaction with a pregnant family even proposing this at this point I think is premature. So I can say that I think our idea was to be able to do the consent after the individuals had already tested positive and received that information back to the parents when they've had their first contact with their genetic counseling and received that they have a positive screening result to see if they would be interested in this as a research project that could potentially provide additional information. I think that is different to what I heard because I thought you said if they get consent up front for everything it would cover everything which I think is a very different scenario. I'm sorry if I gave that impression. They would be confirmed screen positive. So I mean it seems to me that you don't also want to exclude the people that are rather inconclusive right that's the case where the genome sequencing might be the most important. I don't know if this dovetails on the unresolved Mendelian cases but you could imagine right that they're going to be different mutations and different populations that you don't know about and that's why they don't test positive they test inconclusive. I don't know if that's a kind of gray zone that we don't necessarily want to open but it seems like I think part of the concern. You're only sequencing it's a disease but you don't know the cause of the disease right? If somebody has sickle cell anemia you're not going to sequence their whole genome to prove they have sickle cell anemia are you? There isn't a limit on the conditions the way that beyond that they are conditions that were screened in any state in the United States though that would be assessed within peer review as to whether or not the application has scientific merit. Wait a minute. I am going to say something if you don't mind because I don't usually comment on these LC type issues but I think this whole idea while there are parts of it that have extraordinary value that somehow the easy piece of this whole concept needs to be looked at first and there are so many things around some of the issues that Pearl raised and I don't recognize them as a pediatrician I recognize them as a parent and there are so many issues around the family the child are you going on a fishing expedition are you recapitulating a disease that's already there I just am not quite comfortable yet that a lot of issues around this maybe they have been considered in a lot of detail but I haven't I don't get that feeling I agree with that but I want to also go back to the other just looking at this list we know the causes of most of these genes that are being I mean most of these diseases that are being screened already beta thalassemia why would you sequence 500 genes from the whole exome or the genome from that what are you hoping to learn it doesn't make scientific sense not to mention no but what is the rationale I thought you were talking about diagnosed with something or meaning a phenotype maybe not even the name of a disease but you're still trying to figure out what it is that's what the Mendelian centers are right no I think she said explicitly tested positive screened positive it didn't register until I just started asking this testing positive means for a known gene known disease for which I think we wanted these for which the test we well and their tests because we know these pretty well studied so much you can imagine looking for modifier low science but that would be the next you this would not be the most efficient way of doing that there is no reason to suspect any modifier gene is going to be Mendelian they're going to be just as complex as asthma so there's right to the guy that's over there so so I don't see this scientific value at all or certainly not that clinical so I this idea was a subsequent fish expedition afterwards that's what made me uncomfortable fishing for what though so part of the idea was to start looking for modifier type loci and trying to determine if there are other genes or other information out there that could help to define a better treatment for specific individuals or specific subsets of these diseases as to like what treatment would work best I understand that and and that's I've always fantasized about doing that for modifier genes and almost every study that people have done this even in inbred mouse strains you don't you don't find it because it's not commonly I mean you you know you find huge numbers of variants and I guess you can do it like a GWAS and an animal study too but but basically there been I don't I think this is true that that that you just don't you know they don't they don't fall off a log and they're going to be much much more complex yeah I share Rick's confusion I don't I'm not saying you're confused I'm confused because it seems to me perhaps naively that the potential of DNA analysis or genomic analysis perhaps in newborn screening is for precisely those things that we don't know how to find through metabolic types of modalities you know like mass tend to mass fact so I too am confused why where the real value would be in doing genomic analysis of people who have been who have tested positive for these extraordinarily well vetted and understood small set of entities so I guess I'm confused it seems to me that the issue that you're going to confront with this RFA is the whole issue of sequencing newborn samples right yes part of it is to address the LC issues related to sequencing newborn samples as well as can using genomic sequencing information produce the same type of results that you would get from doing the current newborn screening paradigm and what could it potentially add to care and treatment of individuals that are tested positive that would seem the secondary goal right because I think I think the thing you're going to crash into is we're sequencing samples from newborns right and let's figure out all the LC issues with that that seems to be the driving thing right what needs to be addressed when you start doing this type of research this isn't meant to address you know what can we add to the current newborn screening test but more of what does the genomic sequencing information add how do we need to address this from an LC perspective and to start taking those first steps could you apply that then to unknown ones then it would break the whole thing right the unknown it's what Carlos what everybody has said the unknown ones are the reason for doing this maybe that's just redundant with the Mendelian it's something Mendelian is purely research where you're now talking about maybe applying this in a way where you're dealing with the how you would deliver the information it does have the added problem that if they're unknown you're going to find stuff and they might be actionable and then they probably won't be so and then I'm not sure it's useful from a research point of view but it may not be something that would apply yet but all the unknowns aren't at newborns I mean by the time they now have been worked up now we're not so then apply it to I mean there are lots of newborns where you have no idea what it is part of the problem here which our colleagues at Child Health there's been a lot of round and round about exactly how to do this is that both institutes absolutely believe this is where we need to be doing some research to figure out what the future is going to bring we need data and it seems to me where I see from an observing point of view things go round and round is how do you get your foot in the door when you just started talking Rick about using this truly as a diagnostic of the unknowns I would think the pediatrician well you got very nervous very quick as mom may have gotten very concerned very quick because there's so much unknown so our idea was let's work on a population of individuals who have already tested positive so they're already into a mode of oh my gosh I have a genetic issue I'm already facing and would we add value could there be a research design that would then get us into a circumstance for individuals are already motivated to be involved in this where we would learn more and then we would set up a circumstance to do the kind of LC research we feel is needed we can't figure in part of what everybody is talking about this if we just say we're going to do newborn screening sequencing everybody gets very uncomfortable very quick if you say we got to just go do LC research because I wait a second but we need a real situation to do this and otherwise it's just all hypothetical so the council try to help and meanwhile Child Health Institute had there who are far more knowledgeable and far more experienced in the nuances of the hard issues around newborn screening I mean they've guided sort of they've been trying to again try to find the right balance of where to you know sort of comfortable so that's what we're struggling with and I'm not surprised there's a little bit of struggling around the table Amy you have a second? I think there are areas and we've heard about a lot of them today where it is appropriate and really beneficial to do the science and study the LC alongside it this perhaps is not one of those areas because I think the LC issues are so entrenched and complicated and deeply seated in the public debate and domain recently most recently that I think it could there could be a lot of backlash around that and perhaps what you need is first some LC study about sort of some of the issues and then to do it and there may be scientific questions that can be addressed like I don't know if one of the questions is technically can we do this that's a separate issue but I mean if it's clinically can we do this this might be one of those areas where there's such social controversy about this that it would be worth it to tease out some of those LC social issues prior to jumping it to the science Let me just press you on it, do you strongly believe we could design LC studies in the absence of getting our toes wet at all? It depends what you think the LC issues are one of the major LC issues is that the public has a huge amount of distrust around newborn screening and so doing research around some sort of public perceptions doing public engagement things like that certainly you can do in the absence of in anticipation of the science I think there's a lot of LC issues I think there's issues around the laws the laws are all over the place from state to state I think there's a lot of normative questions that yeah I think you could do in anticipation of the science that could help inform the science in a better way but I'm not saying that's the way you have to go but this might be an area based on sort of we've got reactions of I don't know if we should go here right now that perhaps some preliminary work would be helpful David? I think it's all admirable goal and to a certain extent some of the LC issues have already been pioneered the fact that there are newborn screening programs that already exist is an example of people having worked through the issues before for standard blood testing and I think what carried the day then was being screened for was actionable if you set up a glyctosemia test in a PKU test a child that's positive could be offered a dietary modification that was could follow the bad news to a mother or family that their child was positive so the whole thing was actually for the benefit of the patient and it focused on those things for which there was something that could be done I think part of this comfort here is our realization that if you do genome-wide sequencing you may now couple the good news of oh we have an actionable thing we caught on your child with a bunch of bad shoes that we have now done genome-wide sequencing and here's things that you may or may not want to know that we can't do anything about I think one way around that could be to focus on how well the DNA testing does actually come up with the same result as the blood testing for those patients who already you know or have a good reason to have their blood test and for which you're delivering actionable stuff and you could focus the additional DNA discovery on other things for which there is actionable items but which are not currently screened for right so I mean just a trivial example that no one is screened for lactose tolerance but a very high fraction of children actually are lactose tolerant and there's very simple modifications that yeah intolerant and there's very simple things that can be done right so that's a case where if you designed the study that was focused on positives you could get information about how well the DNA tests recapitulate the results of the blood testing and I think there'd be a small number of things like lactose and tolerance and other stuff that parents and families would see in the same way that they see galactosemia and PKU that there is it's useful to know that for my child there are things that I can then do and I think focus that way it may be possible to get the put in the door. But that would be responsive I mean you gave an example in application that might very well be responsive but... it seems to me what you want to do is maximize both the medical outcomes that could be good and minimize the LC problems. I think that dealing with only a population of parents where their child has already had something wrong found on newborn screening I don't think most of those people see that as good news I mean we know it is good news in many ways I don't think most of them see it immediately as good news. So it seems to me that a focus on what conditions could a DNA based newborn screen actually benefit people and study the LC questions in that context. So I would think about not doing genomic sequencing in a sickle cell patient I don't know what you're going to find out there but to say okay what are those conditions where DNA might have something to offer. So I think about some of the immune defects hearing loss right things for which tandem mass spec is ineffective right now. So immediately what you said is we're going to have the potential to pick up useful things because they're actionable in these kids and then study the LC questions in that because you're giving them some possibly positive outcome whereas if you're already picking kids who have a newborn screen positive I'm not sure what you're offering those families. So what you said would be the unnoted hearing loss or in ways of having hearing loss and say you know. And DNA might have something to offer. Sure but if you I mean hearing loss is on the list. Yeah. No I know but out of this list almost all of them are single gene where they're really really really well defined. If you sequence first of all they do if there's beta thalassemia in the family or alpha thalassemia they'll do some kind of their tests that you can do often they sequence the gene and figure out the mutation it's a small gene and so you the only thing you're going to learn would be if their compound heterozygotes or something like that and maybe something about knowing this is a harsher mutation than that one. But you don't need to sequence more than this is a DNA for beta globin tiny. I mean why. But what I'm saying is for example for hearing loss one could imagine a panel of several dozen genes. Absolutely. It's on the phenotypes but most of them don't make sense in my view. Like sudden cardiac death. Right. Like that's one of the ones where you would totally want to screen it and we can't. But those are unknowns. Those are unknowns right or you know the genes. You might know some genes. You know some of those genes screen then like people would get that information you know like athletes that die at 19 and then you find these mutations right then that's one of those things like you totally would want to know that early on. When it's multi sorry when it's heterogeneous meaning it's even heterogeneous Mendelian then yes you want to and we don't know all the causes of them then I think you have a really good chance of doing something about it. I mean if this was you were talking about Huntington's disease I know you're not because it's not newborns it doesn't do you're not going to learn anything from sequencing the rest of the genome you're certainly not going to get anything about modifiers that and I think that's true for most of the things on the list. I think I just think that that's important to it just doesn't make sense to do deep sequencing on something where you know the genetic cause and it's not heterogeneous. I think the suggestions that have been made especially the most recent ones are are really good and are much more positive and feel better than what I'm going to suggest but another area where there's a need for an answer is in the context of autopsy and not I don't mean traumatic autopsy but for newborns who suddenly die and I'm not even talking about just SIDS even dead at birth stillborn et cetera where often families do want to know an answer it would help them through the grieving process in a way that they often don't have and that's not a very cheerful place to do the study and maybe wouldn't get quite the press but if you want a need that is certainly one where there is a need for an answer in that context and they're almost all unknowns I'm just curious whether part of the motivation here was a pilot of what it might look like for somebody to have a genome sequence in their sort of electronic medical record recognizing you're not going to actually put it in the record but from birth and that's something that a lot of people have talked a lot about as we think about genomic medicine is how much of a game-changer that would be in terms of not having to ever go out is it really the case that you wouldn't have to go out and test all these other things one by one was that part of the motivation for doing this or Yes, that was something that came up about the workshop At some point we're going to need to do that kind of a pilot test now I'm sort of agnostic about whether we do the LC stuff first and then do that but one of the things that comes up over and over again in these genomic medicine workshops and the discussions is the difference between having a DNA sequence in somebody's health record so that a physician doesn't have to go out and order a test because they can just look it up it's a very different scenario from a scenario where you have to go out and order a test and then people don't do it because there are other ways to warfarin being a great example if it were there you would look it up it's a test, it's not worth it because you can figure out other ways of dosing the patient's medication appropriately so I just wanted to get that out at least in the discussion part of the goal here was to pilot that aspect of genomic medicine I think that puts a little bit of a different reflection on this I think it still doesn't take away the LC issues but it may provide another scientific reason for doing this with the Mendelian gene disease genes where we already know what the Mendelian disease gene is so I'm mindful of the time here, we still have more work to do and it's 5.15, I think we've heard a lot of concerns where are you at as a group do you want to take a vote on this straight up, do you want to try to I guess we want that concept so before we do that is Council's view on how important is it for NHGRI to be involved in these kinds of studies because if the feeling I've heard in the past that we're really needed here we have a natural partner in the Child Health Institute who have domain expertise far greater than ours about many of these nuances we have a proposal that's cleared their Council their enthusiastic and so I'm a little I'm not saying therefore you have to clear, I'm just saying that we're trying very hard to navigate a circumstance where I'm hearing slightly different views even around the table of oh well I see the safe aspect of doing it for individuals already screen positive no no it has to be a real situation we're going to learn something new and then I even heard of a proposal that's even very different of autopsy material and so forth and everybody's nervous about this which is what has been the case at the workshop and has been the case right and so I'm I can't figure out whether we should sort of recoil completely but at the same time I can't figure out sort of how to get our toe in the water and we need to do this in coordination with another institute so it's a long-winded way of saying this is really complicated and I knew it was going to be really complicated it's been from the very beginning but I guess I'd like to start with the premise I saw heads but let me hear more completely is this something that NHGRI should be involved in in a serious way in partnership with the Child Health Institute well this area this area of research would include clinical research LC research and technical research we've got to technical stuff in a bit but these are sort of three major areas and I believe that the technical stuff is going to be the least controversial and I know the clinical stuff is the most controversial and everybody believes we should be doing LC research in this area and the problem is for us but for the card together in parallel that's what we're struggling with and none of this is a surprise because we've been struggling for months about this Amy was going to raise her hand but can I just get a quick show of hands is there enthusiasm for NHGRI having a research initiative in newborn sequencing? Okay so that's important to know now it's just an issue of how do we cast it correctly in a coordinated fashion with another institute so Amy now I was just going to say I think this is hugely important I think it needs to be done I hear concerns about the way this is set up and I'm particularly concerned in this area because there are such vocal activists who have really raised a lot of issues about newborn screening that this in particular needs to be designed very very carefully well I mean I'm talking about the class and lawsuits in the different states that have been really championed by a small group of people who are extremely persuasive and active and vocal about their opposition to how the newborn screening programs have been set up and utilized and research has been done using those samples so I think we have to be particularly sensitive to those issues or it's going to be a firestorm. But don't you say some of the particulars of this situation minimizes the risk of the global newborn screening because of people who have already been screened positively for some things but to me isn't it a little different with the issues? I don't think it has anything to do with the issues frankly I think it's public perception I don't think the initial round of attacks had anything really a whole lot to do I mean I had some to do with the issues but I think it's a public perception, public relations issue around the LC issues associated with this I'm not saying we shouldn't do it I just think that the way that this concept is being put forward doesn't give enough in my mind attention to the sensitivity around this. It seems to me that it would be very helpful to have more justification on the population that's being selected for this and it seems to me at least that by having some very significant benefit to the patient population would mitigate a lot of these issues I'm also curious as to for this type of study would it not also be useful or at least in some types of studies to consider sequencing the parents as well has that been considered? We have considered potentially doing trios as well as being responsive I agree it's a critically important area and I actually think the fact that it's in partner with child health is really good as well because if there's any institute that should be particularly sensitive to exactly the kind of things that are coming up around the table it's also them so I think that's a great partnership and it's a great opportunity I personally having expressed my own concerns I would also be happy if the call for proposals is written in such a way that you make clear that you want proposals that will also address LC concerns in the area and what you may get from the RFA is exactly the same range of diversity of things that have come up around the table there may be proposals to focus on genetics of early childhood death or genetics of other positively actionable items and that decide at the time that the proposals come in whether you think the various groups are addressing what you want to see addressed and doing it in a way that will avoid opposition and look like a positive contribution to the field so that's my bottom line on what I think is an opportunity I like the partnership with child health and my concerns could be addressed by seeing what actually comes into the public. So I'm hearing two different things let me float two balloons and see what you think and attempt to try to get some consensus. One possibility is we'll call it the Kingsley model is that we go with this RFA Could we rename that? The David model no I don't know we will that I heard that to approve the RFA but crafted in a fashion that let the review process see the diversity of options not overly constrained and see what comes in and let the review process dictate what ultimately gets funded. There is another model I was just floating with my colleagues is the other model recognizing that this is a really complicated area and that there is tremendous history and expertise of the child health institute that I don't pretend for a minute to fully have compared to them is that maybe we should because of some of the concerns raised and some of the contradictory concerns about how to get our toe in the water would be to defer this for now and ask we would recruit a subset of council to help us work with some of their experts and maybe some advisors that they would bring in and to try to do through conference calls some coming of the minds and recrafting of the RFA and bring it back in May where we could bring it with both institutes would be happy and both sets of advisors in this area would be happy. So those are two options maybe there is a third option I don't know Terry if you like those are sort of two so what are people's reaction of those two different just put your down side of having an SRO at the council table is that review committees don't comment on programmatic issues so write a very clear RFA and ask them to review the scientific and technical merit they're not going to sort this stuff out you'll just get a wreck but the study design I mean what I think the study design is still the big issue here for me and I think you really want to I mean maybe you would get a lot of people writing in to say yeah we'll do this with sequencing 500 genes but I think that's a mistake to put something like that in it needs to be that I'm very much in favor of doing don't get the wrong I agree with all of the issues it's really important but I think that piece needs to be better defined because what if you get ones where they're doing a great job on the LC and the other issues and it just makes absolute I mean you're not and you gain zero scientifically from it because it's not a well thought out design it's like I had so many people come to me over the years wanting to do a GWAS on four samples that they had I mean you need to really have it well maybe yeah but no but I mean but I'm serious about that I think that's the important I don't know what it should be I'm struggling with that because you know some of them yes but most don't know I would vote for the second option because I think the problem with David's proposal is that it's just this one sentence in here it's written out says with a confirmed positive newborn screen and on the basis of all this discussion well we could take that up I mean I think David's model was take that out and have it be more people could come in and whatever study and they want and the peer review process I think it's worth weighing in to say I prefer the Eric model so the second one no so is there can I quickly see people not should we are we leaning towards the second model so we should defer this and partner some of you we will be calling on you to work with Child Health and some of their advisors and I'm sorry I have a hard time seeing how we're going to have any other discussion five months from now four months from now I mean I think David's Eric model let the marketplace decide what's the right study including the LC yeah yeah right if we go and circle around and come back to the council meeting what else are we going to say we're going to say the same thing I think the main objections were confining it to that one population right that was where I got confused I think if you took that up and then emphasize the importance of the LC investigations as part of this I think like you say then you see you'll probably get some very good proposal so David and if there are LC concerns they'd get raised that review right somebody proposes something that very clear with Caesar's that the LC stuff because the kind of things like Amy mentioned have to be the major driver but you also want to have some interesting and it'll come back here I mean whatever comes through the study section will come back here again so you wouldn't get out without Amy giving you a thumbs up so what we don't know at this moment in time is whether the Child Health Institute will be comfortable with an RFA that has removed that sentence now you can approve it we can go back to David's model we can modify it pull out that sentence approve it we'll go back to Child Health if they're not comfortable then we go to my model where we'll have to sort of get the groups together and come up with something that both institutes can be comfortable with and I think I'm sensitive to the fact that it is an institute collaboration which means there may already be resentment if they've approved it that NHGRI comes back and says you know NHGRI council rewrote the RFA I think just politically and because there's so much expertise there it would be good if we have to refine the wording of the RFA to do it with them rather than to try to rewrite it ourselves right now Michael so if we go with the disowned model I'd like to get rid of the 500 genes I think 500 genes rather than whole exome and whole genome doesn't make sense personally but I'm happy to go with Eric model in which case it becomes irrelevant I would start to support that based on the comments I made earlier if this is really meant at least in part to be a model for having pre-existing genomes 500 genes doesn't make any sense okay Pearl I guess if we go with the disowned model I would further emphasize my concerns to me that is the bigger concern and I think that's LC issues would have to come first on that one before dipping a toe in the water because I think even that first subject you got I mean we don't know what's actionable we're just funding other people to figure that out so now we're going to do it on newborns you know in lactose intolerance isn't there I mean people you know they want to know what their kid is so it sounds like you would even be opposed to I'm even more opposed to that well I think I think no but I really want to emphasize Pearl's view of this is you know we have heard this I mean you know this is a lightning ride issue we know so there are many opinions out there and there's a lot of sense to this and we truly are trying to find some middle ground here so I'm not surprised that there's not unanimity around this table there's not been unanimity associated with any of our discussions so or at the workshop so this is very hard and but we're not being chickens we're hitting it head on but it's hard okay so you know where we are already okay excellent I think we're ready to vote I'm not sure what we're ready to vote well here's what I think we should do maybe it would help if we had an up and down vote on David's amendment which removes that sentence and also Michael's amendment which removes the sentence so it's free game to sequence or and it removes the 500 genes well that's why we would have to bring this back to NICHD right but we at least what we can at least if we remove that sentence it means that the grand the applicant would tell us the experimental design and what population of individuals and you emphasize else could be heavily emphasize right and so and we take out the 500 genes and then we have something to go back to child health with that's the that's the one virtue of having a vote now and and if it's if we need to for something then we get back together and talk about when you go back to child sorry when we feel comfortable with it saying diagnosed or undiagnosed and then you could have some folks that might propose a screening program and then you might have some that would propose a screening plus some degree of looking at unresolved cases because you don't if you say undiagnosed then you're totally opening it up right you know in the other direction so you leave it up to again you leave it up to interpretation of what is a newborn screening program and you let the best idea maybe a grantee if they were doing only the ones that are diagnosed maybe a grantee will have some rationale for why you'd want to sequence genome wide that I can't imagine but I but or what I could imagine is somebody doing a mixture of diagnosed and undiagnosed where they would choose some set of things that they know are going to work and then then use that as a way to build up some more complex questions that they might want to answer. One thing I think is important is that when you do go back to child health you need to discuss that issue because the issue is why are you doing this? What are you doing? They're all watching this on the left so they're hearing this discussion which is great it's very helpful because we're going to have this discussion for a long time. They're hearing all this and they're going to form the basis of our discussions with them. So I didn't know if we really wanted the undiagnosed or diagnosed or we wanted just to take that sentence out I don't have it in front of me but it seems to me it's just easy to take the sentence out. Take the sentence out, take out 500 genes and I think that's the proposal on the table and I think we should do an up or down vote and I think if the vote passes then we go back to child health and if that's we can work out a framework with them we go with that and if it does not pass then we go back immediately to discussions with them to figure out how we can get our advisory groups and their staff all comfortable assignment. And with the understanding that there is strong support for something like this. Yes, right. So is it clear what we're voting on? We're going to vote on this amended version of the concept clearance. Okay, take it out. Go ahead and read it. It's most specifically each applicant will be expected to collect the genomic data set from infants with a confirmed positive newborn screen brackets for any condition currently screened for by a state newborn screening program close brackets and analyzes those data in the context of a scientific question relevant to the diagnosis or treatment of a medical condition relevant to the newborn period. Are we just taking out the part that refers to them having to have a confirmed positive newborn screen and leaving the rest of the sentence? Yes, I think we should just take out that it has to be confirmed because I think we want all the second half of the sentence is definitely what we want. Has to be relevant to the newborn period, etc. Which is to just not even try to pass the concept clearance. Yes, that is absolutely an option. I think that this very specific requirement in this sentence suggests that there's some thinking behind that and maybe it makes more sense to go back and revisit that with people who really understand the thinking behind it. If you take out all the diagnosable here and you're looking for the symptomatic kid in a newborn period who's going to populate this database, you've got to think about what you're looking at.  Are you going to include that? Are you going to really look for things where you don't have an answer? We don't even know what that population is. So I think that would need a lot more work in terms of ferreting out. You know, if kids who aren't picked up by, this is just a list. Or you can take anyone with a symptom. Newborn period, are you talking one month or six weeks? It probably is mine. Anyway, so I think that needs some more feathering out too. The reasons I think it's hard to rewrite it, the NOVO, because issues are important and there is a companion institute who has a lot of expertise and cares a lot about it. So I'm hearing support from my model. That's table the concept clearance for now and come back after a joint venture discussions as I described. I don't know if we can defer or table it. I think we have to vote on it. I'm asking for a vote on the concept clearance that's before us and then there's another message that's going to go back to child health. So all in favor of the concept as proposed in this document. All opposed? Any abstentions? Okay. Thank you.


Hi welcome to Physiology Open. Try to solve this question on functions of insulin. In this question you have to state which statement is true and which statement is false. You can pause the video and think about the answers. We will come back to the question at the end of the video again. Okay now let's discuss the concepts on functions of insulin or effects of insulin on metabolism. The main function of insulin is to store the excess fuel during times of their availability for future use. Thus insulin is released in the fed state when the availability of the fuel especially carbohydrates is high. As these substrates are absorbed from gastrointestinal tract their concentration in blood rises. However with the release of the insulin they are quickly moved from the blood into their storage depots. So how does insulin promote the storage of nutrients? By affecting the entry of nutrients into cells and their metabolic cycles. Well before we go into the concepts we will just see in brief which metabolic cycles will decrease the nutrient concentration in blood and which will increase the concentration in blood. Factors which cause increase in blood glucose concentration are intake of food and then digestion and absorption of nutrients into the blood stream. Then glycogenolysis meaning breakdown of stored glycogen into glucose and then gluconeogenesis which causes synthesis of new glucose mainly from amino acids. Now factors which cause decrease in blood glucose concentration are storage of glucose as glycogen that is glycogenesis which occurs mainly in liver and skeletal muscles. Also storage of excess glucose as fatty acids this also occurs in liver and finally utilization of glucose by peripheral tissues. Similarly for fats and proteins concentration is increased by lipolysis and proteolysis respectively and decreased by promoting their entry into cells and further fatty acid synthesis and protein synthesis respectively. So logically you can tell from this that to lower nutrient concentration in blood insulin should promote glycogenesis synthesis of fats from glucose and utilization of glucose by peripheral tissues while it should decrease glycogenolysis and gluconeogenesis. Similarly it should promote fatty acid synthesis and storage and inhibit lipolysis and it should also increase protein synthesis and inhibit proteolysis. So what it is specifically does to have these effects? Well this all happens mainly in three tissues that is the liver skeletal muscles and adipose tissue. In liver it increases the activity of enzyme glucokinase which converts glucose to glucose 6 phosphate. Thus it keeps the concentration of glucose low in the liver so that glucose can enter the hepatocytes. Then it promotes glycogenesis by increasing the activity of the enzyme glycogen synthase while it inhibits glycogenolysis by inhibiting glycogen phosphorylase. Also excess glucose which has not been converted into glycogen enters into glycolysis pathway and produces acetyl coenzyme A in liver. Now this acetyl coenzyme A is used for synthesis of fatty acids. Since insulin promotes the activity of the enzyme acetyl coate carboxylase which is very important enzyme in lipogenesis and hence insulin promotes fatty acid synthesis. Also in the process of synthesis of fatty acids malonyl coase formed which inhibits carnitine palmatoil transferase enzyme that is CPT enzyme present on the membrane of mitochondria which causes entry of fatty acids into the mitochondria. So when this enzyme is inhibited beta oxidation of fatty acid doesn't occur. So what is happening only synthesis of fats is occurring from extra glucose. Well now the formed fatty acid should now go and get stored in their depose that is adipose tissue. So they are transported from liver to adipose tissue as triacetyl glycerol in VLDL via blood. Insulin increases the expression of lipoprotein lipase in the walls of capillaries of adipose tissue. This lipoprotein lipase releases fatty acids from triacetyl glycerol in a VLDL which then enter into the adipose tissue and is stored. So these were the actions of insulin in liver and some on adipose tissue. Now insulin also promotes the entry of glucose in most cells except neurons and RBCs. It does this by causing fusion of glute pore transporters which are present inside the cell to the membrane. This increases their number on the membrane. Since glucose is in higher concentration in blood it enters in those cells along its concentration gradient via these glute pore transporters by a facilitated diffusion. So most cells start using glucose as a fuel in presence of insulin and hence usage of fats as fuel is spared. We have already seen that beta oxidation is not occurring in liver right. Now note here that insulin increases the entry of glucose into apatocytes also but not by increasing these glute pore transporters instead by increasing the activity of glucokinase enzyme right. Anyways now in skeletal muscles excess glucose is also stored as glycogen while in adipose tissue the glucose which enters acts as a substrate for glycerol portion of triacetyl glycerol. We have already seen that fatty acids from VLDL enter the adipose cells. So the glycerol from glucose and fatty acids combined upon triacetyl glycerol in adipose tissue. This is how excess glucose is stored as triacetyl glycerol in adipose tissue. Also insulin inhibits hormone sensitive lipase in fat cells. This lipase breaks down stored triacetyl glycerol into fatty acids and glycerol. Thus by inhibiting hormone sensitive lipase insulin prevents hydrolysis of triglyceride in adipose tissue. So we have seen two lipases here lipoprotein lipase causing entry of fatty acids into the adipose tissue this is promoted by insulin and the one causing glycerol triacetyl glycerol from adipose tissue that is hormone sensitive lipase it is inhibited by insulin. Okay now what about this action on protein metabolism insulin also promotes amino acid uptake by cells and promotes protein synthesis simultaneously inhibiting their breakdown. Well now let's come back to our original question. In this question first and second statements are correct. We have seen that glucose is not only converted to glycogen but also to fatty acids in liver and then fatty acids are transported as triacetyl glycerol in VLDL to adipose tissue where lipoprotein lipase facilitates the entry of fatty acids into the tissue. Well the third statement is wrong since insulin spares the use of fatty acid instead it promotes its synthesis. Fourth statement is also wrong since we have seen that in liver insulin increases the activity of the enzyme glucokinase due to which glucose entry into hepatocytes is increased. Well thanks for watching the video if you liked it do not forget to subscribe to the channel Physiology Open. Thank you.


Keep that handy dandy yellow reference sheet out the front of it face up Probably you want to keep it so you can see it and all we're going to do from now on Jordan is what we've been doing Except you're going to hear me say why convince me prove it and what you need to train your brain is When you see the answer to ask how do I know that that's true? You see the extra step Devin We're going from simply saying here's the answer to saying and this is why it's right shut up Really in a court of law so Example one it says find the measure of each angle and give a reason first of all how big does angle one have to be? Jordan, I totally agree Why what I'd like you to do is find the word on your yellow sheet that describes that I? Think there's a word that begins a letter C that matches this diagram even more is there not Right angle was the definition of the angle, but I think two angles and add to 90 What do we call that from the sheet? So if we were in a court of law Taylor, it would go something like this Jordan would have said 22 degrees I would have said objection your honor calls for speculation and Jordan would have said complimentary and the judge would have said objection over Well, because you've given me the evidence This is the extra step court and you have to memorize all the rules Sydney No, you're gonna not be allowed to have that sheet in front of you But you gotta know like where they are and how to find them Okay angle three how big Marcus Objection your honor calls for speculation Now this one you can either use that or you'll notice just underneath it There's another rule called angles on a line now I'm gonna be really technical Technically you use angles on a line when it's three or four or five angles forming a straight line and Supplementary when there's only two angles forming a straight line that's technically Joe I don't care you can use either of those and I'll figure out you include in that It's a straight line adds to 180 so you can either use supplementary or angles on a line To me they're interchangeable My court of law is a little bit more linear Okay Question seven Angle See F okay C F E That's I'll mark mine up you guys don't need to but that's that one there. How big sorry I heard someone say it 90 objection your honor calls for speculation convince me. I have no idea what you said It is a right angle. I don't think that's the reason though By the way, 90 degrees and saying it's a right angle. Here's what you're saying It's 90 degrees because it's 90 degrees. Did you hear it? We have a special name for that.  You're well. No, you're not giving evidence You're repeating your argument in a different form and hoping that I don't notice that you've done that You've heard me actually confront kids. Why are you late because I just got here That's saying I'm late because I'm late Hear it and you've seen kids do that. So I need a better. I'm gonna say I agree with the 90 How did you know that was 90 Jordan? I? Don't think you looked here Where did you look to figure out that this one had to be 90? This is 90 and what are these two form? Okay, what did we call two angles that formed a straight line? You know what I'm gonna argue that the rule that you used is Supplementary is that okay Emily? Okay, next angle C F D that's That one how big yep Convince me objection your honor calls for speculation. I don't see a rule on there called 35 minus 90 on the yellow sheet Sorry Okay, so Taylor said look if this is 90 these two add to 90 and now We're going to abbreviate complementary as comp. We wrote it out the first time. Yes You can abbreviate that as comp. There is another argument. You could have made as well. You could have also said what Marcus You could also have said or So or What was that when you said? Okay ready angles on Align, and I'm saying you can't abbreviate these because it's lots of writing The same way they do in a court of law. They don't tell you the whole case They say oh in Johnson v. Smith, and you're supposed to look it up and clue in whatever Either of those I would have to accept and now we're getting into diagrams that are complicated enough into arguments That are complicated enough that there's more than one reason Best friends always BFA is that I know BFF is best friends is BFA anything No, okay You can use that now best friends always B F a now that is That one How big Yes, I know you know this and you're doing good and thank you for raising your hand But I want to get other people involved now. I Agree no wait a minute objection your honor calls for speculation. Ah Okay, so here is where we saw the X Which I think is also on your sheet top right corner if I'm remembering correct or near the top right corner Sorry, no never mind. I gave you two columns On the first half of the page near the top right of the first. It's there You find it. Yes. Yes. Yes. Yes. Okay Matt, what did you say the rule was? What did you say the rule was? How about vert? And I'll clue in that that's what you're talking about By the way, I don't know if I've showed you how I remember that rule. Can you all look up for a second? Matt, what letter is that? What letter is that? What's the top half of the X look like?  This was one way You okay with this? Let's keep going this one We're arguing but we're getting marks for arguing which most teenagers don't normally do Be at BFC. That's that guy. How big? Yeah How'd you get 125? Vertically opposite, let me see so you said you looked at that and you added 90 you know what I didn't even see that I agree that works It's not the first one I would have spotted I actually went well Yeah, I trained myself if I'm not sure what to do always look at the previous question because often the previous question is What I need to find the next one so I looked here and I said 50. Oh, I also said or sup or Angles on a line or Alex do we know this? Do we know this? Do we know this? Do we know this? What's that add to? Okay, where is that rule on the sheet? Can you find it? What do we call that one find it on the yellow sheet somewhere? Okay, we're gonna call that the course the court case that we're gonna refer to from now on Aaron for that one is or Angles at Point that means on a quiz from now on I'm gonna ask you for the angle and for the reason It's probably gonna be a half mark and a half mark but for this answer Joe I would take that or that or that now did you hear me say to Alex I didn't even think of that one you guys heard me say that on These quizzes what I'm gonna be doing afterwards all the time is saying now come lawyer with me You may have seen one that I didn't see and I might have marked it wrong And you may actually say no I saw this and it's not oh, I didn't see that and you are right So for this unit when I hand stuff back argue with me because that's part of what we're also trying to practice Jeremiah It's the art of mathematics of logic and reasoning Bifta Be a Bfd be oh Be Fd What angle is that? As a number first of all, please How many degrees okay 180 degrees What's that called on our court reference sheet? It's there No, no, I think I think that I think this is they're not actually one of those on there somewhere. Oh what? Straight is that what it says straight angle? There you go There's our rule. So you should find this sheet handy. Let's do a few more through the page Okay angle one how big now if you're stuck Where would I go looking to try and figure out how big angle one is Joe? What's the only angle they gave me in this question? They gave me a 180. What's the only angle they gave me in this? So, you know what? Because I've told you do these an or if you're finding trouble now I'm seeing some of you are seeing these right away great You can probably drop your guard down and almost do them in any order But if you're having trouble I've said to you do them in order because you can think like the test creator I'm sure this 70 is going to tell me how big angle one is and it's either going to be the same size or add to 180 Because that's the only rule we've ever learned angle one how big well sorry I heard somebody say e and I 70 I agree objection your honor culture speculation. How come? Oh, she even found the rule she said mr. Do it when you have two parallel lines And a line cutting across which you do have a picture of yes. Yes. Yes. Yes. Yes If you can slide one line one angle like snakes and ladders along the line that's cutting across and they overlap perfectly we call that Can I abbreviate corresponding with c o r r? We're gonna Angle two how big Marcus Convince me. You see letter x. Yep Angle three how big Jordan why Sup Or we said you could also call that angles on the line. I'll take that now If somebody said to me joe Well, couldn't I use angles at a point add to 360? This is where I would say Since you don't know this angle yet You can't use a rule that assumes that you know this angle to try and find another angle So Try not to add extra angles if you can avoid it We want the cleanest case. We don't want a bunch of extra legal information that the judge doesn't need It may be right But if the judge doesn't need it why confusing? Does that make sense Courtney? Let's keep going Courtney, what's the only angle they gave me in question 10? So that angle four it's either 65 although They don't look the same size Or it's probably 180 minus 65 is only with two relations. We have I'm pretty sure it is 115 what I'm really saying is why How come Marcus? Uh, let's see that would mean these two formed a letter zed and I don't think they do Matt Okay, now you all have your reference sheet. Yes The one that I forgot to print into here. Give me one second here foundations of math 11 My geometry reference sheet because we're gonna we're gonna handle else on this sheet So you all want to get out that reference sheet for a second And where it says interior angles on the same side of the transversal we're going to add two things First of all if you want the abbreviation it was I a O T T IOT sought first letter of each word But a few years ago after this handouts were made up somebody came along in math in bc and said You know in britain and in europe they use a shorter word for this and people said Oh, they do that would be great because i'm tired of writing interior angles on the same side of the transversal So what i'd like you to write next to here if you want to is co interior You can use that to describe this as well co dash interior The only reason I don't like that is kids get alternate interior and co interior and co responding a little bit mixed up But wait a minute.  I'm gonna say I think you can handle it Okay, so back to our notes to your angles on the same side of the transversal Coint or iot sought it's the same thing In fact, it was the letter c rule right There's your capital letter c their tangles a big zangle five Objection your honor calls for speculation. You're right. How come? What letter are you looking for alternate interior angles? Zed here's how I remember that these go together zed is the last letter a is the first letter. I kind of remember zed Goes into the a sorry. I don't know works for me Zoro angles one year my kids named them zangles. I've had some kids call them But alternate interior is the official court rule Try to think try 12 on your own. I'll do it up here 12 is trickier if you get stuck You can always look up in a few seconds I got these Yes, no Oh, I'm sorry. I hit the button I thought try that again. I got those Where do you guys are we? by the way Jordan in situations where I'm getting two rules you you only have to use one of them But what I'm saying is I take that I take that now This last one and this one you might lawyer with me because there is another way to get angle three Did anybody see the other way to get angle three? What There is a zed So I would have to also accept on a quiz Is there another way to get angle four that I haven't seen? I'm not really seeing Anything there Great question Okay No, no, it's a good quick. What did you do? Did you get 110 or not? So first of all, here's what I said I heard you say did you say the one in the three? What angle are you finding right now? No, no, you what angle did you said you want you asked me what angle two didn't you? Oh, how did I get angle three you asked? I thought he asked me how did I get angle two? Sorry, okay So two ways Like that to the zed or X marks the spot just imagine that line's not there And there you have to use your Sesame Street imagination, which means these two are the same angle Vertically opposite Okay, let's try a couple more In fact a few more and we're done How big is angle one Boston? You might need your calculator for this one unless you're good arithmetic in your head Is it 58? Yes, no. Yeah 58. We're good to 58 Convince me Okay, now what are we going to call that one? Can you find that rule on the gold sheet somewhere? I think it's right above where the triangles start It's all on the front page right now. We haven't done anything from the back page yet It's in small typing. I think right above where the triangles start. I think oh, I think oh, I think What's it say? Louder, I can't hear you. So here's how we're going to abbreviate that one angle sum of triangles Some you're adding them up the angles Triangles except we're not going to write that much. Oh, we'll write it up just this once in our notes But we're actually going to write it this way angle sum of triangle shorter Is that okay? So Your court case that you referred to Boston is I know every triangle adds to 180.  I think I Yeah, I agree with Sam 29 convince me More specific. What type of a triangle is this? I sock triangle Now the fancy word for this is angles opposite equal sides of an isosceles triangle or equal We're using the properties of the isosceles triangle and I think I gave you a picture of an isosceles triangle on your gold sheet Yes, and I listed the properties. Yes. Yeah Oh, wouldn't it be 34? I don't know. I wasn't doing the math. Is it 34? 180 minus 112 and then divide by two. Yes You also did use angle sum of triangles But really your final step was isosceles triangle having said that Jeremiah I would accept both rules if you said to me. Well, I used angle sum of triangles I'd say fair game But most of you also would have said that's awesome So Alex, how big is angle five then? 146 convince me What's up or angles on the line Or I guess you could argue Hey, this adds to 360 and this one here is 180. You could use angles at a point But hopefully nobody would do that much extra work. I'm also trying to teach you Emily to be lazy and deficient There are often longer ways to get that's probably a short way to get there last page Does getting the hang of this a little bit One extra step. We're saying ask your brain how you know. All right angle four Now you'll notice they didn't give you any numbered angles here.  If you look at the definition of the equilateral triangle on that gold sheet Yes, Joe, what does it say next to an equilateral triangle on the gold sheet now that you've got it right side up so you can read it and and Does it say anything else? Okay, I think it says Three sides equal three. What's the sudden abbreviation for? Okay, so read that too. That's the phrase. I'm looking for it And if they're all equal they each equal 60 because they've got to add to 180. So you know what if you write Equa triangle equilateral triangle. Okay, how big is angle five? Now if you're not sure how the heck to find angle five What angle should you look at as for a hint? I would look at angle four first of all I would also look at any other numbered angles that they gave me if there's like a 42 degrees kicking around some But I'm looking at angle four and when I do that I'm going to argue. I think that makes the Zorro's angle zed easier to see Yes, how big is angle five?  Can you show me what your reasoning is? And for those of you who say where am I going to use this stuff? This stuff probably never But arguing and trying to convince people that you're right. That's the skill we're practicing Marcus. You going to make it? I'm not so sure No up in there You know what I missed you I was aiming for you and I aimed a little bit to the left there didn't I because danielle boy that got her attention Sorry danielle. You know what next time I'll aim at jordan. That should get Marcus square between the eyes Last one What's the great big shape that you have here? Circle So here is mr. duix one of the many tricks portney if they ever give me a circle did they give me a circle? If they ever give me a circle, I always find all the radiuses all the radii And I put equal hash marks on all of them That's the same length as that is the same length as that is the same length as that You know how I know jordan Because the radius like the definition of a radius was from the center of the circle to the edge A circle is defined as all the same radius Do you see as soon as I do that did you notice a whole bunch of isosceles triangles suddenly appeared? See them So devon they give you a circle put hash marks on the radiuses Okay, I'm going to use the proper math on the radii So All right, how big is angle one? Matt I think you're right if I read your lips correctly.  Taylor 110 convince me I think you went like this These are all These are all angles at a point. You said those add to 360 So I think Taylor you went 360 minus this angle minus this angle And then you said if the two remaining angles are the same size What will I do with the degrees that I have left over? Yeah, and the geometry rule you started out using was angles at a point. I agree angles Do we have an abbreviation in English for the word at? Yes, we do I'll take that even Angles at point and you'll notice I didn't even write the word So that's what we're going to be spending leading up to Christmas and after Christmas going over Okay Says homework work on finishing geometry package one just so that I know has anybody finished geometry package one yet Just one person Okay, I was gonna It says once you finish geometry package one hand it in and start on geometry package number two I'm going to hand out geometry package number two on thursday of next week So if you're done, I'm not going to give you new homework. Okay The rest of you you have the remainder of class


Now, in business, the federal government has signed an agreement with the United Nations Office for Project Services, UNOPS, to strengthen ties towards achieving the goals of the Sustainable Development Goals by 2030. The Minister of Foreign, Geoffrey O'Yama, expresses his confidence as he says, signing the agreement at a period when the world is faced with a pandemic is essential and will provide the framework towards implementing important SDGs projects. We hope that this host country agreement will provide an enabling environment and the framework, and it is a platform for UNOPS to be able to partner with us as a country to help us in implementing the projects in our priority areas. Of course, these are legions, even energy, agriculture, you name it, UNOPS is very versatile and does engage in literally all the sectors. So we look forward to a very fruitful and productive partnership with UNOPS. We believe this agreement is timely, given the increasing presence of UNOPS in Nigeria. Just two days ago, UNOPS launched a new project in Boronu State to provide life-saving oxygen therapy to support the COVID response and the treatment of children suffering from respiratory illnesses. We are in discussion with some states in Nigeria to mobilize investments for affordable housing in those states. We've already started off with AQT State. This host country agreement will facilitate UNOPS operation in Nigeria and enable an agile and nimble process. UNOPS commits to honor all clauses of the host country agreement. Hello, hope you enjoyed the news. Please do subscribe to our YouTube channel and don't forget to hit the notification button so you get notified about fresh news updates.


An angle measures the amount of turn, so how much has been turned? They're measured in degrees which are written like this. A quarter turn is 90 degrees, a half turn, so turning on a straight line is 180 degrees, and a whole turn is 360 degrees. Angles come up everywhere in life, which is why we need to learn about them. The slope on roofs so that rain and snow can slide off. Pilots use angles to make sure they stay on course. They also use angles for taking off and landing to make sure they don't come in too steep. In construction and by animators. Angles of different sizes have different names. Acute angles are less than 90 degrees. Think of small cute puppies. Cute, acute means small. Right angles are exactly 90 degrees like in squares. Notice how right angles are always shown with a box rather than a curve. That's only for 90 degrees. Next up we have obtuse angles. These are bigger than 90 degrees but smaller than 180. They go from right angles to straight lines at 180. So less than 90 is acute, exactly 90 is right, and from 90 to 180 is obtuse. To a straight line at exactly 180.  These are called reflex angles. An easy way to remember the smallest is acute, then obtuse and the biggest is reflex is just to know that they go in alphabetical order. A-O-R. Be careful which angle you're being asked for. This is obtuse, but this one is reflex. An acute and obtuse and acute and reflex. Here are a few questions for you to do. Pause the video, answer them and click play when you're ready. Did you get them right? So there we have the names of different types of angles. Just remember, acute, obtuse, reflex go in alphabetical order. Please like and share our videos with your friends. If you have any questions, comment below.


Okay, let's do this problem here. Are we ready to do it? Yeah, okay. C, L, 2, and F. How do you put this together? Okay, so the first thing you want to do is draw the Lewis structures of the various atoms. Or put the atoms with their valence electrons around them. So what does chlorine look like with its valence electrons around it? Draw chlorine, for example. Or I guess another good question would be, how many bonds can chlorine make? You should know that. That's how many valence electrons it's got. That's what chlorine looks like, right? How many more electrons does it need? One. So how many bonds can it make? Just one, okay? You're making this way too hard on yourself, okay? You're making it way too hard. Okay, so let's draw the other chlorine. Looks like that, right? How many bonds can it make? One, okay? What about flooring? Let's draw that. How many bonds can it make? One as well. Now let's draw nitrogen, okay? How many bonds can it make? How many valence electrons does it have? Five. So how do we do it? We go one, two, three, four, five. How many bonds can nitrogen make? Three. Okay, so which one's going to be in the middle? It has to be, right? Why? Because the other ones only make one bond, right? Can something that makes one bond be in the middle? No, just like what I said. It's the one that makes the most bonds, you know? So let's draw it now, right? So let's just take this flooring and put it over here. Like that, right? Like that, right? Okay, so now let's draw what that looks like, okay? So that's the Lewis structure of it. If you wanted to know what the structural formula was, you have to remember Vesper theory, right? You got these four electron groups. So it's effectively, they want to be as far apart from each other as possible. That bond angle there, 107.3, because you've got this lone pair being very big around there. So it makes that 109.5 smaller than what it should be. Uh-huh. Betty? Uh-huh. Any questions on that? Before we... What do you mean? What do you mean? So this looks like... That's what that looks like. All of these things are trying to be as far apart from each other as possible. Yeah, they're all trying to be, because they all have a lot of electron density around them. So they're trying to be away from each other. It doesn't matter. Look, you're just putting it... You're wanting it to be different. If I turn it this way, if I made it this way, it's a different thing than if I made it... It's not. Remember, I was telling you. Like I... Okay, if I sit like this, right, I'm still heath, right? Or if I'm like this, you know, I'm heath, right? Or if I'm like this, I'm still heath, right? You know? No matter with... Yeah, I'm just turning around, you know? So it's just like this. Like I can draw it like this, you know? Let's draw it like this and see what it looks like, okay? Let's draw it like this. Let's draw it like that, okay? So we would do... So when we're drawing it like this, all three of them are coming out towards us, right? It would look something like this. It's a little harder to draw, right? And the lone pair is behind the nitrogen now. So you can't see it, you know? Because it's like this. That's exactly what it looks like, okay? Do you see? Why? Because that's what you do when you want to show something that's just forward. That's how you show something's forward is these triangles. They're called wedges. And dashes mean it's going behind, right? So the difference is this looks like this one here. Looks like that. See the fluorine's going behind, right? And this chlorine's in the plane and this chlorine's going up front. That's why it's in there. Wait, this one looking like that with all three of them going forward. You know that the dashes mean go back. We'll talk about that in different ways. Is everybody okay with this one, though? You okay with this one?