We Accelerate Discovery



The Good afternoon or good morning if you're joining us from a Pacific or Mountain Time Zone location. My name is Christine Colvis. I'm from the National Institute on Drug Abuse and I'll be moderating today's workshop. I'd like to welcome all of you whether you're here in person or joining us by webcast or joining us by phone. I do ask that if you've called in and you're listening in by phone, that you please put your phone on mute and that will help keep down on the background noise for us. And, for those of us who are here in the room, maybe we can put our blackberries and cell phones on silent mode.

Before we begin the workshop, I want to quickly go over the agenda. So, we'll begin with opening remarks by video by Dr. Nora Volkow. Dr. Volkow is the Director of the National Institute on Drug Abuse and she co-chairs this Roadmap Epigenomics Program with Dr. Sam Wilson who is the Acting Director for the National Institute of Environmental Health Sciences, Dr. Jim Battey who is the Director of the National Institute on Deafness and Other Communicative Diseases, and Dr. T.-K. Li who is the Director for the National Institute on Alcohol Abuse and Alcoholism.

So, following Dr. Volkow's presentation, we will hear a brief overview from Dr. Wilson on the Roadmap Epigenomics Program. And, after that overview, I will have the NIH program staff come up and give an executive summary on each of the different RFAs for this program. And, those presentations will occur in the following order: We'll start with the Mapping Centers, and then go on to the Data Analysis and Coordination Center, and then the Technology Development RFAs - both the R01 and the R21 - and then the Novel Epigenetic Marks RFA - again, the R01 and the R21 RFAs for that.

So, after we've heard all those presentations, I'll invite those NIH staff members to join me up here at the front for a question and answer session. I ask that everybody hold their questions until we've heard all of the presentations. We'll be taking questions from people who are here in the room. Those of you who have called in by phone, can either ask their questions over the phone, or if you'd like, you can e-mail your questions to the e-mail address that shown at the bottom - epigenomics@nih.gov. And, of course, if you're joining us by webcast, you can also use that e-mail address to ask your questions. Again, I ask that you hold questions until the end, unless you're sending an e-mail - you're welcome to e-mail questions at any time during the workshop - we'll be taking those live throughout the workshop. And, I think that's about it for me. With that, I guess we'll go ahead and get started with the video presentation from Dr. Volkow.

Good morning, I'm Nora Volkow, Director of the National Institute on Drug Abuse, and I want to welcome you all to this workshop, which is a technical assistance for the RFAs that are coming up as part of the Epigenomic Initiative of the Roadmap. As you know the Roadmap was initiated by Dr. Zerhouni to integrate resources and efforts across the various institutes to tackle problems that are of scientific interest and can advance the mission of more than one institute and that is something that will have public health impact. This year, there have been two new Roadmap initiatives selected - one of them is the Microbiome and the other one is the Epigenome, which is the one that you're going to be hearing about. Epigenetics is not a new science - it has been around for almost 50 years. However, the interest of epigenetics has increased dramatically over the past five years. This is in part a result of our better understanding of genetics, but also the development of technologies. And, it has become clearly evident that epigenetic processes are actually indispensable in the revelation of how genes are expressed and therefore in normal development, as well as aging.

It also has become evident that epigenetic processes are crucial in helping us understand how the environment interacts with the organisms and how that interaction ultimately can result in a healthy individual versus one with diseases.

Through the Epigenomic initiative, we're putting forward five RFAs, the goal of which is to develop the science in a way that will accelerate the process in new discoveries in epigenomics. While there has been already, as I say, particularly over the past five years, significant research, most of the research on epigenetics has focused on the mechanisms and processes and yet a relatively small amount of research has been done in understanding the disease.

From the knowledge that we've gained about epigenetic processes, several mechanisms have been identified such as DNA methylation, histone modification, microRNAs. But, it's also clear that it's likely that many other mechanisms by which epigenetic process can occur, and in one of the RFAs it's targeted to accelerate the discovery of those processes.

Another RFA is targeted to generate standard epigenomes such that they can be utilized to understand changes produced by environmental stressors and disease. Another RFA will be targeted to help develop and advance the investigation of epigenetic processes in diseases. We know that they are clearly involved, because that's where most of the research has been done on cancer. But, it's also evident that they are involved with obesity, with asthma, with neurodegenerative diseases, with drug addiction among others.

So, finally, as you go through the process today, I encourage you to be bold and to ask questions and suggestions you may have. And, I also encourage you, of course, to participate in this really exciting area of research.

Okay. Before we continue, I just wanted to remind those of you who are calling in by phone please put your phone on mute so we can't hear what is going at your end of the line. We will continue now with an overview from Dr. Sam Wilson, who is the Acting Director of the National Institute of Environmental Health Sciences.

Thank you, Christine. And, I would like to join Christine and Nora in welcoming you to this very exciting and important workshop. The program that we'll be discussing is part of the NIH Roadman, and in the case of many of the Roadmap activities the program development is a team-oriented activity, and that is certainly true of the Epigenetics Program.

On this next slide, as you can see here on the screen, we've listed the members of the team that has been involved in fashioning the Epigenomics Program. And, just a quick glance down through these names, you can see, for example, that the National Cancer Institute has been extensively involved in helping. As Nora just said, the National Cancer Institute already has a substantial investment in the area of epigenetics and epigenomics. But, just glancing down through here you can see the Genome Institute and on and on. NIDA, of course, one of the co-lead institutes on this activity, and many other institutes, including NIEHS, as you see, very well represented. And, also down here, on the right-hand side at the bottom, you see individuals in the Office of the Director, who have been working with us toward advancing this program. Now, by way of a general introduction to the program, let's go to the next slide.

And, first of all, there is the hypothesis here that epigenetic mechanisms underlie the origins of health and susceptibility to disease. Now, we already know that many permanent genetic changes, like mutations or DNA lesions, can be involved in susceptibility to disease, but the point here is that other types of changes to DNA also need to be taken into account, and I'll come back to this in just a second. Now the goals for the program, are 1) to establish international partnerships, standards and practices and platforms, new reagents and new informatics technologies to be able to advance this field; 2)to develop epigenetic mapping data and infrastructure to facilitate research in human health and disease; 3) evaluate epigenetic mechanisms in aging, development, environmental exposures (broadly defined) and disease processes; and, finally, to develop new technologies, even penetrating to the single cell analysis, and remote imaging of epigenetic changes and activity in cells, tissues, and whole animals. So, these are the broad programmatic features that we look to promote and develop over time in this program.

Let me back up a little bit now and talk about the topic that we always need to have in mind - that is the working definition. First of all, epigenetics, as we've been using this term for many years, applies to the study of the regulation of gene activity that is not dependent on gene sequence. Epigenetics, of course, includes heritable changes, and expression differences that occur in progeny of individuals or cell types and stable long-term alterations in transcriptional potential of the cell that are not necessarily heritable. So, as Nora just indicated, for example, histone changes, other kinds of post-translational modifications that occur within a cell generation would apply in this second item.

Finally, epigenomics is defined as epigenetics that relates to single genes or sets of genes, while epigenomics refers to global analysis of epigenetic changes. So, these are more or less definitions that are in keeping with the definitions that we have for genetics and genomics themselves.

Now, moving on to the RFAs - and, again, we've already heard a little bit about this from Nora - there are five RFAs overall in the works, but today we will focus attention on the four listed here, and I'll just repeat them. Christine also mentioned a little bit about this. But, the first one has to do with Mapping Centers; the second RFA, Data Analysis and Coordination Center; third, Technology Development; and fourth, Discovery of Novel Epigenetic Marks. So, these are the specific topics for detailed discussion as we go through the workshop. And, also something for you to keep in mind, although it is not a topic for discussion today, the RFA that, internal to the program we call RFA 2, but it's actually an RFA on Epigenetics of Human Health and Disease, where we can link the information derived through the research in the top four RFAs you see here, and use this information in understanding linkages between epigenetic changes and human health and disease. We anticipate that this RFA will be released in 2008. And, once again, we will not discuss this RFA today.

So what is the vision for this workshop today? It's an opportunity for all of you, and we hope there's wide interest and detailed evaluation of these RFAs to fill in all the blanks and get some hands on experience as to how to respond, but an opportunity for potential applicants to seek clarification on scientific and programmatic aspects of these new initiatives.

And, the format as Christine as already summarized, is that we're conducting a live session here in an auditorium at NIEHS in North Carolina, we'll have some presentations on the RFAs, and very importantly, an extensive period of time for questions and answers through the mechanisms that you see here at the bottom of the slide. So with that, I'll turn the podium back over to Christine.

Thank you, Dr. Wilson. So I guess we'll go ahead and get started with the individual RFAs. And, again, I ask that you hold questions until we've completed the presentations for all of the RFAs. And, I'm also going to ask for my colleagues to introduce the next speaker for the RFA that follows you. They're looking surprised. So, again we'll do the Mapping Centers first, and then the Data Analysis and Coordination Centers, followed by Technology Development, and then the Novel Epigenetic Marks. So with this, I will hand the podium over to Dr. Fred Tyson.

Thank you, Christine. And, I'll see if I can do as well as Dr. Wilson did and move these things forward. The first RFA we're going to talk about is the Roadmap Epigenomic Mapping Centers. And what we want to do is establish a set of centers that will be ... we have a goal of three to five mapping centers we want to set up. The ultimate goal will be to develop epigenomic mapping ... comprehensive epigenomic mapping data to go across the human genome. And, we want to use production level approaches to establish these. We'll be looking at various different epigenomic marks, including DNA methylation, different types of histone modifications, which will include phosphorylation, ubiquination, methylation, acetylation, these types of various different things, as well as including non-coding RNAs. We want to do these in human embryonic stem cells. Of course, the stem cells we would be using will have to be those that are already approved by the federal government for use, as well as using differentiating ... and I should say normal ... I thought I put normal in there, but it's not ... but normal, we're talking about normal stem cells, as well as normal differentiating cells ... cell lines ... and I'm sure somebody might say something about cell lines ... not really wedded to the idea of cell lines ... or human tissues ... primary cells of human tissues that are relevant to development and disease.

Again, I said we'll have three to five Mapping Centers. The goal is to spend, per center, $1.5 to $2.5 million per year in direct costs for each center. Off course, budgets will be contingent on the number of types of things that people are trying to accomplish within their centers, with regards to cell lines and different types of mapping data that they plan to establish or develop. And, again, we have that list down here of some impacts we expect to see from doing this and that would be to really establish references for the field. If people want to know why we are doing this again, there have been a number of different epigenomic workshops, conferences, meetings, over the last three, four years, where recommendations have almost uniformly all stated that we should be doing maps, or epigenomic maps, or epigenomes if you would, of human embryonic stem cells. And, these are going to be a very good, valuable resource, so that's one reason why we've emphasized within the RFA human embryonic stem cells.

Okay, I just want to briefly hit on what we require for the Mapping Centers, and they're listed here, and I shouldn't read them, but I will anyway. People are going to need to have production level capabilities in doing mapping types of things. I think, I have not mentioned this up here on the slides, but certainly the types of efforts that are being done with ENCODE and these types of maps ... these are the type of production capabilities people are going to need to have within their centers. Second thing would be for the ability to utilize normal human embryonic stem cells and differentiating cells.

I've had questions come up throughout the time since the RFA has been released about capabilities to do human embryonic stem cell culture within centers. Within centers, we are requiring that people have that capability - some component of your center must have that capability. So I just want to kind of stress that is an essential point. They're going to have flexibility so that they can adapt to new technology. As you've heard, we have a new technology development RFA that will be talked about shortly after this. And, we're going to expect the centers to have enough flexibility to be able to take advantage of state-of-the art, late breaking techniques that are made available through the technology development component of this program. So that's ... they have that type of flexibility and capability to adapt new procedures or enhance the procedures is vital. The informatics component is going to be very important. There's going to be a lot of data that's generated that will be talked about ... and how this is going to be ... the data is going to be integrated and compiled will be talked about later with the next speaker, in terms of talking about the Data Analysis and Coordination Center. But, the informatics capabilities are going to be critical and people are going to ... centers are going to need to have that type of expertise available to them within their centers.

And, again, the goal is to, is again, to be able to develop these initial set of reference maps. Supplement is probably not the right, correct word I should use up here, but the RFA that Dr. Wilson talked about that should be released in 2008 will be one that's going to take advantage of the data generated by these centers. And, by supplement, basically what I should have said was that these RFAs that are going to use that data will probably want to interact with the centers and perhaps have some additional mapping or different types of things, analyses within the centers, and those people are going to have to make arrangements with the actual centers that are operating to make some type of budgetary arrangement with them and they should ... that will be talked about when those RFAs come out ... but they need to be able to allocate budgets so the centers won't be responsible for using the budgets they have to interact with the new RFAs, but the new RFAs ... the new awards would have to interact with the centers.

And, something else we thought we should put up here would have to do with the steering committee, which is then addressed extensively within the RFA. The steering committee is going to have a lot of input and involvement in terms of how ... what marks are looked at, what cells are used - particularly, the cells are going to be very important, in terms of also making a lot of, I guess, implementation of policy or what not - how the centers actually will operate. âAnd, the steering committee members will consist of the individual center PIs, if there are co-PIs for a center, for instance people have multiple PIs in a center, than each of those people will be part of the steering committee as well. The Data Analysis and Coordination Center PI will be involved in this as well, and we will have one NIH program staff who is also a voting member, even though there will be more NIH program staff involvement, or at least discussion that goes on with the steering committee, but there will be only one vote coming from that.

One of the roles will be, again, to select the normal cells and tissues, or whatever, that are selected for mapping. Although each applicant will propose what they are going to do with their cells, or propose which cells and justify which cells they want to use, or tissues, so that we have something that is comprehensive, yet not redundant, the steering committee will meet shortly post award, to determine what actual cells they will use to give us the most comprehensive and global type of program we can have.

I've already mentioned an interaction with the RFA #2 will have ... again, the RFA #2, again, is the disease and health RFA that has not yet come out. â But, these individuals, or these awards from there, will have an opportunity to interact with the steering committee and inform the steering committee in terms of decisions the steering committee might need to make with regard to the centers.

There are new technology development awards that will be made. Those PIs will also have opportunities to interact with the centers we mentioned before ... that there will be interaction - centers need to be able to ... fluidly be able to adapt new processes or technologies that are made available and, through interactions, again, with PIs from those awards, as well as with the steering committee, that's one way we expect that to be implemented.

And, finally on this, we also have the RFA that will be on novel marks in the ... novel epigenomic marks - marks that are explored and discovered that will be useful for generating these comprehensive maps. There will need to be interactions between those investigators, as well as the steering committee, to decide which of those things needs to be incorporated in these maps, as well, as they become available. And there's also possibility to bring in ad hoc members that won't have votes but also can have interaction with the steering committee to influence what the steering committee actually does.

Okay, I just wanted to put a couple of questions up that we've seen, and things that have come up as we were actually writing the RFA, that came up numerous times, and one would be "How much technology development are the centers expected to conduct?"; â The centers really are not going to be there to do technology development. There is an RFA for that. However, we do anticipate that during the normal conduct of research and doing maps, people may find things that enhance the way that they've been doing things or they may have discussions ... we're hoping ... we're actually insisting that there are collaborations certainly between the centers, and there may be ways to tweak techniques or enhance things or bring something new onboard, but in terms of actually doing technology development, it's not a focus of the RFA and it should not be considered as part of that when people actually develop their proposals.

Another one is "How much informatics and data analysis will be expected to occur in each center?"; First of all, each center, again, must have their own IT person or people or staff or group, whatever, to develop ... so that they can develop the informatics things that need to go into these centers. They also need to be able to cooperate extremely well with the investigators who are part of the Data Analysis and Coordination Center. I think, collectively, they will be able to set up formats, and the next speaker will be able to tell you more about how that's going to happen. But, they'll be able to develop formats where they can put things together, and be able to submit those data in the formats that are developed, to the EDACC.

I think that may conclude what I have to say. The next speaker is Dr. Christine Colvis ... excuse me ... is Dr. Joni Rutter from the National Institute on Drug Abuse.

Christine is much taller than I am, so it's rare that we get confused, but it's a compliment nonetheless. Good afternoon or good morning. Oh, the podium moves down. Thank you.

I'm here to talk to you about the Epigenomics Data Analysis and Coordination Center and this RFA was led by NIDA ... myself at NIDA, and Kim McAllister at NIEHS, as well as a cadre of several other folks around the NIH campus. So, this was a group effort. The ... I will call it EDACC for short ... the EDACC requirements are shown here. The EDACC will be a single award, so one award will be issued for this RFA. It is again, a center - a U01 mechanism, and it will be for five years. For this center, we expect that the investigator applying for the EDACC will have a significant amount of analytical and statistical expertise, and leadership within those fields, along with a strong epigenetics background and expertise. We expect the PI and the EDACC center to work collaboratively with the Reference Epigenome Mapping Centers, however many mapping centers there may be - Fred mentioned three to five centers - as well as the NCBI and other project PIs that are funded through this program and perhaps other PIs who are doing epigenomics work throughout the nation or throughout the world.

We expect the EDACC PI to serve on the mapping center steering committee, or the steering committee that Fred just went through. And, we also expect the EDACC to provide tools for data analysis. And, it's not necessary that novel or new tools be developed; but we do expect that any existing tools or new tools that are developed to be provided to the general scientific community. In addition, one of the other things that is unique about this center, is that we expect the EDACC to provide workshops for the scientific community so that the data can be readily displayed to the community and analysis can happen through a collaborative effort, and people will know how to draw data from the mapping centers and/or NCBI. And, finally we'll ... the EDACC will provide monitoring of progress and status reports for the project that may include the Reference Epigenome Mapping Centers, as well as the EDACC.

Here are some key facts for the EDACC RFA. The letters of intent are due February 7, 2008, and the receipt date is March 7, 2008. We expect review to take place in the summer of 2008. And, again, one award will be ... we expect one award to be funded, and the total cost for this project will be $1.5 million. So, we expect direct costs to be under that amount. Again, total costs are $1.5 million for this award.

Again, it's a cooperative agreement, and foreign applications are not allowed for the EDACC - for the center applications - however, domestic institutions may have a foreign component. So, this is an important thing to remember.

The EDACC has two major roles. The first role is to develop and implement a cyber infrastructure for coordinating, tracking, and transferring the Reference Epigenome Mapping Center data to the NCBI. And, the second role to provide data analysis for the data that comes from the mapping centers and to provide analytic tools and coordinate all these activities. So, the EDACC will be the primary coordination center for generating the reference epigenome maps, in collaboration with the mapping centers.

The goals are really to integrate the diverse epigenomic data sets that we expect to see within and across the mapping centers and other Roadmap projects. We expect the EDACC to develop and apply the standard data output formats, along with NCBI, to make sure that these data are transferred in a standardized format. The data transfer from the mapping centers and the projects to NCBI will be done, and NCBI is expected to create a database infrastructure for collecting these data, and they will interface with additional public data resources that are also available with NCBI.

So, the impact here, we expect the EDACC to facilitate the development of consortium and program-wide publications. And, really the EDACC is there to provide the programmatic thread across all of these initiatives, as they will be the coordinating center for the data that gets put into the EDACC and then sent out of the EDACC to NCBI.

And, finally again, the EDACC is expected to provide workshops for the scientific community, in order to understand how these data can be visualized.

Here's just a graphic representation of how we envision the data release structure. The RMCs, or the Reference Mapping Centers, are shown on the left, and it's sort of one big blob there, but we don't know how many centers we expect, but three to five is sort of the target range. And, all of those mapping centers will submit their data to the EDACC, where they will go through quality control checks, the data will be verified and validated, if that hasn't already been done so by the mapping centers, and, again, the data will be formatted appropriately to go to NCBI. And, EDACC, really again, is the map coordination and generation site.

So, then the data flow will go to NCBI for public visualization and public availability for people around the world. And, this will allow us to have maximum utility of community epigenome reference map resources and analysis.

So some key facts that I have heard about so far, are shown here. The first one that I encountered is "What kind of expertise do I need to apply as a PI of an EDACC?"; And, in the RFA, it is very clear about this, in that the PI must demonstrate that they have prior experience in leading and coordinating large data sets, and they have to have prior experience in leading analysis of large and disparate data sets, and they also must have a strong epigenomic scientific expertise and background.

So, the follow-up question to that was well "If I cannot demonstrate the required expertise do I need a co-PI to be considered responsive?";, and the answer to that is yes. You need to have all of those expertise represented as the PI or co-PI. There is a contact person at NCBI with whom you can coordinate your submission. His name is Greg Schuler, and I've listed his e-mail address here. And, please note that you do not need a letter of collaboration from NCBI, because it is expected that you will work with NCBI. So, you don't need a letter of collaboration, but I do strongly encourage you to contact Greg Schuler, and talk to him about the data pipeline and cyber infrastructure that will be set up, in terms of coordinating the data formats.

And, finally, "What advice do you have for applicants?"; Well, I would encourage you to read both the center RFAs carefully and completely. Make sure that you get the big picture for what we're envisioning for these center RFAs. Be clear and concise with your proposed management structure - How do you propose to work with the mapping center PIs, how do you propose to work with mapping center staff, how do you propose to work with NCBI and coordinate the data flow from the mapping centers to NCBI? And you also need to be clear and concise with your milestones and your timelines within this RFA.

And, with that, I believe I will end and introduce my colleague John Satterlee, who will be talking about the Technology RFA.

Thank you, Joni. So, I'm John Satterlee from the National Institute on Drug Abuse, and David Balshaw, who's at the National Institute of Environmental Health Sciences, was a co-lead on this pair of RFAs. As well ... and we had help from maybe ten to twelve other people from across the NIH, so this, again, is really another group effort. So, Technology Development in Epigenetics - the problem here is that the available technologies that we have are good and improving but they're limiting; and, so one solution to this problem would be to try to develop new technologies that could significantly change the way that epigenetics research could be performed.

And, our priorities here are either the development of technologies that could enable epigeneticists to do something that was previously impossible, to allow them to do something really new and different, or that are an order of magnitude improvement in what the current state of the art is. And, the current state of that art would be defined in terms of cost, or sensitivity, or resolution, of whatever technology is being used.

And, there are two main scientific areas that are being focused by this pair of RFAs. One area is that we would really like to revolutionize epigenetic profiling or whole epigenome studies. And, associated with this is a long-term goal of eventually enabling epigenetic profiling or whole genome studies of single cells. Now, right now, I think the lower limit is something like 10,000 cells would be necessary to do like a chromatin immunoprecipitation kind of experiment. So, single cell is definitely a long-term goal, but it's something that I think is worth striving for over the long-term. â The second major scientific area we're interested in is to revolutionize the imaging of epigenetic changes, and the long-term goal here is to enable the imaging of epigenetic changes in living organisms.

And, sort of the details of the pair of RFAs are, for 2008, the funds committed are $3.5 million, and that's the total amount for both the RFAs together. The first RFA utilizes the R21 mechanism, so this is primarily aimed at earlier stage project development. For the R21s, preliminary data is not required; however, you would want to, of course, show that your project was feasible and that it had a sound scientific rational behind it. The maximum amount of support that you could request would be two years and the maximum amount of direct cost that you could request would be $200,000 a year. And, this budget is a little bit higher than the typical R21. The associated RFA utilizes the R01 mechanism and this would be for later stage, more mature projects. The preliminary data that you have should be sufficient so that it shows that your project is feasible, and you can request a maximum of four years of support.

And, I just want to touch on three special pieces of information that we are requesting in the application, or actually requiring in the application. What we would like to do is have you provide no more than one page that you can use to describe two things, the one is technological innovations, so what we'd like you to do here is describe why the new technology that you are using would enable epigenetics researchers to do something that was impossible or is an order of magnitude improvement. So we want you to explicitly state this. And, then we'd also like you to explicitly state what the significance of this research that you are proposing to do would be to epigenetics researchers. And would it ... and also to give an indication of how ... maybe how many epigenetics researchers would be affected; like, is your technological developmentâ that you're doing, would that just help three labs, or would it help everybody? And, then the last thing that we'd like you to provide are quantitative milestones.

And, I will just briefly go through three frequently asked questions that I've received. So, "Are these RFAs restricted to mammalian cells or tissues?"; The answer is no; yeast, worms, flies - you can apply with any of those model systems, provided you're responsive to the other aspects of the RFA.

Another question is "Would a purely computational application be responsive to these RFAs?"; And, the answer to that is no, it would not be; however, if you sent in an application with aims that addressed the scientific goals of the RFA, sort of the wet lab goals, if you will, and there were an associated computational component to that, than the application would be considered to be responsive.

And, then the third question is "Will these RFAs be reissued?"; And, we hope that for 2010 these RFAs will be reissued. Of course, this is contingent upon the success of the program and the availability of funding.

So, that's all I have to say. And, next I'd like to introduce Dr. Philip Smith, who is from the National Institute of Diabetes and Digestive and Kidney Diseases.

I'm going to [ Indiscernible ] two of the road map epigenomics, only as a person --

Thank you, John, and good morning, good afternoon, good evening, wherever you happen to be. I'm Phil Smith from NIDDK. I don't have to say it, since John did. I'm going to briefly review two of the Roadmap Epigenomics RFAs, only as a point person, and really representing a group of individuals as NIH, across many institutes ... excuse me ... that have helped to draft this set of RFAs.

The two RFAs that I am going to discuss are both under the umbrella of the title Discovery of Novel Epigenetic Marks in Mammalian Cells. Just for the record, they're RFA RM-07-015, which is soliciting RO1s and RFA RM-07-016, which solicits R21s. And, the key points that I want to emphasize about both of these RFAs and about the Epigenomics Roadmap program in general, is that the program is really aimed at providing high resolution maps of epigenetic marks across the full human genome, for a representative selection of cell and tissue types. The mapping centers are a necessity to begin with, to establish methodologies, and the purpose of the Discovery RFAs is to develop and validate additional marks which would be incorporated into the comprehensive mapping strategies of the centers. And, so, that should make clear everything else I'm going to say. If you don't pick up anything else that I'm about to say, that's the take home message that I'd like you to remember.

So, the field of epigenetics research, which Nora had actually touched on, is in a long-growth phase. You can mark this by number of publications or the exciting publications that are occurring in all of the top flight journals. But, this long-growth phase presents somewhat of a problem when one is trying to establish a large infrastructure to map, on a global sense, some sort of process.â And, the Discovery RFAs really reflect the fact that there's not only been a tremendous number of new findings in the last couple of years, but we're all aware of many, as yet, unpublished findings that are out there, that are equally exciting, that may well impact how we view mapping in the near term. And, so, the Discovery RFAs are designed to give the community the opportunity to explore the potential role of putative marks in mammalian gene expression with the notion of feeding them into our comprehensive mapping strategy.

The mapping centers will focus on established marks such as histone methylation, for example, in human cells and tissues. Whereas the R01RFA, RFA 015, is going to solicit R01s, to validate putative marks in any number of model systems including human, but in mammals. The R21 discovery RFA is really aimed at identifying potential new epigenetic marks in virtually any eukaryotic system with the goal of eventually feeding them into validation and then into mapping. And, I'd like to credit Google with most of these images. This is from a friend of mine, Kevin Grove, but all of these can be gotten on Goggle Images - "model systems"; gets you a whole lot of these.â

Very briefly, some of the technical details. The number one critical thing you need to know is the date February 14 - you miss it, you know, see you next time. But, the Letter of Intent is not binding, is not required, but will help us get started on the review. And, since the review is critical to a good outcome for an RFA, I would really encourage you to let us know that you might apply. And, that would be tremendously helpful to us. The review for this set of RFAs is, again, in the June/July timeframe. We're very fortunate that a Special Emphasis Panel (SEP) is going to be set up from an existing cluster of study sections - the Genes, Genomes, and Genetics Integrated Review Group (IRG), which already has substantial expertise and experience in reviewing these kinds of projects, so that's a very fortunate thing, as well as having a number of talented Scientific Review Officers to help.

The funds that we're committing for this current fiscal year are $3.5 million in total costs and those are going to be divided amongst the R21s and R01s, as the opportunities arise, and we will take the flexibility to maximize the potential outcome for this particular set of RFAs. These will be reviewed in the same SEP, and so there will be some ability to compare and contrast.

Foreign applications are allowed. And, once again, within the RFA, there are details about what a foreign applicant must do in terms of their application, to come in.

Briefly, I want to highlight a couple of things about these RFAs. First off, the R01 RFA is ... requires that you study your potential mark in â mammalian systems, with the notion being that you're going to validate that as a bona fide epigenetic mark so that one could then imagine mapping it across the genome. The budget for these should be commensurate with the work proposed. We haven't established a particular budget, because this is a field, depending on the technology used, can vary tremendously in price. But once again, we'll be looking for the best opportunities to maximize the output from these RFAs in a short period of time.

The second RFA, which solicits R21 applications, 016, can work virtually in any eukaryotic system, including humans. And, the notion here is to, again, identify as yet unappreciated novel epigenetic marks, with the notion that one might then be able to, either in this arena or perhaps subsequent R01 applications, validate those for use in mapping. The budget for this is not the normal R21 budget; we actually are allowing up to $175,000 per year, for two years. And, the electronic systems at NIH have actually been adjusted to accept this, and the same is same for John's R21. We'll be monitoring closely to make sure that happens.

I have already been getting quite a few e-mails, so I'm glad to see that the contact information did get out, but this is probably the most essential part of this RFA, beyond the receipt date, is that you actually know if you have questions about the program itself to contact me, and this is by far the best way to get a hold of me. And, if you have questions about the review, for now, since a particular review administrator has not been selected, Richard Panniers, who heads that Genes, Genomes, and Genetics IRG will be taking those kinds of questions. I just want to go over a couple of key points that I have already been apprised are of interest to you, in the community, because I've been inundated with questions on these issues. As I stated in the earliest ... the first slide, this is about feeding the mapping centers for global epigenetic mapping. So, what we're not looking for is a particular study, a particular mark or marks in some disease process, or after some particular exposure, which may be highly relevant to disease or to a particular institute, but is not going to be within the sort of rubric of this set of RFAs, and is certainly not within the responsiveness categories for these two.

The other issue comes to mechanisms of establishing those marks. I want to make it quite clear, again, that this RFA is not about studying in depth how a particular mark gets established in a particular place, in a particular time. That's the kind of work that we actually support to a fairly significant degree already in a number of the institutes at NIH. And, I would certainly encourage you to submit applications in that area. All the institutes are keenly interested in this area. But it would not be responsive to this particular set of RFAs.

Now we're going to have all of the panelists come to the front of the room and take their places at the table, and we'll be able to address any questions that you might have over the next couple of hours. Thank you.

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