Jeffrey Schloss: I just -- it’s a little -- [clears throat]
excuse me, it’s a little awkward now, because so many people have left.
But we’ve heard about a lot of amazing opportunities at the meeting, and you’ve also heard that
the funds are not infinite.
So I guess a question to ask is, among the various things you’ve heard, what are the
dependencies?
And so, are there some of these that -- where, if certain things don’t happen, then the
rest of it can’t go forward anyway?
And so, in terms of thinking about priorities, which are the things -- you know, we don’t
want to throw -- the problem with asking for priorities is, there are always ones that
are lower.
So let’s talk about the higher priorities.
Which are the things that need to go forward in order to make progress in this field, and
without which the other things that we would like to see happen are not likely to happen?
Is that a reasonable question, if a hard one?
Nobody’s going to want to answer this, I know, but --
Joseph Ecker: I’m going to take a stab at this.
I think I heard some consensus on the value of continuing to build the catalog.
There are examples, Manolis Kellis using -- from the roadmap data, talked about the connection
between Alzheimer’s and the immune system, which came out of, you know, unbiased production
of data from many different tissues.
And if you had focused on Alzheimer’s in the brain, you would miss the -- you would
have missed the immune connection.
It was a very stimulating, you know, talk.
And so, I think there’ s an argument that says, I don’t know who said it earlier,
that you really don’t know what you’re missing until you, sort of, see it.
And you -- and, to some extent, that catalog is going to be dependent on the practical
realities of what cells you can get.
And so, groups need to be able to get access to the material if they’re going to make
a proposal.
So somewhat, it’ll be directed by, you know, what’s out there in the community already.
So by its very nature, the project has to connect to the community for samples.
I think that’s the way it’s been in the past.
It’ll probably be the way it will be in the future.
But the systems have been evolving.
There are all sorts of organoids now.
My colleagues at Salk -- kidney organoids, brain organoids, et cetera.
And so, I think there are other ways to get -- but I think getting at this catalog is
going to be very valuable, not -- in a way that you can couple it with function.
I think they’re not an either-or.
I think, if you pick the right system, you -- and, of course, this is a ground-up, actually,
right, because investors are going to propose different systems, you know, if the project
goes forward.
And if your system couples with an assay that’s high throughput, so be it.
We want to get to that encyclopedia.
I think all the PI’s think that that’s an important goal, but it has to be coupled
to the continued development of the catalog, so.
Jeffrey Schloss: Well, and in fact, if you’re going to have
a path for community-generated cell types to enter a pipeline once the -- once the cells
and the technology are available, there has to be that infrastructure, I think, of some
production -- some level of production activities, right?
Joseph Ecker: So we -- let me just jump in back.
We have a project, Mike Snyder and I -- this California Institute of Regenerative Medicine
has a stem cell genome center.
And that project is to enable genomics in the stem cell community.
And some of the funds from the center flow to those investigators to prepare the cells,
okay?
That was on a competitive basis that those groups were chosen.
Say, “Hey, here’s an interesting biological system.
We’ll help you do the genomics, and you got to have, you know all the cells.”
So there are groups that have, you know, hundreds of different, you know, cardiomyocytes or
whatever.
It’s not necessarily a cell catalog, but focused around -- more around the disease.
So I think that’s a reasonable thing to do.
The groups that have the ability, either they’re brought into the consortium directly, as part
of a proposal, as we did -- Bing Ren did with Jamie Thomson -- or as John has a lot of collaborators
getting samples, you know, within the -- within his community in Seattle, that it’ll have
to be an integral part of the project either way.
Jeffrey Schloss: Yeah, and we’ve -- you know, as you -- as
many of you know from the sequencing program, we’ve -- we’re trying to invent ways to
engage as much of the community as possible in developing those samples opportunities.
I’ll be over there in -- the other one -- I wanted to -- comment that I wanted -- or the
other priority that I wanted to mention, which we haven’t -- well, we -- I guess we have
talked about, but not explicitly as a priority, was the collection and vetting of data through
the DAC and the DCC.
It seems like this cannot go forward without a robust effort for those to -- for those
activities.
Is that -- is there a fairly good agreement on that?
No.
Okay, so --
Mathieu Lupien: Yeah, I just want to stress that one point.
If, indeed, the goal is to move forward in having more cells added to the list, which
I fully agree with -- and this is something others have said, and I will just voice my
-- I’ll put my opinion in the same direction -- it’s not that they need to be fully characterized,
but characterized on a subset of specific features that need to be defined, so that
we know exactly which ones we should prioritize, and at the same time, keep investing in in-depth
characterization of a small subset of cells, such as what we have right now for the MG2,
the K562, and the GM12878 cells.
I think those are -- you need to stretch the grid on both ends, not just on one end.
Jeffrey Schloss: Will.
Male Speaker: Yeah, I guess I wanted to echo the idea that,
sort of, ENCODE -- the tier-one lines are incredibly valuable for -- they’re kind
of like model organisms for cells, right?
We choose a few model organisms because they’re useful, and you explore them.
And ENCODE is choosing a couple cell lines to go really, really deep on.
And, at least as a methods developer, that’s incredibly powerful, to have that mountain
of data to synergize with when developing potentially new things.
And I would also argue that, just as far as -- like, just understanding cell biology,
it almost doesn’t matter what kind of cell you choose, in some sense, to understand these
broad, sort of, organizational principles.
But going into those tier-one lines and trying to get at functional validation or magnitude
of effect for these regulatory elements would be very, very powerful, I would argue, and
add another dimension, a validation dimension, to these cells that are, sort of, model organisms
of cells.
And I think that that, I think, fills a lot of the principles of what ENCODE should be,
in terms of, sort of, breadth first -- understanding of a small number of things, and also depth
first, but much less dense, as was just recently said.
Jeffrey Schloss: Thanks, Will.
Any comments on that?
Yeah, Jay?
Jay Shendure: I -- Will said it, but I’ll just echo it,
is -- you know, I think there was consensus around it, maybe there wasn’t, but validation
as a theme, right, meaning that -- as a more significant component of what’s going on,
even if it’s directed at validation of things that were predicted by ENCODE one through
three, right?
Aviv Regev: I strongly agree that there was a consensus
around the notion of validation.
What I struggle to understand is what people actually mean when they say “validation.”
And I asked that, actually, multiple times, because I know what I mean --
Jay Shendure: I know what I mean, too.
[laughter]
Aviv Regev: -- for very specific purposes that I happen
to care about -- I actually don’t even want to say here, I don’t think it’s relevant
here.
But I’d love to know what it is that is in back of people’s minds when they say
the word “validation.”
And it’s usually coupled to the F-word: function.
So it’s kind of --
Jeffrey Schloss: And I don’t think it should be -- yeah.
Aviv Regev: [unintelligible] notion of it, I don’t understand
what it means.
Jeffrey Schloss: And I don’t think it should be overly specified,
meaning, it’s the sort of thing that is -- one could look at a bunch of --
[talking simultaneously]
Aviv Regev: No, but it would be nice to know -- it would
just be nice to know the spectrum --
Jeffrey Schloss: Sure, yeah.
Aviv Regev: Yeah -- know the spectrum of what it means
for someone, that something has been validated.
Yeah.
Jeffrey Schloss: So one of the discussions that we’ve been
having with our council is -- it’s really awkward, I can’t see Aviv, and I can’t
see the people -- that’s all right --
Female Speaker: Most people don’t deserve [inaudible].
Jeffrey Schloss: -- is about, you know, the balance between
top-down and bottom-up, investigator-initiated, and consortium, and so forth.
So are some of these various things that we’ve talked about, including perhaps validation,
the kinds of grants that could come in if we would say we’re going to set aside some
portion of the ENCODE budget, whatever that is -- whatever the total is and whatever the
set-aside is, to -- that we anticipate that there will be really interesting applications
that will come in, that won’t be part of a cooperative agreement, but they’ll be
working on ENCODE-type problems, such as this validation problems, that would use ENCODE
data sets in an interesting system and look at validation, and could these be reviewed
effectively at a study section like GCAT?
I’m really getting down into the weeds now.
But these are the kinds of things that we are going to have to start grappling with,
starting at 4:30 this afternoon.
Right?
I mean, seriously.
So you know -- or is this the sort of thing -- you know, there -- so, now you’re asking
that -- we describe, in a program announcement or something, what we mean by validation,
versus letting people come in with ideas about what they mean by validation -- and there
may be different ones.
And so, they -- and so, we could do that.
And we could either have our review office set up a review of people who are really thinking
about this, where the reviewers are really thinking about this, or let it come in through
CSR.
So just -- yeah, John.
John Stamatoyannopoulos: I think, if you maybe made it one level higher
and didn’t call it validation, and, for example, called it a program in in-depth functional
studies of ENCODE elements, I think that’s something that could catalyze people, you
know, generally, because you don’t want to -- I think the word “validation” --
Jeffrey Schloss: I was using validation as an example of the
sort of thing that might come in under this.
John Stamatoyannopoulos: Yeah.
Yeah.
And so, in-depth -- but that in-depth functional characterization -- and, you know, to include
-- essentially becomes de facto validation.
But that -- I think that would organize -- rather than just wait for the stuff to come in, that
would organize a response, because a lot of people are interested in it.
Jeffrey Schloss: We go down here for a second.
Karen Adelman: So I mean, I -- Paul -- okay.
So I think that what you suggested, sort of, initially, that instead of having a small
group of people decide what validation means or what assays are the best, to just, sort
of, put out a -- you know, an RFA -- put out something and say, “We want ideas.
Give us your best ideas,” and have a grant review panel look at the ideas.
Because, I mean, we’ve talked about this over and over again in the past day or so,
that we all agree that validation and characterization of these things is essential, but there’s
been no consensus on what’s the best way of doing that.
That’s one big hole, as Aviv said, that we all are struggling with.
And we all may have our own ideas, but I don’t even know if we have formalized projects yet.
But I think that’s something where that’s the -- sort of, the best of science, when
you let little people come up with their own ideas, choose the best of those, give them
money, and then see what comes from that.
So I like the idea very much, of having that be an investigator-initiated approach.
Paul Sternberg: Yeah.
And talking to people -- various people in the community, they were, you know, excited
about functional tests and validation, but they didn’t want -- they were really adamant
about it not being the same production centers.
You got to really bring in some new blood, or open it up, let everybody compete and get
the best ideas, as Karen said.
Aviv Regev: I would put in two comments.
The first is, I wholeheartedly agree.
I think there are two scales to it.
There is functional validation done by the expert for a small number of things at exceptional
depth of follow-up on the mechanism, which has huge value.
And there is functional validation that is done more on the breadth scale: still in the
biological system, still with an assay that needs to be done by the -- by, you know, investigator
-- and there has to be a balance in the portfolio between these, because there is value in each.
And whether they are both done through the same mechanism, I don’t know.
And the other, because you posed it very specifically, about the study section, this should be a
special emphasis panel.
I do not think that you would get the necessary expertise in the room in the standing study
section, definitely not in GCAT, which is a great study section, but that’s not its
area of expertise.
Jeffrey Schloss: Other comments.
Are there other questions that other NIH staff want to ask?
Yeah, John, go ahead.
John Stamatoyannopoulos : I want to make one comment regarding the,
sort of, RFA versus GCAT -- and I will disclose, I’m a member of the GCAT study section,
that the problem with RFA’s is that there’s a timing issue, right?
In some way, you just flush out what’s ready, and you don’t wait for things to develop.
And I think the advantage of a program announcement, maybe with rolling receipt or whatever -- and
I think a study section like GCAT, as long as it was prepared and knew -- I don’t know.
I don’t know, I haven’t tracked the number, but my impression is that at least 20 percent
of the members, if not more, are recruited ad hoc to deal with the specific grants that
come in.
It could be -- that number, could even be much higher.
So I don’t think it’s impossible, but there -- you know, I think the rolling aspect
is the most important, is the fact -- not to capture one point in time.
Jeffrey Schloss: Yeah.
Right.
Okay, anything else?
If not, I’ll turn it over to Elise.
Thank you.
Elise Feingold: So I just want to thank you all for being
here.
I have just a -- some brief slides, really just thanking everyone who -- who’s helped
organize this meeting, the organizing committee and the ENCODE Consortium.
And do we have -- do we have all that coming up?
Just this one?
Okay.
So we really couldn’t do this with the organizing committee.
It really was huge in organizing the meeting, as well as leading the discussions and synthesizing
this.
It’s been really, incredibly helpful, as well as the Capital Consulting Corporation.
So the ENCODE Consortium obviously needs to be thanked again, as well as the ENCODE external
consultants panel.
And a big thanks to our colleagues in the NHGRI Communications and Public Liaison Branch,
specifically Alvaro Encinas and Kiara Palmer, who are in the back, who have been here with
us the last two days and are -- have made it possible to have the webcast and are doing
this with a very rapid turnaround.
It’s already available, last night’s already available.
So thank you very much for your hard work on that.
And then, finally, my NHGRI colleagues.
But most of all, I want to thank you, especially those of you who have stayed till the very
end.
And you’re hardy, and we really appreciate -- everyone really did participate.
We tried to keep this a small meeting so everyone felt comfortable to speak up, and I think
it really worked.
So thank you so much, appreciate your help.
[applause]
[end of transcript]