Novel Nucleic Acid Sequencing Technology Development – Michael Smith


Bettie Graham:
So, the next item on the agenda is a concept clearance for the novel nucleic acid sequencing
technology program. As many of you know, this has been a program
that’s been going on for about 15 years. It was started by Jeff Schloss and it’s been
very, very successful. So, Mike is going to present to you today
a request to renew this program at the same level that it’s been for couple of times around. And that’s $2 million. So, Mike? Michael Smith:
So, this is a concept clearance for a novel nucleic acid sequencing technology development. This program has been going on — you could
argue that sequencing technology development has really been a part of the institute for
as long as Eric talked about earlier today, just the kinds of sequencing technology development
has changed over the years. So, we’re still very interested in investing
in this area. And today you’re going to hear about what
are now expired RFAs from a concept clearance of three years ago; and the awards that we’ve
made, some examples of the kinds of research that came in under those RFAs; talk to you
about a grantee meeting that we hold to help this community work together well; and then
we’ll get to the objectives of the concept, some potential research topics, mechanisms
in funding that we’re planning on using, and the timeline with which this will take place. So, someone intentionally used the word “expired”
because the RFA, you know, NIH RFAs have a life. They’re allowed to be three years long. That’s how long the last set was. The numbers are indicated here. So, they’re RFA-HG-15, -031, -32, -33, and
then -39. And you can look them up online if you’d like
to read them. I just pulled a few words out of them, and
I’m not going to read them to you fully. Certainly, you can read the slides faster
than I will read them to you. But certainly, a goal to improve quality and
efficiency of DNA sequencing, enable direct RNA sequencing, wanted to read the links,
faster turn-around times, et cetera. And novel chemistries, new physical approaches,
instrumentation, and also, again, direct RNA sequencing. And really with the idea that we want to push
the field forward with an investment in sequencing — nucleic acid sequencing technology development. That’s what we were asking for then, and this
is a renewal. So, we’re largely planning to do more of the
same because I think it’s been rather successful. It also dovetails in well with the strategic
planning that you heard about earlier today from Eric. So, these are the R01s and R21s that were
funded in the first two years of the RFA. And so, you’ll see some protein nanopore work
from Gundlach, and also Winston Timp doing some modified Cs. There are some solid-state nanopores, Stuart,
Shepard. Wanunu is using zero-mode waveguides to look
at picogram amounts of material, which you start thinking about one cell’s worth of DNA
in a sense. Phil Collins has a very interesting method
for seeing a polymerase polymerize. It’s different than the way Pat Baio [spelled
phonetically] is doing it. And Tim Buster’s also on modified cytosines. And then the last one is using liquid chromatography
and mass spectroscopy to go at RNA sequencing. A very different approach but reviewed well
and we are hopeful. So, these are the kinds of things that are
coming in. And one of the messages is we’ve got some
nice breadth. We’re investing in places we have invested
before, and we’re also invested in places that are possible to work in today. So, this group does get together. Jeff ran a technology development meeting
for many years. I inherited that because he retired. And we ran one last May at Northeastern University. It was hosted by one of our grantees, Meni
Wanunu. There were 24 grants represented there, which
was 100 grantee participants. And we had the subsequent public meeting,
which picked up about another 30 individuals. What we saw, what we heard was it was — certainly
it was informative and interactive. It was a good collaboration for catalyst,
people got to know each other that hadn’t necessarily met each other before. We got good, positive feedback. And you bet we took some lessons learned that
we’re going to apply to the next meeting. So, that’s one of the ways we’re trying to
take — you know, one of the things about this sequencing technology development RFA
is we’re really just asking people to come in with their best ideas. And then, we’re trying to give them some help
to do good science, but not direct the science that they’re doing. So, some of the concept objectives are developing
new DNA sequencing technologies, direct RNA sequencing technologies, and then substantial
advances to existing sequencing technology. Again, I encourage investigators — this is
on the concept side covered by your three-pager, all right — encourage investigators to pursue
their best ideas and make an accompanying investment in foundational sequencing technology
development. And it’s just worth pointing out that there’s
talk at times about “solicited” and “unsolicited,” this actually falls under the solicited category,
okay. Because it’s an RFA. And yet, there’s a lot of freedom for investigators
to come in with what they think is a great idea. And just some examples of the potential research
topics, these are very similar to what was in the last RFAs that I referenced. Novel chemistries exhaustively sequencing
every RNA or DNA molecule in the sample. Very long reads of 150KB are not sounding
so long anymore, but still there’s a definite need for long reads and de novo assembly — especially
perhaps de novo phase disassembly. Modified bases, direct RNA sequencing without
CDNA, and then again orders of magnitude improvement to existing technologies. Which sound a little familiar to what the
last RFA said. So, what we’ve put in the concept clearance
is, for R01s and R21s, total of $2 million per year for three years — FY19, ’20, and
’21. And similar amounts for R43s and R44s which
are small business grants, also the same fiscal years. So, this is the timeline. You know, we’re currently early in 2018. And we would expect to accept applications
later in 2018, then again in ’19, and 2020. And certainly, that places us very well for,
hopefully, another concept clearance, so we can accept applications in 2021 as the planning
process includes a publication. So, this concept is investigator-focused. It’s foundational for sequencing technology. It’s a continued investment by the institute
in nucleic acid sequencing technology development. And I’d just like to thank a few people. Melpi Kasapi, really, you know, helped make
these slides smooth and did so many other things. And many of these slides are pulled from some
other presentations we’ve used internally. Chris Wellington, likewise. Carolyn Hutter helped with some good comments. And I certainly want to point out Ken Nakamura
who’s done all the reviews for these applications. And Dan Gilchrist and Mike Pazin really stepped
up and helped me during the fall with some times where I needed some additional help
managing this program. So, happy to take questions or comments. Female Speaker:
Go ahead. Male Speaker:
So, it’s a $4 million a year project. Two for the — Michael Smith:
So, it’s $2 million in one fiscal year, and then that follows out over a number of years. And then $2 million — let me go back a little
bit. So, in FY18 we will be making FY19 — so,
in FY19, ’20, and ’21 we’ll invest $2 million of new money in each of those years. So, and then that has out year commitments. Male Speaker:
But you said an equivalent amount for the business awards. Female Speaker:
For the SBIRs. Michael Smith:
For the SBIRs. Male Speaker:
Yeah. Michael Smith:
Yeah. Yes. That’s correct. One thing to keep in mind with SBIRs is they
tend to not be quite as competitive. And so, we’re going to take what we find there. Which, based on what we’ve seen so far, we
didn’t really get as much as $2 million worth of activity. And that’s driven by a number of factors like
our once-a-year deadline doesn’t meet a business’s go-go-go very well. But the — Male Speaker:
[inaudible] next slide. Michael Smith:
Sorry. Male Speaker:
[inaudible] Michael Smith:
One back. Male Speaker:
Yeah, right there. Similar amounts — so, it’s a two to $4 million
a year project. Michael Smith:
Yeah, it’s going to be closer to four in terms of what the investment is. But I think, you know, this group is largely
focused on the academic side, so that’s why the presentation is largely on the academic
side. Male Speaker:
Steve? Male Speaker:
I just want to voice my support for this program, I think it’s incredibly valuable. And in fact, I would say essential. And I’d just like to point out that virtually
all the sequencing technologies that are on the market today are disseminated, have their
roots in some sort of grant funding where people actually have to take risks in order
to actually try to make something work. And this is an area that companies are not
very good at, at taking risks. Getting these grants, I think, not only gives
some credibility to the approach that an investigator wants to take, but also involves them within
a community that gives them support to advance the technologies. And it also gives them validation, as these
technologies a require a tremendous amount of money to actually get to the marketplace. There needs to be some peer-reviewed process
where people that invest money in these things can see that, you know, this has merit and
that there’s some validation of that. And so, for all those reasons I would just
really support this program. And my only question would be whether or not
it’s enough. Michael Smith:
I would just — one small thing. You know, you mentioned that there’s a substantial
further investment, and I’ve certainly heard numbers of 30, $40 million that might be coming
in after. And that’s a small — that’s just to get it
started. Male Speaker:
[inaudible] Michael Smith:
Yeah. Male Speaker:
[inaudible] Michael Smith:
Right. Male Speaker:
[inaudible] Male Speaker:
Yeah, so I’d just like to echo my support for this program. I think it’s great, and I think these are
the kinds of things that have the potential to transform the field, and years downfield,
that we have no idea, we can’t really anticipate. And again, I think — like the last two councilmembers
commented — is this really enough? I mean, are you getting more applications
that you could fund deeper given more resources, or? Michael Smith:
So far, it’s been reasonably well matched. Of course, when you have an amount of $2 million,
the interest tends to reflect that, right, towards the number of applications you get. Our internal stream processes, I think, leave
some room if we got another really good one to go ahead and fund it. But there’s obviously an internal discussion
that squeeze other sides. Bettie Graham:
Yes, Carol? Carol Bult:
Do you have a sense of how many of the people that attend the group meetings, the grantee
meetings, that aren’t currently funded by this program actually go on to submit a grant
or are planning on submitting a grant to this program, sort of bringing in new blood and
increasing the pool from which the grants could be supported? Michael Smith:
So, I think one answer to that is the grantee meetings are heavily attended by not just
the grantees themselves, but also by their postdocs and graduate students. It’s a, you know, the meeting size is not
much smaller — not much larger than this room, and so it’s very conducive to people
actually talking with one another. There certainly are some cases where what
we’ll be talking — so, there are some cases where grantees are there. And maybe they’re on a no class extension
and they will come in for an application later on. So, there’s a little bit of people who are
still in the field, still working on the field. And there’s definitely new people coming in. If we went back to — there’s an easy way
to answer this. Gundlach’s been in for a while. Stewart’s been in for a while. Meni has been in. Collins is new. Shepherd’s been there for a while. Timp is new. I think Buster was there for a while. And Zhang is new. So, was that about a third? I didn’t sit there and count, but. Carol Bult:
So, when you have your meetings, the people who are currently funded in the program obviously
come and bring their postdocs. But do non-grantees people who aren’t involved
with any of these groups come? And is it a way to increase the visibility
of the program to get additional people submitting grants? Michael Smith:
So, the way we structure the meeting — we’re still moving it around a little bit based
on lessons learned. But the way we’re going to run it this year
is a little different than last year. So, this year there’s going to be two days
of grantee meeting, followed by one day of an open session meeting. So, people who want to come in and be involved
in the open session with many of the grantees still around, because we try to make it worth
their while to stay, get that opportunity to learn a little bit more. And then we have some of the grantees present
in the open session meeting because it makes sense. Male Speaker:
This is back to the budget question. So, on the slide it looks like, if my rough
math prevails, it’s about actually 4 million in — Michael Smith:
It’s about 4.5 or 4.4. Male Speaker:
So, this was more than twice the — Michael Smith:
It’s two years-worth. Male Speaker:
Oh I — oh, I see. So, these are two years at a time? Michael Smith:
Well, it’s — we awarded half these in FY16, and the other — [talking simultaneously] Male Speaker:
Thank you. Got it. Michael Smith:
— Half in FY17. And the extra 500,000 or so largely reflects
the supplement. Jay Shendare:
So, I’ll start by echoing my enthusiasm and not a ton to add to the comments that Steve
and others made. One thing that I really like about the way
that you structure this is really focusing on niches of sequencing — not really niches,
but aspects like direct RNA sequencing that haven’t really been captured by commercial
platforms so far. And just to something that Carol said, I think
from back when I was a part of one of these awards one thing that was really nice about
those meetings — and the private part of those meetings — was that it was a pretty
open forum where people could discuss unpublished results. I’m not sure if opening it up completely would
change the tenor of that, but it might. But I think that’s always a balance with that
kind of thing, so. Bettie Graham:
Any other questions? Comments? So, I think we will call the vote. And I’m — what I would like to say before
saying that is that I think staff has heard that there is enthusiasm for increasing the
amount of this program. But we will vote on the two million that’s
being requested. So, could I have a motion? And a second? All of those who approve? Abstentions? Any no votes? So, the motion carries. Thank you.

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