>> Eric Green: Hello, everyone. It is now spring of 2023,
which means we are in the midst of celebrating the 20th
anniversary of the completion of the Human Genome
Project, a major milestone in the history of science. The story of the 13-year
Human Genome Project was one of great accomplishments and in
many ways incredible audacity. In reality, the Human
Genome Project consisted of many smaller narratives,
some scientific, some political, and some sociological. Some of these narratives
have never been told or at least not told
in much detail. Now one such narrative
involved the efforts of five genome sequencing
centers who worked closely together in the Human Genome Project's
final stages, a group known as the G5, a name
affectionately used to mirror well-known
groupings of countries, such as the G7 political group. Of course, there were some who might have falsely thought
the G part of the name stood for genomics, but it didn't. In this video conversation,
we aim to highlight and even uncover new insights
to the story of the G5. For the first time in
many years and in honor of the 20th anniversary, we at the National Human Genome
Research Institute have gathered together, virtually of
course, the G5 for a reunion to toast the 20 years
of great science since and to share stories that couldn't have
been told back then. We are here today
to hear from those who participated in the G5. And before I introduce
my guests, let me provide a little
bit more context to this. As the Human Genome
Project pursued its last and most difficult goal, that
is generating the first sequence of the human genome,
there were groups around the world
contributing to that effort. In fact, by the end of
the Human Genome Project, something like 20 different
countries contributed to the generation of that
first human genome sequence. To effectively get the job
done on time, it was decided that a small group of people from the largest genome
sequencing centers would need to take the lead to
make sure the goal of sequencing the human genome
was completed in an organized and a coherent fashion. And at the end of the day, five such centers
producing the largest amount of sequence data came
together, hence the G5. The G5 worked very closely
together in the final stage of the Human Genome
Project to generate most of the human genome
sequence to ensure that the human genome sequence
produced was high quality and to organize the
worldwide effort. But of course, the importance of this achievement cannot
be emphasized enough. The first human genome sequence
was the signature accomplishment of the Human Genome Project with its successful generation
representing the project's finish line. With that background, let
me introduce my friends and colleagues representing
different parts of the G5 who have joined me for
today's discussion. So first, Jane Rogers, then at the Wellcome Trust Sanger
Institute, previously known as the Sanger Centre
in Hingston, UK, along with Michael Morgan, then
a leader at the Wellcome Trust. Second, Ari Patrinos,
representing the efforts of the Department of Energy's
Joint Genome Institute in Walnut Creek, California,
in the United States. Third, Eric Lander of the Broad
Institute, Whitehead Institute of Biomedical Research at MIT in
Cambridge in the United States. Fourth, Richard Gibbs,
Baylor College of Medicine's Human
Genome Sequencing Center in Houston in the United States. And then fifth, Bob Waterston, then at Washington
University School of Medicine's Genome
Sequencing Center in St. Louis in the
United States. And of course, any outstanding
group needed a leader to drive them to success. And that key leadership was
provided by Francis Collins, then the director of the National Human Genome
Research Institute, or NHGRI, at the U.S. National
Institutes of Health. Well, welcome to each
and every one of you, and thanks for joining
me virtually today. And let me just immediately say,
we all look just as youthful as what we looked
like on the final day of the project 20 years ago. So with that incredible
stretch of the truth, let's pull back the curtain
and discuss the true unfettered and untold story of the G5. Now memories are, of
course, not always complete, and they can morph as
the years have passed. But that's why I think it's
wonderful to have all of you, because the group as a
whole will provide a check and balance to the facts. I will welcome anyone to speak
up when your memory is different than any other person. And I will be the moderator and
the host for this conversation. And I have my cup of tea
here, and I am ready to go. So to start, let's discuss
how the G5 came to exist and why its creation
was so important. So thinking about that, tell
me, what was your memory? You know, our history archive
that we keep here at NHGRI shows that February of 1999 was the
starting point for the G5 group. Does this ring true in
other people's memories? No. No, I don't think so. That sounds really late. So we believe that it was
around February of 1999. If that's not the case-- No, I don't think
that's the case, Eric. I think the first time we
got together was in December, of the preceding December. And that was an important
meeting. John had sent off his
infamous friendly fire note about a month before that. And I think it was that-- the realization that people were
going in different directions that led to us getting together. John was summoned, as he put it, to appear before the
NHGRI Advisory Council. So he was coming to Washington. And I think there was a
meeting of the five of us, or the five centers, that
was associated with that. And Bob, do you think that
Sulston Salvo was the trigger that led to the creation
of the G5? Or was it just the facts, the
way they were coming together at the time, that was the
trigger to create the G5? I mean, the G5 was
really created by funding decisions, right? I mean, in essence, the fact that the three US centers
represented here got the bulk of the NHGRI funds, and the
Sanger Center had its commitment from the Wellcome Trust,
and the DOE had committed. And so it was clear that
those five groups had the bulk of the resources. So I think that's how
it settled on five. But Francis, can somebody
else comment on that? I think Bob's memory is better
than mine in this circumstance. But I certainly do
have a clear memory of the friendly fire
message, which got quite a bit of attention, well beyond our
community of genome sequencers. Man, certainly did
point to the need of having a more coherent plan
amongst the major producers of sequencing. Just a little background here,
Eric, because people jumping in on this may wonder, well,
what was going on before that? We had quite a gaggle of genome
sequencing centers involved, starting back in about
1996, when it became clear that you could actually start
working on the human genome. We were all encouraged by the
successes that were happening with model organisms,
particularly what Bob and John had done
with C. elegans. But it was kind of a gaggle. And as you might expect, some of
those centers had grand ideas, but didn't really kind
of live up to those. Before the G5 really
fell together, we had 20 genome centers that
were contributing in some way. And that was impossible
to manage and to hold everybody
accountable. So the notion that we had
to kind of get serious and take the five centers
that really had the capacity and turn this into a production-minded
effort, it was time. And I guess even though that
letter from John was sort of painful, especially to me,
it got us in a good direction. But Francis, if I could chip
in here and say the stimulus to really get going and
concentrate was really provided by Celera, by their announcement
that they were going to work on the Human Genome Project. At Sanger, we'd already been
in to ask for increased funding from the Wellcome Trust. It was actually prior to that,
because of having met at one of the, it was the
third Bermuda meeting. At that point, our
perception was that people really weren't
focused, they were at sea. And we needed to up our ante
to, from a sixth of the genome to a third of the genome, to get
people to take notice and start to chip in if they
wanted to join in at all. So I think, you know,
at that point, things started getting moving. But Celera's announcement that
they were going to do the human, I think that was the
catalyst to get us thinking about how we would go
about doing the sequencing. And there was a meeting
at Daley House, not long after the Cold
Spring Harbor meeting, that I think focused
on what could be done, how should it be done, and
what should the product be. My memory is that
the crucial thing that really was catalytic was
in fact the formation of Celera in the Cold Spring Harbor
meeting that I attended with John Sulston, at which we
announced that we were going to sequence, pay for the
sequencing, the Wellcome Trust, of the whole genome, even if
the American partners left. In my mind, that was the thing
that really focused minds, and we then had to be properly
organized to get the job done. And that's when it moved from individual labs
doing their thing to really a coordinated
industrial activity. That's my memory. So, Richard and Eric, I saw your
hands go up at different times. Do you still have comments? I'll just add one thing that
you may or may not recollect. I think between that
May meeting in 1998 and the Celera announcement,
and all of those events that happened before the March
1999 gathering in Houston, I think that's what
we could have a lot of conversation about. But at the meeting in
Houston, we weren't funded yet. I think the process of
refunding was happening, but there were no
official announcements, so we could not declare
ourselves the anointed group to be supported to
finish the job. But nevertheless,
we came together to discuss the principles, and that was the
tenor of that meeting. So to me, why that meeting
or even one after it was sort of the first official G5. But no doubt we all coalesced after our fun meeting
in May of 1998. Eric, do you want
to add to that? Sure. I think trying to figure
out when the G5 started is hard because the G5 means
many different things. I would date the G5 to several
years earlier in the sense that it was becoming apparent
that there were five centers that were prepared to take
serious responsibility and who intellectually
respected each other. Not to say we didn't fight
with each other and all that, but there was a lot of intellectual respect
and responsibility. And I think Francis's point about the original Bermuda
meetings when people showed up from all over the world
and made land grabs for, "I'm going to take this part of
the genome and I'm going to take that part of the genome,"
without necessarily being able to back it up with the
confidence that they deliver, represents the tension
between a project that at its core is trying
to be inclusive of everybody in the world and at
the same time has to get a concrete job done. And so I would say there was
an evolution from early Bermuda into a little later and
then kicked into gear of, "We must actually put ourselves
on a deeply organized footing," as time went on,
and particularly with the Celera announcement. But I would say the G5 was
not created in a big bang, but coalesced out of the
inchoate original genome. And it has lessons for how such
projects should be organized, because had that had been
designated at the beginning of who is the G5, it
wouldn't have been as good as if it had evolved
in the way that it did. Howard Baetjer And
we're going to get into that in a couple minutes. Actually, I want to ask two more
questions before we move on. One is just a simple question, although I'm not
sure we'll remember. Who named the G5? It coalesced. I remember that, but at some
point that became a phraseology. Eric, do you remember? Eric Flint Yeah, I
at least, of course, we can all compare memories, but
I like giving things cute names. And so I remember
having said, "This was, you know, like the G7." Now somebody else may
have said that too, but my recollection was it
was one of these cute names that we tossed out in passing
as a semi-joke, and it stuck. My recollection is we
started off with the G15. It was inclusive. And we then had the G5. I think Francis made
this comment. The G5 was the Security Council. Howard Baetjer I think I did. And I think it was the
G20 was the overall group, but I don't think we named the
20 until we already named the 5. Eric Flint I think
it was the other way. Howard Baetjer Yeah, we had the
5, and then what are we going to call the rest of them? Okay, they must be the G20. Eric Flint That was
my recollection. And that actually leads me to my
last question in this category. I mean, I'm going to direct
this either at Michael or Jane, because G5 had four
U.S. components and one non-U.S. component. Michael and/or Jane, was that
sort of difficult in terms of was there adequate
international representation? Did you feel it was
too US-centric? It ended up that way with
the collection of five, but what were your memories
then or now in terms of making sure there was that
right balance internationally? Jane Pitchford I think some
of John's excitedness came from feeling at times that
if we hadn't been as big as we had been, you know, whether we would actually
be a part of it at all. But we were very
conscious, I think, on our side of the Atlantic, of the need to represent
the centers who were left out of the G5 when that formed. There were centers who had been
working really quite hard to try and get the funding needed. Jean Weissenbach in Paris
for one, Sakaki in Japan. And I was very conscious that what we shouldn't be
doing is doing something that would exclude them in a way that was detrimental
to the project. Yeah, go ahead, Michael. Or maybe Michael
first and then Ari. Michael I think you
have to include in this the meetings
that we had. We went around the countries. So we went to China,
we went to Japan. And so there was
always this bigger group that were kept informed. This is why I've used that term
of the Security Council as part of the United Nations. Ari? I remember very well, and
I have the notes to back it up, about how aggressively I fought
to make sure Huanming Yang and the BGI that was there at
the early stages played a role. Of course, they did
sequence a few things, but it was pretty trivial. But it was important
that a country like China be represented
significantly at the table here. Indeed. I also worked pretty
hard to try to be inclusive of Huanming Yang and
his team, which started from a very relatively
rudimentary state and scaled themselves
up very quickly. And look what's happened. China has become so
remarkable in genomics from that early start. I still, even in this current,
today's climate, I'm very, very close and working
closely with Huanming Yang. So for the record,
it's Huanming Yang. But anyway, I just wanted
to echo what Jane said. I mean, I had lots of
conversations with John, where he was very worried about
the US-centric nature of things and whether the US was
just going along on its own and making sure that John
Weissenbach, Andre Rosenthal and so forth were
included where we could. Richard, you were going
to make a comment? Oh, yeah. You know, I wrote
a small piece a couple of years ago about the
project, as many of us have, and I kind of rushed it out. And I think I've got one thing
right and one thing very wrong. The right thing is that I called
it the Human Genome Project Changed Everything. And I'm kind of proud
of that sentence. But what I got really wrong was
not emphasizing the community and just how strong what
everybody's talking about, how much that contributed
to the way that I think we all
think about science. And like some of you, I'm
still close with Henry. And it would, but for
that, that, you know, that connection would
not be there. And I wonder what we can do
to, if we rekindle anything, it would be that sense of
international community. I agree. So a couple
of you mentioned in describing how the
G5 formed the importance of getting it right in
executing a big science project like the Human Genome Project. And a couple of you
alluded to the fact that we really did
learn some lessons about how to do this right. And so I think it's worth
discussing a little bit about how the G5
actually interacted, because I think it helps
illustrate what might be necessary in other big science
projects that have taken place since then or might take
place in the future. And, you know, how do you
even coordinate all of this when there's so many
people involved? So my understanding, and I
never participated in a G5 call. I was in a different stage of
my responsibilities at NHGRI, but I heard a lot about it. And I then, and I heard
a lot about it recently, is that you would mostly
meet by conference call. A couple times a year, you would
try to have face-to-face's. That it was decided that every
conference call would take place, or the great majority of
them would be routine to have it on Friday at 11 o'clock
Eastern time, which ironically is exactly the
time we scheduled this call, and in part to deal with
different time zones and the various participants. And that was very regimented. So I'm seeing heads nodding, so
I think I got those facts right. I guess one of the questions I
have is, you know, who decided and how was it decided who
could join these G5 calls? What were the rules for
having additional people join, either at the designated
sites or guests, or were there always
other people? I know that some databases
were invited to join at least some of the calls. How were those sorts of
decisions made and coordinated? So I'll jump in. And much credit here to
Mark Geyer, Jane Peterson, Kris Wetterstrand, who
were part of the team to put those calls
together every Friday. And yeah, I still have an
anxiety attack occasionally on Friday at 11 o'clock,
but oh my God, are we ready for the G5 meeting? Is the agenda ready to go? One of the things
we tried to do was to make it scientifically
interesting. So there was, at least
for some of the meetings, the first half was a
lab meeting where one of the G5 would have something
they wanted to talk about, maybe a new sequencing
technology or a new assembly or some new insight
about the genome. And then we'd get into
the really nitty gritty. And a lot of what had to happen
was to develop these tools that allowed us to assess
production on a day by day or at least week by week basis. And those were not
trivial to put together, but then that became
understandably a big focus. Are we on track? Can we project where we're
going to need to get to in order to meet the goals, especially
with the Celera threat? And what do we need to do if one
center is maybe a little ahead of where they thought
they would be and somebody else is
a little bit behind? Could we do some shifting
of territory to try to make sure we get the whole
genome done at the same time and not with some places that
we're still falling behind? All of that had to
kind of fit together. So I think Mark and
Jane and Kris and I would often be
the one to try to figure out what the agenda
was going to be. But it was very much a
group kind of decision about what are the
most important things. And we would often end, I
think, each talk with a-- each meeting with a sense
of what should we talk about next week that needs
particular attention right now. It was super intense. It was super collegial. There were times where there
were some butting of heads because there are no small egos, including me in the
G5 community. But I don't think
there was ever a sense that we were anything other than completely united
to achieve the goal. And Francis, did
you moderate this? Like you were the one
that cut people off and it was always an hour. I mean, it was all this
pretty tightly controlled? Pretty tight because
people had lots of other things they were doing. And yeah, I guess
that was my job. And I'm not sure whether
I was very good at it. I'd like to hear
from some others. Was it good the way
these agendas got formed, how these meetings got run? I want to know when we
actually started calling. So I have the memory
of the December meeting and Richard's right,
another big step. When did we start actually
having weekly calls? It was pretty soon. It was face to face, right? I assume it was shortly
after Houston. It must have been when
the funding was announced or something like that,
when our self-designation as the G5 became
more legitimate. Jane, was that your memory? Yeah, I had a feeling that we
were, that the calls came later, that they didn't really
start until autumn of 1999. I think we really got
going when Celera announced that they'd sequenced the fly and were turning their
attention to the human. At that point, we really had to
accelerate and that, I think, was a real stimulus to
go to the weekly calls. Before that, we had
face to face meetings. I think, what would they be? Were they quarterly? We think face to face
were roughly twice a year. That's what our records show. Sometimes there were
three or four times. I thought they were more
often than twice a year. I believe that's
the case indeed. But I really am curious
when the calls started on a regular basis. I just, I don't have a
clear recollection of that. Eric Green, I thought
you said you had minutes of the first call and you
were saying it was something like March of 1999. Did I make that up? We don't know. We're scouring our database. We're literally looking
at our archives now. Well, there was a difference
between where we have evidence for the G5 being referred to
as opposed to call minutes. So that was the distinction. We have records of
the word being used, but not necessarily
our call minutes. I have a little different
recollection of the calls that Francis did. I think they were, we
were clearly united in having the goal, but I
think the meetings were often very contentious. And there was a lot of back
and forth between the groups about who was doing what
and why we were doing it. And they were vigorous
discussions. I'll accept your amendment. They were in. I'm in with Bob on this and
that's what made them so good. I mean, you know, Francis, you
said there were strong egos. I think they are true, but I think the important thing
was there were strong views on what was important,
how to do things. And those arguments, which were
strong and sometimes heated, were about principles and
different approaches and things. And I think because
it was a collection of five super smart centers
that had opinions about the ways to do things, you know, I
think this was all strength of the human, of the public
Human Genome Project was it was not a monolithic point of view. And by the time we were done
with a couple of weeks talking about something, we had moved
each other or, you know, somewhat we had said these
kinds of data are needed. And that's frankly
why I love the G5, because he always got
you got off the phone, exasperated sometimes. But you always got
off better, you know, from having having
hashed stuff out, even if you didn't necessarily
want to admit it every week. I was going to say that's it. That's in hindsight, I
can I can accept that. In hindsight, in hindsight,
you had a you had a comment. Yeah. I have a slightly
different take on this because the British effort
was in no way competitive with any other British effort. It was the British effort. And there was only
one source of funding. There was no competition
for funds. My recollection is
that there was a lot of competition amongst the
US big labs for funding and for the rest of it. So I think the British
end of it was in a slightly different
position, very privileged, really. They just had to tap
at the Wellcome Trust and it was basically
on most of the time. I agree with Michael. I didn't feel like that. You weren't supposed
to feel like that. What were you going to say? Well, you know, I guess I weigh in a little bit with
Bob and Eric. I think we had some
spirited conversations. I want to say that I learned a
lot of that from the process in and how the rest of my career
and working life has unfolded. It's OK to have ferocious
discussions if you've got strong leadership
and a willingness to execute or make a decision and have
everybody execute on it. And that's what we had. I think we had a leadership
that and a structure that allowed we knew no matter
how much we argued that sooner or later someone there
would be a process, things would get decided one way
or the other for the argument. I think the other thing is,
you know, we looked at graphs of progress, real data. So, you know, it's a lot
of the arenas we work in now are not anchored
to real data and the discussions
are all over the place. But, you know, the genome
veterans look at these kind of meetings and other gatherings
and say, well, if we had a graph about what's actually
being done, the discussion would
be different. And we learned that from the G5. So Francis, you know, I want to endorse what Richard
just said there and go back to the first quality assessments
when genome centers had to sequence stuff
and send them around. I think the genome Project
really promoted a transparency, which was deeply uncomfortable. I hated opening that
brown envelope when the quality assessments
came back and you saw, you know, what your quality had
been judged to be. But it was the heart of what
made this project get better and better. And then, as Richard says,
with the graphs going up, real efforts at transparency. So I don't want to lose that
as one of the key features of the project overall
in the G5 in particular. Yeah, I'm really glad
you brought that up because I was going to also. It wasn't just about how many
base pairs are people claiming they have sequenced,
but are they reliable? And that was quite a complicated
process to set that up in terms of this sort of round robin
for doing quality assessment. But it was critical. And we learned some
stuff about the way in which we were
approaching this. If we had not done that,
we might be still reeling from people complaining that what we produced was
not a quality product. And it was actually much better than most people
thought it could be. That's absolutely correct. I mean, we learned a
lot from those things. And in terms of transparency, it
made us-- when we said things, we knew we had to be
able to back them up. We did have a lot
of different views about how things were done. We did come together. And I think the reason
we came together was that we really did have
this overarching goal that we all very
strongly shared, that we had to get
the sequence there. And we had to do it at
the same time as Celera so that the data would be out
there for everyone to use. It was not just getting
the genome done. It was getting the
genome out there for everybody to use for free. Yeah. And we're going
to come to that. We will actually come
a little bit more to Celera in a little bit. Michael, you want to say something before
I ask another question? I just want to make certain
it's not misunderstood that Sanger was on its own. Sanger benefited
enormously from being part of the whole enterprise,
the learning aspects and all the rest of it. So if I gave that impression,
it's not one that I really want to leave on the table. Right. No. Yeah. So back you
up on that, Michael, because we did learn a lot. Yes, as Eric and Richard
have already said, it was very painful sitting
in those Friday meetings, especially when people were
haranguing us for not doing as well as we were expecting to. We had problems galore. And on the finishing side, I
still remember Eric having more than one go at me for
keeping our finishing going when the emphasis
should have been on getting the shock through. But so you'll live in my
memory forever for that, Eric. And for the record,
she was referring to Eric Lander and
not Eric Green. Just one other point
on all this. I think, as Michael pointed out, there was a funding competition
issue that drove some of the behavioral
patterns that you saw. But for a lot of the period,
Michael, funding was stable. It was all the other
things, the egos and the scientific
genuine disagreements that drove the vociferous
nature of the discussion. I think to Richard's point, there was no way any
one center could succeed over the other centers. There was a goal, which
if we failed to deliver, we were just going to all fail. And if we delivered, it was
going to take all of us. So as much as I remember, we
had our friendly competitions or something like that. The major thing was we had a
job that we had to get done and we can only do it together. I think you made
a new word, Eric. I remember. "Cooperitition." By the way, we did just jump
into our history database and we now have more
evidence to suggest that the first conference call
of the G5 was February of 1999. Wow. Oh, lovely. So February of 1999. All right. I'm going to ask one more
question in this area and then we're going to move on. But I can't help
but ask it partially because I'm a technology geek. You all dealt, you all
interacted the most by conference call, staring
at polycoms probably. And you know, the world's
in a different place now with virtual connections that include video
like we're doing now. I'm just curious if any of you have done the
thought experiment, what might the G5 have been like if there would have been
video capabilities or this kind of an interaction
instead of polycom, Would have all been the same? Would it have been a little
bit of a different matter or or it would have been
a little different? Less facial expressions
and rude gestures, I think. Exactly. The conference
call meant we could throw up our hands and
screw up our faces. And hit the mute button
and say something. Hit the mute button and talk
to everybody around the table and say whatever you wanted. Right. Therapeutically valuable. All right. So I what I'm hearing is that Zoom would have made
everybody behave better, but therapeutically it
wouldn't have been as good, that you needed to that mute
button to blow off steam. Anybody have anything to add
to that before we move on? Zoom call has a mute button too, but you can see people's mouth
moving unless you're going to turn off the video too. It's a little more. People are pretty
good at reading lips and that might ruin
the community sense of working together. But I will point out, I mean,
we all laugh about that, but, you know, NHGRI now has
major consortia we're running and the way the groups are
interacting is by Zoom. So it's not by conference call. And so there is a new dynamic
with these kinds of efforts that your behavior has to
be a little bit different because you can be seen. Looking at my screen,
looking at my screen, Eric, I see eight pictures. What if it were 25? Would that make it
easier or worse? It would make it worse for
me because I can keep track of at least a handful of you. And you can hit the mute button and nobody knows
that you've hit it. That's right. That's right. So again, you could misbehave
more when it's just the phone. That's what we keep hearing. And you're on better
behavior when it's by Zoom. So let me transition
because this sort of, I immediately started hearing
about personality traits coming out from these G5 interactions. And as time goes on,
the personal side and the personal anecdotes
sometimes are the hardest ones to recover. I mean, we look in our digital
archives and we learn a lot about the facts of
what happened, what got discussed,
what was concluded. But you don't really
get a very good sense of sociology necessarily, or you
have to read between the lines. So I could imagine that,
and it's true of any group that is dealing with
high-powered issues, that people take on
different personas. I'll give you examples. Some people are optimists
and cheerleaders. Some people are pessimists
and Debbie Downers. Some people just like to kvetch
all the time and complain. Some people like
to be very funny. They're the jokesters,
the comedians. Some people can be little
rascals and be really bratty. I'd be curious to hear in
like one word or one phrase, how each of you believe
you are characterized or how did you behave
on those calls? So Richard, I'm going
to start with you. How do you think you were, what
was your persona during most of those interactions? I find that almost impossible
to answer, but I can tell you that one person at one moment
told me I was the nice guy in the Genome Project and
another person within an hour in my local environment told
me what an a-hole I was. I think I'll leave it at that. Bob, what do you think
your persona was? Oh, I'd like to think that I was
the reasonable one in the room. Okay. Jane, what about you? I felt that I was sort
of the face of the people who were actually doing
the work at the Sanger. I'm a listener, so I
did a lot of listening. John and I used to take
these calls together on a Friday afternoon for us. And when it got particularly,
fractious is not the right word, but stimulating, I
suppose, we always had to go to the Red Line on the way home. And the time that we spent there
was proportionate to the air at that time on the
call, I think, or the heatedness of the call. So I think I was a listener and a very reasonable
person on those calls. I'll let you say, and then
I'll be curious if Bob or others have a thought. What was John Sulston's persona? Excitable when there
was an issue to discuss. So he was excitable. Bob, do you agree with that? Yeah, he certainly
he had his buttons. Eric Lander, how are you? How do you think
your persona was? Well, I'm going to go with
excitable and stubborn, which I would agree that John
also was excitable and stubborn. And I had like so
much respect for John, because we didn't
always agree on things. But I just always respected. And Bob was the reasonable one. Yeah, Richard might
have been the nice one, but Bob was always
the reasonable one because he would come in
with the with the calm voice and then bring us
back to, you know, we're all in this together. And and and Jane was was always like incredibly sensible
in these things. No, but I mean, these calls got to to sometimes be
very excitable. And I think of you
as being grounded and sensible in a lot of this. And I think all this dynamic
was like really critical. You couldn't just be complacent
about your thinking because, yeah, you had to deal
with your G5 colleagues. I think hearing about all this
excitability and so forth, I think I'm right,
Francis, that at one point. The calls had gotten
so fractious. That you called me up
and said, what can we do to solve this problem? Because we were we
were spending more time at each other's throats
and not resolving things. And I think that's when we
started rotating the leadership of the calls. Or I mean, you are still
the moderator or whatever. But then one group was
in charge each week. Yeah, Bob, you're exactly right. And I hadn't had a
clear memory of it until you brought
it back to mind. And yeah, that was
what we tried to do. And since you were
the reasonable one, I guess you're the
one I called and said, how do I make this whole
thing more reasonable? And yes, we did then start
at least the rotation where each group would take a
turn in the lab meeting part of it and say what they thought
the group would learn from and get us back into
getting excited about the science instead
of arguing about this curve or that curve or whether we
were doing too much shotgun or not enough clone by clone,
which tended to be the place where usually things got heated. But yeah, you're right. That was there. There were times where
it got pretty tense. There were well, more than
one of the people I see on this screen, I had to call
and say, you know what you said to your colleague that
really wasn't very friendly. So yeah, a little bit of visits to the woodshed occasionally
were needed, but not very often. >> Howard Bauchner
Ari, what about you? What was your persona? >> Ari Slaver: I was pretty
stressed out because of some of the internal DOE problems
that were very unique to me that you had absolutely no idea
I was under the pressure for. So that was what I remember
the most, the internal problems that I was facing that were
understandable and in fact, perhaps even more difficult
than what I had expected. So that's my persona. >> Howard Bauchner Ari, and
Michael, were you on many of these calls and
participating? What was your persona? >> Michael A. Reilly I think
everybody would agree I was Mr. Nice. >> Howard Bauchner
Ari, and you still are. All right. Well, that then leaves
just Francis. Francis, what was your persona? >> Francis Collins I
hope I wasn't excitable, but I was excited
about the science. And I think mostly I was
an optimistic peacemaker. >> Howard Bauchner Ari, you
were frustrated about progress. >> Francis Collins Oh, yeah. >> Howard Bauchner Ari, yeah. And sometimes that came through. >> Francis Collins It did now. Well, yeah, because we were
all on the line, Of course, This was not a place where
failure was an option. I remember going to Richard,
to that meeting that you held in Houston, and I brought with
me an entirely new proposal about how the G5
should get the job done, which I hadn't even
discussed with my staff. I sort of had worked on it in my
own head over a couple of days. And the room blew up, and
people were not sympathetic with this approach, which
was very much along the lines of doing more hybrid
and less clone by clone. Eventually we figured
out what to do. >> Howard Bauchner Ari,
that was a feisty part of the discussion, Francis. I remember your opening
speech, though, which was Churchillian quote. Do you want to recall it for us? >> Francis Collins Yeah,
Churchillian would be very kind, but it was one of those, like,
we are at the moment here, this is the precipice that we
might either succeed or fail, and we have got to
reorganize our approach, because if we continue on the
current path, just mark it out here over the next few
years, we are not going to achieve what we
have promised to do. >> Francis Collins I
remember when you are going through hell, keep on going. >> Howard Bauchner Ari, I
still use that sometimes. >> Francis Collins But, Francis,
because this is archival here, when you say if we keep doing
what we are going to do, we would not have achieved
what we wanted to achieve, what exactly do you mean? We would have achieved
a finished sequence. So we set the right goal, and
we stuck to the right goal that we were going to
finish the sequence. And a lot of the arguments
we had were about order and what we needed to
have by a certain date and a draft and things. And I agree with you that
that was, in the end, a critical decision, on
the one hand, to say, because we had a competition, we had to have a draft
product out there early. But on the other hand, everybody
holding feet to the fire saying, and we must swear to each other
in blood that we are not giving up on the goal and the
timeline we had set. We're rearranging. And that was something where
there was a lot of worry in the group, particularly
on the part of some, that we would not actually
hold ourselves accountable to finish it. And so I think we would
have gotten the thing done in the same time frame, but
I think we would have lost in the court of public
opinion had we not done it. And it was great
to balance those. >> Point very well taken, and I
also get riled when people say, well, it's only because
of Celera that you guys actually finished
the genome project in 2003. That's simply not true. But the trajectory we
traveled was altered. Yes. >> By the way, before we move
on, Ari, I can't help but I feel like I was baited a little. You said there were
some DOE issues that were making you nervous. Is there anything you can tell
us that maybe you didn't want to talk about then, but you
feel comfortable 20 years later setting the record straight? >> Of course. You know, it may take a longer
conversation, but in short, my colleagues, competitors
within the Office of Science in the Department of
Energy, couldn't wait to see the human genome end
so that they can use the money that was funding it to fund some of these other much
less important projects. That was a real problem that,
in fact, at the end contributed to my leaving the
Department of Energy. >> I just wanted to follow up. When you say end, they
didn't care how it ended. >> It's just done already. >> Is that right? They just wanted --
they didn't worry about whether the project
was actually finished or not. They just wanted your
participation ended. >> Correct. >> Yeah. >> We're going to move on. Some of the discussion earlier
about the creation of the G5 and some of the major values of the G5 were very much
intertwined with the presence of Celera and also
this notion that we had to get the sequence done
at least at the same time and we had to get
that sequence shared. There was just so many aspects
about Celera coming on the scene that were the antithesis of
what those of us involved in the Human Genome Project
thought was important and valued. So very much that had a -- we
really need to make sure we talk about that more directly. So to stimulate that
conversation, I can't help but -- I'm going to
just show a photograph. I took this photograph
and I'm going to share it. To me, to this day, when I
looked at this photograph as recently as yesterday, I have
an emotional wave that comes across because -- and the
photo captures it in part because I was influenced by this
because I was part of working with Bob Waterston and Rick
Wilson and others at Wash U. And this is an example of a
photo really telling a story. >> Oh, yes. >> And interestingly, the camera
I was using even put a time stamp on this. So this was -- many
of you recognize. This was a photograph
in the dining room of Cold Spring Harbor
Laboratories in May of '98 during the Cold
Spring Harbor genome meeting. I think the time stamp -- I would have guessed
this was sometime in the middle of the night. The time stamp, I
think it was 1 a.m. and it's just not a
zero after the one. But I'm pretty sure this
was probably 1.03 a.m., maybe a 38-second
sign like that. And you could just read people's
faces and body language. You see on the right Bob
Waterston whose just legs were incredibly muscular and
handsome at the time. It was so clear he was in
great running shape then. Sitting next to him
was John Sulston. And then you just go around. And this is basically
the Wash U contingent. And you can see Rick
Wilson, Stephanie Chisell, Elaine Martis, Mark
O'Mara, John McPherson. And I was there in part
because I tended to hang with those folks even
though I was at NIH at the time I was collaborating
with my old friends at WashU where I had come from. And boy doesn't that picture
just say a lot about -- and I will just tell you that
every one of the people except for John and Bob were fairly
early in their career and felt that in some ways their
career was being jeopardized because of the threat
of what was happening because everything negative about the human genome
project was coming to the fore. And we were all worried. And I will tell you that Bob
and John were cheerleaders. They really spent hours, I don't
know how many hours we spoke there, and cheered us up and
just said this is not the end of it, we're going
to figure this out, we've got a rally,
blah, blah, blah. So let me start by asking Bob, since you're the only other
person in this picture, is that your memory and what do
you remember about that evening, that time, that discussion. >> Yeah, so this is probably
the first night of the meeting, maybe the second night
after Craig had shown up at the G whatever
it was meeting that happened the
two days before. Craig showed up and
took Gerry Rubin aside and said he was going to do fly. And he presented his plans
for the genome project in front of everybody. We asked him lots of questions,
he got prickly and so forth. And the announcement had
been made the weekend before in the press. All our people had
heard about it. This was the first time that we
really had a chance to sit down and talk through what
our response should be, what was going to happen,
and what we should do. And it was a tough decision,
tough discussion, because even within our group, there were
lots of different opinions about how we should react,
whether we should bother at all. I mean, after all, it was
just a press announcement. There was no, there
was nothing of reality. Craig hadn't done all that
much as part of the G20. I mean, that's important
to remember that he was actually
part of that group. And Eric is right that
people sat around the table and decided who was doing what. And Craig was sort of
on the edge of all that. He wasn't really
producing a lot of sequence. And yet here there was
this big announcement. Anyway, it was a
tough discussion. And you're right, we had to encourage people
and bring them along. It was a long night. Bob, do you remember the I think
it could have been that night or it's the next night,
but the Italian restaurant in Huntington, Long Island? Oh, yeah. Yeah. You and me and Francis and
Richard, were you there? And John. Yeah, John. And we had John because
this was, I think, really the G5 before
the G5, in essence. And there was this I
forget what the name of the Italian restaurant
is, but I'm never going to forget that dinner. We were taking different
positions. John was taking the position. Just damn the torpedoes,
full speed ahead. We got to do what we're doing. It's not going to matter. Nobody's going to
take it seriously. And because, you know, John can
provoke me to take the opposite. I was I started rattling off
notional headlines of what Craig and Celera were going
to announce that when they done a
certain number of reads that constituted one X
coverage of the genome, they would announce that
they had done 67 percent of the human genome because it's
one minus e to the minus one. And a little later, they would
announce they had done 90 some odd percent of it. And they wouldn't have
assembled the damn thing. But the press releases, we could
envisage what they were going to be. And you, of course, were
reasonable in the middle. And we were just trying to play. I don't know. You were you were strong,
but not compared to me. But but we were trying to
play out how it was already by within a day or two. We were playing out
the you know, to what extent are we are we
sticking to our guns exactly and to what extent are we
going to adjust to this and what what was it going to
look like publicly and and all. And it was very intense. So I wasn't at that thing
in in the in Blackford. But but I remember
how intense it was. We all left exhausted from from that dinner in terms
of extremes. I think you're right. John was, you know, we're
going to finish this and we've got we
know how to do this. And we know that a shotgun
is going to be very scattered and complete and it'll
all come out in the wash. And I think at one point
you were actually advocating that we should do exactly
what Craig was doing. We should be doing whole genome
shotgun so that we can keep up. Otherwise, we had no chance to win the headlines
as you're putting it. And we explored by the end of that night all
the models already that that we were eventually
going to do is did we have to really do the
finishing or something? We explored a great deal. And I don't know if I was being
reasonable, but I think John, maybe because he he did have
a privileged English position, was much less worried about the
public opinion aspect of it. And in the US, you couldn't
not be aware of that. And I I'm just curious
at some point, Francis, maybe you can tell us
some of the something about the pressures you
were facing on that front. Oh, they became intense. So yeah, I'll just tell a
quick story about how I learned about the announcement of what
became called Celera was I get a note saying Craig
Venter would like to talk to you on a Friday night. And that's unusual. And ultimately, we figured out
I was on the way to Los Angeles for some weekend thing. And so we would meet at
Dulles Airport in one of those airport lounges. And I turn up and here's Craig,
but here is Mike Hunkapiller. I don't think we all quite
realized how far down the road that relationship had been. And actually, Hunkapiller
did more of the talking than Craig did. And I began to realize
this is probably a pretty serious endeavor. This is not smoke and mirrors, which I might have
otherwise expected from Craig. Subsequent to that, I got on
my plane to go to Los Angeles and who sat next to me for
five hours, Mike Hunkapiller. That was a nightmare. And pretty much the whole time, told me all the reasons
why the sequencing capacity that they had developed
at ABI was going to make Craig Venter's dreams
come true and then some. So I became very
seriously worried that this was potentially
a real threat. So when we got to the Cold
Spring Harbor meeting, first a G5 conversation
where Craig talked and got, as you say, a little bit ruffled
because we didn't all applaud. And then that meeting
in the restaurant, which I do have an
intense memory of and particularly came away
from feeling very troubled because we didn't
come up with a plan. I kind of thought maybe in
the space of a couple of hours over Italian food,
we'll have a plan. But we didn't resolve it. We had these options. We could do this. And they were pretty
wide in their approaches. And they were not coalescing. And I really worried, my
gosh, is this the moment where our public project
is going to stumble and we could not afford to? You asked about the pressures. Well, shortly after Nick
Wade's Sunday morning, big front page New
York Times piece, Congress was immediately like,
oh, so what's going on here? And maybe we don't need
a public project anymore. It's a good thing. The private sector is
going to take care of it. They generally missed the
point about access to the data until it was hammered repeatedly
into the stories about this. And just after much
back and forth, the person that we
should always recognize who we just lost the last six
months or so, John Porter, the Republican chair of the
House Appropriations Committee that oversaw NIH, became a
total convert to the importance of the public project continuing
and even expanding its work. And that's exactly the
way it came forward. If it had not been for
Porter, we could have been in a lot more trouble. So can I follow up on that? I mean, you say Congress, but
was it, did Porter call you up and say, well, what are
you guys going to do? Or are you no, no
longer necessary? It's no, it's the usual dance,
usual dance where I figure I got to go see Porter, who I had a
pretty good relationship with. So you figure out how your staff
talks to his staff and gets him to ask you to come
and do a briefing because you're not allowed
to just go knock on the door. And that's what happened. He had previously extended his
support for genomic approaches, even allowed himself to
be considered a lead, a white knight for us on this. And so I was hoping that
he would stick to it. And that meeting was very clear. And then subsequent hearings of
the Appropriations Committee, he made it really clear as
the chair that he was going to continue to be
a big supporter. For people who are listening
in 2023 or years afterwards, it should be noted
that John Porter, Republican of Illinois,
was doing this. And this was an incredibly
bipartisan thing. A vanishing species. I know John very well. Actually babysat when
I was at Northwestern. So I had from another point
of view, and I agree with you, Eric, it was a very
unique individual, the kind that we
don't have anymore. Before we move on, I'm just
curious to hear from Michael or Jane, sort of to get
the UK view of Celera. Was it pretty much
aligned with what the folks in the US were seeing and
what they're saying now or was there a slightly
different view about Celera? I think working so closely with
John, the main concern for us that came across was the
American project funding would stop. The support, if Congress said
that, you know, didn't need it, Celera would do the job. Then we were concerned
about what was, you know, we were really worried about
what we were going to do and what was going to happen. But as Michael said earlier,
the Wellcome Trust had already, I mean, just complete
coincidence, the Blackford meeting
coincided with us being at the Wellcome Trust, having
our sort of grilling session about our increased funding. And Michael and John went
straight from that meeting to Cold Spring Harbor. You know, when Michael
stood up the next morning, because he obviously picked
up what the atmosphere was and said the Wellcome Trust
will fund the whole project if there's going
to be a problem. I have not heard that before. I don't know whether he actually
had any authorization for that, whether he made it
up on the spot. But Michael, you can comment. This really was an
extraordinary time. I was traveling in
a taxi to solicitors on the Friday afternoon
where the news came through of the Celera thing. And that weekend was one spent
running around trying to sort out what could be done. And it was fortuitous that the
Wellcome Trust were having one of their regular meetings on the
Wednesday of the following week when we were looking at budgets. And with a little bit
of pizazz, shall we say, we ended up with getting
the governors to agree that if necessary, they
would fund the whole project. And they told me to go
off and tell the community at Cold Spring Harbor
that's what we would do if it were necessary. The public program
could not fail. That was the message. And I think it was one
that righted the ship. Whether that's an exaggeration on my behalf or not,
I don't know. But that's the impression
I've always had. And I'd be interested for others
to comment one way or the other. Oh, it was a huge shot
in the arm, Michael. It really did change the dynamic
from feeling sort of beaten up and knocked down
into, "Well, damn it, we're going to do this anyway because Michael has
said we can do it." You remember Craig's idea was
that Celera should do the human and the public can go
on and do the mouse. Yes. And that, we
all understood, was a way to guarantee
a data monopoly by saying it would be wasteful for the public to
do the human also. And it was a transparent
part of a business plan. So I think we all knew
there was no chance, not just that it would get
delivered to the public later, but there was a real risk
it would never get delivered to the public. And so for what it's worth, this was not an ego-driven
competition. This was like the
strongest way in which we had to defend what the purpose
of public science was. And I think it pulled
us together a lot, that there was no way we were
going to stop this project. So I have a question for
Francis then, since Francis, I just learned you spent that
five hour flight with Mike. And part of the history of this
is that the James Webber model with Gene Myers presentation
all the way back at the Bermuda meeting
finally got published in Genome Research. And Mike told me that, and James
told me that Mike had read that and in discussion with
Michael, Tony White, I came up with Celera as the
model, thought it would work. And then they reached
out to Craig and said, would you be our
front man for that? So my question really is,
Francis, in your discussions with Mike, did Mike have
much of an opinion or thought about all the nuances
of data ownership, data release, all that stuff? But my impression was Mike was
more about, he was more sort of in the spirit that we had, which is let's get
this project done with the best thing
we can do it. Exactly. No, he did not
seem to have much nuance about just how critical
it was going to be to have the sequence
public in the same way that the public project
had been doing. And I think Craig was probably
pretty good at kind of covering over the seriousness of why the
business model was not going to make that kind of public
accessibility possible. Hunkapillar is much more
interested in the technology. And I vaguely remember
him talking particularly about it being influenced
by that Gene Webber paper. And it's almost like Craig
was like a convenient partner to get Mike Hunkapillar's
dream to come true. I feel it's important for us to
remember because I regard Mike as one of the heroes
of the whole program for all the things he did. And his role in Celera, I think
is probably not the one we want to reflect on most
of all, but in fact, that was where he
was coming from. And of course, he did fine being
an arm supplier to both parties. Let's be clear about that. Well, he was almost the
arms builder, you know, the guy who designed it too. Yeah, no, he was the designer. So that's correct
then that he sort of saw the Myers
Webber paper and thought that with his new
capillary machines, they would have the
firepower to do it. Yeah. Well, there's another
little twist in this, because, of course, Jim's presentation
at Bermuda did not go over well. And he tried to have that
manuscript published in Science. It was rejected. I visited him coincidentally
the next month in Wisconsin and suggested he send
it to Genome Research. It was reviewed and thoroughly
grounced by Phil Green. And the editor said,
we can't publish this. And I convinced everyone. Eric, I don't know if you're
on board by then, were you? No, I was. And I actually remember that
we collectively or some subset of us came up with
this idea of making it into a point- counterpoint. Yeah. So there's papers on that
appeared in Genome Research. And that's what Mike saw. So what's again for somebody
20 years later who's listening to this or even further
in the future, what's hard to appreciate is
it was really an open question at the time. There was no question
that if you had a genome that was all unique sequence,
you could shotgun sequence it. We knew that you could
do it in bacteria because the computer
could assemble things. It was all about repeat
structures in a genome. And so for a human genome with
that much repeat structure, was it going to fall
together right without getting all tangled up? So it was a moment that
lasted several years where we really weren't sure. And we got the answer in the two
papers that came out in February of 2001 when the public
sequence was vastly better than the Celera only sequence. Now, of course, in
retrospect, we now know how to do a whole genome
sequence much better by adding in libraries of different
sizes and things. But it was an open question
that really drove the strategy of whether or not you
could or couldn't do it. Eric, your view of that
is completely right, because I find even
now when you talk about the Human Genome
Project to young people, they think we had a playbook and they think we just
followed the playbook and it was so straightforward. And of course, it wasn't. Eric, Francis? Yeah, for historians, it would
be interesting for people to go back and look
at a transcript of a congressional hearing
in front of John Porter. I know it was June 16th of
1998, because I got married to Diane four days later. And this was not my idea of a
nice way to plan for my wedding. And the witnesses
were me, Craig Venter, somebody I can't remember the
third one, and Maynard Olson. And John Porter was
really quizzing about is this shotgun
strategy going to come together for a genome as riddled
with repeats as the human. And Maynard delivered this
absolutely devastating takedown of the whole approach,
which turned out to be just about right. I think he predicted, you
know, catastrophic failure to assemble 130,000 unanchored
pieces, something like that, pretty close to what happened. That was one of them. And we talked about John Porter,
the fact that he wanted to hear that in a public hearing, and that it was very
effectively taken on by Maynard, helped us a lot in the
view of the other members of that committee
who were in the room. So you know, we've heard a lot about how Italian food
was really important in the early stages of the G5. But I also know that
another type of Italian food was
really important as we were driving
towards the draft sequence, because it has been written,
for example, in Time magazine, how pizza at Ari Patrinos'
townhouse was critically important for bringing together
relevant parties to make sure that there was a coherent way
to announce the draft sequence of both the genome
project's, efforts, and Celera. So I've read about this in Time. I've heard it anecdotally. But Arie, will you tell us a bit
about your convening of Francis and Craig in your, I guess it's
Rockville or is it Bethesda, or North Bethesda townhouse? And what kind of
pizza do you serve? We want to hear it all. What can you tell us? >> I have to make it
a short presentation because we don't have a lot of >>time. So I'll try
my best to be laconic. As you may know, and
perhaps you've been too kind, all of you, not to mention it, I was aware of what
Craig was planning to do for quite some time
before you did. And that was the
understanding I had with Craig, that he would share
that information, but that I would not disclose. It was a similar relationship
with Francis, you know, at times when I would share
some things with Francis that I wouldn't be telling, or
Francis would share some things with me that I wouldn't
be telling Craig. And I felt almost
as an outsider. I was not an outsider. I was quite frankly an insider
as part of the DOE program. But the DOE program
felt to many ways as an outside program
to the rest of NIH's. That was something that probably
is subject for another story. So I had that unique
perspective for both programs. And I know both of
these individuals that I had tremendous
respect for and admiration. And I felt at the time,
and I still feel that way, that both of them were
heading towards a collision that was not going to be
helpful to any one of the two. So I was lobbying
Francis strongly for him to have this off-the-record
meeting with Craig and see whether we
could reconcile. I wasn't sure it would work,
but I felt it was worth a try. Now Francis was too committed
and loyal to the rest of you that he didn't want to do
anything unless, you know, he got the okay from
the rest of you. Craig didn't have that qualm. And I was in fact surprised
that he was willing to do it. But I believe that around
that time, he was starting to get really worried that,
you know, the collision may end up hurting him more
than it would hurt us. So it was perhaps appropriate
for him and to his credit to see whether there
was another way. And these kind of things
I've done in my career because of being an
outsider on many aspects. So it was worth a try
and it worked out. You know, it was one meeting,
one evening or multiple? It was several meetings. In fact, if you include the
final one where we had lots of brandy and so on,
it was four meetings. But the individuals,
the three of us were in fact three meetings. Respect to, apropos to the
questions you had earlier, I have all these things recorded
on a day to day and hour to hour basis at times. But during this move
that happened last week, all these records are in boxes
that I haven't yet to open, so as I open them slowly, if
there are any other issues that perhaps are left unanswered
at the end of this conversation, I'll come back to you
all and share them. So Ari tells it well. Let me just go back
a little before that. So at the end of
1999, as it was clear, we're on this collision course. The public project is really
rocking at that point in terms of sequence production. We had our billion
base pair bash and a few other things
to document that. Harold Varmus had stepped
down as NIH director, I think in November, but he
was willing to stay in a role of trying to broker some
kind of a peace arrangement between the public
project and Celera. And there was a meeting
at Dulles with Craig and a couple other people from
Celera and me where Harold tried to come up with some sort of
a way that this could be a win for everybody and
basically fell apart. Craig was unwilling to
make any kind of commitment to anything other than
pure victory for himself. Subsequent to that, now
with Ruth Kirschstein as the acting director of
NIH, Ruth was very worried about the way this looked. Somewhere along the way,
I think Bill Clinton said to his science advisor,
this is bad, fix it. So Ruth suggested that we
have another effort to try to make peace and
asked Rick Klausner to convene a conversation
with Craig and me and some other folks. That also went very poorly. And after a month or so,
especially because Ruth got wind of Craig's behavior, she said,
no, we're not going to do this. She was offended by the
way he approached it. And I think he leaked
some stuff to the press. So now it's getting to be
like March, maybe of 2000. And it's pretty clear that we
are headed for what's going to be a really messy, awful
circumstance in a few months. And I did go to Ruth
and I said, look, Ari Patrinos has been keeping
in close, friendly relationship with both me and with Craig. What do you think about
our trying to just in a very informal, quiet,
secret way, have a conversation to see whether something
could be worked out? And she said, what
the hell, go for it. And that's when we had
that first meeting. And I felt bad because I did
not tell you other G5 folks that that meeting was
happening the first time because I thought
it had, you know, in which case, why
even bring it up? It was only after the second
or maybe the third meeting that it seemed like, oh,
something might really happen, and we all kind of got into it. That was awkward for me. I felt like this
was the one time where I had not really
worked with the whole team from step one to try
to achieve something. And I guess in the long run, it
probably would have been hard to do it any other way. But ultimately, Craig's
willingness, because I think he saw the
handwriting on the wall for a really bad, messy
outcome, to basically say, let's call it a tie, kind of dominated his
otherwise strong resistance to being flexible
about anything. And Ari, you helped a lot by
being the sort of neutral party who could kind of call him out
when he was acting in a way that was not going
to get us to yes. I don't profess to have had any
great talents or capabilities. It's just being at the right
place at the right time. And that worked for us. I don't know how the
rest of you feel, but I think the outcome was
probably an optimum among all different other options that
we were facing at the time. Francis, was that one of the
outcomes of those meetings? The arrangement that two
publications would go ahead on two products and it
would be at the same time? No, no, that was not. I mean, originally... I think there was a conversation about having one joint
publication, and that was when Kennedy from
Science was very involved in the deliberations. But I think the outcome
still was a pretty agreeable and successful one, I feel. Yeah, publications
were in a later phase. Not too much later? Not much. It was
July or maybe June. The agreement then was to have
a simultaneous announcement of a tie. Correct. Yeah. I hope. My memory, my
memory for what it's worth, the Brits felt betrayed. Yes, I remember. I remember. Jane, do you want to comment? No, I know this was, you know,
one time when John really felt that Francis had
acted against the G5 and against the spirit
of collaboration. This was the friend. This was John's friendly fire. No, no, that was earlier. That was another topic. Well, there was another
one then. But you know, back to
the late '99 meetings that didn't go so well. I was the G5 representative
at that meeting with Harold and Martin Bobrow and Right. Yeah. Who was the? Tony White? Well, Tony, Tony White and
Gillum and somebody else and Craig were the
Celera people. Eric had started a framework
with Craig earlier in November. We were frustrated with Eric because he was doing
this on his own. But we worked with that and we
thought that Solera had more or less agreed to these
kinds of things that we went into this meeting thinking
that we were pretty close to having some kind
of arrangement to hone down the acrimony in the press. And we got in there and it
was clear from the start that Tony White had
none of this. I don't know. I mean, Craig was Craig was
sort of in that ballpark, but it was Tony White was just
not going to have anything that would compromise
his ability to monopolize the sequence
for months for years. That's right. And and it was clear that
their business plan was to have that sequence and
everything derived from it so that they would have
control of the annotation and use of the sequence. Go ahead, Richard. I was going to ask you about
the timing of the fluctuations in the stock market
and its its influence, because there was a
giant market upheaval. But there was also
the Celera moment when after the joint
announcement of free data access. How did that tie into
the whole dynamic there? That's a piece I've never
been able to connect. I do remember that the follow
up to that December meeting led to a letter from
Francis to Craig Celera, and that letter went just before
Celera had its stock offering. I believe that's right,
isn't it, Francis? That is right. You're remembering
something I'd forgotten. And how could you forget that? Too many things. Well, I remember partly because
Michael's writing about this. And anyway, it was then there
was the joint announcement about no patenting and so forth. And then the Celera stock price
was going up and up and up. And then they had rumors
that they were making a deal and that the intellectual
property was was came into being with Blair and Clinton's
joint announcement. And then their stock went down. The whole market
went down, right? There was $30 billion in a
day or something like that. Because the White House press
secretary got the message wrong in his early morning
announcement. There will be no more
gene patents for anything. And then Congress got
involved and it was a mess. But it was clear that both
sides were trying to come up with some kind of way
to to moderate things. And fortunately, the one that
Ari brokered actually worked. It was the right
people in the room. And so I want to move on. I want to move on. It's just the classic
diplomatic solution, which is both sides
need a victory speech. The only way you ever get to a
peace treaty is each side has to have a victory
speech it can give. And that's what this
accomplished. You know, a tie was the only
way we were going to get there. And I do joke that, of
course, there was no data to support the genome
being finished that last week of June of 2000. There was no data to
support it being a tie. So it was a data free thing. And I think it was an
announcement of the completion of the human genome to
many people that allowed us to actually get on and
complete the human genome. That's a perfect segue to
what I wanted to ask next, which is that we have
the June announcement and then you get the
February 2001 publications. How did the G5 interactions
change from that point until the end of
the genome project? Because it would seem to
me the whole focus changed. The Celera thing
started to evaporate. Was it a whole different
dynamic in the G5 interactions? Francis? Sure, it was. And let's not skip over the
intensity of what happened between June and February,
trying to put together that landmark paper in Nature. And of course, to have an
assembled genome sequence that could be appropriately
annotated as best one could with a draft. And so yes, a little tip
of the hat here to Jim Kent and David Hassler for the role that they played
to help with that. I think that was a
wonderful period, actually, scientifically. That was just exhilarating to
be able now, instead of looking at the production every day, although we still were doing
that, to actually figure out what's in this thing. And the meeting we had, and
one of them in Philadelphia, really trying to dig through
that, assign who was going to do which kinds of analyses, looking
over each other's conclusions and trying to take
them apart to see if there was something
missing there. That was a lot of fun. And we waited a long
time for that. So I don't want to skip that
phase, Eric, before we go on to finish the sequence. And can we also note that the
papers were originally going to be in science, back to back. Yes. And there was
a lot of G5 debate over whether Celera was going
to make their data available as scientific publication
should require. And a lot of unhappiness that
eventually led us to Nature. And I recall the utterly random
thing of, I was at something in New Jersey and met the
physics editor of Nature around the time we were
talking about this. And I asked this person, do you
think Nature would be interested in the human genome paper? I said, no, just curious. And the next morning, a Monday
morning, Nature was all over. We'd been already discussing,
could we be in Science? And so I think that also changed
the dynamic of publication too, because I think had they
both been back to back papers in Science, it might have
been a little different. This got the journals
invested in a way, and it gave us more space because the other
party had more space. So I think it was good for the
scientific community that Nature and Science were kind of
competing by making territory for the genome because they
had a competitor in a way. You know how things changed. Francis is right. We stopped talking so
much about production. We still paid attention to that. But the issue became
what is going to happen with the publications. And the first was
the first issue was when it was going
to be published. And John was very
much of the opinion that we should just get it out
there and get on with the job of getting the real thing, that
this was just a transitory thing and we shouldn't
focus too much on it. Eric was on the other
hand, of course, John and Eric were
at opposite ends. As usual. And so I think we
had initially we were going to do a data freeze in July or
something really very to sort of codify the to justify
the June 26th announcement that we were going to
actually have a paper that would prevent it from
being completely data free. And but we you know. I think Eric was was
right that, you know, there was just a tremendous
amount that we could learn from what we did have. And and your driving of it was
was really a critical thing. Jane, did you notice the change
in the in the style of the calls and the focus of the
calls after that? Yeah, the production was one
thing, both enhancing the draft, filling in gaps that we needed
to improve the assemblies and making that a
focus of what we did. But then it was, you know,
getting on to to think about how to how to finish it. That's really where
my focus came in. But it was certainly the
first the most immediate thing after the June announcement,
I think, was, you know, what have we really got here? And we I know we all went
away scurrying to sort of find out what you know,
what have we covered? What what did we need to
do immediately to be able to get some analysis done? And as Bob said, John was
pushing for a very quick, you know, freeze
and publication. I think by the time there
was a meeting in Paris, I think in September, before
that was before Philadelphia, but the Paris one, I think
was where John came round to thinking, yeah, no, we we
can do more analysis on this. I have a question
for you, actually. I mean, prior to that, the
Sanger's first triumph, I suppose, in the human genome
was to get chromosome 22, you know, the finished
sequence written up and published in December 99. How much did doing that
influence both the push on to get the finished sequence,
but also the types of analysis that you felt, Eric, especially,
you know, needed to be done for the for the finished
for the draft paper? I think it was very
influential, because like a lot of our issues were we
didn't know what the genome looked like. And trying to assemble
and analyzing a genome from fragmentary
information without a glimpse of better information was hard. And so I think it sort
of raised, you know, raised up the categories of
things that we should do. And then we asked, how much
could we do with a draft in that nodding in
that direction? So this is, again,
another example of where these diverse points
of view and diverse, you know, activities, I think,
informed each other. I mean, I think the hands down
lesson is that as unwieldy as some of these
consortia can seem, they are so much more powerful because of the intellectual
diversity. So I can speak to
that, too, if I may, that I think the chromosome
22 paper was beautiful and influential. It set a standard for what a
chromosome specific finished paper should be. But in terms of the motivation,
I feel like we were all on this autopilot, this phase,
we were going to get a finished or essentially complete
product done. And so the commitment was there. It was more influential in the
sense of how it was presented and what the published
product would look like. I have a self-serving question. How much was the Bermuda
meetings an influence on following through with
the G5 and the G15 meetings? How influential was
Bermuda or not? You're shaking your head, Eric. I never found the
Bermuda meetings to be intellectual
driving forces. Just saying that I found
there were many meetings that were critical, but I
thought Bermuda was important for inclusivity and all that. But they didn't seem to me
the intellectual drivers of a lot of these decisions. They were important to have, but I think they were
important for other reasons. Well, most important of
all, of course, the decision to do immediate public
data release that when everybody hears
Bermuda, that's what they think. And they should. That decision was critical. But my recollection is not
everybody even agreed to it. The Japanese had
issues with this. They weren't authorized to
actually make a decision. Yeah, but getting that
idea out there is, I think, the critical thing from Bermuda. When did the April 25th
deadline come into place? Because we're all saying,
oh, it was, you know, we're all going to get it done. But we did set ourselves another
utterly artificial deadline that forced us again. And I don't remember
who did that. No, it was the publication
of the... It was not arbitrary. It was not arbitrary. No, of course it's
not arbitrary. It was poetic. It's poetic. It was to commemorate the
Watson and Crick paper. Of course, but we didn't
have to tie ourselves to the mast to get to that date. You could have picked
another date. No, no, Francis did that. Francis did that. And I'm sure he did it so
that he could drive us harder. And I think it helped. You think it helped me? What? Okay, we're
getting near the end. But I want to, before I sort
of ask the final question, I want each of you to think
about, is there a memory of the G5 experience, either
a call or a feeling or a story or saying that we haven't said? I mean, I want this to be
very brief, but is it sort of in a word or a phrase
or, you know, a sentence? Is there something about the
G5 experience that you have as a key memory, but
you haven't said it yet during our conversation
today. Is there anything that comes
to mind about the experience? Bob? I don't know that this
is about the G5 calls as much, but we haven't talked
about the map. And I have to talk about
the map because that's where we put a lot of
effort into the map. And it really was what
drove the golden path to a successful outcome. It supplied the clones to
us and Eric and others. And I don't know, I think Marco and I calculated he did
63 liters of agarose gels in the course of a year. The map, the fingerprint,
more than 350,000 clones. Ladeana worked tirelessly
with Jim Kent to feed him. You know, we could essentially
fingerprint the sequenced clones and put those on the map. And that was key for Jim Kent
to be able to assemble things. And it was also what Celera used
to put their sequence together. Otherwise they had 119,000
random pieces and they put them on chromosomes through the STS
maps and the fingerprint maps. Richard, what's your memory
that we haven't mentioned yet? So I'll be closing out because
we're getting to time, right? Just a general comment first. This has been a great discussion
about all the exciting stuff that happened up before 2000,
but so much stuff happened between then and 2003,
which is our anniversary. I wish we had another two
hours to talk that through. But the thread that will come
through that is about the map and the clone availability
through from that period in '99 when we changed tactics
through to where we arrived at our finished model, you
know, our finished pieces and how we pulled those
pieces together and kind of what happened in between. I suspect that's part of the
ingredients for Francis having to call people and say,
"Tone it down on the G5" because that was a pretty
contentious set of issues. But anyway, we're celebrating
today this completion. The thing I remember,
and I can't even say when that moment was, there
was a particular moment in the whole thing when we
stopped kind of looking up and saying, "What
should we do generally?" and all looked at each other
and said, "What would it take to get the whole job done?" And so this idea of completion
as the starting thought for building the model,
which to me, that's a product of the Genome Project. I don't exactly remember
when it was. It was somewhere in '99 or '98. Jane, what's your memory? One thing we haven't mentioned,
you know, is the work that went on to get the databases and the
annotation pipelines working. This was another diverse
activity at Sanger, but when we came to put that
sequence together, yeah, Jim Kenton put up a web browser
for you in the US especially, but the Ensembl Pipeline
was ready to go. It had already put some
data up and it was ready and there was an annotation
pipeline that could work and that could give us the
first view of the contents, etc. And I think
the work that went in that is worth remembering. But I think one other very
quick memory that I've got, I can remember, I think
it was the Paris meeting when I met Rick Wilson one
morning and he just came up and gave me a big hug and then
he said to the others, he said, "You know, being able to
hug other people," okay, I was the only, you know, well,
I'm the only woman on this call. I was often the only
woman in the room, both in the Sanger
and, you know, sort of at other
meetings that we had. But he said, you know, having a
mix and having a different view, having different
perspective is important. Eric, your memory? So my G5 memory I'm going to
say is actually a G16 memory. It was, Francis, the
National Building Museum. We had the party celebrating
the paper, the publication in February, I think it was,
of the draft sequence paper. And what sticks most
in my mind is that the G5 conversations were
all so internal and so intense. But coming over to the National
Building Museum that day, Laurie and I took a cab
and the cabbie asked where we were going. And I said, we're going
to this big celebration of the sequencing of the
human genome and this paper. And the cabbie, you know,
turns around and he's, "Oh, the Human Genome Project. Are you the guys who are giving
away the information for free?" And it was the moment that
I realized, oh my God, there are people all over
the world, cabbies in DC, who are on top of
this, followed it. And despite all the turbulence
and noise, they got the point. And I will never
forget that cabbie. I should have gotten his name. Francis. That's a
great story, Eric. My mom came to that particular
party a year before she died. And I'm cherishing those
pictures of what happened. And we had a band and the band
sang some silly genome songs that were written
for the occasion. So, yeah, it seemed
an appropriate moment to get outside of our very
focused work-oriented effort and just kick up our
heels a little bit. But my memory that I was going to mention is it
was at Airlie House. And I'm not sure when
this one happened, but it was during
the clear threat of whether the public
project was going to be eclipsed by Celera. And I remember Bob and John
were sitting in a couple of lounge chairs somewhere
out there in the Airlie campus and sort of holding court. And I walked by and we got in
this conversation where Bob, you and John basically said,
look, Francis, you're going to have to really
stiffen your backbone. You're going to have to be ready
in the court of public opinion and the media to be able to
be the best you've ever been in order to explain why the
public project is still relevant and why it matters
because of the data access. So don't go soft on us. Do you remember that? I was like, OK, I
got the message. I do. I mean, we
talked, you know, Celera had this incredible
PR machine. And we had the government. I want to hear from
Ari and then Michael. Well, for me, the most
important memory is the memory of my good friend and
colleague, Marv Fraser, who was on my side during
all the deliberations. And he, as you may remember, was going through some very
serious health problems at the time. But nevertheless, he persevered. He was in the office on
a lot of the G5 calls, even though he was one
step away from death. I owed him almost all the
success if I had any success, because he was the power and
the force behind the DOE Human Genome Project. Michael? My memory obviously has
to do with the famous meeting where the Wellcome Trust
announced that they were going to fund the human genome,
irrespective of anybody else, and in particular, arriving
at Cold Spring Harbor after a long flight from
London and going into the bar. And as I said it in somewhere
else, people were running around like chickens that
had their heads chopped off. Everybody was in a
total state of dismay. Everybody thought
the end had come. And I was the second
coming, I guess. So I think I've covered
everybody on the memories, correct? Yes. So last question. And I know we're
coming up against time. So I want you to answer this
question either in a word or a phrase, maybe a sentence. So we're now 20 years
past to the end of the Human Genome Project. We've discussed extensively how
the G5 played a central role in getting the genome project
across the finish line. I want you to think back on the day the Human Genome
Project ended, April 25, and think about the
last 20 years. What singularly, what singularly
has surprised you the most about genomics over
the last 20 years? Richard, can we start with you? I know it's a hard question. Yeah, it's a tough question. You know, I think the gap
between what we know is logical and can be driven by the
use of genomics and genetics to understand biology and life,
and how it's getting implemented and rolled out to
the front line. We hoped, some of
us hoped back then, that the whole world would
be genetically literate, namored of DNA. Wake up every morning
thinking about that as a part of their lives. And it's taken a
while to get there. Jane? What has surprised
you the most? How much it's already
being applied in medicine. Bob? That's a gap. I would say how pervasive
genomics has become. You know, we thought about it
as the Human Genome Project, and obviously I thought about it from the worm standpoint
and model organisms. But it's just everywhere, in every field, it's
driving biology. And I've been amazed
at how pervasive it is. Ari, what do you think? Well, you know, as somebody who
had to compete almost violently with high energy
physics and the rest of the physical sciences
community, it is just so wonderful
to see them shoved aside by what the Human Genome
Project did to biology. It's something I rejoice and
celebrate almost every day and look forward
to further siding, sidestepping these other
programs, because we have so much more that
we can produce. You know, as I like to say,
we can almost stoop down and get the gold nuggets
that are on the surface, whereas they have to
dig deep, very deep, and spend way more
money than we can to produce these
type of results. Michael? A couple of weeks
ago, I went to a meeting for the first time in
many years in London. Genomics - there
must have been two, three thousand people there. The place was stuffed
to the gills with new instrumentation,
new technology. It was quite staggeringly
amazing to me. Genomics is now everywhere. Eric? The stunning thing to me is just how the progress
has been so much faster and so much further than
I ever could have imagined on April We talked then
about, oh, it would be great to have a reference
sequence of the human genome. And what's unfolded since -
the catalogs of all the genes, all the variants, all the RNA
expressions, all the cell types, you know, the ability
to edit that, the ability in the coming years
to find all the programs - I think this concept of
a reference and the power of foundations in biology have
totally changed what biology was about. From the days when
everybody was wandering around finding their gene
or doing their thing, to making it a broadly
understandable domain. So I don't think people are
going to be able to go back - I mean, my students still ask, "How did you do anything before
the Human Genome Project?" Because they can't
conceive of that anymore. So that's what surprised me. I thought there'd
be good things, but I had no idea
they'd be this good. And appropriately so, Francis. I'm going to give
you the last word. Well, so many good words
have already been spoken. One thing we have to
mention, of course, is just the amazing
advance in the technology that that first genome that
we celebrated on April 25th, cost us somewhere in the
neighborhood of $400 million. And I know of no other
technology that has come down in cost and gone up in
quality and gone up in speed. You usually can't get
faster, better, and cheaper. We got all of those in a
remarkably effective way, thanks to all the investments
that were made as part of the genome project, and that's encouraged the
technology to keep going. And I also, even taking
Richard's concern, which I share, that this should
have gone faster in terms of the medical applications,
I do celebrate where we are 20 years later. That's particularly,
say, with cancer. A lot of lives have
been saved as a result of our ability to
sequence a cancer. A lot of newborns have had their
diagnosis made clear right away instead of going through many
years of a diagnostic journey, an odyssey that led nowhere. And let's not forget
infectious disease. If we didn't have genomics
now spread across the world, including in South
Africa and Nigeria, we would have seen a whole lot
worse things happen with Ebola and then with COVID-19. Genomics has spread
into that space also in an incredibly powerful way. We should not rest,
however, to try to be sure that that trajectory goes
forward, and we shorten the time that Richard points out,
which is still way too long, between when we know
something will help people and when we actually
get it done. Eric, when you make this video, you should calculate how many
human genome sequences were sequenced, how many human
genomes were sequenced during this call. Just report that to people. That's another measure of
what these 20 years are about. I was thinking the
same thing, Eric, that we spent how many
years and how many dollars and how many people doing this, and you can actually get a
whole genome, not 95% of it or whatever we have,
and get the whole thing, Telomere-to-telomere. And they're doing
that in thousands. There you go. This was fun. Well, we are at the end. I want to do nothing short of
profoundly thanking all of you for joining today and sharing
your memories and your ideas and filling in a lot
of bits and pieces that we didn't have
already about the G5. I will just tell you, as I
said earlier, I wasn't a member of the G5, but I was a
great admirer and a fan, and in the last 20 years,
I've only come to admire each and every one of
you even more so. And I'm not at all surprised we
had a wonderful conversation. In fact, I enjoyed this
conversation so much, I've made the command decision,
we're going to do this again in 10 years for the 30th
anniversary, so please be on the lookout for an
email from me in about nine and a half years to get
it on your calendars, because we'll want to reconvene
and see what our memories are like Totally different by then. Totally different. And we will compare, and that's
the fun part of all of this. So with that, I will
say we're done. Okay, now we're still recording,
but now we can be more informal. So thank you all. This was fantastic, better than I possibly could
have dreamed of. I hope you enjoyed it, and I know we just went
a few minutes over. Any last comments
anybody want to make? It was fantastic. It was fun seeing you all again. [no audio]