Eric Green: Okay, well, it's a pleasure to have Kathy
Hudson here.
I introduced the topic briefly with a slide in my director's report, but we specifically
wanted to have Kathy come and talk to council.
I know council would be interested in this topic, but also, it really is an interesting
chapter.
I didn't even know what the title of her talk was going to be, but it really is an interesting
story to be told, how this played out.
I will tell you, Kathy put in countless hours, if not days and days, of effort navigating
a very complicated circumstance.
I, and several of us from NHGRI, in particular Laura Rodriguez and Mark Guyer, and a couple
others, were quite involved on a regular basis on phone calls with Kathy as she sort of used
us as partners, and -- but as advisors, and helped to sort of navigate what was a much
more complicated quest for her than it was for us.
But I saw enough of the front line of the story to just see how challenging it was,
and Kathy was just masterful at it in many ways.
I also think that the perspective that she co-authored with Francis, although I'm sure
she did most of the writing, was fantastic in the end, and if you haven't read that,
you really should.
But I am going to let her just tell this story, but I really thought it would be special.
The timing couldn't be any better for a council presentation directly from Kathy on this interesting
story, so, Kathy.
Kathy Hudson: Thanks, Eric, for the invitation, and it's
nice to be here with you all, with some friendly, familiar faces around this table and in the
back of the room.
Thanks very much.
So this is -- has been an interesting story to be a part of over the last several months.
I'll start with -- uh-oh.
So I will start with a little bit of background, which I'm sure you're all very familiar with,
about Henrietta Lacks.
She was born in 1920.
At the young age of 31 she was being treated at Hopkins for an aggressive form of cervical
cancer.
Researchers took cells from her, and ended up being able to successfully start a cell
line, the first human cell line, as it turns out.
The family, of course, has been dealing with this situation ever since they learned that
their mother's cells had been used in this way.
So how her identity became known, and how the family's identity became known, I think,
is relevant here.
So, in 1951, George Gey at Hopkins was able to get the HeLa cell line to grow in culture.
In 1971, there was a commentary, actually an obituary, published in "Obstetrics and
Gynecology," that identified Henrietta Lacks and included a photograph of her.
The obituary was of George Gey, and it was written by Howard Jones, who was otherwise
known to many of you as the father of IBF.
In 1976 Victor McKusick, the father of human medical genetics, published a paper describing
the Lacks' pedigree, and specifically, was looking at HLA typing because, at the time,
it had become well-known that many later derived cell lines were contaminated with HeLa, and
so if you get any cell line near HeLa, HeLa takes over.
And so Victor McKusick and his team contacted family members and had them come back to Johns
Hopkins to provide blood samples.
If you've read the book, "The Immortal Life of Henrietta Lacks," you get a perspective
of how there was a lack of clarity on the family's -- from the family's perspective
in terms of what exactly they were being asked to provide and why.
So there was a perception that they were being tested to find out whether or not they might
have the same disease that their mother died of.
In 1997 there was a documentary, and then probably most importantly for the general
public's understanding of this situation and identification of who the family is, and who
Henrietta Lacks was, was the publication in 2010 of "The Immortal Life of Henrietta Lacks."
So how many people in the room have read "The Immortal Life of Henrietta Lacks"?
It seems like you can't even get on an airplane nowadays without seeing somebody reading the
"The Immortal Life of Henrietta Lacks."
So it is very, very, very widely known.
So if you do a Google search today for HeLa, you'll generate 2.5 million results.
There have been 74,000 scientific publications using HeLa cells and mentioning that.
In the last 10 years, most of the Nobel prizes have used HeLa cells as a part of their work,
and even our youngest scientists, of course, are using HeLa cells; and here are two examples
from the Intel Science Search and from the Siemens Competition.
So I don't think that many of us -- you know, all of us read the book, but I don't think
many of us gave much thought to what we were doing in our laboratories and the connection
to the family until March of this year when researchers in Germany posted the first whole
genome HeLa sequence in EBI, and, of course, it was mirrored in NCBI.
Fairly quickly the Twitter world lit up.
Rebecca was aware that the sequence had been published.
Rebecca Skloot, the author of the book, was aware that the sequence was posted.
She contacted the family, and the family requested that the sequence be taken down.
And, in fact, the authors agreed to have the sequence taken down, and it was taken down
quite rapidly, both from EBI and NCBI.
As we started to look into the situation, we learned that there was another publication
pending with Nature that was funded by NHGRI.
Of course, the German publication was not supported by NIH.
So there was an editorial that was published in the New York Times by Rebecca Skloot, and
in the process of generating that op ed, Rebecca reached out to her.
And I knew her from my days at Johns Hopkins at the Genetics and Public Policy Center because
she was a stringer for the Washington Post, and she wrote a very flattering article about
the Genetics and Public Policy Center soon after we launched, and we had remained in
contact ever since.
So she talked to Francis Collins and myself, and ended up including a quote from Francis
in her editorial, and during our conversations, we asked if she would connect us with the
family.
And she said she would think about that and talk to the family about it.
And that was very important for what's the rest of this story.
So in thinking about how to address the problem of what to do with the sequence that had been
taken down, and what to do with the sequence that was pending at Nature, we gave a lot
of serious consideration to how to make sure that we generated a solution that was the
right size for the problem; so not to create a solution that was ginormous and sort of
super-sized, but not also to create a solution that was too modest for the importance of
the situation.
So in generating the solution to this problem, there were a lot of people who played really,
really important roles, notably Eric, Mark Guyer, Brad, Laura, and Larry Thompson from
the Genome Institute, as well as a slew of people from NCBI who were instrumental in
working with us, and folks in the Office of the Director.
And this was also a topic of conversation among the NIH leadership on a number of occasions
with the Institute directors from across the NIH.
So we had an opportunity, with the help from folks at Johns Hopkins, to meet with the family
over a series of months, and that was a fascinating experience.
This is Francis taking a selfie -- I'd never heard of a selfie; that's how under a rock
I live -- on the day that we announced our agreement with the Lacks family at Johns Hopkins,
and standing directly next to Francis is Jeri Lacks, her brother David Lacks, and their
mother, standing there together.
There were many other members of the Lacks family who were present when we announced
our agreement.
So, on -- I can't remember the date, and I don't have my glasses, so I can't say it.
So we managed to reach an agreement, which I will talk to you a little bit about, and
also talk to you about how I think that this agreement is something that is going to be
evolving, and your input and thoughts would be really welcome.
We did manage to reach an agreement, and Jay Shendure's paper was published with the second
full human genome sequence, a commentary by Francis and I, and, at the same time, the
German sequence was reposted, but this time in dbGaP, so both Shendure sequence and the
German sequence were made available at the time of this publication.
So over the course of our time with the Lacks family -- and let me just say a couple of
words about the Lacks family.
So the Lacks family is multi-generational, and it was multi-generations that were participating
in these discussions.
They attended these meetings with me, and Francis, and a couple of folks from Hopkins
over a period of months.
Where we began with trying to just understand what the circumstance was, and then, over
time, working towards what would be the options for how we move forward, and then what were
the respective pros and cons, good, bad, and ugly, of each of those options.
There were anywhere between nine and 12 family members at any given meeting, and during the
intervening times between our meetings, they had discussions with their broader family,
and at the end of the day, they had a consensus position, which I think is a remarkable thing.
I can't reach a consensus agreement with my nuclear family about where to go to dinner.
[laughter]
So they really, you know, they are a remarkable, remarkable family.
So, elements of the agreement.
So we opted to put the two whole assembled genomes into controlled access in dbGaP, and
require that researchers apply for access in order to get to that.
And the terms for access that a researcher must agree to in order to get access is that
they will use the sequence for biomedical research only; that they won't attempt to
contact the family; that they disclose whether they have plans for intellectual property,
or to develop a commercial product or service; and that they include a commitment to include
an acknowledgement in publications and presentations.
And, in fact, I should note that Jay Shendure's paper includes such an acknowledgement, and
it's sort of the model of the first application of that -- of that policy.
So the policy also requires that future whole-genome data be deposited into dbGaP, and we already
have another submission that is in process, so that would be the third HeLa sequence that
will be in dbGaP.
In order -- so the way that dbGaP works for GWAS data, and this was a real learning experience
for me, and hat tip to Laura Rodriguez for walking me very slowly through this because
it was new; dbGaP sort of emerged after I left NIH the last time.
So, ordinarily, there's a Data Access Committee that looks over requests for access to data
sets and determines whether or not the researcher's proposal meets those criteria that were laid
out in the original consent.
In this case, there is no consent.
So what we are relying on are these conditions that were set forth by the family, and it's
important that this is a very unique circumstance, and a point that we've tried to make over
and over again about how this is not a precedent for anything.
This is an agreement that we've reached with the family to address a particular, unique
circumstance in science and ethics.
So our working group is going to operate much like a data access committee, but current
NIH data access committees are made up of NIH employees.
It became apparent to us that it would be advantageous to include members from the family
in the review process, and so that meant it couldn't be a DAC in the old-fashioned ways,
and there are legal issues in mixing feds and non-feds, so we ended up creating a working
group of the Advisory Committee to the Director, which is the highest advisory group to Francis,
and we have had advisory groups on a slew of important issues over the years.
We currently have a working group to the NIH director working on developing the scientific
plan for the BRAIN initiative.
We have now the HeLa Data Access Working Group, and they will review each of these requests
as they come in.
The requests are submitted through a dbGaP study page; so there is a parent page about
HeLa, and then there are two, soon to be three, sub-pages.
And on this page are special instructions for researchers that really lay out the requirements
that we want them to address in their data access requests, and then also information
about the data access working group, and also the mechanism of how to submit another HeLa
genome, if you have one.
So the HeLa Data Access Working Group was put together on the day that we announced
all these things that we announced.
It is chaired by Renee Jenkins, who is an adolescent medicine doc at Howard University.
Also included are folks who you certainly know: Russ Altman; Ruth Faden from Johns Hopkins,
who was involved in discussions with the family, and so she has a pre-existing relationship
with the family that I think will be really helpful; David Lacks, the grandson who you
saw in the picture with Francis; Veronica Spencer, who was a great-granddaughter from
another son of Henrietta's; and Clyde Yancy, who is a member of our advisory council.
I will just skip that, we got lots of press.
So where are we now?
We have, since August 19th, received -- actually, that says four.
We now have, over the weekend, a new one, we have five requests for access to HeLa data.
So working group is meeting for its inaugural meeting on September 12th, this week.
They will be reviewing those five data access requests, and we are optimistic that they
will be operating by consensus so that they can, as a group, send forward consensus recommendations
to provide -- to recommend to the Advisory Committee to the Director that access be granted
or not, or they can also request that there be more information solicited from the investigator.
There are a couple -- so one thing has been really important, particularly to Francis,
but I think it's been important to all of us, that this controlled access work effectively
and efficiently.
So we want to be able to not have this stand in the way of research moving forward.
And, of course, you know, as researchers, would not like to have anything slow us down
by more than about three nanoseconds, so we are trying to have this process move as quickly
as possible.
It is a new process, so this first round through, you know, we were sort of getting our sea
legs underneath us, but we -- if all works according to plan, when we move these data
access requests forward later this week, and on to the advisory committee, which meets
on September 16th, they will take action on them, and we will have finished the entire
review process in under a month.
Hopefully, we'll be able to even shorten that over time.
So one of the things that I think would be interesting to get your input on over time,
or any thoughts that you have, is what kind of data, HeLa data, needs to go into dbGaP?
We were, of course, responding to these assembled -- two assembled genomes that we knew about,
and now more, and so when we were thinking about what data goes in, we basically took
everything that was associated with the whole assembled genomes from both of the groups,
okay?
So everything that they had, we slurped it into dbGaP.
We were very candid with the family all along, and we learned lots of interesting things
about how much HeLa sequence actually exists out there, and public databases today, and
when the first sequences were around, and it's just a massive amount of data, and so
we were just very clear with the family that it would be impractical, and, frankly, impossible,
to take all that data that was already out there and put it into controlled access, because
it has already been downloaded, and published, and recycled so many times that we couldn't
really do it.
So at this moment in time, the data that's in dbGaP for HeLa is the whole assembled genomes
and sort of related sequence files.
The question moving forward is, do we expand the policy to ask that researchers generating
any HeLa sequence date also submit it to dbGaP?
And that's an issue that Francis has asked the working group to take up.
I think they probably won't take it up robustly at this first meeting because they've got
to sort of work through these initial applications for access.
But I'd be interested in thoughts that any of you have either now, or send me an email,
or give me a call.
It's going to be an issue that we're going to have to struggle with and get some resolution
for the research community in the near term.
So I think that's all I wanted to say.
Yes, it is all I wanted to say.
So I'd be happy to answer questions, or respond to comments, or whatever.
Eric Green: Okay.
Thank you, Kathy.
I'm sure there will be discussions.
So, council members or others.
Amy, we'll start with you.
Female Speaker: Thanks, Kathy.
That was very helpful.
So in coming up with -- obviously, this was a unique case, and there's with a lot of unique
sort of circumstances surrounding the case, but in coming up with this policy solution
for this case, did you guys have broader discussions about policy around the rights of relatives,
of individuals who were generating sequence data on, and either prior to their death,
after they died, and how we're going to handle that, and how we're going to create policy
that is more scalable than this solution.
Or do you see it as just unique?
Kathy Hudson: I really do see it as just unique.
So we had the conversations probably 15 years ago about consent from family members, and
what role do family members play, and I think that -- my own position is that if an individual
opts to participate in genetics research or to learn about their genome outside of a research
setting, that that decision should not be overridable by family members.
There certainly are people who have taken the approach that if you are going to be in
this genetic study, or if you're going to get this genetic information as a part of
your clinical care, that you should seriously think about how you talk to your family members
about that.
But I don't think that this circumstance -- you know, there were some erroneous representations
of what we were doing here is suggesting that family members can sort of dictate what happens
to sort of proband genetic information, and that really is not the case.
We have -- this situation has certainly fed into the department's consideration about
its revisions to the common rule more broadly, but the issue of what are the regulatory and
legal requirements for family members is really not something that we're taking up as a policy
initiative at the present time.
Eric Green: Carlos.
Carlos Bustamante: So, I want to thank you also for the presentation.
I think it's, you know, fascinating, and it's great to see the right thing get done.
Sort of following up on Amy's question, not so much focused on family members but focused
on cell lines.
So, you know, there are a large number of cell lines out there that are sort of in this
nether region where they were produced well before, say, 1,000 Genome consents and other
consents that explicitly say, look, you know, these are going to be broadly disseminated
and dot dot dot, so I'm thinking, if things are in Coriell, or other cell lines that are
out there, some of which we ourselves have sequenced, what are the thoughts there in
terms of policy?
Is it a sort of case by case, or is there a sort of -- thinking of grandfathering some
of these in?
Have you had those discussions, and if not, is there a plan to have that?
Kathy Hudson: So that's a great question.
So one of the unique features of HeLa is how widely known who she is and who her family
is, and so we have tried to look into whether or not there are other similar situations,
other similar cell lines.
And from our review, there is probably one that is not on the same scale, but where the
donor's identity is known, where the cells are widely used, and where the donor has known
or knowable progeny.
So we -- that's sort of a special case.
And then there's all the cells and specimens that are out there that have been procured
for research, either with consent being waived or used in a de-identified way.
And I think that the department is seriously thinking about how do we handle those that
we already have versus how do we handle ones that we will acquire in the future, given
that DNA analysis now makes samples so readily identifiable.
So it's something that we're thinking about.
Male Speaker: Kathy, can we back up a little bit and talk
about the data that exists for the HeLa cells, in, I think, it was in about 160 gigabases.
And then thinking forward, there's a number of large projects that are ongoing today that
are using HeLa cells, and what the criteria might be for deciding what would go into dbGaP,
or what's the working group thinking.
I know you're not, you know, a mind reader, but there are a lot of considerations about
ongoing projects.
Kathy Hudson: Yeah.
Male Speaker: And how would they be distinguished from,
for example, all the kinds of data that are already in NCBI.
Kathy Hudson: That's a great question, and it's one that
we really are just starting to ruminate about, and, you know, you guys -- this council is
in a very interesting position to be able to even just raise what are the considerations
here that we -- that the working group should know about.
You know, we did look at what data is out there already, but we haven't done a systematic
look at what are the current funded or ongoing research projects where HeLa data is sort
of embedded in those initiatives in a thorough way.
So this is really something where we're just starting to -- starting to think through the
ramifications of all of this.
Male Speaker: Maybe I missed a bit, but what is being done
to help the Lacks family interpret the available genome in terms of health or medical relevance?
Kathy Hudson: So, a couple of things.
One is that in our early discussions, and Jeri Lacks says that she felt like she was
in Genetics 101, we were in a conference room at Johns Hopkins, and there was a white board,
and low and behold, Francis was up drawing pictures.
So we -- I think a lot of our time with them was providing some of the basics about, well,
what is a genome anyway, and what can it tell you about you, and what does it mean if it's
not your genome but your parents' genome or your grandparents' or your great grandparents'
genome.
And then, as a part of that conversation, we made -- we made the family aware of ongoing
research studies in which they could obtain their own genomic information rather than
trying to divine probabilities from their great-grandmother or grandmother.
So we shared with them that could participate in some of these research studies where they
would affirmatively consent and learn this information, potentially, about themselves.
We also made available to them a genetic counselor and a medical geneticist who were provided
with data and a 60-page printout from somebody -- and I actually don't know who it was -- who
pushed the sequence, when it was up on the EBI site, pushed that sequence through SNPedia,
and had a variant readout, and so our medical geneticist and genetic counselor walked through
that data with the family, or some members of the family who were interested.
So that's sort of what we have provided.
We have offered that they can meet with those folks once again.
We've offered that they can participate in protocols like ClinSeq.
And then I think that, in an ongoing way, especially the members of the working group,
the family members on the working group, are gonna continue to be in a-- well, let me back
up.
Everybody on the working group is going to be in a learning mode here because this is
sort of uncharted territory.
David Lacks sent me an email after I sent him some materials about the working group
and about what the first meeting was going to be, and he is actively engaged in understanding
the nuances and sort of exploring this.
So I think -- I think we're enjoying that exploration process, but we are trying to
provide what we can.
And it's, you know, it's -- they got dumped into unfamiliar territory here.
So...
Eric Green: [inaudible]
Female Speaker: Thanks, again, Kathy.
I would just ask -- wanted to ask you a question about, in the list of the considerations when
they're reviewing the applications, was plans for commercial -- disclosure of commercial
plans -- could you tell us a little more about that?
I think that's really interesting, and where that's coming from.
Kathy Hudson: Yeah, so I think the family, historically,
has had the issue of, "Is somebody getting rich and we're not," has been a theme for
some members of the family forever.
And it certainly came up in the context of our discussions.
We, interestingly, between the second meeting we had with the family and the third meeting
we had with the family, we got the Supreme Court decision about the patentability of
non-manipulated genomic sequences.
And that actually helped us a lot, right?
So in trying to think through -- so the family asked us questions like, "Can you imagine
what would be immediately sort of a first order commercializable thing from the HeLa
sequence?"
And, you know, we thought long and hard about what that would be, and we were -- we came
up with a few ideas, and then we disproved our own idea.
So we didn't come up anything that was sort of obvious, but we also aren't all-knowing,
so we didn't want to say, "Absolutely nothing will come out of this that will be commercializable,"
and you'll read about it in the Wall Street Journal.
And one of the things that we have been extremely sensitive to is this family keeps on getting
surprised.
Right?
Whoops, another surprise.
So we cannot legally tell somebody who is trying to access sequence that they have to
vary their intellectual property, or give up their intellectual property, or whatever.
But they can -- we can ask them to disclose it.
And so if they disclose it, and it's known, then if the family seeks to reach out to them
and have a conversation, that's outside of our sphere.
And just knowing about it was really important to them, so we also have a requirement that
if, when you submit your application or data access request, and you say, "No, I don't
have any immediate plans," if those plans change, they're required to update it.
Female Speaker: Okay, but the implications of this -- so that
this might be grounds for no access.
Kathy Hudson: No.
Female Speaker: No?
No, okay.
Because it is interesting in the common rule -- I mean, in the informed consent documents
right now, it's often disclosing you have no commercial interest, this could be commercially
developed, so it sort of set that as the standard, contextually anyway.
Kathy Hudson: That's right.
Female Speaker: Okay.
Kathy Hudson: Yeah.
Female Speaker: Is the demarcation for the biomedical research
only that that means not ancestry research, or is there something else, just that?
Kathy Hudson: Could it be something else?
I haven't really thought about it.
But yeah, so there have been categories that have been used in dbGaP in the past, and we
sort of presented those to the family.
And ancestry was out, but there are other, based on informed consents, there are lots
of data sets in dbGaP that have much narrower data access criteria, so only breast cancer,
only this or that.
So this is actually incredibly broad.
And the working group, of course, can modify -- make recommendations for modifications
to this policy over time if it turns out that it's needed, but...
Male Speaker: Kathy, I know you don't want to try and set
precedent with this, but I'm just wondering, looking at those criteria, as we've been talking
to human genetics researchers a little bit about using dbGaP, I can -- thinking about
some of those conversations, I can hear them saying, "I would like to be able to exercise
that provision on my dbGaP data.
I'd like to be able to tell my study population that any commercial plans would be disclosed,
to me at least."
Is there any possibility or thought about -- I mean, obviously, dbGaP has its own rules
about use, but you could almost imagine a menu, a checklist, of a couple of things like
this maybe investigators could sort of put on there, their own dbGaP databases.
Is that something that's been talked about at all?
Kathy Hudson: Not directly, but there are, you know, there
are cohorts out there that have restrictions on who can access data, so I'm looking at
Teri.
Isn't it true that Framingham now has some ability of cohort participants to say that
the data can't be accessed by private sector?
Teri Manolio: There are -- actually, there are a couple
cohorts that have [inaudible].
Kathy Hudson: Yeah, yeah.
So there are things -- it's not so much that you can't commercialize it, but if you are
a commercializer, you can't get it.
So...
Eric Green: Any other questions, comments?
So, as Kathy offered, I'm sure they're interested to hear any other thoughts you have.
Send her an email, or I'm sure she'd get on the phone and talk to you.
This is still a work in progress, but -- okay, thank you, Kathy, for visiting with us.
Kathy Hudson: Yep.
Eric Green: And we're staying right on time, right?
Rudy Pozzatti: Okay, this is good, we're doing well.
So next up is Teri Manolio, who's going to give a report from the Genomic Medicine Working
Group.