 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 Geyer and a couple others were quite involved on a regular basis on phone calls with Kathy as she used us as partners, but as advisors and helped navigate what was a much more complicated course 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 the writing, was fantastic in the end and if you haven't read that, you really should. But I'm 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. Thanks, Eric, for the invitation and it's nice to be here with you all with some friendly, familiar faces around the table in the back of the room. Thanks very much. So, this has been an interesting story to be a part of over the last several months. I'll start with, uh-oh. Just a question anywhere on your feet. 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 the 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 Guy at Hopkins was able to get the Heal a 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 Guy. And it was written by Howard Jones, who was otherwise known to many of you as the father of IVF. In 1976, Victor McCusick, 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 Heala. And so if you get any cell line near Heala, Heala takes over. And so Victor McCusick 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 families, 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 Immortal Life of Henrietta Lacks. So it's very, very, very widely known. So if you do a Google search today for Heala, you'll generate two and a half million results. There have been 74,000 scientific publications using Heala cells and mentioning that. In the last ten years most of the Nobel Prizes have used Heala cells as a part of their work and even our youngest scientists of course are using Heala 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, 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 Heala 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 Sklut, 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 a editorial that was published in the New York Times by Rebecca Sklut. 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 the 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 supersized, 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 Geyer, 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 had never heard of a selfie. That's how under a rock I live of on the day that we announced our agreement with the Lax family at Johns Hopkins and standing directly next to Francis' Jerry Lax, her brother David Lax, and their mother standing there together. There were many other members of the Lax 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 this agreement is something that's going to be evolving and your input and thoughts would be really welcome. We did manage to reach an agreement and Jay Chinduri'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 the Chinduri sequence and the German sequence were made available at the time of this publication. So over the course of our time with the Lax family, and let me just say a couple words about the Lax family. So the Lax 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. So they really, 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 D.B. Gap 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 Jason Dury's paper includes such an acknowledgement and sort of the model of the first application of that policy. So the policy also requires that future whole genome data be deposited into D.B. Gap and we already have another submission that is in process. So that would be the third HeLa sequence that will be in D.B. Gap. In order, so the way that D.B. Gap 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 D.B. Gap 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-fed. 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 Hila Data Access Working Group. And they will review each of these requests as they come in. The requests are submitted through a DB GAP study page. So there is a parent page about Hila. And then there are now 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 request. And then also information about the Data Access Working Group and also the mechanism of how to submit another Hila genome if you have one. So the Hila 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 our folks who you certainly know, Russ Altman. Ruth Faden from Johns Hopkins, who was involved in the discussions with the family. And so she has a preexisting 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 is a great granddaughter from another son of Henrietta's. And Clyde Yancey, who is a member of our advisory council. I'll 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 Hila data. The 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 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 that has been really important, particularly to Francis, but I think it's important to all of us, that this controlled access work effectively and efficiently. So we wanna be able to not have this stand in the way of research moving forward. And of course, as researchers, we would like to not have anything slow us down by more than about three nanoseconds. So we're trying to have this process move as quickly as possible. It is a new process, so this first round through, 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. 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 overtime 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 genome 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 in public databases today and when the first sequences were around and it's just a massive amount of data. And so we were 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 been downloaded and published and recycled so many times that we really couldn't 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 data also submitted 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. 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. Okay, thank you, Kathy. I'm sure there'll be discussion. So council members or others, Amy, start with you. Thanks, Kathy. That was very helpful. So in coming up with, obviously this was a unique case and there's 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 die and how we're going to handle that and how we're going to create policy that's more scalable than this solution? Or do you see this as just unique? 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 overriding by family members. There certainly are people who have taken the approach that if you're 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, 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 pro bands genetic information and that really is not the case. We have, this situation has certainly fed into the department's considerations 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. Carlos. So I want to thank you also for the presentation. I think it's 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 there are a large number of cell lines out there that are sort of in this other region where they were produced well before say thousand genomes consents and other consents that explicitly say, look, these are going to be broadly disseminated and dot, dot, dot. So I'm thinking things that are in Corielle 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 sort of thinking of grandfathering some of these in, have you had those discussions and if not, is there a plan to have that? So that's a great question. So one of the unique features of Hila 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 then 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 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's 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. Kathy, can we back up a little bit and talk about the data that exists for the Hila cells in, I think it was about 160 gigabases. And then thinking forward, there's a number of large projects that are ongoing today that are using Hila 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 a mind reader, but there are a lot of considerations about ongoing projects. How would they be distinguished from, for example, all the kinds of data that are already in NCBI? That's a great question. And it's one that we really are just starting to ruminate about. And this council is in a very interesting position to be able to even just raise what are the considerations here that the working group should know about. 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 Hila data is sort of embedded in those initiatives in a thorough way. So this is really something where we're just starting to think through the ramifications of all of this. Maybe I missed it, but what is being done to help the Lax family interpret the available genome in terms of health or medical relevance? So a couple of things. One is that in our early discussions, and Jerry Lax says that she felt like she was in genetics 101, we were in a conference room at Johns Hopkins and there was a whiteboard and, lo and behold, Francis was up drawing pictures. So 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 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 they 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 in 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 SNPEDA 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've offered that they can meet with those folks 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 going to continue to be in a... Well, let me back up. Everybody in the working group is going to be in a learning mode here because this is sort of uncharted territory. David Lax 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 we're enjoying that exploration process, but we are trying to provide what we can. It's, you know, they got dumped into unfamiliar territory here. So... Karen? I was just going 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 bit more about that? I think that's really interesting and where that's coming from. 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 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 asks 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 ideas. So we didn't come up with anything that was sort of obvious, but we also aren't all knowing. And 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 that this family keeps on getting surprised, right? Whoops, another surprise. So we cannot legally tell somebody who's 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 your data access request and you say, no, I don't have any immediate plans, if those plans change, they're required to update it. Okay, but the implications of this are this might be grounds for no access. No, 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 we've sort of set that as a standard in contextually anyway. That's right, okay, yeah. Is the demarcation for the biomedical research only that that means not ancestry research, or is there something else? Just that. Could it be something else I haven't really thought about. But yes, 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 what make recommendations for modifications to this policy over time if it turns out that that's needed. But... 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 that maybe investigators could sort of put on their own DbGaP databases. Is that something that's been talked about at all? Not directly, but there are cohorts out there that have restrictions on who can access data. So, I'm looking at Terry. 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? Yeah. Yeah, yeah. So there are things, it's not so much you can't commercialize it, but if you are a commercializer, you can't get it. So... 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's going to the phone and talk to you. This is still a work in progress, but... Okay, thank you, Kathy, for visiting with us. And we're staying right on time. This is great. Right. And we're doing well. So next up is Terry Manlioz, going to give a report from the Genomic Medicine Working Group.