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Andrew Adey

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The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line.
Aug 08, 2013   Nature
Adey A, Burton JN, Kitzman JO, Hiatt JB, Lewis AP, Martin BK, Qiu R, Lee C, Shendure J


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My HeLa Story

Sep 04, 2013
Way back when I was just a fledgling graduate student, even before the NYT bestseller The Immortal Life of Henrietta Lacks by Rebecca Skloot, I proposed to my PI the idea of sequencing the genome of HeLa cells. At the time all I knew was that they were ubiquitous, fast growing and robust enough that a post doc in my undergraduate lab taught cell culture techniques to me with them, stating “don’t worry – you can’t screw up with HeLa”. Years later I can say with confidence that I am no longer that fledgling graduate student – and have spent more time studying HeLa than I ever would have imagined.

At the time I first proposed the project, we agreed that it would not be all that useful to have simple shotgun sequencing, which only provides a basic level of information. It wasn’t until after we had published a haplotype-resolved diploid genome using a fosmid-clone pool approach developed in the lab ( see Kitzman et. al. 2011, in Nature Biotechnology) that we decided to go full force on the HeLa genome. We decided to not just sequence it – but throw the kitchen sink at it and provide the first haplotype-resolved cancer genome that is hopefully worthy of the first and most widely used immortal human cell line of all time.

In short order we had already generated deep shotgun sequencing data, fosmid pool data for haplotype resolution, several levels of mate-pair sequence data for structural rearrangement identification, and downloaded >100 sequence files from the ENCODE project to reanalyze in the context of haplotype. I am not going to go into detail on all of the findings of the paper – you can read it for that. Though I will say my favorite story is Fig. 2 in the paper – the complex rearrangements involved in the HPV integration into the HeLa genome and being able to use that and the sequencing we did of 9 other HeLa strains to piece together the progression of events that happened during tumorigenesis and the establishment and passaging of the cell line.

Figure 2: HeLa HPV integration locus.

Once we were feeling pretty good about the paper – it was submission time, not just of the manuscript, but the data. It was not until this point that we realized "hey… this sample is not de-identified … Should we submit to dbGaP? " (dbGaP is a controlled access server, and is ultimately where the data ended up). However, dbGaP requires consent, which could not be obtained, so we started setting up to submit to the open-access server (SRA) – where a large amount of previous HeLa data is posted and at the time was compliant with NIH policy. We also made plans to contact the family via Rebecca Skloot at some point after acceptance, likely through the editors of the journal.

After submission to Nature on Nov. 28th 2013 we got reviews back a few weeks later and then began revisions where the supplement went from less than 20 to just under 100 pages. My PI’s philosophy is to do every experiment/test the reviewers ask for and then some. After a roughly one month turnaround working nearly around the clock and then a two week re-review it was provisionally accepted! We just had to get the word count down a bit, and had it back to Nature a few days later. All the while we were scanning the internet for any evidence of possibly getting scooped (I had presented the project at a couple conferences) when we found an accession on the EMBL site referred to as the HeLa genome.

Panic set in.

Was Nature going to cancel the provisional acceptance if another paper came out?

Two days after our final version was in we got the official acceptance from Nature in the morning of March 11th. That same day the G3 paper (Landry et. al. 2013, G3) came out on shotgun sequencing the HeLa genome of a different strain than the 10 that we analyzed.

Was it dumb luck that ours was accepted just before? I don’t think I will ever know.

About a week or so after the G3 paper came out, the internet exploded with attacks on the EMBL group for not acquiring consent from the Lacks family prior to releasing the genome. This even included a NYT commentary by Rebecca Skloot entitled The Immortal Life of Henrietta Lacks: The Sequel. I am not going to comment on the arguments that went back and forth on Twitter and blogging websites, but it is certainly quite a read. Shortly after, the data was pulled from the EMBL site. We were then contacted by the NIH regarding our work on the HeLa genome asked to delay publication until new NIH policies were put in place, which we were more than happy to do – we agree that new policies should be in place for HeLa where the identity is so widely known, and consent was not given. Over the next five months NIH director Dr. Francis Collins and deputy director Dr. Kathy Hudson engaged in talks with the Lacks family – we were updated here and there – mainly due to those working at the NIH asking for specific details about our study. I have to say – I am thoroughly impressed with how fast the NIH acted towards finding a responsible path forward with the Lacks family. It was a mere two weeks after the G3 paper that first meeting with the family occurred. The NIH clearly made this a top priority.

The Lacks family has expressed that they are proud of the contribution of Henrietta’s cells to the medical field and to science as a whole. After discussions with the NIH, the decision was made to have two of the Lacks family members on a board that controls access of the genetic information – not to limit accessibility to researchers, but to prevent use of the information in any unethical way.

After the decision was made, the NIH, Nature, and our group coordinated fast to get the paper published along with a companion piece in the same issue by Dr. Collins and Dr. Hudson describing the talks with the family. We also added to our paper an acknowledgement to Henrietta and the Lacks family that will now be included in every paper using HeLa genetic information:

"The genome sequence described in this paper was derived from a HeLa cell line. Henrietta Lacks, and the HeLa cell line that was established from her tumour cells in 1951, have made significant contributions to scientific progress and advances in human health. We are grateful to Henrietta Lacks, now deceased, and to her surviving family members for their contributions to biomedical research."

The sheer number of scientific advancements that were made possible by or utilized HeLa cells is astonishing. When I started this project the number of PubMed hits for “HeLa” was ~68,000, now around three years later it is over 76,000. It is really an honor to be an author on one of the first papers to officially acknowledge to officially acknowledge Henrietta and the Lacks family. I am in no way taking credit for this - that belongs to the NIH for getting the policies in place. I also believe that any scientist that has used HeLa cells in their research agrees that the recognition and public gratitude from the scientific community is long overdue. I think this new policy and the official acknowledgement is a fitting end to the most recent chapter in the HeLa story that has been ongoing for over 60 years – a chapter that I played a part of in my own small way.

Andrew Adey in the lab.

A bit more on the science:
I just want to comment/speculate on one thing I think is extremely cool that we did not discuss in the paper since we did not want to overstate the findings. Keep in mind – this is speculative and based on what I think makes the most sense. Do not take this as something I am claiming as an actual finding of the study.
Using the information we gathered from the study, specifically:
    1. The HPV integration is highly complex and thus not likely to occur in the same configuration more than once.
    2. The complex rearrangement is identical on three copies of the same haplotype.
    3. The marker chromosomes (chromosome fusions / translocations) have well defined breakpoints shared across multiple different HeLa strains.

We can piece together the most parsimonious ordering of events in the genomic history through tumorigenesis / cell line establishment.
    1. HPV infection.
    2. HPV integration into 8q24.21 in a complex and highly duplicated way with local genome instability at the locus.
    3. Stabilization of the HPV integration locus.
    4. Aneuploidy (since there are 3 identical copies of the complex rearrangement it most likely occurred after 8q24.21 stabilization) and global genome structural instability resulting in a large set of marker chromosomes
    5. Stabilization (either during tumorigenesis or cell line establishment)
    6. Multiple different strains established containing different founding populations of marker chromosomes.
    7. Marker chromosome copy number drift during passaging (but not likely genome instability)

I just think this story is pretty cool. Again, it is based on my own interpretation of the data based on what makes sense to me and is not an actual finding that we reported.
Copyright: © 2013 Andrew Adey. The above content is licensed under the Creative Commons Attribution License (CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.  
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