Thursday, April 20, 2017

Time to Retire HeLa?

A TV movie produced by and starring American culture mogul Oprah Winfrey is about to hit screens which dramatizes Rebecca Skloot's The Immortal Life of Henrietta Lacks.  If you haven't read this remarkable book, you really should.  It should certainly be required reading for anyone entering biomedical fields.  That's not to claim it is perfect; one of Lacks' sons has objected to the way his family is portrayed.  But it is a searing human story of how the most famous cell line in the world came to be.  Even if you excuse some of the injustices done as compatible with then contemporary ethical standards, it is a thought-provoking piece on the topic of what our biomedical ethics should be.
However, I'm not going to discuss ethics here; I don't feel properly-armed. What I am going to propose is that much of the continued use of HeLa doesn't make sense and that biomedical researchers should start thinking hard about abandoning this cell line.  

The core of my argument is that we are in an age of precision oncology, and using HeLa makes no scientific sense in that world.  Now, the day of untargeted cytotoxics is hardly over and I won't claim I'd reject out-of-hand the opportunity to work on a candidate drug that had that mode-of-action, but the mindshare in oncology has decisively shifted to targeting specific pathways and mutations. 

In that context, HeLa has multiple liabilities.  HeLa is derived from a cervical cancer, a relatively rare cancer type due to successful screening and now human papilloma virus (HPV) vaccines.  That doesn't mean we've conquered cervical cancer; an appalling number of women still suffer and die from this disease -- estimated incidence of 12.2K new cases per year in the U.S. and 4.2K deaths.  But given that cervical cancer may be 100% caused by specific HPV subtypes, improving screening and vaccines would likely be a better route to driving cervical cancer towards extinction. Such research is also likely to have broader impact, given that HPV infections may be at the root of growing oral cancer rates in young adults. 

Now, at times a purely pathway-oriented view of cancer has been entertained, with tissue-of-origin receiving little or no weight.  I think that this view isn't very popular, as the tissue-of-origin context greatly influences the impact of oncogenes.  Even if we ignore tissue-of-origin, a key part of HeLa's oncogenic transformation were the HPV oncogenes.  So in a precision oncology sense, lessons learned in HeLa are unlikely to shed light on other tumors.

But worse, is there really a distinct entity called HeLa?  All cancer cell lines exhibit variability, but HeLa has a strong reputation.  Indeed, one of my colleagues remarked that HeLa cultures at two ends of the same building might not resemble each other.  I can believe that; the ATCC page for their HeLa line lists the karyotype as "modal number = 82; range = 70 to 164"!!! 

In general, the idea that cancer cell lines are genetically homogeneous and stable is an awful lie we tell ourselves.  I've seen this first hand, trying to exome sequence multiple lines of the same cancer cell line and discovering that each branch had scores of mutations absent from other branches.  So we must acknowledge that cancer cell line studies are inherently have a dubious potential to be repeatable between labs.  But if we are going to have any chance, something as variable as HeLa seems like a poor bet.

This variability undermines a standard rationale for not changing in science: we have a lot of data with the old system.  If the system is fundamentally flawed, then that data isn't really comparable or particularly useful.

Now, some HeLa research appears to simply use it as a model system in its own right or as a source of proteins for proteomics research.  The notoriously fast-growing phenotype of HeLa, which has helped it contaminate and take over numerous other cell lines, is a positive advantage for such work.  That's harder to argue against; if the results are very general then they could be useful.

The final argument I'll advance against HeLa in cancer research is the fact that it has been in culture so long.  HeLa should be seen as something like a bizarre new species found only in laboratories, not a representative of human cancer.  All that time in culture has certainly enabled HeLa (or all the different HeLa) to evolve far away from the tumor which killed Henrietta Lacks.  Again, this is a flaw in all in vitro propagated cell line studies, but given that HeLa is the oldest it is likely the most affected (granted, what we'd really like to know is actual time in culture).  Patient-derived xenografts are far more likely to be informative of tumors, but their expense and newness has meant they haven't yet fully displaced in vitro lines from research programs.

HeLa was a remarkable milestone in biomedical research, though tainted by the questionable means by which it was obtained. HeLa has contributed to advancing human health in the past, but science has moved into new realms and gained new sophistication.  It's long past time to examine when and whether HeLa still makes sense in modern biomedical research.     


Mike said...

Disagree with the message here. The disadvantages the author describes are characteristic of all cancer cell lines (as he acknowledges himself?). The argument in support of patient-derived xenografts makes sense in that these models are developed from human tumor material and implanted into animals. Unfortunately, even patient derived xenografts are models and do not fully recapitulate the disease in the clinic and show phenotypic and genotypic drift over time. Pre-clinical models are not perfect, this doesn't mean they are not valuable. Biology and Medicine have been absolutely transformed by the ability to grow cells in vitro in the lab. This was not possible a shockingly short time ago and HeLa played an essential role in developing the methods required.

With regards to ethics, we should take the experience of Henrietta Lacks and her family as a lesson to improve patient rights. This does not in any way diminish the scientific value of cell lines. We should also take this story as motivation to improve the quality of scientific education in American society.

Anonymous said...

@Mike, Keith's argument here was not against cell lines in general, but specifically against one particular cell line that may have outlived its usefulness as a model.

I've not seen much use of HeLa as a model lately (though I've not been looking). It seems to be more popular as an expression system, which Keith acknowledges is still a viable application for the cell line.