HeLa is the most widely used cell line in human biology: Since 1952, HeLa cells have contributed to over 60,000 publications, including the development of the polio vaccine and research that led to two Nobel prizes. But how much do we really know about these cells?
analysis of the first full HeLa genome sequence published this week in G3: Genes, Genomes, and Genetics demonstrates that HeLa cells have a chaotic combination of gene duplications and chromosomal rearrangements (1). The HeLa genome includes chromosomes that have been shattered and then haphazardly pieced back together, genes with five or more copies apiece, and aberrant gene expression pathways that differ dramatically from normal human tissues. These findings could have a profound impact on how HeLa cells are used in the laboratory, the authors say.
Scientists have long known that fast-dividing, hardy HeLa cells are not normal, “but nobody had sequenced the genome to figure out, at nucleotide resolution, where the rearrangements are in this genome,” said Lars Steinmetz of the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, who led the project. “I was really struck by how abnormal these cells are.”
Despite the cells’ extensive use, the HeLa genome had not been previously sequenced. Now, decreasing sequencing costs make it possible to do so. Steinmetz and his team at EMBL sequenced both DNA and RNA—1.1 billion DNA reads, each 101 base pairs in length, and 450 million RNA sequences—from the HeLa Kyoto cell line.
Analyzing the genome, the team was surprised to see a dramatic phenomenon called chromosome shattering, in which chromosomes appear to have broken apart then reassembled with countless regions inverted or in the wrong order. Chromosome shattering is a recently described phenomenon that is associated with 2-3% of all cancers. In this instance, it was likely original to the source of the HeLa cells, Henrietta Lacks’ cervical tumor.
Other HeLa characteristics probably evolved as the cells adapted over decades to life in the lab. Through RNA analysis, the team found that HeLa gene expression is dramatically different from gene expression in normal human tissues. Cell cycle and DNA repair pathways are upregulated, which would be expected for rapidly dividing cells, while genes associated with the immune system and environmental sensing are downregulated, which would be expected for cells adapted to an isolated, nutrient-rich lab setting.
“We’re using these cells as our workhorse to study human biology,” said Steinmetz, “and if we have these genomic rearrangements, that’s clearly going to have some impact on the interpretation of gene function that we’re carrying out.”
Steinmetz sequenced the HeLa genome with the intention of using the cells to study human heterozygous alleles, but that would only work well if there were two alleles of each gene, not up to six alleles as he found in the HeLa genome. “For that experiment, HeLa is not a good system, and we didn’t proceed with that,” he said.
For experiments in which genomic abnormalities don’t matter and scientists just need a lot of biological material quickly, HeLa cells are still suitable. But for genetic studies, the researcher must decide if HeLa cells are an appropriate model for addressing the research problem at hand. If that is the case, scientists can now use the HeLa genome rather than the Human Genome Project reference genome as a basis to better interpret experiments.
1. Landry, J., et al. 2013. The genomic and transcriptomic landscape of a HeLa cell line. G3, doi: 10.1534/g3.113.005777.