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HeLa, a human bauplan in the Petri dish

Scientists from EMBL have recently sequenced the genome of HeLa cells, which are the world’s most commonly used human cell line. They found that the HeLa genome and that of normal human cells reveal striking differences, caused by chromothripsis and other aberrations. Some evolutionary researchers believe that HeLa cells are developing a new human bauplan as they adapt to cultivation in the Petri dish.

Henrietta Lacks (1920-1951); more than 60 years after her death, her cells still survive in many laboratories around the world. © The Baltimore Sun

HeLa cells originate from a particularly aggressive cervical cancer tumour taken from an American patient called Henrietta Lacks in 1951, who then died of the cancer eight months later. However, her cancer cells still survive in many laboratories around the world. HeLa cells are the first human cell type to be successfully cultivated in the laboratory and have since become the most common and widely used human cell line in biology. For many decades, HeLa cells have provided effective and easily usable biological models for researching human biology and disease. More than 60,000 papers have been published about research done on HeLa cells. Amongst other things, HeLa cells were used by Jonas Salk to test the first Polio vaccine in the 1950s, and they also played a key role in Harald zur Hausen’s identification of papillomaviruses as the cause of cervical cancer for which he was awarded the Nobel Prize in Physiology or Medicine in 2008. The function of chromosome telomers and the enzyme telomerase (Nobel Prize in Physiology or Medicine awarded to Elizabeth Blackburn, Carol Grieder and Jack Szostak in 2011) was also discovered using HeLa cells. The cells are popular systems both in academic and industrial research and are widely regarded as the ‘industry standard’ tool for studying human biology. Modern molecular genetic studies using HeLa cells are typically designed and analysed using the Human Genome Project reference.

Havoc in the HeLa genome

Dr. Lars Steinmetz, Joint Head of Unit and Senior Scientist, Genome Biology, EMBL. © EMBL

It has long been known that the genetic composition of cancer cells differs significantly from that of normal human cells. And this is even more true for HeLa cells, which are characterised by numerous chromosome duplications and other aberrations. In addition, over time the cells have acquired many mutations, which have led to the emergence of numerous sub-cell lines that are extremely different from one another. However, the extensive differences have only recently become obvious when scientists from the European Molecular Biology Laboratory (EMBL) in Heidelberg announced that they had successfully sequenced the genome of a HeLa cell line. The study, which was published in March 2013, provides a high-resolution reference that reveals the striking differences between the HeLa genome and that of normal cells, and “underscores the importance of accounting for the abnormal characteristics of HeLa cells in experimental design and analysis,” said Lars Steinmetz from EMBL, who led the project. The results have the potential to refine the use of HeLa cells as a model of human biology.

The EMBL scientists were also quite surprised about the genetic complexity of the HeLa cells in comparison with the Human Genome Project reference. The HeLa genome revealed abnormalities in the number and structure of chromosomes; they found extra chromosome copies (aneuplody) and many chromosome regions were arranged in the wrong order or completely lacking. They also found extra or fewer copies of genes. These comprehensive genomic rearrangements are a telltale sign of chromosome shattering, a recently discovered phenomenon associated with 2-3% of all cancers and known as chromothripsis (see link in top right-hand corner: "Genomic structural variations can cause cancer"). In addition to the DNA sequence, Steinmetz and his team have also analysed the gene expression profile of the HeLa cells and found that the expression of several important signalling pathways, including cell cycle and DNA repair signalling pathways, differed considerably from that of normal human cells.

HeLa cells in cell culture; photo taken with a phase contrast microscope © Wellcome Trust

Steinmetz pointed out that his team’s analyses do not allow conclusions to be drawn on the genome of Henrietta Lacks or on the tumour that led to her death. This is because 1) the EMBL researchers analysed a HeLa cell subtype that had spent decades in labs, dividing and thus undergoing mutations and changes. It can be safely assumed that current HeLa cells are very different from the original cells that started growing in 1951. 2) Like all cancers, cervical cancer is a disease of the genome. Without genetic information about the original tumour (which is not available) it is impossible to tell which parts of the sequence are derived from Mrs Lacks, her tumour or which parts have developed over time in the laboratory. The purpose of the current study is to provide researchers using HeLa cells with a more suitable basis for their experiments than that provided by the Human Genome Project DNA sequences.

A species adapted to laboratory conditions?

Canine transmissible venereal tumour (CTVT) or Sticker's sarcoma cells. © GNU-Lizenz Joel Mills 2007

In 1991, Leigh Van Valen, a famous American evolutionary theoretician, proposed that HeLa cells should be defined as a new species – a single cell, albeit derived from a human individual had adapted to cell culture conditions and accumulated mutations over time. Claiming that HeLa cells were no longer human but rather an own species, he even gave HeLa a scientific name (Helacyton gartleri), which, however, has hardly ever been used. Van Valen substantiated his bizarre hypothesis with the following argument: there is chromosomal incompatibility between HeLa cells and humans, which means that the HeLa karyotype differs from that of normal human cells. Although this karyotype is flexible and variable, it nevertheless remains stable within certain borders. HeLa cells have their own, defined ecological niche. The cells are even able to maintain and spread beyond the borders of their human breeders and seem to be potentially immortal. Van Valen referred to cases of researchers who, in the belief that they were carrying out research with specific cell lines, eventually found out that their cell lines were contaminated with HeLa cells.

Although Van Valen’s view remained unaccepted and was either refuted or ignored by the majority of biologists, it is not as absurd as some might think. For evolutionary biologists, HeLa is not the first case of a completely different bauplan that developed under extreme environmental conditions (see text box).

The majority of cases related to a dramatically altered bauplan or blueprint within a well-defined group of organisms or species can be seen as an adaptation to parasitic lifestyles or cancerous tumours. The best known example of this is probably Rhizocephala, barnacles that parasitise decapod crustaceans. Their bauplan is reduced in an extreme adaptation to their parasitic lifestyle. Darwin also focused at length on Rhizocephala. They belong to the Cirripedia class and are relatives of free-living barnacles, i.e. parasites that form a network of thread-like extensions that penetrate the body of the host (crabs).  

Another example, which is more similar to HeLa than the barnacles, is Sticker sarcoma, also known as ‘canine transmissible venereal tumour’ (CTVT). CTVT is an infectious cancer of dogs, which mainly affects the genitalia and is transmitted from animal to animal during copulation or from biting and licking the tumorous sites. Infection is not due to the transmission of infectious agents such as human papillomaviruses (HPV), which lead to the transformation of host cells, thereby leading to cervical cancer. In the case of CTVT, the cancer cells themselves are the infectious agents and the tumours are not genetically related to the host. Genetic analyses of diseased, unrelated dogs from different continents have shown that all cancer cells are almost identical and of clonal origin: they originate from a single dog cell that transformed into a cancer cell line several hundreds of years ago and has since spread across the entire globe as the canine cancer cell line. Another known transmissible cancer is devil facial tumour disease (DFTD), a cancer which occurs in Tasmanian devils. In this case too the cancer cells are spread by the Tasmanian devils biting each other’s heads when fighting. The disease was described for the first time in Australia in 1996 and has since spread extremely rapidly, endangering the remaining population of the largest living carnivorous marsupial.

Although it is difficult to prove, one can nevertheless assume that the aggressiveness of the tumour that led to the early death of Henrietta Lacks is also related to the unbroken vitality of HeLa cells, which have gone through thousands of cell divisions ever since the cells began to be cultured. This makes them similar to another popular cell line, the CHO cells (Chinese hamster ovary cells), without which modern biopharmaceutical production would be impossible. The CHO cells used in pharmaceutical industry laboratories around the world originate from cells taken from the ovary of a Chinese hamster female in 1957 (see link in top right-hand corner: "Cell culture technology: hamster cells and the production of biopharmaceuticals"). The genomes of the hamster and of the CHO cells have not yet been sequenced, but it can be safely assumed that it will not be long before this happens. Then, the comparison between the CHO and HeLa genomes might provide information on the likely causes of this exceptional vitality.

 

Publication:
Landry J, Pyl PT, Rausch T, Zichner T, Tekkedil MM, Stütz AM, Jauch A, Aiyar RS, Pau G, Delhomme N, Gagneur J, Korbel JO, Huber W, Steinmetz LM: The genomic and transcriptomic landscape of a HeLa cell line. G3: Genes, Genomes, Genetics, advance online publication 11th March 2013 – DOI: 10.1534/g3.113005777

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