HeLa Cells 50 Years On: The Good, The

Bad and The Ugly

John R. Masters

HeLa cells — the first continuous cancer cell line — have been a mainstay of cancer
research ever since their isolation from the aggressive glandular cervical cancer of a young
woman more than 50 years ago. Knowledge of almost every process that occurs in human cells
has been obtained using HeLa cells and the many other cell lines that have since been isolated.
So why does fraud an ignorance surround the use of these and other human cancer cell lines?

Fifty years ago, there was intense competition among cancer-research scientists for their
laboratory to be the first to develop ‗human cancer in a test tube‘. Rodent cancers had been
cultured for many years by Warren Lewis, without any appreciable change in their appearance1.
But, despite thousands of attempts, nobody had grown human cells in the laboratory for more
than a few weeks. Tissue culture was nearly 50 years old 2–4 and permanent cultures of animal
cells had been established 5, so surely it was possible?

The breakthrough came on 8 February 1951 at The Johns Hopkins Hospital in

Baltimore, Maryland. George Gey (FIG. 1) was given a small sample and took it back to his
laboratory. It was not a tissue-culture laboratory as we know it today. There were no laminar-
flow cabinets or bottles of sterile culture media and sera. Tissue culture was done on the open
bench, with the help of a bunsen burner to give a small window
of relatively sterile air, using materials collected and prepared on an almost daily basis. Before
starting work in the laboratory, a trip to the slaughterhouse was needed in order to obtain plasma
— taken by plunging a needle into a chicken‘s heart.

A visit to the abattoir was next, as calf embryos were collected, which could later be
homogenized for extract. Finally, a trip to the labour ward was made, to suck off human
placental blood from umbilical cords. This gruesome mixture of ingredients was collected for the
human cancer to feed on, and this time — for George Gey — it worked 6-7.

The cancer sample came from the cervix of a young black lady called Henrietta Lacks, a
30-year-old mother of five living on New Pittsburgh Avenue in Baltimore. Cervical cancer is
normally slow growing, and most patients survive for at least five years after diagnosis. But this
was not an ordinary cancer, according to the gynaecologist Howard Jones. It was purple and soft,
and he had never seen anything like it before (or since,
according to a television interview screened in the United Kingdom in 1997). It did not respond
to radiotherapy and was subsequently shown ‗without a doubt‘ to be a glandular cancer — a rare
adenocarcinoma 8 — and not the usual epidermoid cancer of the cervix, as the original
publication on HeLa 6 incorrectly described it.

On 4 October 1951, eight months after her cancer was diagnosed, Henrietta Lacks died,
leaving her husband, David, a widower, and her children motherless. The autopsy report stated
that her abdomen was filled with cancer deposits.
 PERSPECTIVES

To cancer research, HeLa is the equivalent of the goose that laid the golden egg — a
constant supply of a precious and essential resource. Within a few years, HeLa cells had been
distributed worldwide and became the laboratory model of the cancer cell that would be used for
much of cancer research. But they are not just used for cancer research — HeLa cells are used
throughout biomedical research to study the biochemical pathways of normal and diseased tissue
in human cells. Although thousands of continuous cell lines from almost every type of human
cancer have since been established — mainly in the 1970s and 1980s 9 — HeLa is still the most
widely used human cancer cell line. What was special about the cancer from which HeLa cells
were grown? Generally, the human cancers that grow permanently in culture are a selected group
of very aggressive cancers that have acquired the necessary phenotypic and genotypic changes 10.
Almost all of the continuous cell lines are derived from high-grade, high-stage cancers. It is
possible to grow some less aggressive cancers permanently, but very few scientists have had the
patience, tenacity or skills to overcome the technical hurdles 11. A short cut is to immortalize the
cells with viral genes, the products of which bind and inhibit key proteins such as p53 and
retinoblastoma (RB). So why do normal human cells usually senesce and die, rather than undergo
spontaneous transformation in vitro to produce permanent cultures, as normal rodent cells so
often do? One possibility is that the difference is related to the higher capacity of human cells for
DNA repair 12.

Why was ‗human cancer in a test tube‘ such an important goal? With cell lines, it is
possible to go back to the same cancer again and again, bladder was almost entirely replaced with
the tumour. By this time, her cancer was also growing like wildfire in the laboratory. The cell line
was called HeLa, taken from the first two letters of Henrietta Lacks‘ names.

The failure to preserve complete anonymity was regrettable, but, to give a measure of
confidentiality, the donor was said to be Helen Lane or Helen Larson. It was not customary then
to ask for written permission to obtain such samples for research purposes, and there is no
record that Henrietta Lacks consented to the use of her cells. Attitudes were different then —
prison inmates were shown on television being injected with HeLa cells, proud that they were
repaying some of their debt to society (The Way of All Flesh, BBC TV documentary screened on
19 March 1997 in the United Kingdom).

When Mrs Lacks‘ children eventually discovered — more than 20 years later — what had
happened to her tissue, they were shocked that cells from their mother had been distributed
worldwide and no one had ever sought their views or permission. The requirement today for
documented patient consent for research samples is, in part, a consequence of the HeLa cell
story.

The Good

Fifty years ago, the HeLa cell was seen as a great breakthrough, and possibly even the key
to a cure for human cancer. The war on cancer and the worldwide hunt for the virus that was
believed by some scientists to cause human cancer was soon to follow. Our knowledge of every
fundamental process that occurs in human cells — whether normal or abnormal — has
depended to a large extent on using HeLa and other cell lines as a model system. Much of what
we know today, and much of what we do tomorrow, depends on the supply of HeLa and other
cell lines.
George Gey was a brilliant and highly respected scientist. By 1951, he had been growing
cells for nearly 30 years, and until 1937 had worked with Warren Lewis. He was the first to show
in vitro transformation; he also made some of the first phase-microscope time-lapse films of
living cells and developed roller tubes for culturing cells. His goal was to cure cancer, and he did
not take time out to write papers. Crucially — for the success of HeLa cells — his wife Margaret
was the chief technician and ‗the meticulous director of day-to-day operations in the laboratory‘.

TIMELINE

1907 -- Ross G. Harrison develops the ‗hanging drop culture‘ to study frog nerve-cell growth.
1910 -- Montrose T. Burrows and Alexis Carrel grow chick embryo cells in tissue culture.
1940 -- Wilton R. Earle and George Gey generate a rodent continuous cell line.
1951 -- Klaus H. Rothfels and colleagues show interspecies cross-contamination.
1958 -- George and Margaret Gey and Mary Kubicek develop HeLa, the first human cancer
continuous cell line.
1967 -- Walter Nelson-Rees shows widespread HeLa cross-contamination.
1974 -- Cross-contaminated cell lines are used at record levels.
1990 -- Dennis Gilbert, Stephen O‘Brien and colleagues apply multilocus DNA fingerprinting to
cell-line authentication.
2002 -- Stan Gartler shows intraspecies cross-contamination.

Timeline | The development of human cancer cell lines

Figure 1 | George Gey. Courtesy of Alan Mason
Chesney Medical Archives.

PERSPECTIVES

The Bad

Once George Gey had shown that it was possible to culture human cancers, everyone
was able to do it. Suddenly, not only human cancers could be cultured, but also normal human
cells became ‗spontaneously transformed‘ and proliferated at great speed in the laboratory. The
number of cells could double about every 24 hours, and soon this was happening in biomedical
laboratories worldwide.

But of course it was not that easy to establish a cell line from a human cancer — it
remains very difficult to this day for most types of cancer — and normal human cells almost
never spontaneously transform. It soon became clear that many of the cell lines were not what
they were claimed to be. Monkey cells turned out to be human cells; human cells were shown to
be mouse cells 18.

But it took more than 15 years before the full extent of the problem was revealed. Until
1967, it had not been possible to distinguish between cell lines that were derived from different
individuals of the same species. Stan Gartler then introduced the concept of biochemical
polymorphism to the study of human cell lines 19 : some proteins have several different forms,
and these forms can differ between individuals.

In 1962, the American Type Culture Collection (ATCC) was set up to collect ‗authentic
cell cultures‘. Stan Gartler was supplied 18 supposedly unique human cell lines by the ATCC and
other sources, and investigated the expression of the enzyme glucose-6-phosphate
dehydrogenase.
 Individuals have either the A or the B form of the enzyme, and these are distinguished
according to mobility in a gel. The A form is almost exclusively found in black individuals, at an
incidence of ~30%. HeLa and the other 17 cell lines that were tested expressed the type A form,
and also had an identical phenotype for another polymorphic enzyme, phosphoglucomutase 1.
Stan Gartler suggested that perhaps all of these
cell lines were HeLa cells 20.

So most of the new human cell lines that had been established since George Gey‘s
success back in 1951 were not new, they were just more HeLa cells. Scientists in dozens of
laboratories had been careless and mixed up the cells. But Stan Gartler might as well have talked
to himself — even scientists who must have known that his conclusions were correct attacked
him. Too many people had written grants and publications on the basis of the false cell lines
from the ATCC to admit that there might be a problem. and have an endless supply of cells.
Genetic drift and pheno-typic change will be minimal within a laboratory 13 , provided that the
cells are not grown continuously — instead, the cells should be replenished from frozen stocks
every few weeks — and standard quality control measures are used.

A chromosomal analysis has show that―the HeLa genome has been remarkably stable
after years of continuous cultivation‖14 . However, it is also relatively easy to select strains of
HeLa that have particular properties by applying selection pressures — deliberately or
accidentally — simply by altering the culture conditions, such as the medium or serum. For
example, it is possible to select HeLa cells that grow in suspension rather than attached to the
culture dish, or HeLa cells that are resistant to cancer drugs.

One of the first applications of HeLa cells was in the fight against polio. George
Gey and colleagues in Minneapolis showed that polio virus grew easily in HeLa cells, and killed
the cells, which provided a simple diagnostic test 15 . Large numbers of cells were needed to grow
the virus in order to produce the polio vaccine that Jonas Salk subsequently developed. A HeLa
production facility was set up at the Tuskegee Institute in Minnesota — which was not ideal, as
both the summer and winter temperatures could be lethal to the cells during shipment.

Nevertheless, about 600,000 cultures had been shipped within two years 16 . Jonas Salk
even injected some patients with HeLa cells, although at the time he thought that he was
growing the vaccine in normal monkey cells 7. HeLa cells are even more important
today than when they were first described. Every year for the past 20 years the number of
citations for HeLa on MedLine has increased, with more than four times as many hits in the year
2000 as in 1980. Many more publications use HeLa cells without acknowledgement (see BOX 1).

HeLa and the other human cancer cell lines that have been established since 1951 are the
bedrock of laboratory cancer research. Analysis of the frequency of use of cell lines in papers
that were published in one recent issue of Cancer Research indicated that three-quarters of the
publications used cell lines, and, in total, more than 112 cell lines had been used 17.

Perhaps the main reason underlying the continued use of false cell lines is certain cell-line
banks. Despite being aware of the problem and being the most frequent source of cells, some
have continued to sell cells under false descriptions. The small print has sometimes indicated that
the false cell line might have ‗HeLa characteristics‘, which in itself is misleading — of course
HeLa cells have HeLa characteristics.

What is the significance of the rising mountain of incorrect data? The implication is that
~20% of publications using cell lines contain false data, but that does not mean that all of these
publications are misleading. In the description of HeLa cross-contamination published in 1968,
Stan Gartler summarized the position. If the investigator‘s requirement was for any human cell
line, Stan Gartler has always felt that the identification of cross-contamination is relatively
unimportant, as any competent scientist can easily authenticate the cells. But because many
scientists did not seem to be
making these checks, one man went into open battle to expose the problem. Walter Nelson-
Rees (FIG. 2) was head of the Oakland Cell Culture Laboratory and Bank, part of the University
of California at Berkeley.

In the 1970s, Walter Nelson-Rees developed techniques for authenticating cell lines.
With little consideration of the personal cost or of the sensibilities of the people whose mistakes
and scandals he revealed 7, Walter Nelson-Rees ruthlessly and relentlessly pursued and exposed
the HeLa cross-contaminants 21–23. By the early 1980s, every human cancer cell line, false or not,
was a HeLa suspect. So when Nelson-Rees retired in 1981, it was a battle won. Or was it?

The Ugly

Sadly, the battle was not won 24. In 1981, the editor of an influential journal described
individuals such as Walter Nelson-Rees as ‗self-appointed vigilantes‘ and said it would be tragic if
they corrupted the civilized habits of scientists 25. With such attitudes holding sway, and Nelson-
Rees retired, the ‗civilized habits‘ of ignorance, complacency and deception were, again,
unchecked.

Today, it is estimated that ~20% of cell lines are falsely labelled (mainly due to
intraspecies contamination) 26,27 and the problem has spread to many other human cancer cell
lines 28–30. HeLa cells are used under many other names with false descriptions.

Continued use of a cell line that has been contaminated with HeLa cells is often based on
claims that the HeLa cells have acquired the specialized properties of the other cell type, making
the false cell line — despite being composed of HeLa cells alone — a useful model of some
other tissue. These findings are remarkable, as the HeLa cells would have shared the same
substrate as the other cell type for only a few days, if at all. There is
no evidence that the cross-contaminated sublines have a mixed parentage, underwent any form
of somatic cell hybridization or exchanged any genetic information.

How could HeLa cells have acquired specialized characteristics of normal and cancer cell
types, such as lung, amnion, liver and heart? If it is possible for one cell type to gain
characteristics of another cell type, simply by growing the two cell types together for a short
period, an important scientific breakthrough has gone unrecognized. Many journals do not want
to take responsibility for the widespread publication of false data. The usual excuses are that the
problem is already widely known (so should it continue to be ignored?), the information is not of
sufficient scientific
interest or there is not enough space available for this (trivial?) issue. Some journal editors
consider that it is not their responsibility to set standards, referring to scientific societies and
funding bodies instead.

The peer-review process has almost completely failed in the respect of false cell lines. If
scientific journals required that each cell line used was authenticated before publication, all but
the most deliberate fraud would disappear. DNA profiling provides a simple and cheap method
of authentication, it is available to everyone and could prevent most of the problems 31.
Box 1 | A sample of the better known HeLa cell cross-contaminants
Comprehensive lists of ~100 early examples of cross-contamination are given in the
references of Walter Nelson-Rees 21–23. The cell lines described briefly in this box are authentic
HeLa cells, and there is no evidence that they contain any genetic information from any other
cell type.

As a result of genetic drift and being subjected to different conditions in various

laboratories, each strain might have genetic and phenotypic differences. There is no common
stock of HeLa cells, and consequently every batch from each source will be slightly different.
The differences between the various cell stocks labelled HeLa are probably as great as the
differences between these various strains given different names. Within the last year, some of the
false cell lines listed below were catalogued and sold by some cell banks under the false name
and false description.

•HeLa (KB). The HeLa subline KB was thought to be derived from an oral cancer 33 . It was
cited more than 300 times during the period 1998–2000 in MedLine, and some of these studies
used the cells as a model of skin or head and neck cancer 34,35. Few of the papers mention or
seem to be aware that the cells are derived from a glandular cancer of the cervix.

•HeLa (HEp-2). The HeLa subline HEp-2 was thought to be derived from a cancer of the larynx
36
. It was cited more than 300 times during the period 1998–2000 in MedLine and is frequently
used by virologists as a human epithelial cell line 37,38. Usually, there is no mention that these cells
are a HeLa subline and are derived from a cervical cancer.

•HeLa (WISH), HeLa (AV3) HeLa (FL). These three sublines of HeLa were all thought to be
derived from amnion cells, the most well-known and widely used one being WISH 39. Despite
their origin from cervical cancer, these cell lines are sometimes used in the fields of reproduction
and endocrinology, and are described as being normal human amnion cells 40,41.

•HeLa (L132). The HeLa subline L132 was thought to be derived from normal human
embryonic lung cells 42. These HeLa cells are sometimes described as being normal embryonic
human lung epithelial cells 43,44.

•HeLa (Intestine 407). The HeLa subline INT 407 was thought to be derived from human
intestinal epithelial cells 45 . Despite its origin from a cancer of the cervix, it is still used as a
model of normal human gastrointestinal cells 46,47.

•HeLa (Chang liver). The HeLa subline called Chang liver was thought to be derived from
normal liver cells 48. Despite being cervical cancer cells, Chang liver cells are sometimes used in
studies of hepatic-cell physiology 49,50.

Whether or not it was HeLa or another cell line does not seem important. However, in
those cases in which the investigator has assumed a specific tissue origin of the cell line (such as
liver or lymphocytes), the work is of dubious value 20. There is, at present, a campaign to have
the false cell lines renamed with their correct designation 32.

The future
 HeLa cells are even more important today than they were when first grown by George
Gey 50 years ago. Cell lines have been, and will continue to be, the model system of the cancer
cell that is used by most cancer research scientists. However, the HeLa story also shows the
consequences when peer review fails and there is a lack of quality control.

John R. Masters is at the Institute of Urology,

University College London,
67 Riding House Street,
London W1W 7EY, UK.
e-mail: j.masters@ucl.ac.uk
DOI: 10.1038/nrc775

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Online links
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The following terms in this article are linked online to:
CancerNet: http://www.cancer.gov/search/cervical cancer | head and neck cancer | laryngeal
cancer | oral cancer | skin cancer
LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/glucose-6-phosphate dehydrogenase |
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