70 years of slavery
The Adventures of HeLa Cells in the Service of Humanity
Polina Loseva, N+1
Henrietta Lacks died on October 4, 1951 from a cervical tumor. On October 4, 2021, her grandchildren sued the pharmaceutical company that sells the cells of this tumor — HeLa culture. We tell you how their life turned out after the death of the hostess, where they managed to visit, who to kill and who to save.
Journalists are 23 percent less likely to write about articles with mice in the headlines — such studies, they say, are not as important and serious as experiments with humans. But just try to imagine a world in which laboratory mice do not exist. Each experiment in such a world lasts no longer than a couple of years (mouse life is short), and there is no question of representative samples: the subjects are exactly those mice that the experimenter managed to catch in the nearest basement — young and old, sick and healthy.
This is exactly how things were in biotechnology until 1951.
Most human cells simply refused to reproduce in captivity: at best, they survived when moving to a Petri dish — but they gradually died there. The only cells that somehow adapted to life in the laboratory were embryonic, they were obtained from the tissues of stillborn children or fetuses after abortion. At least they did not die immediately, and virologists grew human polioviruses in them.
But any cells—both adult and embryonic—had to be caught and domesticated anew every time. Each laboratory kept its own small cell herd and did not risk sharing it with colleagues. And without a common standard, it is impossible to reproduce other people's results, and even more so to combine efforts — for example, to search for new drugs.
What exactly did not suit human cells in culture, no one really understood. Right now we have instructions on how to take care of each type of tissue: what to feed (sugar, blood serum, essential amino acids, hormones, vitamins, antibiotics), where to settle (temperature, humidity, oxygen in the air), what to plant (glass, plastic, biopolymer substrates), when to change liquid and how often to transfer from cup to cup. A hundred years ago, histologists poked at random, trying to find conditions acceptable to the cells, but for the first half century they did not succeed.
To master the art of cultivation, it was necessary to find unpretentious cells that would agree to endure discomfort and experiments on themselves. Tumor cells were best suited for this role: they are much less fastidious than ordinary ones and are reluctant to die — which allows them to win competition within human tissues. Scientists have been trying to domesticate the tumor since the 1910s. But the first to achieve this was a biologist from Johns Hopkins Hospital. His name was George Guy.
How to tame a cage
Guy turned out to be in this role for a reason. As the journalist Rebecca Skloot writes in the book "The Immortal Life of Henrietta Lacks", the scientist wanted to find a cure for cancer and therefore spent several decades learning how to grow tumor cells in culture. His laboratory assistant fed them fresh blood (for which they had to go to the slaughterhouse, then to the maternity hospital). His wife, a former surgical nurse, trained the staff to disinfect all surfaces in the laboratory. And Guy himself, using improvised means, built a rotating incubator for the cells: something similar to a concrete mixer, he did literally a couple of revolutions per hour - and, according to the creator's plan, was supposed to simulate the slow flow of blood in human tissue.
But the cells were dying anyway. Some overheated, some could not put up with the laboratory diet, and some displaced stray bacteria from the culture. Some cells, however, managed to stay afloat (in the literal sense of the word — they did not grow on a substrate, but in solution): The record-breaking culture lived in Guy's laboratory for about five years. However, there were no cells left in it that he actually tried to grow — they died at the very beginning of the experiment from overheating, giving way to their neighbors in the tissue.
In the early 1950s, Guy completely switched to cervical cancer: a colleague at the hospital wanted to test one of his hypotheses about this tumor and therefore began to supply Guy with tissue samples from all his patients. On February 8, 1951, he handed over a sample extracted from the body of a young African-American woman, Henrietta Lacks. The test tube, as was then customary, was signed by the first letters of the name: HeLa.
A few days later, Guy's lab assistant noticed that there were twice as many cells in the test tube. Then more, and more. For the first time, the tumor cells not only did not die — they turned out to be a pure culture without impurities and were divided every day. HeLa did not stop growing after either a month or two. They are still far from breaking the record of the previous tumor culture, but Guy already guessed that a unique object had fallen into his hands — and called them immortal.
This is an epidemic
The rest of Henrietta Lacks's cells were not so tenacious. Simultaneously with the tumor sample, the surgeon cut out a section of healthy tissue from the cervix, but its inhabitants did not take root in Guy's incubator. In Henrietta's body, they too soon began to lose. After the doctors took tissue samples, they inserted a radium tube into the cervix — that's what radiation therapy looked like at the time — but it didn't help. As Henrietta's attending physician later recalled, "from a clinical point of view, things never went well for her." After therapy, the tumor did not wither, as usual, but continued to grow, capturing other internal organs, while the other half of it settled in Dr. Guy's incubator. They grew in parallel for several more months, until at the end of September 1951, the doctors gave up and stopped giving Henrietta medications, not counting painkillers. Soon the laboratory HeLa were orphaned.
Immortal culture didn't have to wait long for the first work assignment. A polio pandemic was raging in the US — Jonas Salk had already come up with his own vaccine, but had not yet started clinical trials. To make sure that it works, it was necessary to check whether antibodies to poliovirus appeared in the blood of the vaccinated. But there were no antibody tests at that time, and the only way to detect them was to take blood serum, pour it on the cells and try to infect them with a virus. If this fails, there are antibodies in the blood.
So, we needed cells into which poliovirus could be planted — and many cells at that. Just a couple of years before HeLa was born, virologists found out that poliovirus can infect not only neurons, but also some other cell types. But it was not easy to get embryonic cells, and Guy suggested trying the unpretentious and prolific HeLa in this role. The idea turned out to be successful: the cells obediently accepted all three varieties of polioviruses, allowed them to multiply and died after 12-96 hours, and new ones came to replace them.
The New York Times editorial with a photo from the HeLa "factory" (Debbie Herman / flickr / CC BY-SA 2.0).
When it turned out that Salk's polio vaccine was working, HeLa found a new job — to grow viruses in itself, which will become the raw material for the "killed" vaccine. So that there would be no shortage of Henrietta Lacks cells further, a separate plantation was built for them — a laboratory at Tuskegee University, from where thousands of new bottles of HeLa were sent around the country every week.
George Guy himself willingly distributed his hard-working cells: first to colleagues in neighboring laboratories, then to other cities and countries. Putting another batch of HeLa on the plane (pilots sometimes had to carry test tubes right in their breast pocket so as not to deprive them of the warmth of the human body), Guy joked that his cells were preparing to "metastasize" once again. Over the next couple of decades, he had plenty of chances to appreciate how prophetic his joke turned out to be.
HeLa proved to be suitable not only for the reproduction of polioviruses. They have become a new model object and the gold standard — the embodiment of the average human cell. Biologists began to grow other viruses in them: mumps and measles, herpes and chickenpox. HeLa were frozen, thawed, stored in refrigerators and sent by mail, they were turned into hybrids, forced to merge with mouse cells, and they were the first human cells to be cloned — that is, they figured out how to grow a whole crowd of genetically identical descendants from a single HeLa cell. HeLa even flew into space on the Soviet "Sputnik 6" — and it turned out that in zero gravity they reproduce no worse than on Earth.
At the same time, while some scientists bred HeLa and helped them "metastasize" again and again, others — in search of a cure for cancer — tried to kill them. HeLa cells were X-rayed and blown with oxygen, watered with bacterial toxins, antibiotics and rabbit antibodies. Sometimes the experiments were successful, and the same substances that worked against HeLa are still being treated today.
At the same time, someone was trying to turn Henrietta Lacks' cells themselves into medicine. In the mid-1950s, they were planted in the organisms of several dozen prison inmates from Ohio — virologists hoped that meeting with someone else's tumor would work as a vaccination against their own. And for some patients, HeLa cells were injected simply as a test: it was believed that if the immune system could not cope with them, then it was weakened, and an undiagnosed cancer was hiding somewhere in the body. The organisms of many experimental people resisted the invasion of HeLa, but some tumors still grew, and sometimes metastasized for real. So how many people were killed by these cells, not counting Henrietta, is unknown.
Then other cell cultures of various tissues appeared, from human skin to the cornea — dozens of different variants, both cancerous and healthy. It has become easier to grow them: either because scientists have filled their hands, or because even ordinary cells in laboratories sometimes acquired immortality — turned into tumor cells and began to multiply willingly.
In the mid-1960s, geneticist Stanley Gartler suspected that some of these cells were not really what they claimed to be. To understand this, he began to look for biochemical labels in them: since different lines are obtained from different people, they must have different variants of the same proteins. The first 20 cultures analyzed by him carried the protein glucose-6-phosphate dehydrogenase in A-form — a variant that is relatively rare and almost only in African Americans. The geneticist considered it unlikely that all the cell donors were of the same origin, and when 18 of these cultures matched the variety of another protein, he concluded that they were all HeLa.
Since then, Henrietta Lacks cells have been found every now and then in a variety of cultures. HeLa posed as intestinal, liver and embryonic lung cells. They penetrated into the cultures of the kidney and rectum. Even a few unique tumor samples that the USSR handed over to the United States in 1973 as part of joint plans to find a cure for cancer — and those on the way from one laboratory to another were displaced by HeLa cells.
Attempts to figure out who is who really do not stop now. In 2017, it turned out that the results of almost 33 thousand scientific papers were obtained on incorrectly identified cells, and half a million other articles cite these results. Journals regularly withdraw published articles when it is discovered that the experiments described in them were carried out on the next "metastases" of HeLa under the guise of some other culture. Currently, there are only 576 cell cultures on the blacklist of the international committee for the authentication of cell lines that do not correspond to their name. Of these, 140 are HeLa in various guises.
What are you
Over the years of working with HeLa, biologists have learned almost everything about them: what they eat and how often, when and how they reproduce, how they fight back against immunity, which genes they use and which proteins they build. And the further scientists peered into the bowels of these cells, the clearer it became that HeLa are not at all like ordinary human cells.
They differ at least in that they are cancerous. In their eighth chromosome sits the human papillomavirus type 18, and its presence makes the c-Myc gene work — and this is a well-known oncogene that regulates the work of other genes and encourages cells to divide. Apparently, it is thanks to him that HeLa regularly reproduce once a day for the past seventy years.
Ordinary human cells have problems with such rapid division. Even in the body, they do not have to multiply so actively, so they do not do this in the laboratory. Those who agree to divide in vitro quickly get tired of it, because they lose telomeres — the tips on the ends of chromosomes, which become a little shorter with each division. But HeLa, as it turned out, has a special enzyme called telomerase, which increases telomeres and gives the cell the opportunity to divide indefinitely. For the first time in human cells, it was noticed in HeLa.
In addition, HeLa has a completely indecent number of chromosomes. There are 76-80 of them instead of 46 human cells, and 22-25 of them are abnormal, that is, not just extra copies of some already existing chromosomes, but their fragments or chimeras from several parts of the genome in general.
Genotype of one of the HeLa varieties: chromosomes are grouped by numbers, some of them are "glued together" from fragments of two different chromosomes (E Smirnov et al. / Folia Biologica, 2006).
Apparently, chromosomal disorders inside HeLa occurred somewhere at the dawn of their lives: either when the human papillomavirus had just settled in Henrietta Lacks' cells, or when HeLa was being mastered in Dr. Guy's rotating incubator. But for decades in laboratories, the number of chromosomes has hardly changed. This amazing stability suggests that such a genomic anomaly turned out to be very successful. Other attempts by HeLa to rearrange its genome were unsuccessful — at least, the late tumor samples that the doctors took from Henrietta Lacks did not take root in the laboratory.
Finally, even for cancer cells, HeLa turned out to be atypical. Henrietta Lacks' attending physician, Howard Jones, later wrote that this tumor seemed suspicious to him from the very beginning. The size of a 25-cent coin, bright purple in color, it reminded him of a grape made of jelly, and it felt so soft that it did not differ at all from the main tissue of the mucous membrane. Not believing that it was a real cancer, Jones initially assumed that it was a chancre — since Henrietta had been a carrier of syphilis since childhood. And only after the smear did not show its pathogens-spirochetes, the doctor recognized that it was a tumor. However, he incorrectly identified its type: only 20 years after the birth of HeLa, reviewing his notes, Jones noticed that it was not a mutated cervical epithelium, as he had thought all this time, but an adenocarcinoma — it is formed from the tissue of the uterine glands and is less common, but more aggressive.
So HeLa owes its birth to a rare coincidence. Two pathogens met in Henrietta Lacks's body: the human papillomavirus and the causative agent of syphilis, one of which turned ordinary cells into cancer cells, and of a rare type, and the second, apparently, diverted the suspicions of the immune system from them and allowed the tumor to grow. Her cells began to divide, randomly rearranging their chromosomes — and at some point, when the combination became particularly successful, the cells fell under the surgeon's knife and moved to George Guy's laboratory, from where they began to spread around the planet.
Cells seek Freedom
Now we already know that the "laboratory mouse" of cell biologists actually turned out to be a rare monster. What for many decades played the role of a typical human cell in laboratories turned out to be completely unlike any of them. Moreover, today there is a suspicion that individual HeLa lines from different parts of the world have already diverged quite a lot and even have not much in common with each other anymore.
But most importantly, we do not understand at all how much this monster has to do with Henrietta Lacks herself. In her own cells, of course, there were not 80 chromosomes, but 46, otherwise she would not have been able to live to the age of 30 and become a mother of five children. But at what point 46 turned into 80 — inside her tissues or already outside — it is now impossible to say. There are no other biological samples left of Henrietta herself, and we cannot read her real genome — which means we cannot find out how far HeLa cells have gone from their mistress and whether this culture should still be considered part of her body.
In 1991, two scientists from Chicago proposed to grant HeLa cells independence — and isolate them into a new species, Helacyton gartlerii (in honor of Stanley Gartler, who was the first to talk about the HeLa epidemic in laboratories). They appealed to the standard criteria of a biological species. For example, genetic: the set of chromosomes in HeLa is not only different from what Henrietta's cells carried, but also generally goes beyond what is possible in humans. Or reproductive: HeLa are not able to interbreed with humans. Although in the laboratory they can be forced to merge with some other cell, there is no question of any gene exchange. Finally, ecological: HeLa occupy their own niche in nature, in which they do not compete with Homo sapiens in any way. True, Homo sapiens created this niche — but did he not do the same for many domesticated animals?
But the idea did not arouse enthusiasm, and other, more biased, checks on the species isolation of HeLa did not pass. For example, scientists have noticed that these cells lack a clear pedigree — it is unclear what their typical representative looks like and what were the transitional stages between him and Henrietta. In addition, HeLa continues to compete with human cells — not only in the laboratory, but also in the body of hapless patients — which means that their ecological niche is not so unique. So the scientific community denied HeLa independence. Although there is hope for revenge: recently there has been a lot of talk about "contagious" (transmissible) tumors — in particular, they were suggested to be considered an intermediate stage on the way to new species. Therefore, scientists may still change their minds.
In the meantime, HeLa remains — both biologically and legally — human cells. And this seriously complicates life not only for themselves, but also for those who breed and maintain them.
On the one hand, the biological material that the patient leaves in the doctor's office is no longer considered his property — at least, judges have repeatedly made such a decision. On the other hand, HeLa has a lot in common with other Henrietta Lacks heirs — for example, part of the genome. Therefore, in 2013, when the HeLa genome was sequenced, it had to be removed from public access — Henrietta's grandchildren considered it an invasion of their privacy. And now they have filed a lawsuit against Thermo Fisher Scientific, demanding compensation for the fact that the company traded Henrietta Lacks' cells without her consent. This is not the only seller from whom you can buy HeLa today, so this lawsuit will surely be followed by others.
70 years ago, doctors separated the tumor cells from Henrietta Lacks' body, but the connection between them did not break — it turns out that the contents of the Petri dish can be treated humanly. HeLa are not alone in this: a similar story develops with the HEK293 culture — its unknown owner was an embryo and became a donor before he lived to be born. HEK293 also worked for scientists for decades — both as a model object and as a protein manufacturer — and in 2020 it was contracted to produce coronavirus vaccines. In the United States, the Catholic Church immediately called for the abandonment of these vaccines and the use of more ethical drugs. Although CanSino and AstraZeneca grow most vector vaccines in Johnson & Johnson, as well as the Russian Sputnik V, and only Johnson & Johnson use a different line, however, also embryonic), and mRNA vaccines (which created Pfizer and Moderna) are testing on it.
And while doctors, histologists and relatives of Henrietta Lacks are fighting for ownership of HeLa, the cells continue to work. They no longer participate in the creation of modern vaccines, having worked their way on polio plantations. But they continue to serve as a human model cell even in the covid era: for example, scientists learned about the fact that the coronavirus enters cells using the ACE2 receptor, trying to infect HeLa culture with a new virus.
Having lived in the world more than twice as long as Henrietta herself, having conquered all continents and been in space, bringing scientists a dozen Nobel Prizes and protecting millions of children from polio, HeLa cells have not earned their independence. But they are not going to give up: evolution does not stand still — mores change and genomes change. And right now, in thousands of incubators on Earth, the eternal fragments of Henrietta Lacks are persistently copying their DNA, preparing to mutate, evolve and continue to fight for their freedom.
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