Fever medicine
Why did a Chinese doctor infect cancer patients with malaria
Polina Loseva, "The Attic"
In pursuit of scientific breakthroughs, Chinese scientists are launching increasingly risky clinical trials. Recently, a professor at Guangzhou University, Chen Xiaoping, spoke on Chinese television about how he treats cancer with malaria. While the scientific community is outraged by the unethical nature of his experiments and the lack of evidence, "Attic" tells how malaria turned from a deadly infection into a medical tool and what else can be expected from it.
Humanity has been suffering from malaria for a very long time — according to some estimates, since the very moment of separation of its evolutionary branch from the chimpanzee. Despite the discovery of the antimalarial properties of the bark of the cinchona tree in the XVII century and quinine in the middle of the XIX, millions of people continue to become infected and die from it to this day (according to WHO, in 2017, 219 million people fell ill with malaria and 435 thousand of them died from it). Nevertheless, during this time we have had a good time to understand how this disease develops, who provokes it and how it can be useful to us.
The causative agent of malaria is a unicellular eukaryote malarial plasmodium. To be precise, this is a group of four species — Plasmodium falciparum (responsible for the most severe form of malaria), Plasmodium vivax, Plasmodium ovale (cause three-day malaria, in which attacks occur every three days), and Plasmodium malariae (causes four-day malaria). Plasmodium enters the human body with a mosquito bite, although cases of transmission with donor blood are also known, and colonizes liver cells. There it multiplies, goes back into the blood and penetrates into red blood cells (red blood cells). In them, it multiplies again, but with such force that the red blood cells burst and the parasites again end up in the blood, from where they can be sucked out by a new unlucky mosquito. The rupture of red blood cells causes, in fact, an attack of malaria: many substances from blood cells enter the bloodstream, including toxic ones, in response to which an immune response develops with a high temperature.
Despite the fact that fever can kill a patient, sometimes it becomes a valuable ally in the fight against other diseases. Hippocrates also noticed that fever (regardless of why it arose) relieves psychosis and epilepsy attacks in patients. And in the XV century, doctors discovered that malaria also "makes it easier" for syphilitics. Syphilis is caused by another well—known parasite, although it is no longer a eukaryote, but a bacterium - pale treponema, which gradually affects all organ systems. The attack begins with the genitals and skin, then the lymphatic system, and then the foci of tissue destruction throughout the body. The most severe manifestation is brain seizure — neurosyphilis, which can lead to paralysis and dementia.
However, until the 20th century, infection with both malaria and syphilis could only be considered a "happy" accident. The situation changed when, in the 1900s, the existence of malarial plasmodia was proven and it became possible to infect patients intentionally. It was first invented by the Austrian psychiatrist Julius Wagner-Jauregg for the treatment of the last stage of syphilis — progressive paralysis. He transfused 10 ml of malaria patient's blood to patients and waited for them to survive 10-12 bouts of the disease (then and subsequently, "gentle" plasmodia were used for treatment, which cause a three- or four-day, milder form of infection). After that, the patients received quinine, which stopped the course of malaria. Apparently, the poor pale treponema could not withstand such high temperatures and died. The method turned out to be so successful that only nine years after the first experiment, in 1927, Wagner-Jauregg became a Nobel Laureate.
Up to the second half of the XX century, neurosyphilis provided European psychiatric hospitals with work: the proportion of patients with progressive paralysis ranged from 10 to 40% in them. And malariotherapy has remained mainstream for a long time. They even say that there were special "mosquito farms" at European hospitals, where infected mosquitoes were bred and sick donors lived, in whose blood the necessary level of parasites was maintained. However, now the medical community is expressing doubt about the effectiveness of burning out syphilis with malaria, since the exact mechanisms of this method are unknown, and full-fledged clinical trials, despite its widespread use, it has not passed.
He also had one more unpleasant feature: from 5 to 13% of patients died during treatment — either from complications of malaria, or directly from syphilis. At one time, this was considered an acceptable risk — the scale of the epidemic was too large. Malaria was also tried on other patients of hospitals suffering from epilepsy, schizophrenia and manic-depressive psychosis.
And then they discovered penicillin. And it turned out that syphilis can be defeated much easier and with fewer health risks, and the story of plasmodium's victories over treponema is over.
However, the effects of heat (hyperthermia) for some time they were used in medicine. In American clinics, malaria therapy was replaced by visits to the so-called Kettering rooms: patients with syphilis were placed in a special chamber for heating.
A patient in a hyperthermic chamber, 1937, New Orleans.
Later it was discovered that in some cases fever helps in the treatment of tumors. And despite the fact that hyperthermia is no longer used in Western medicine, in Russia you can still buy pyrogenic (temperature—raising) drugs - "Sulfosin" (a substance with a bad reputation and severe side effects, which was once used in punitive psychiatry) and "Pyrogenal".
At the end of the twentieth century, malaria was talked about again. Another famous scientist, Henry Heimlich, resurrected a long—forgotten idea (the same one who invented the eponymous technique to save a choked person from suffocation). In 1990, Heimlich proposed using malaria against Lyme disease (also known as tick-borne borreliosis), which is caused by relatives of pale treponema and whose symptoms sometimes resemble neurosyphilis in the later stages. The medical community did not heed Heimlich's call, at least simply because he is a surgeon by education, not an infectious disease specialist. Nevertheless, there are two known cases of patients with Lyme disease who independently infected themselves with malaria in order to be cured (whether they succeeded or not is not known for certain).
But Heimlich's affair with malaria did not end there. A few years later, despite all the objections of his American colleagues, he and his Chinese colleagues moved from words to deeds and set her against another enemy of humanity - the human immunodeficiency virus. The scientist drew attention to the fact that in addition to heat, malarial plasmodium causes an active immune response, which means that it can be used as an immunostimulator. In a pilot clinical trial, Heimlich managed to restore the normal number of lymphocytes in six HIV patients, and then his colleagues achieved similar results in a dozen more patients.
Nevertheless, Heimlich failed to rehabilitate malariotherapy. His experiments were severely criticized by colleagues: the resolution of the American Center for Disease Control and Prevention (CDC) mentions that there is no strict evidence that malaria can favorably affect the course of HIV infection (CDC said this to Heimlich when he refused to finance his experiments, in particular, that's why he started working with the Chinese). As an additional argument, doctors cited overlapping foci of both infections (malaria and HIV): if one really saves from the other, then why are African countries suffering from them at the same time?
Heimlich's case, however, lives on in his Chinese students. In 1999, together with their teacher, they conducted the first studies in which malaria became a weapon against several types of cancer.
The result did not look very optimistic: out of five patients, only two managed to achieve improvement, and no one was completely cured. We had to stop testing on humans and, waiting for the right moment for a new offensive, proceed to testing the technique on mice that malaria helped get rid of lung cancer; another group received similar results.
And now this moment has come. Chinese science has embarked on a desperate pursuit of scientific breakthroughs, trying to get ahead of its Western colleagues in this. A good example here is the story of Jiankui He, who did not wait for universal confidence in CRISPR technology and hurried to create the first genetically modified children. And now, against the background of the approval of China's first immunotherapy for cancer and the awarding of the Nobel Prize in 2018 for the discovery of immunotherapy, a large-scale campaign to find new antitumor drugs has unfolded in the country.
Currently, about 70 clinical trials of immunotherapy are underway in China at the same time. Apparently, the adherents of malaria therapy decided that they could not find a better moment to come out of the shadows. This March, a former colleague of Heimlich, Chen Xiaoping, spoke on the Chinese state channel about the results of his experiments. According to his colleague Zhai Xiaomei, out of 10 patients with oncological diseases, two got rid of tumors completely, and in five the disease stopped progressing.
Strictly speaking, the idea of treating cancer with malaria is also not new. The first observations of how a cancerous tumor goes away under the influence of infection date back to 1775. Nevertheless, the relationship between tumors and plasmodium remains ambiguous. On the one hand, it is known that malaria really suppresses tumor growth — in the case of sarcomas and carcinomas. The exact mechanisms of this phenomenon remain unexplored: perhaps plasmodium stimulates the general immune response of the body or has some antigens similar to tumor ones and causes a cross-response. Or maybe during the infection, the growth of blood vessels stops and the tumor remains without blood supply. But there is also evidence that an infection can, on the contrary, provoke the development of lymphomas (forcing immune cells to divide more often) or even directly have a mutagenic effect.
So can malaria be a cure for cancer? The epidemiology of these diseases does not provide a convincing answer. According to some reports, cancer began to spread in Europe just in the second half of the XIX century — against the background of the fight against malaria. In 2017, Xiaoping collected his own morbidity statistics for different countries and also concluded that the spread of cancer negatively correlates with the incidence of malaria. However, in his analysis, Xiaoping did not take into account, for example, blood cancers, but limited himself to sarcomas and carcinomas, for which such a correlation is indeed possible. In addition, it is worth remembering that with a mosquito bite, a person receives not only malaria plasmodium, but also a whole range of other parasites and their toxins. Therefore, it is hardly possible to talk about a clear relationship here.
In addition, the attitude to risky methods of treatment in medicine has changed significantly over the century.
If at the beginning of the twentieth century the principle of "desperate diseases justify desperate medicines" (desperate maladies justify desperate remedies) was in effect, and the apparent benefits of malaria therapy were significantly greater than the harm, now the proposal to treat one disease by infecting patients with another disease seems to doctors madness.
As in the case of previous diseases against which malariotherapy was used, the molecular mechanisms of its antitumor effect are still unclear, and there are no evidence-based preclinical studies, except for old work on mice. And this is an important argument against subjecting the body of already exhausted patients to additional tests. Finally, despite the fact that malaria is not as dangerous today as it was a hundred years ago, and medicines for it are widely available, this disease has not yet been completely defeated. And therefore, many experts seriously fear that such experiments may provoke a new epidemic.
Attempts to rehabilitate malaria therapy were condemned not only by Xiaoping's foreign colleagues. The critics were also joined by compatriots, including the director of the Bioethics Center of the Chinese Academy of Medical Sciences, for allowing himself to make loud statements before the publication of a peer—reviewed article with the results.
It seems that the history of Jiankui He repeats itself: in the pursuit of fame, researchers have incurred the wrath of the Chinese authorities and the scientific community, whose degree of concern about the moral side of biomedical research is now higher than ever. Now the Chinese article risks being rejected by scientific journals, and, as in the case of genetically modified children, the world will not see the results of their work and will not know how effective their proposed method could be. And malariotherapy is waiting for another period of oblivion, until the next enthusiast picks up its falling banner.
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