2.15 Intellectual The Intellectual
HIV virus | Image source: istockphoto.com/ClaudioVentrella
Editor's Note
On February 8, French virologist Luc Montagny, who was famous for discovering the human immunodeficiency (HIV) virus and won the Nobel Prize in Medicine and Physiology in 2008, passed away at the age of 89.
Montagny combines great achievements and great controversy. Although he made outstanding achievements in medicine, in his later years he was controversial for publishing many unscientific views, including the "artificial theory of the origin of the new crown".
In 2009, he claimed that DNA emits electromagnetic radiation and that some bacterial DNA continues to send signals long after the infection has cleared; in 2012, he spoke at a conference on autism in Paris, France, claiming that long-term use of antibiotics can successfully treat autism; in a video last May, he claimed in a video that vaccine plans are "unacceptable mistakes" because vaccines can cause the virus to mutate; and in January, he told the Wall Street Journal that the wall street journal In a review article co-authored with Yale law professor, he criticized US President Joe Biden's vaccine policy.
An accomplished scientist can also "unbelievably" behave quite amateurishly, confusing and confusing. Fortunately, these "delusions" of his do not naturally possess the attributes of truth because he is an "authority."
Today, we resend Bemontani in the old 2020 text, hoping to remember and thank him for his remarkable discovery. Hopefully, one day, AIDS, an infectious disease that has hitherto been intractable, can have an end.
Written by Wang Chengzhi | Li Runhong, editor| Di Lihui Tang Peilan
● ● ●
Figure 1 The 2008 Nobel Prize in Physiology or Medicine was awarded to the discoverer of HIV and HPV viruses| Source: nobelprize.org
On June 5, 1981, the U.S. Centers for Disease Control and Prevention (CDC) reported that five gay men in the Los Angeles area developed Pneumocystis carinii pneumonia.
The disease is very rare and generally occurs only in people with extremely low immunity. Soon, the CDC found more patients with similar symptoms, who also had other symptoms of low immunity, including Kapozi sarcoma, giant cell infections and so on.
At the time the disease was called "gay men's disease". But it was soon realized that people in all populations contracted the disease, mostly through sex or blood transfusions. As a contagious disease, the discovery of its causative agent has become a top priority for disease control.
In the competition to discover the cause, the Frenchman Luc Montagnier finally stood out and found and proved that the virus HIV is the fatal culprit. This discovery process was accompanied by a controversy between him and another American scientist, which also led to high-level intervention and even court action between the U.S. and French governments.
1
Refugee Montagny
Montagny was born in 1932 in Chabris, in central France, a town famous for agricultural products such as goat cheese and white asparagus. As the only son in the family, Montani was naturally pampered by his parents and could have had a carefree childhood. But the accidents of life and the torrent of the times followed, breaking Montagni's peaceful life.
At the age of five, Montagny was hit by a speeding car on a main road. After two days in a coma, Montani was awakened. Although he escaped the disaster, the accident caused him serious injuries and left scars.
Figure 25-year-old Montagny is | Source: Nobel Prize official website
One day two years later (1939), when 7-year-old Montagny was picking grapes from his uncle's vineyard with his family, France declared war on Germany. By the following year, with the german invasion, Montagny's family fled and became refugees. Since then, they have not had enough to eat, and often endure the torment of hunger. During the four years of the war, Montani, who was in the stage of adolescent development, did not gain the slightest weight.
To make matters worse, Montani's grandfather was diagnosed with colon cancer and died after experiencing great suffering. Witnessing the pain of his grandfather, Montani had a desire to study medicine and study cancer.
In high school, Montagny's grades were among the best, and he became increasingly interested in science. He built a simple chemistry laboratory in his family's cellar and prepared hydrogen and scented aldehydes himself, and even began making his own nitro compounds. At the same time, he also read a lot of books on physics, especially in cutting-edge fields such as atomic physics.
After entering college, out of a strong interest in medical research, he decided to make this his future career direction. But there was no medical major in his city at the time, so he went to the hospital in the morning and took classes in botany, zoology, and geology at school in the afternoon.
Fortunately, Professor Pierre Gavaudan, who teaches botany at Montagni, is not limited to textbook knowledge. He told his students about the latest advances in biology at the time, including the double helix of DNA, the synthesis of proteins with ribosomes in in vitro systems, and the structure of viruses, which opened new doors for Montagny.
At this point, Montagny received two gifts from his father: a time-lapse camera and a microscope. He used these devices to study how algal cells regulate the arrangement of chloroplasts based on the intensity of light. By using filters of different colors, combined with time-lapse photography and microscopy, he demonstrated that algal cells indirectly regulate the orientation of chloroplasts by absorbing red light not through chlorophyll, but by absorbing blue light through yellow pigment. At just 21 years old, Montagny used this result to complete the defense of the Faculty of Sciences of Poitiers.
2
First venture into the world of viruses
At the age of 23, Montagny became a research assistant at the Sorbonne Université in Paris, during which time he studied cell culture techniques. In 1957, scientists such as Heinz Fraenkel-Conrat discovered that tobacco mosaic viruses use RNA as genetic material and can infect plant bodies through RNA. Montagny was deeply moved and decided to conduct virus research through molecular biology, which was just emerging at the time.
He then moved to the lab of Kingsley Sanders in Castleton, England, to study foot-and-mouth disease viruses, where he demonstrated that RNA can be replicated like DNA through the principle of base pairing.
Soon after, the famous biologist Michael Stocker established a new institute of virology in Glasgow. Montani also came here to begin researching the polyomavirus, a virus that causes tumors. Montani and his collaborators demonstrated that the virus's DNA itself has the ability to cause it to cause tumors. Although this is not unusual from today's point of view, at the time, it broke the traditional concept that all life activities are inseparable from protein.
After finishing his studies in the UK, Montagny returned to the Curie Institute in France to continue his research on oncoogenic viruses. At the time, the virology community had a huge mystery waiting for scientists to answer: How do RNA viruses replicate? Montagny tried to discover the double-stranded RNA produced by the virus, using the Rous sarcoma virus (RSV) as a model, and did find double-stranded RNA in the cells it infected, but its sequence was not derived from the virus. At the same time, he also found double-stranded RNA in cells without virus infection, which proved that this double-stranded RNA had no relationship with viruses. Montani later recalled that the discovery was actually partially close to the small interfering RNA that was later discovered.
In 1970, two laboratories across the ocean in the United States (Howard Temin and David Baltimore) independently discovered reverse transcriptases in RSV. This enzyme can synthesize the corresponding DNA using viral RNA as a template. This not only explains the replication problem of RNA viruses, but also breaks the dogma of synthesizing RNA from DNA templates in the law of the center of biology, making people realize that the process of transcription can also be reversed.
On this basis, Montani discovered that viral retrotransration OF DNA can be integrated into the genomic DNA of host cells. Since then, retroviruses have become the center of Montagni's lifelong scientific research.
In 1972, Jacques Monod, director of the Institut Pasteur in France, approached Montagny and wanted him to establish a center for the study of viruses at the Institut Pasteur. At that time, the United States invested a lot of money to start a virus cancer program, tumor-related viruses became a research hotspot, and Montagni also created the Viral oncology unit at the Pasteur Institute.
In 1973, J.C. Chermann and his collaborator Fran oise Barré-Sinoussi joined montagny's research center. Barré-Sinoussi is experienced in detecting the activity of reverse transcriptase. Montagny persuaded them to work together on retroviruses that could cause cancer in humans. In 1977, they began testing patients' blood and tissue collected in Paris hospitals to see if retroviruses could be found.
At this time, the research of two other laboratories was of great help to Montagni's experiment.
Because replication of the virus is inhibited by interferons in the human body, Montani speculates that blocking the effects of interferons would make it easier to detect the virus. It was at this time that the Ion Gresser laboratory in Villejuif, France, prepared an antiserum that neutralizes interferons. After testing, Montagny and Barré-Sinoussi et al. found that endogenous retroviruses increased expression by a factor of 50 after treating cells with this interferon antiserum. This greatly increased the sensitivity of their experiments.
At the same time, the laboratory of American virologist Robert Gallo invented T cell culture technology. By adding a growth factor (TCGF, then known as interleukin 2) to the culture medium, human T cells that would otherwise be difficult to grow in vitro can be expanded in vitro.
Figure 3 Robert Gallo | Source: medschool.umaryland.edu
With the help of these two methods, Montagny et al. began studying retroviruses in T cells extracted from breast cancer patients.
However, just as the Montagny laboratory was preparing various techniques for studying retroviruses, a new retrovirus, HIV, began to circulate in humans with serious consequences.
3
Between the square inches, the world is different
After June 1981, the U.S. Centers for Disease Control and Prevention reported an increase in cases of AIDS. What exactly causes this terrible disease? This became an urgent issue at the time.
Gallo speculated that the new disease may be caused by a retrovirus. As a pioneer in retroviral research, Gallo's speculation is well reasoned.
His lab not only invented T cell culture technology, but also isolated the first human retrovirus, the human T-cell leukemia virus-1 (HTLV-1). Many of the new diseases are similar to HTLV-1 infections, such as CD4-positive T cells, the symptoms of HTLV-1 infection in animal models are similar to those of the new disease, and the transmission of HTLV-1 is similar to that of the new disease - it can be transmitted through blood transfusion, sexual behavior and mother-to-child transmission. These clues led Gallo to believe that the new disease was caused by a retrovirus similar to HTLV-1.
In 1982, Gallo's lab detected DNA sequences similar to HTLV-1 in blood samples from patients with the new disease. In early 1983, they found 2 of 33 samples containing HTLV-related DNA. It was later discovered that this was because the two patients were infected with the HTLV virus at the same time, but these experiments misled Gallo into thinking that the pathogen of the new disease was a new member of the HTLV family.
It turned out that Gallo's speculation that the new virus was retrovirus was correct, but it was not a new member of the HTLV family.
Gallo's conjecture was spread through a number of clinicians and immunologists in the field. Montagny was also informed of these conjectures, and in 1982 he collaborated with his student, Fran oise Brun-Vezinet, on a new pathogen.
On 3 January 1983, Brun-Vezinet obtained a lymph node sample from a patient numbered BRU. Montagny personally ground the sample and cultured the T cells in the sample. After 15 days, Fran oise Sinoussi detected reverse transcription activity in the culture supernatant, confirming that the new pathogen was indeed a retrovirus. They called the virus lymphadenopathy-associated virus (LAV).
At the time, the HTLV-1 and HTLV-2 discovered in Gallo's lab were the only known human retroviruses. Using Gallo's HTLV antibody, Montagny's lab examined their samples and found that the HTLV antibody did not bind to their newly discovered virus. This shows that the new virus is not the HTLV that Gallo speculated.
Montagny was lucky that the first sample gave him the right direction. He later recalled that they later received a sample of the patient, code-named MOI, who was infected with both the new virus and HTLV. If this were the first sample they tested, they would most likely be as misled as Gallo.
Meanwhile, Montagny's collaborator, electron microscopist Charles Dauguet, also found that the new virus under electron microscopy has a different morphology from HTLV. Virologist Edwald Edlinger suggested that Montagny compare the new virus to the lentivirus found in animals, and through electron microscopy, they found that the new virus looked almost identical to the lentivirus.
Figure 4 HIV virus | Source: pixabay.com
Montagny and Gallo exchanged their findings, and Gallo suggested joint publication of their results. In May 1983, Montagny and Gallo simultaneously published their respective isolated new viruses. Unbeknownst to Gallo at this point, however, the virus he isolated was actually a mixture of the new virus and HTLV, and that the LAV isolated by Montagny was a pure virus. This may be the main reason why Gallo later failed to share the Nobel Prize with Montagny.
From the second half of 1983 to the first half of 1984, Gallo Labs technician Betsy Reed-Connole and collaborator Mika Popovic isolated a number of new strains (RF, IIIB and MN). During this time, they published a series of papers detailing the isolation of these viruses, the method of in vitro amplification, and the evidence that this virus is a pathogen of new diseases. These strains also became the standard for subsequent blood tests.
At this time, Montagny's experiment also encountered problems. The virus (LAV) they isolated from BRU patients was unable to expand in T cells. Gallo went to Paris to visit Montagny's lab and brought him samples of the IIIB strain, which could proliferate continuously in T cells. Gallo wanted Montani to compare the IIIB and LAV strains, and they agreed to hold a joint press conference if the virus they isolated was the same.
4
The controversy alarmed the French and American top brass
However, the news somehow leaked out. A reporter contacted Margaret Heckler, then secretary of health and human services, to urge her to urgently recall Gallo back to the country and hold a unilateral press conference in the United States in advance.
Not only that, but in May of the following year (1985), the U.S. Patent and Trademark Office granted a patent for a blood test for the new virus to Gallo's research institute. But in reality, France has filed almost the same patent application before Gallo.
Between 1985 and 1986, Representatives of France initiated four legal proceedings, and the two governments engaged in a two-year debate. It wasn't until 1987 that then-U.S. President Reagan and French Prime Minister Mitterrand signed a settlement agreement proposing to share rights and interests. However, the agreement gave the United States more interests until it was renegotiated in 1994, when the two sides agreed to have a 50% interest in each other.
The hasty press conference held in the United States not only caused a political storm later, but also formed many controversies in the scientific community. And some coincidences that followed exacerbated these controversies.
Montagny isolated a strain that could proliferate after LAV, called LAI. Probably due to the virus's strong proliferative capacity, it contaminated MONTANI's previous LAV samples. Montagny had sent the sample to Gallo, which led to contamination of the Gello laboratory strain. Gallo later discovered that the IIIB isolated in his laboratory was also contaminated with LAI, and that the contaminated strains spread to many laboratories. Although contamination between these strains was not gradually recognized until the 1990s, this did not affect scientists' understanding that they caused diseases that caused human immunodeficiency.
Figure 5 After Montagny won the Nobel Prize at the Stockholm Concert Hall on December 10, 2008| Source: nobelprize.org
After discussion in the academic community, the new virus was eventually named human immunodeficiency virus (HIV), and the diseases caused by it were collectively referred to as immunodeficiency syndrome (AIDS), so HIV was also referred to as HIV.
Despite many twists and turns, Montani's contribution to isolating HIV was recognized by the academic community. Gallo's comments, published in the journal Science in 2002, also explicitly acknowledged that because his team failed to exclude HTLV in a strain published in 1983, Montagny's team was the first to isolate the real HIV.
In 2008, Montagny and his collaborator Fran oise Barré-Sinoussi were jointly awarded the Nobel Prize in Physiology or Medicine for the discovery of HIV. He later became one of the co-founders of the World Foundation for AIDS Research, contributing greatly to human understanding of HIV and AIDS.
bibliography:
1.Montagnier L. Historical essay. A history of HIV discovery. Science. 2002;298(5599):1727-1728. doi:10.1126/science.1079027
2.Gallo RC. Historical essay. The early years of HIV/AIDS. Science. 2002;298(5599):1728-1730. doi:10.1126/science.1078050
3.Gallo RC, Montagnier L. The discovery of HIV as the cause of AIDS. N Engl J Med. 2003;349(24):2283-2285. doi:10.1056/NEJMp038194
4.Luc Montagnier Biographical : https://www.nobelprize.org/prizes/medicine/2008/montagnier/biographical/
5.Gallo RC, Sarin PS, Gelmann EP, et al. Isolation of human T-cell leukemia virus in acquired immune deficiency syndrome (AIDS). Science. 1983;220(4599):865-867. doi:10.1126/science.6601823
6.Barré-Sinoussi F, Chermann JC, Rey F, et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science. 1983;220(4599):868-871. doi:10.1126/science.6189183
Plate editor| Ginger Duck