The story of mRNA will not end here with COVID-19: its potential extends far beyond the scope of this epidemic.

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Editor’s note: Last year, 48 hours after Chinese scientists announced the gene sequence of the new coronavirus, Moderna developed an mRNA vaccine formula at an astonishing speed. But what many people don’t know is that the reason why mRNA technology is so amazing is that it is the accumulation of efforts and failures of many scientists for decades. Derek Thompson unveiled the development history of mRNA technology for us. The original text was published on the Atlantic Monthly website with the title: How mRNA Technology Could Change the World

Key points:

With the help of manually edited mRNA, in theory we can order our cell machines to make almost any protein under the sky

The mRNA vaccine can fake the “spike protein” of the new coronavirus, thereby training our immune system to recognize and kill the virus

The story of mRNA may not end here with COVID-19: its potential is far beyond the scope of this epidemic

The classic two speeds of scientific progress are fully reflected in mRNA-first slowly, and then suddenly reach a climax

mRNA technology is expected to find us a fast and efficient way to treat cancer

The victory of mRNA is not a journey of lonely heroes, but a journey of heroes

Synthesis of mRNA, which is the original technology behind Pfizer-BioNTech and Moderna’s new crown vaccine. This technology seems to be an accidental breakthrough, or a new discovery. Only a year ago, almost no one in the world knew what an mRNA vaccine is, but this is justified, because no country in the world has approved this vaccine. But a few months later, it was this technology that drove the two fastest vaccine trials in scientific history.

Just like XuLike many breakthroughs, this superficial overnight fame is actually a work of decades. From the 1970s (when Hungarian scientists took the lead in conducting early mRNA research), more than 40 years have passed since the United States approved the first mRNA vaccine on December 14, 2020. On the long road to this idea finally becoming feasible, the career opportunities of several people were destroyed, and several companies were near bankruptcy.

Part of the reason why the dream of mRNA is maintained is that its core principle is extremely simple, even to the point of beauty: The most powerful pharmaceutical factory in the world may reside in all of us.

Almost all human body functions depend on protein. The role of mRNA (messenger ribonucleic acid) is to tell our cells what kind of protein to make. With the help of manually edited mRNA, we can theoretically order our cellular machinery to make almost any protein under the sun. You can produce molecules that are naturally present in the body on a large scale to repair organs or improve blood flow. Or, you can ask our cells to forge a protein that is not on the list, and our immune system will learn to recognize it as an intruder and destroy it.

For the new coronavirus that causes COVID-19, the mRNA vaccine will send detailed instructions to our cells to make them produce unique “fibrillin”. After detecting foreign invaders, our immune system will target these proteins to destroy them, but it will not disable the mRNA. Wait later, if we are faced with a complete virus, our body will recognize the fibrillin again and launch a precise attack on it like a well-trained soldier, thereby reducing the risk of infection and blocking it Serious illness.

However, the story of mRNA may not end here with COVID-19: its potential extends far beyond the scope of this epidemic. This year, a team at Yale University also obtained a similar patent for RNA-based technology that can be used to make a vaccine against malaria, perhaps the most devastating disease in the world. Because mRNA is easy to edit, Pfizer said it plans to use it to deal with seasonal influenza that will continue to mutate and kill thousands of people around the world every year. The company that partnered with Pfizer last year, BioNTech, is developing personalized therapies to generate on-demand proteins related to specific tumors to guide the human body against advanced cancers. In mouse experiments, synthetic mRNA therapy has been shown to slow down and reverse multiple sclerosis. Özlem Türeci, Chief Medical Officer of BioNTech, said: “Now I am more convinced than before that mRNA has a wide range of transformative properties. In principle, proteinEverything we can do can be replaced by mRNA. “

In principle, this is a scale of billions of dollars. The advancement of mRNA is broad, covering everything from expensive but experimental to brilliant but speculative. But the past year reminds us that after a long period of incubation, scientific progress may occur suddenly. John Mascola, director of the National Institute of Allergy and Infectious Diseases, said: “This must be a gathering of mRNA budding. In the scientific community, RNA technology may be the most important story of the year. We didn’t know whether it was effective before. But now We know.”

1. The long road to breakthrough

For more than 40 years, synthetic RNA has actually been unable to do anything useful. In 1978, Katalin Karikó was a young scientist at the Biological Research Center in Szeged, Hungary. At that time, she began to make this idea a reality. In the 1980s, she left Hungary for the United States. At the University of Pennsylvania, she encountered difficulties in designing mRNA that the human body does not reject. When her research failed to attract government funding and support from university colleagues, she was demoted.

After ten years of intermittent efforts, Karikó and his research partner Drew Weissman finally made a breakthrough in the early 2000s. In order to allow synthetic mRNA to break through the cell’s defense system, the two realized that they had to adjust one of the components of the molecule, the nucleosides that make up the RNA chain. Reporters Dianian Garde and Jonathan Saltzman wrote on the scientific website Stat: “The solution that Karikó and Weissman discovered is equivalent to a biological tire change.”

In the United States, this paper attracted the attention of a group of postdoctoral researchers, professors, and venture capitalists. They founded a company whose name is a combination of modified (edit) and RNA: Moderna. In Germany, Ugur Sahin and Özlem Türeci, who are engaged in immunotherapy research, also saw its great potential. The two established several companies, one of which is researching mRNA-based cancer treatment methods: BioNTech.

Türeci said: “When we first started, the industry had a lot of doubts about this, because this is a new technology that has not yet been approved. Drug development is subject to strict supervision, so everyone does not like to go away. The road traversed.” Thanks to the support of philanthropists, investors, and other companies, BioNTech and Moderna were able to move forward for several years without an approved product. Moderna and the National Institutes of HealthThe National Institutes of Health (NIH) cooperated and received tens of millions of dollars in funding from the Defense Advanced Research Projects Agency (DARPA) for the development of vaccines against viruses, including Zika virus. In 2018, Pfizer signed an agreement with BioNTech to jointly develop influenza mRNA vaccines.

Philip Dormitzer, head of Pfizer’s virus vaccine research and development program, said: “The reason why this technology attracted us at the beginning was the flu because it was fast and flexible. Editing mRNA can be very fast. For For viruses like influenza, this is very useful because it needs to be updated twice a year, once in the northern and southern hemispheres.”

When the outbreak of the new crown virus caused the lockdown of Wuhan, Moderna and BioNTech have spent several years fine-tuning their technologies. As the epidemic spreads all over the world, Pfizer and BioNTech are ready to immediately shift their research direction from influenza to SARS-CoV-2. Dormitzer said: “This is actually our researchers replacing the flu protein with the new coronavirus spike protein. It turns out that this is not a big leap.”

After decades of basic research on mRNA and several years of clinical research, scientists discovered the mystery of SARS-CoV-2 at an alarming speed. On January 11, 2020, Chinese researchers published the genetic sequence of the virus. Within about 48 hours, Moderna had formulated the mRNA vaccine. In late February of the same year, a batch of vaccines were shipped to Bethesda, Maryland, USA for clinical trials. Vaccine development has also been unusually accelerated by the Trump administration (billions of dollars have been invested in a variety of vaccines, including Moderna vaccine). After about 40 years of hesitation, mRNA research finally ushered in an epic perfect time for Hollywood movies to enter the promised land. The classic two speeds of scientific progress are reflected here incisively and vividly-first slowly, slowly, and then suddenly reach a climax.

2. Hurry up, hurry up!

Speed ​​and agility were the characteristics of DARPA and Pfizer’s initial interest in mRNA. Moreover, if this technology releases more breakthroughs after the epidemic, speed and agility will play an important role.

Malaria causes more than 400,000 deaths each year, most of which are young children. Malaria is not caused by viruses or bacteria, but by a separate organism (called Plasmodium). Plasmodium has a variety of strategies to evade our immune system. For most diseases, a human infection can gradually form a defense mechanism. However, malaria has broken through our cellular defense capabilities, making it possible for people to contract this disease over and over again. ThisIt also makes it difficult to vaccinate malaria: even after four vaccination shots, the only available vaccine does not work well.

Last month, a patent for an RNA-based anti-malaria vaccine was approved. This vaccine has shown its promise in mouse experiments. Richard Bucala, co-inventor and scientist at Yale University School of Medicine, said: “We have been working on this vaccine for these years, but due to the success of the COVID vaccine, the entire landscape has changed in the past six months.”

The malaria vaccine uses self-amplifying RNA (saRNA), which is slightly different from the mRNA technology used by Moderna and Pfizer. The vaccine against COVID-19 pre-injects all the messenger RNA you will get. Self-amplified RNA is to replicate itself in our cells. In theory, this copy-and-paste function means that everyone only needs a small dose of the vaccine to produce a larger immune response.

Bucala said: “The replication function of saRNA is very important, because it is not a vaccine to prevent infection, but a vaccination to prevent infection.” There is no magic medicine that is not distributed, and it is nothing like useless medicine that has never been approved. Different. He continued: “Pfizer and Moderna’s vaccines require a large amount of mRNA and are expensive to manufacture. This is why they enter many countries outside the United States much more slowly. If saRNA is used, we only need to inject one. One percent of the dose can achieve the same effect. For widespread diseases, saRNA is easier to scale.”

Then there is cancer. Scientists may never design a vaccine against cancer, because cancer is not a single disease, but a group of diseases composed of more than 100 diseases. We often use the location of origin to name cancer. However, what if we can use our own treatment groups that can train the body to attack specific tumors to deal with these hundreds of cancers?

This is the idea behind BioNTech’s cancer immunotherapy research. Its working mechanism is roughly like this: For every cancer patient, BioNTech will extract a tissue sample from the tumor for genetic analysis. Based on this test, the company will design a personalized mRNA vaccine, and then use this vaccine to tell the patient’s cells to produce proteins associated with specific mutations in that specific tumor. The immune system will learn to search for and destroy similar tumor cells in the human body.

This analysis and design process, with BioNTech and Moderna, obtained the sequencing of SARS-CoV-2 by Chinese scientists and quickly analyzed them. There is not much way to identify the fibrillin to be attacked and carry out effective treatment.different. BioNTech’s Özlem Türeci said: “We hope that everything we have learned from COVID about the production and manufacture of mRNA can provide inspiration for my research on cancer treatment out of the box.” She said that the company is currently working on cross-pollination. Clinical trials are being conducted for personalized vaccines “basically equivalent to every solid tumor”, including melanoma, breast cancer and ovarian cancer. In an analysis published in the journal Molecular Cancer in 2021, researchers at the University of North Carolina pointed out that in recent years, the progress of these cancer treatments has been relatively slow, but the breakthrough of COVID-19 and cancer vaccines are “promising” clinically. The experiment is consistent. They concluded: “We foresee rapid development of mRNA vaccines for cancer immunotherapy.”

3. Lucky to win by yourself

In March 2020, Peter Hotez, a vaccine scientist at Baylor College of Medicine, made his own judgment. He believed that mRNA technology could not win the competition against COVID-19. He bet on Merck Pharmaceuticals. The company recently developed a vaccine using an improved poultry virus called vesicular stomatitis virus, or VSV for short, which has achieved amazing success against the Ebola virus. However, when Merck’s promising new technology failed in clinical trials, the company stopped the development of the COVID-19 vaccine.

Hotez regards Merck’s failure as an important lesson of science and a warning fable for mRNA. He said: “Technology that is effective for one epidemic may not be effective for the next. It is too early for the vaccine to be called a miracle. Maybe the mRNA will not be able to deal with the next target.”

Even the biggest supporter of mRNA admits this. Pfizer’s Dormitzer said: “This is not a panacea, and mRNA is not the perfect choice for everyone.” His partners at BioNTech agreed. Türeci said: “I don’t think mRNA is the holy grail of everything. We will find that mRNA can be surprisingly successful for some diseases, but not for others. We must prove this one by one for each infectious disease. A little bit.”

In the next ten years, mRNA may not be able to produce such a successful effect as this time, or it may never be. Perhaps scientific institutions will conclude that this technology can behave like this in the epidemic because of a simple and unique virus nemesis. Hotez agrees: “The coronavirus may be one of the simplest vaccine targets we have seen in modern times. Everything we threw to it has worked.”

Or maybe because we are lucky. But luck will only be reserved for those who are prepared. The reason why the coronavirus is an easy target is simply because science makes it easy. Four years ago, when the Middle East Respiratory Syndrome broke out in the Arabian Peninsula and South Korea, 18 scientists from the National Institutes of Health, Vanderbilt University, Dartmouth College and other institutions announced that they were most significant against the coronavirus. Characteristics-the result of a detailed examination of the shape and behavior of the spike protein. Long before anyone knew that this tiny pathogen would soon be confined to the world, this paper has explained the mystery and vulnerability of this virus. They concluded in advance in this 2017 paper: “Our research has laid the foundation for the structure-based design of coronavirus vaccines.” Without this detective work, mRNA may not be A breakthrough will be made.

Today’s vaccine is made by scientific success, but it is also inseparable from failure. For decades, researchers have been working hard to design a viable HIV vaccine, and many observers believe that this field has reached a dead end. But a new paper argues that these continuous failures have forced AIDS vaccine researchers to spend a lot of time and money on unfamiliar and unproven vaccine technologies, such as synthetic mRNA and the viral vector technology used by Johnson & Johnson vaccine. The author of the paper, MIT economist Jeffrey E. Harris, wrote that 90% of the COVID-19 vaccines that have come to clinical trials use technology that “can be found in prototypes tested in HIV vaccine trials.” He pointed out that if an AIDS vaccine is successful, the company behind it will also be a big success. But not. All competitors in the vaccine field have learned lessons from collective failures and contributed to collective wisdom. The many failed beginnings of HIV vaccination led to the subsequent explosive growth of new technologies and helped usher in a new golden age of vaccines.

4. Tree of Progress

We can call this record-setting vaccine development process good luck. Or we can give it a real name: a strong recognition of the important role that science plays in this world.

Mascola of the National Institutes of Health (NIH) said: “Five years ago, we were still ignorant of mRNA. But five years from now, we will understand that we are actually right now. In another state of ignorance. This is why mRNA is such a beautiful scientific story. So many researchers, philanthropists, government organizations, and companies have taken such a huge risk for a technology with insignificant initial response . But they worked together and finally figured out a way to make it work.”

As a fable of scientific progress, I sometimes imagine the life cycle of a tree. Basic scientific research sows all kinds of seeds. Some of these seeds failed completely. Research has nowhere to go. Some seeds have become dwarf shrubs. Although the research has not completely failed, it has little value. Some seeds are thriving, luxuriant, and fruitful. After being picked by scientists, companies and technicians, these seeds become products that change our lives. For many years, mRNA technology looked like bushes. But in 2020, it will bear fruit.

In the early stages, you can’t know if you planted a dud or a revolution. Even if it is a revolution, you don’t know what kind of revolution it is. Pfizer has invested in research because mRNA has the potential to fight influenza, but it has made history in fighting a completely different virus. However, because of this risk of uncertainty, countries like the United States should encourage more basic science and highly innovative research.

From research in a pool of stagnant water to breakthrough technology, the victory of mRNA is not a journey of lone heroes, but a journey of heroes. Without Katalin Karikó’s hard work to make mRNA technology effective, there would be no Moderna or BioNTech in this world. Without government funding and charitable support, these two companies may have gone bankrupt before they could produce a vaccine in 2020. Without the failure of HIV vaccine research forcing scientists to explore new and unfamiliar fields, then we may still have no idea how to make this technology work. A few years ago, without an international team of scientists uncovering the secrets of the coronavirus spike protein, our understanding of this pathogen might not be sufficient to design a vaccine to defeat the virus last year. . The tree of mRNA technology is the result of many seeds.

Translator: boxi.