The picture is from mit.edu
Introduction
In the emergency response to the new crown epidemic, the first vaccines to be launched are based on mRNA technology. Recently, the "double mutation" mutant virus that appeared in India, the mRNA vaccine has once again highlighted the advantages of short research cycle and other advantages. One of the developers, BioNTech, told CNBC on April 29 that BioNTech has launched relevant vaccine tests for the "double mutation" mutant virus. Confidence fights this stubborn virus[1].
Just a year ago, mRNA was not a scientific term with public appeal, and no country had approved an mRNA vaccine. It can be said that mRNA became famous through the new crown epidemic. Even the legendary Elon Musk , following his imagination of space exploration and brain-computer interface, also aimed at mRNA technology, believing that mRNA is like the computer program of the human body, which can be programmed to perform any operation, such as stopping aging To rejuvenate and be a little more crazy, you can even turn a person into a butterfly[2], and directly upgrade "Zhouzhuang Dream Butterfly" into a big butterfly. Faced with such an interesting future technology, as a doer, Musk has announced that Tesla will build a RNA micro-factory for CureVac, which is headquartered in Germany.
There is no doubt that the launch of the mRNA new crown vaccine is an important medical revolution, which has caused major media around the world to report, but in a sense, this concern actually conceals the significance of mRNA technology beyond the epidemic itself, including this article. Introducing the mRNA cancer vaccine .
Welcome to other cancer popular science articles written by the author:
Katarin Kariko, picture source: [4] Kariko was born in a butcher family in Hungary and wanted to become a scientist since childhood.After finishing post-doctorate in Hungary, Kariko and her husband, who is also a Ph.D., decided to immigrate to the United States because of funding problems for research at University. In 1985, the Carrico couple and their two-year-old daughter embarked on a flight to the United States with 900 pounds hidden in a teddy bear, and began their "American Dream" journey.[4]. After arriving in the United States, her husband had to give up academics in order to make a living and identity. Carricko found a position as an assistant professor of research at the University of Pennsylvania and started the earliest mRNA research. In Calico's view, mRNA can guide cells to make any protein , which is like a god-like existence. mRNA vaccine principle diagram, picture from orleanscommunityhealth.org In fact, mRNA was discovered as early as the 1960s[5, 6]. If the human body is compared to a machine, then the millions of tiny proteins are the parts that keep the machine running, and mRNA is the commander-in-chief of making the parts. Therefore, human cell itself is the most perfect pharmaceutical factory in nature, which can produce any desired protein according to mRNA instructions, unlike traditional methods, which require time-consuming and labor-intensive protein expression and purification through in vitro genetic engineering. Taking the new crown vaccine as an example, after the new coronavirus genome RNA sequence is injected into the human body, it skips the process of in vitro protein synthesis and directly produces viral proteins in human cells. Recognize viral proteins to generate an immune memory for COVID-19. When the real new coronavirus enters the human body, the immune cell is like a well-trained soldier, quickly identifying the virus and launching a precise attack on it. In theory, mRNA is omnipotent, but the clinical application of mRNA has not been recognized for decades. A major reason is that mRNA is very fragile and easily degraded by the ubiquitous RNA enzyme in the surrounding environment. It is no exaggeration to say that studying mRNA in the laboratory is a nightmare. If you are not careful, it will disappear from your eyes, let alone reach the human cells through many obstacles. Therefore, mRNA is just an academic term followed by textbooks and does not get much attention in the real world. It was not until 1990 that Wolff et al. of the University of Wisconsin first reported that intramuscular injection of mRNA into mouse skeletal muscle could indeed produce the protein [7].
At the same time, after countless attempts, Calico successfully used mRNA to instruct cells to produce the urokinase receptor protein. But mRNA still can't get rid of the label of unpopular fields, and has not been favored by capital. After 's funding applications were rejected again and again, Calico received a notice of demotion from school , and was once diagnosed with cancer.
Fortunately, after several setbacks, Carico met the most important Bole in his life, Drew Weissman (Drew Weissman) professor [4, 8].
Drew Weissman, image source: Wikipedia
Professor Weissman proposed to start the subject of AIDS mRNA vaccine. Carrico didn't want to give up as long as he had the opportunity to continue studying mRNA, so he quickly joined the Weissmann working group. It coincides with the emergence of liposome , lipid nanoparticles and other protective devices [9]. These devices can wrap mRNA and escort mRNA to the designated destination, so there is a preliminary solution to the first pain point of mRNA research.
However, the second big problem of mRNA technology emerged. Calico successfully used mRNA to produce the desired protein in cells in a petri dish, but the mRNA had no effect in mice. After repeated investigations, it was found that the original mouse immune system defined mRNA as foreign matter, and directly initiated the immune response to clear the mRNA. This is undoubtedly a basic judgment that the idea of mRNA treatment will not work at all.
But Calico chose to rise to the challenge. Hard work paid off, and Calico was pleasantly surprised to find that tRNA, the brother of mRNA, could successfully escape the tracking of the immune system. After repeated comparison of mRNA and tRNA, clues slowly surfaced: it turns out that tRNA carries a molecule with anti- immune detection function, called pseudouridine.
So, an epoch-making idea was born in 2005: adding pseudouridine to mRNA, the modified mRNA can sneak into cells and escape the immune system to attack [10]. Calico and Weisman published the paper and applied for the patent .
Calico and Weissmann mRNA modification patent, image source: Google patent
This discovery provides new hope for mRNA research at a low point, and also becomes the cornerstone of the sprint for the new crown vaccine field in the future. Therefore, a German company called BioNtech won the mRNA modification patent authorization and continued to support Calico to research mRNA technology. In 2013, Calico was directly hired as vice president.
When the new crown epidemic broke out in 2020, mRNA technology was just ready, which made a historical coincidence at the right time and place. In just a few hours, BioNTech quickly designed an mRNA vaccine based on the new crown gene sequence. On November 8, the results of the first batch of mRNA vaccines developed by BioNTech confirmed that they have strong immunity to the new coronavirus. When Carico got the news, she ate a whole box of chocolate-covered pralines as a unique way to celebrate.
It has been 32 years since Calico first studied mRNA. In the middle of 32, Calico's personal annual income never exceeded 60,000 US dollars. He persisted in working in a field that was unpopular to almost no one, and was rejected and even demoted countless times. When was interviewed by The New York Times, in the face of countless honors and applause, Calico just said lightly, "I have achieved my life's dream" [4].
02 A "Cheng Yaojin"
mRNA technology was conceived in American universities, but German biotech companies did their part and even rushed ahead in clinical practice, such as the aforementioned BioNTech and another CureVac. CureVac has been in clinical trials since 2009. Why is Moderna, which was only established in 2010, more sought after? What is the origin of the "Cheng Yaojin" who was killed halfway? And what skills did the latecomers rely on?
The beginning of the story still has to do with Calico.
Derrick Rossi was still a postdoctoral fellow at Stanford University in 2005 when Carrico and Weisman published their major research [10]. When he read the paper, he was acutely aware that this technology was about to have a profound impact, and even predicted that it would be a Nobel Prize-level discovery.
Derek Rossi, image source: Stat News
Rossi, who became Assistant Professor of at Harvard Medical School in 2007, followed Calico's ingenuity, planning to use modified mRNA to reprogram somatic cells into embryo-like stem cells , and successfully grown embryonic-like stem cells in a petri dish in 2010, which is 100 times more efficient than traditional methods [11, 12].
The young Rossi was excited, but as a junior assistant professor at Harvard , he did not have the social resources to commercialize his discoveries, so he took the lead in his predecessor Timothy Springer. Under the recommendation of (Timothy Springer) , I met the famous MIT professor Robert Langer (Robert Langer) . Lange is not only the youngest academician of the Third Academy of Sciences in the United States, a mentor to the world, but also an outstanding entrepreneur who has founded more than 20 companies. There is a popular saying in the folk: If you want to start a biotech company, you have to see Lange first, whose reputation is evident [8, 13].
Robert Lange, picture source: Wikipedia The potential of thousands of lives also creates limitless business opportunities. After the interview, Lange decided to use his connections to make a big difference. The first person Lange invited to enter the game was Noubar Afeyan, founder and CEO of Flagship Pioneering, a well-known biomedical venture capital institution.
Old friends really see the same thing, and Afeyan also recognizes mRNA technology very much, so in just a few months, he resolutely co-founded Moderna with Rossi and Lange in 2010.
After the establishment of the company, the first priority is naturally to recruit talents. Who has the ability to control this future unicorn in the mRNA field? Afeyan has always admired the management skills of Stéphane Bancel () , and has sent out invitations many times before, but Bancel has a high vision, and those small companies cannot enter his discernment .
Bancel was already CEO of the French diagnostics company BioMerieux when Afyyan offered another olive branch. BioMerieux is well-known in the diagnostic industry, with a market value of nearly 3 billion US dollars and more than 6,000 employees, while Moderna has just started, and there is only one scientist in the company.
Stephen Bansell, picture source: Stat News
Unexpectedly, under Afeiyan's various expressions of determination, pie, chatting, and heart-to-heart offensive, Bansell broke the boat and gave up the glamorous high-paying position , gladly joined this little-known start-up. Later, relying on his personal charm and prestige, Bancel attracted a group of well-known figures in the scientific community, including Jack Szostak, the winner of the 2009 Nobel Prize in Physiology or Medicine.
Backed by the golden mountain of Flagship Pioneering, Bansell leads Moderna forward without distractions, and is committed to solving the three core problems of mRNA technology The foundation is to have a stable patent. Like BioNtech, Moderna was initially licensed to carry out research under the Calico patent. If you have to rely on other people's patents for support in the future, you will inevitably be controlled by others, which is not a long-term solution. Through unremitting efforts, Moderna finally succeeded in finding a compound 1-methylpseudouracil that can replace pseudouridine/5-methylcytidine modification, and won the patent to relieve the hidden worries and laid a solid foundation for the establishment of the mRNA kingdom.
2. mRNA delivery: mRNA drug delivery has been a key bottleneck hindering development. The naked mRNA is easily degraded by extracellular RNase, and even if it enters the cell, it is easy to accumulate in the lysosome , and cannot reach the place where it can function.For short RNA molecules (such as siRNA, about 20 bases in size) , lipid nanoparticles are powerful delivery tools, but mRNAs are too slender and can often be as long as hundreds of thousands of bases. The difficulty factor is very large.
It is very difficult for Moderna to develop its own drug delivery technology platform at the start-up stage. It is not only limited by manpower, but also limited by funds, so it can only be imported externally. At that time, Moderna looked at about a dozen drug delivery platforms, and finally chose Arbutus/Acuitas.
With the continuous efforts of internal researchers, Moderna finally has its own delivery technology, which is 25 times more efficient than traditional methods to escape lysosomal aggregation.[15]. By contrast, CureVac and BioNTech still rely on Genevant and Arcturus/Acuitas, respectively.
3. Regulation of protein production: Whether mRNA is used as a vaccine or a drug, it is ultimately the protein that directly plays a role, so the amount of protein needs to be strictly controlled, more toxic, less useless. But how much mRNA can produce the right level of protein is a whole new issue. To solve this problem, Moderna is using machine learning to model how mRNA sequences control protein production, paving the way for precise regulation later.[16].
was founded in a low-key manner in 2010, exposed to the public in 2012, and its IPO in 2018 set a record high in the history of biotechnology. Then, in 2020, when the new crown epidemic came out of the circle, Moderna became a market value of 100 billion yuan in only 10 years. The unicorn enterprise created another legend after Genentech .
There is no doubt that the backgrounds of several Moderna founders have allowed Moderna to win at the starting line, but it is also inseparable from the management's infinite dedication to technology and the concept of mastering the initiative. The outbreak of the new crown epidemic also gave Moderna a show to the world. opportunity, knowing that Moderna has been on the cusp of public opinion for years. After all, in the absence of any clinical product, it is inevitable to achieve a valuation of billions of dollars.
03 Can mRNA technology carry the banner of conquering cancer?
mRNA new crown vaccine has successfully made Moderna and BioNTech out of the circle, but mRNA vaccine is far from limited to new crown or other viruses. Cancer vaccine is actually a track where major companies are fighting with all their strength before the outbreak of the new crown. The
mRNA cancer vaccine is different from the well-known cervical cancer vaccine . The cervical cancer vaccine is a preventive vaccine.
What is a therapeutic vaccine? Let's first understand the concept of antigen: cancer cells carry many gene mutations -specific protein (antigen) . It stands to reason that these specific proteins should be recognized by the body's own anti-cancer artifact immune cells in time for one-click removal. However, tumor cells have very sophisticated camouflage techniques, pretending to be good people to escape the eyes of immune cells.
Therapeutic mRNA vaccines produce a large number of cancer cell antigens by injecting mRNA, expose these antigens in front of immune cells, and induce immune cells to open their eyes to see clearly. Those who carry these antigens are all invaders and need to be wiped out. Immune cells that have undergone intensive training will naturally learn to be smart now. No matter how deliberately the cancer cells hide the fox tail (antigen) , they can also be keenly discovered.
Tumors will be wiped out after a single injection of vaccine. Thinking about it makes me excited. Therefore, cancer vaccines have always been a dream in the field of anti-cancer. However, after decades of trying, only one vaccine called Provenge was approved. Later, due to high cost and other factors, the sales were dismal. After the bankruptcy of the original research company Dendreon, it was kicked around like a ball. Acquisition by Cell Group.
Is cancer vaccine just a dream after all? Not really. At first, the development of cancer vaccines was basically focused on "sharing" tumor antigens, that is to say, selecting a few cancer cell antigens from different patients with high frequency, hoping that a specific broad-spectrum (universal) vaccine could Unleash the power to remain unchanged. However, the most annoying virtue of cancer cells is that they are fickle. Different patients have different cancer cell antigens, and the same patient is also fickle at different stages. How can it be so easy to deal with.
Therefore, in recent years, there has been a new concept of "personalized vaccine", that is to say, firstly compare the patient's cancer cells and healthy cellsDNA, identify specific antigens, and then customize the production of vaccines against specific antigens, injection In a patient, the immune system is trained to kill cancer cells that carry the antigen.
Personalized cancer vaccine treatment process, picture source: [17]
Such top technologies are not faulty in theory, but not so easy to operate in practice. If the vaccine preparation time is too long, firstly, patients with advanced stage may not be able to wait, and secondly, cancer cells may mutate a new moth (antigen) , and the previous vaccine may not be effective.
It is a race against time, mRNA has fully proved its strength in the new crown epidemic, and is fully confident to stand out in the competition with other cancer vaccine players.After all, cancer vaccines based on cells, viruses, bacteria, proteins/ polypeptides and are not as smart as mRNA, and can use the all-natural factory for protein production in human cells, which greatly reduces the complexity of synthesis and shortens time-consuming.
How about the mRNA cancer vaccine?
BioNTech is a blockbuster. Results released in 2017 showed that of the first 13 patients with advanced melanoma who received a personalized mRNA cancer vaccine, all of them developed an immune response to the vaccine, 8 had their tumors gone without recurrence within 23 months, and the remaining 5 Due to the fact that the tumor had spread at the time of vaccination, 2 patients' tumors shrank, and 1 of them completely regressed after receiving adjuvant therapy.[18].
Moderna is not far behind, and is jointly developing personalized cancer vaccines with Merck . The interim data released in 2020 is also remarkable: 10 cases of HPV head and neck squamous cell carcinoma patients, half of them The patient's condition was relieved.
04 Conclusion
After about 40 years of searching, mRNA technology has finally ushered in a new chapter. Starting from the new crown vaccine, to cancer treatment, in the future, mRNA technology may gradually get involved in more disease fields, as expected by Lange and Carrico.
At this stage, mRNA technology still has a long way to go. The approval of the vaccine is entirely due to the emergency use authorization in the context of the new crown epidemic. Only 9 of the evaluable solid tumor patients responded [19]. Besides, vaccines are actually the low-hanging fruit of mRNA therapy. After all, only a small amount of protein can be produced to induce immunity. How to use cell factories to produce larger amounts of protein is still up in the air.
Fortunately, after the success of the mRNA new crown vaccine, the government and investors may be more keen to support mRNA technology, accelerate the release of its greater potential, and become a real game changer to dominate.
About the author
Dingling
Biochemistry PhD, young writer. He used to work at the Howard Hughes Medical Institute and MD Anderson Cancer Center, and is now engaged in the consulting industry. The picture is from mit.edu Introduction In the emergency response to the new crown epidemic, the first vaccines to be launched are based on mRNA technology. Recently, the "double mutation" mutant virus that appeared in India, the mRNA vaccine has once again highlighted the advantages of short research cycle and other advantages. One of the developers, BioNTech, told CNBC on April 29 that BioNTech has launched relevant vaccine tests for the "double mutation" mutant virus. Confidence fights this stubborn virus[1]. Just a year ago, mRNA was not a scientific term with public appeal, and no country had approved an mRNA vaccine. It can be said that mRNA became famous through the new crown epidemic. Even the legendary Elon Musk , following his imagination of space exploration and brain-computer interface, also aimed at mRNA technology, believing that mRNA is like the computer program of the human body, which can be programmed to perform any operation, such as stopping aging To rejuvenate and be a little more crazy, you can even turn a person into a butterfly[2], and directly upgrade "Zhouzhuang Dream Butterfly" into a big butterfly. Faced with such an interesting future technology, as a doer, Musk has announced that Tesla will build a RNA micro-factory for CureVac, which is headquartered in Germany. There is no doubt that the launch of the mRNA new crown vaccine is an important medical revolution, which has caused major media around the world to report, but in a sense, this concern actually conceals the significance of mRNA technology beyond the epidemic itself, including this article. Introducing the mRNA cancer vaccine . Welcome to other cancer popular science articles written by the author: Katarin Kariko, picture source: [4] Kariko was born in a Hungarian butcher family.Aspired to be a scientist from an early age. After finishing post-doctorate in Hungary, Kariko and her husband, who is also a Ph.D., decided to immigrate to the United States because of funding problems for research at University. In 1985, the Carrico couple and their two-year-old daughter embarked on a flight to the United States with 900 pounds hidden in a teddy bear, and began their "American Dream" journey.[4]. After arriving in the United States, her husband had to give up academics in order to make a living and identity. Carricko found a position as an assistant professor of research at the University of Pennsylvania and started the earliest mRNA research. In Calico's view, mRNA can guide cells to make any protein , which is like a god-like existence. mRNA vaccine principle diagram, picture from orleanscommunityhealth.org In fact, mRNA was discovered as early as the 1960s[5, 6]. If the human body is compared to a machine, then the millions of tiny proteins are the parts that keep the machine running, and mRNA is the commander-in-chief of making the parts. Therefore, human cell itself is the most perfect pharmaceutical factory in nature, which can produce any desired protein according to mRNA instructions, unlike traditional methods, which require time-consuming and labor-intensive protein expression and purification through in vitro genetic engineering. Taking the new crown vaccine as an example, after the new coronavirus genome RNA sequence is injected into the human body, it skips the process of in vitro protein synthesis and directly produces viral proteins in human cells. Recognize viral proteins to generate an immune memory for COVID-19. When the real new coronavirus enters the human body, the immune cell is like a well-trained soldier, quickly identifying the virus and launching a precise attack on it. In theory, mRNA is omnipotent,However, the clinical application of mRNA has not been recognized for decades. A big reason is that mRNA is very fragile and easily degraded by the ubiquitous RNA enzyme in the surrounding environment. It is no exaggeration to say that studying mRNA in the laboratory is a nightmare. If you are not careful, it will disappear from your eyes, let alone reach the human cells through many obstacles. Therefore, mRNA is just an academic term followed by textbooks and does not get much attention in the real world. It was not until 1990 that Wolff et al. of the University of Wisconsin first reported that intramuscular injection of mRNA into mouse skeletal muscle could indeed produce the protein [7]. At the same time, after countless attempts, Calico successfully used mRNA to instruct cells to produce the urokinase receptor protein. But mRNA still can't get rid of the label of unpopular fields, and has not been favored by capital. After 's funding applications were rejected again and again, Calico received a notice of demotion from school , and was once diagnosed with cancer. Fortunately, after several setbacks, Carico met the most important Bole in his life, Drew Weissman (Drew Weissman) professor [4, 8]. Drew Weissman, image source: Wikipedia Professor Weissman proposed to start the subject of AIDS mRNA vaccine. Carrico didn't want to give up as long as he had the opportunity to continue studying mRNA, so he quickly joined the Weissmann working group. It coincides with the emergence of liposome , lipid nanoparticles and other protective devices [9]. These devices can wrap mRNA and escort mRNA to the designated destination, so there is a preliminary solution to the first pain point of mRNA research. However, the second major problem of mRNA technology has arisen.Calico successfully used mRNA to produce the desired protein in cells in a petri dish, but the mRNA had no effect in mice. After repeated investigations, it was found that the original mouse immune system defined mRNA as foreign matter, and directly initiated the immune response to clear the mRNA. This is undoubtedly a basic judgment that the idea of mRNA treatment will not work at all. But Calico chose to rise to the challenge. Hard work paid off, and Calico was pleasantly surprised to find that tRNA, the brother of mRNA, could successfully escape the tracking of the immune system. After repeated comparison of mRNA and tRNA, clues slowly surfaced: it turns out that tRNA carries a molecule with anti- immune detection function, called pseudouridine. So, an epoch-making idea was born in 2005: adding pseudouridine to mRNA, the modified mRNA can sneak into cells and escape the immune system to attack [10]. Calico and Weisman published the paper and applied for the patent . Calico and Weissmann mRNA modification patent, image source: Google patent This discovery provides new hope for mRNA research at a low point, and also becomes the cornerstone of the sprint for the new crown vaccine field in the future. Therefore, a German company called BioNtech won the mRNA modification patent authorization and continued to support Calico to research mRNA technology. In 2013, Calico was directly hired as vice president. When the new crown epidemic broke out in 2020, mRNA technology was just ready, which made a historical coincidence at the right time and place. In just a few hours, BioNTech quickly designed an mRNA vaccine based on the new crown gene sequence. On November 8, the results of the first batch of mRNA vaccines developed by BioNTech confirmed that they have strong immunity to the new coronavirus. After Calico got the news, she ate a whole box of chocolate-covered nuts,as a unique way to celebrate. It has been 32 years since Calico first studied mRNA. In the middle of 32, Calico's personal annual income never exceeded 60,000 US dollars. He persisted in working in a field that was unpopular to almost no one, and was rejected and even demoted countless times. When was interviewed by The New York Times, in the face of countless honors and applause, Calico just said lightly, "I have achieved my life's dream" [4]. mRNA technology was conceived in American universities, but German biotech companies did their part and even rushed ahead in clinical practice, such as the aforementioned BioNTech and another CureVac. CureVac has been in clinical trials since 2009. Why is Moderna, which was only established in 2010, more sought after? What is the origin of the "Cheng Yaojin" who was killed halfway? And what skills did the latecomers rely on? The beginning of the story still has to do with Calico. Derrick Rossi was still a postdoctoral fellow at Stanford University in 2005 when Carrico and Weisman published their major research [10]. When he read the paper, he was acutely aware that this technology was about to have a profound impact, and even predicted that it would be a Nobel Prize-level discovery. Derek Rossi, image source: Stat News Rossi, who became Assistant Professor of at Harvard Medical School in 2007, followed Calico's ingenuity, planning to use modified mRNA to reprogram somatic cells into embryo-like stem cells , and successfully grown embryonic-like stem cells in a petri dish in 2010, which is 100 times more efficient than traditional methods [11, 12]. The young Rossi was excited, but as a junior assistant professor at Harvard,He did not have enough social resources to commercialize his discoveries, so he got acquainted with the famous MIT professor Robert Langer under the recommendation of his predecessor Timothy Springer(Timothy Springer) ) . Lange is not only the youngest academician of the Third Academy of Sciences in the United States, a mentor to the world, but also an outstanding entrepreneur who has founded more than 20 companies. There is a popular saying in the folk: If you want to start a biotech company, you have to see Lange first, whose reputation is evident [8, 13]. 02 A "Cheng Yaojin"
Robert Lange, picture source: Wikipedia The potential of thousands of lives also creates limitless business opportunities. After the interview, Lange decided to use his connections to make a big difference. The first person Lange invited to enter the game was Noubar Afeyan, founder and CEO of Flagship Pioneering, a well-known biomedical venture capital institution.
Old friends really see the same thing, and Afeyan also recognizes mRNA technology very much, so in just a few months, he resolutely co-founded Moderna with Rossi and Lange in 2010.
After the establishment of the company, the first priority is naturally to recruit talents. Who has the ability to control this future unicorn in the mRNA field? Afeyan has always admired the management skills of Stéphane Bancel () , and has sent out invitations many times before, but Bancel has a high vision, and those small companies cannot enter his discernment .
When Afeiyan throws out the olive branch again,Bancel is already CEO of French diagnostics company BioMerieux. BioMerieux is well-known in the diagnostic industry, with a market value of nearly 3 billion US dollars and more than 6,000 employees, while Moderna has just started, and there is only one scientist in the company.
Stephen Bansell, picture source: Stat News
Unexpectedly, under Afeiyan's various expressions of determination, pie, chatting, and heart-to-heart offensive, Bansell broke the boat and gave up the glamorous high-paying position , gladly joined this little-known start-up. Later, relying on his personal charm and prestige, Bancel attracted a group of well-known figures in the scientific community, including Jack Szostak, the winner of the 2009 Nobel Prize in Physiology or Medicine.
Backed by the golden mountain of Flagship Pioneering, Bansell leads Moderna forward without distractions, and is committed to solving the three core problems of mRNA technology The foundation is to have a stable patent. Like BioNtech, Moderna was initially licensed to carry out research under the Calico patent. If you have to rely on other people's patents for support in the future, you will inevitably be controlled by others, which is not a long-term solution. Through unremitting efforts, Moderna finally succeeded in finding a compound 1-methylpseudouracil that can replace pseudouridine/5-methylcytidine modification, and won the patent to relieve the hidden worries and laid a solid foundation for the establishment of the mRNA kingdom.
2. mRNA delivery: mRNA drug delivery has been a key bottleneck hindering development. The naked mRNA is easily degraded by extracellular RNase, and even if it enters the cell, it is easy to accumulate in the lysosome , and cannot reach the place where it can function. For short RNA molecules (such as siRNA, about 20 bases in size) ,Lipid nanoparticles are powerful delivery tools, but mRNAs are too slender, often hundreds or thousands of bases, so it is conceivable that the difficulty factor is very high.
It is very difficult for Moderna to develop its own drug delivery technology platform at the start-up stage. It is not only limited by manpower, but also limited by funds, so it can only be imported externally. At that time, Moderna looked at about a dozen drug delivery platforms, and finally chose Arbutus/Acuitas.
With the continuous efforts of internal researchers, Moderna finally has its own delivery technology, which is 25 times more efficient than traditional methods to escape lysosomal aggregation.[15]. By contrast, CureVac and BioNTech still rely on Genevant and Arcturus/Acuitas, respectively.
3. Regulation of protein production: Whether mRNA is used as a vaccine or a drug, it is ultimately the protein that directly plays a role, so the amount of protein needs to be strictly controlled, more toxic, less useless. But how much mRNA can produce the right level of protein is a whole new issue. To solve this problem, Moderna is using machine learning to model how mRNA sequences control protein production, paving the way for precise regulation later.[16].
was founded in a low-key manner in 2010, exposed to the public in 2012, and its IPO in 2018 set a record high in the history of biotechnology. Then, in 2020, when the new crown epidemic came out of the circle, Moderna became a market value of 100 billion yuan in only 10 years. The unicorn enterprise created another legend after Genentech .
There is no doubt that the backgrounds of several Moderna founders have allowed Moderna to win at the starting line, but it is also inseparable from the management's infinite dedication to technology and the concept of mastering the initiative. The outbreak of the new crown epidemic also gave Moderna a show to the world. Opportunity,You know that Moderna has been on the cusp of public opinion for many years. After all, in the absence of any clinical product, it is inevitable to achieve a valuation of billions of dollars.
03 Can mRNA technology carry the banner of conquering cancer?
mRNA new crown vaccine has successfully made Moderna and BioNTech out of the circle, but mRNA vaccine is far from limited to new crown or other viruses. Cancer vaccine is actually a track where major companies are fighting with all their strength before the outbreak of the new crown. The
mRNA cancer vaccine is different from the well-known cervical cancer vaccine . The cervical cancer vaccine is a preventive vaccine.
What is a therapeutic vaccine? Let's first understand the concept of antigen: cancer cells carry many gene mutations -specific protein (antigen) . It stands to reason that these specific proteins should be recognized by the body's own anti-cancer artifact immune cells in time for one-click removal. However, tumor cells have very sophisticated camouflage techniques, pretending to be good people to escape the eyes of immune cells.
Therapeutic mRNA vaccines produce a large number of cancer cell antigens by injecting mRNA, expose these antigens in front of immune cells, and induce immune cells to open their eyes to see clearly. Those who carry these antigens are all invaders and need to be wiped out. Immune cells that have undergone intensive training will naturally learn to be smart now. No matter how deliberately the cancer cells hide the fox tail (antigen) , they can also be keenly discovered.
Tumors will be wiped out after a single injection of vaccine. Thinking about it makes me excited. Therefore, cancer vaccines have always been a dream in the field of anti-cancer. However, after decades of trying, only one vaccine called Provenge was approved, and later sales were dismal due to high costs and other factors.After the original research company Dendreon went bankrupt, it was kicked around like a ball, and finally it was acquired by China Sanpower Group.
Is cancer vaccine just a dream after all? Not really. At first, the development of cancer vaccines was basically focused on "sharing" tumor antigens, that is to say, selecting a few cancer cell antigens from different patients with high frequency, hoping that a specific broad-spectrum (universal) vaccine could Unleash the power to remain unchanged. However, the most annoying virtue of cancer cells is that they are fickle. Different patients have different cancer cell antigens, and the same patient is also fickle at different stages. How can it be so easy to deal with.
Therefore, in recent years, there has been a new concept of "personalized vaccine", that is to say, firstly compare the patient's cancer cells and healthy cellsDNA, identify specific antigens, and then customize the production of vaccines against specific antigens, injection In a patient, the immune system is trained to kill cancer cells that carry the antigen.
Personalized cancer vaccine treatment process, picture source: [17]
Such top technologies are not faulty in theory, but not so easy to operate in practice. If the vaccine preparation time is too long, firstly, patients with advanced stage may not be able to wait, and secondly, cancer cells may mutate a new moth (antigen) , and the previous vaccine may not be effective.
It is a race against time, mRNA has fully proved its strength in the new crown epidemic, and is fully confident to stand out in the competition with other cancer vaccine players. After all, cancer vaccines based on cells, viruses, bacteria, proteins/ polypeptides are not as smart as mRNA, and can use human cells as an all-natural factory for protein production, greatly reducing the complexity of synthesis.Shorten time.
How about the mRNA cancer vaccine?
BioNTech is a blockbuster. Results released in 2017 showed that of the first 13 patients with advanced melanoma who received a personalized mRNA cancer vaccine, all of them developed an immune response to the vaccine, 8 had their tumors gone without recurrence within 23 months, and the remaining 5 Due to the fact that the tumor had spread at the time of vaccination, 2 patients' tumors shrank, and 1 of them completely regressed after receiving adjuvant therapy.[18].
Moderna is not far behind, and is jointly developing personalized cancer vaccines with Merck . The interim data released in 2020 is also remarkable: 10 cases of HPV head and neck squamous cell carcinoma patients, half of them The patient's condition was relieved.
04 Conclusion
After about 40 years of searching, mRNA technology has finally ushered in a new chapter. Starting from the new crown vaccine, to cancer treatment, in the future, mRNA technology may gradually get involved in more disease fields, as expected by Lange and Carrico.
At this stage, mRNA technology still has a long way to go. The approval of the vaccine is entirely due to the emergency use authorization in the context of the new crown epidemic. Only 9 of the evaluable solid tumor patients responded [19]. Besides, vaccines are actually the low-hanging fruit of mRNA therapy. After all, only a small amount of protein can be produced to induce immunity. How to use cell factories to produce larger amounts of protein is still up in the air.
Fortunately, after the success of the mRNA new crown vaccine, the government and investors may be more keen to support mRNA technology and accelerate the release of its greater potential.Be the real game changer to dominate.
About the author
Dingling
Biochemistry PhD, young writer. Worked at Howard Hughes Medical Institute and MD Anderson Cancer Center,Currently engaged in consulting industry.
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