BioNTech
In 2008, in Mainz, Germany, a new company was being formed by a married team of researchers who would see the vast potential for the mRNA technology, though vaccines for infectious diseases weren’t on top of their list then. The new company is named BioNTech, a blended name derived from Biopharmaceutical New Technologies. Its married co-founders are Uğur Şahin and Özlem Türeci.
Şahin is the chief operating officer (CEO) of BioNTech and Türeci is the chief medical officer (CMO). A native of Turkey, Uğur Şahin moved to Germany after his father got a job at a Ford factory in Cologne. His wife, Özlem Türeci had, as a child, followed her father, a surgeon, on his rounds at a Catholic hospital. She and Şahin are physicians who met in 1990 working at a hospital in Saarland. Şahin is also also a professor at the Mainz University Medical Center. The couple sees themselves as scientists first and foremost. But they are also formidable entrepreneurs. In 2001 they co-founded another company, Ganymed Pharmaceuticals. This company developed the monoclonal antibody Zolbetuximab, which is to be used against esophageal and gastrointestinal cancer. In 2016, Ganymed Pharmaceuticals was sold to Astellas Pharma for an amount of at least triple-digit millions.
Şahin and Türeci have long been interested in immunotherapy, which harnesses the immune system to fight cancer and has become one of the most exciting innovations in medicine in recent decades. In particular, they were tantalized by the possibility of creating personalized vaccines that teach the immune system to eliminate cancer cells. “We are one of the leaders in mRNA, but we don’t consider ourselves a mRNA company; we consider ourselves an immunotherapy company”, said Şahin.
BioNTech develops and manufactures active immunotherapies for patient-specific approaches to the treatment of diseases. It develops pharmaceutical candidates based on mRNA for use as individualized cancer immunotherapies, as vaccines against infectious diseases and as protein replacement therapies for rare diseases, and also engineered cell therapy, novel antibodies and small molecule immunomodulators as treatment options for cancer. The company has developed an mRNA-based human therapeutic for intravenous administration to bring individualized mRNA-based cancer immunotherapy to clinical trials and to establish its own manufacturing process.
BioNTech licensed technology developed by the Pennsylvania scientist whose work was long ignored, Dr. Karikó, and her collaborator, Dr. Weissman. In fact, in 2013, the company hired Karikó as senior vice president to help oversee its mRNA work.
Project Lightspeed, the project to develop a novel mRNA technology for a Covid-19 vaccine, began in mid-January 2020 just days after the SARS-CoV-2 genetic sequence was first made public. BioNTech has partnered on this project with Pfizer and Fosun. The production of the vaccine was followed by clinical trials, the success of which was a prerequisite for the commencement of marketing. On November 9, 2020, BioNTech and Pfizer announced that 43,500 people in 6 countries had received a test vaccine against Covid-19 with more than 90 percent effectiveness. The vaccine was the first Covid‑19 vaccine to be authorized by a stringent regulatory authority for emergency use and the first cleared for regular use. In December 2020, the United Kingdom was the first country to authorize its use on an emergency basis. It is authorized for use at some level in 84 countries including the United States and Canada, countries in the European Union, the United Kingdom, Australia, Ukraine, Israel, Brazil, Bangladesh, Mexico, Japan and Singapore.
Figure 2: BioNTech‘s co-founders: Dr. Uğur Şahin and Dr. Özlem Türeci.
Moderna
Derrick Rossi, a native of Toronto, was a 39-year-old postdoctoral fellow in stem cell biology at Stanford University in 2005 when he read the first paper published by Karikó and Weissman. He recognized their discovery as groundbreaking. But Rossi didn’t have vaccines on his mind when he set out to build on their findings in 2007 as a new assistant professor at Harvard Medical School running his own lab. He wondered whether modified mRNA might hold the key to obtaining something else researchers desperately wanted: a new source of embryonic stem cells.
In a feat of biological alchemy, embryonic stem cells can turn into any type of cell in the body. That gives them the potential to treat a dizzying array of conditions, from Parkinson’s disease to spinal cord injuries. But using those cells for research had created an ethical firestorm because they are harvested from discarded embryos. Rossi thought he might be able to sidestep the controversy. He would use modified messenger molecules to reprogram adult cells so that they acted like embryonic stem cells.
He asked a postdoctoral fellow in his lab to explore the idea. In 2009, after more than a year of work, the postdoc waved Rossi over to a microscope. Rossi peered through the lens and saw something extraordinary: a plate full of the very cells he had hoped to create. The essence of Rossi‘s idea is to modify mRNA first via transfection into human cells, then to dedifferentiate it into bone marrow stem cells, which could then be further differentiated into desired target cell types.
Rossi excitedly informed his colleague Timothy Springer, another professor at Harvard Medical School and a biotech entrepreneur. Recognizing the commercial potential, Springer contacted Robert Langer, a prolific inventor and biomedical engineering professor at the Massachusetts Institute of Technology. On a May afternoon in 2010, Rossi and Springer visited Langer at his laboratory in Cambridge. What happened at the two-hour meeting and in the days that followed has become the stuff of legend – and an ego-bruising squabble.
Langer is a towering figure in biotechnology and an expert on drug-delivery technology, whose patents have been licensed by at least 400 drug and medical device companies. As he listened to Rossi describe his use of modified mRNA, Langer recalled, he realized the young professor had discovered something far bigger than a novel way to create stem cells. Cloaking mRNA so it could slip into cells to produce proteins had a staggering number of applications, Langer thought, and might even save millions of lives. “I think you can do a lot better than that”, Langer recalled telling Rossi, referring to stem cells. “I think you could make new drugs, new vaccines – everything”.
Three days later Rossi made a presentation to the leaders of Flagship Pioneering. Founded and run by Noubar Afeyan, a swaggering entrepreneur, the Cambridge venture capital firm has created dozens of biotech startups. Afeyan had the same enthusiastic reaction as Langer, saying in a 2015 article in Nature that Rossi’s innovation “was intriguing instantaneously”.
Within several months, Rossi, Langer, Afeyan, and another physician-researcher at Harvard formed the firm Moderna Therapeutics, with the name Moderna being a new word created by combining Modified and RNA.
The Moderna Covid‑19 vaccine is a Covid-19 vaccine developed by Moderna, the United States National Institute of Allergy and Infectious Diseases (NIAID) and the Biomedical Advanced Research and Development Authority (BARDA). It is an RNA vaccine composed of nucleoside-modified mRNA (modRNA) encoding a spike protein of SARS-CoV-2, which is encapsulated in lipid nanoparticles. In March 2020, the FDA approved clinical trials for the Moderna vaccine candidate. Phase III clinical trials were completed in December 2020 and preliminary evidence had shown 94% efficacy in preventing Covid-19, with only minor flu-like side effects. On December 18, 2020 and December 23, 2020 the vaccine was issued an emergency use authorization in the United States respective Canada. On January 6, 2021 and January 8, 2021 the vaccine was authorized for emergency use in the European Union respective United Kingdom.
Figure 3: Moderna‘s founders: Dr. Derrick Rossi, Dr. Robert Langer, and Dr. Noubar Afeyan.
Acuitas
In the global fight against Covid-19 and SARS-CoV-2 a special recognition goes to the Vancouver-based biotechnology company Acuitas Therapeutics (Acuitas). Acuitas is a private biotechnology company that was co-founded by Dr. Pieter Cullis as a UBC spin-out company in 2009 (initially as AlCana Technologies). The company specializes in the development of lipid nanoparticle (LNP) technology – a key component of vaccine delivery that protects mRNA and ensures it is delivered inside human cells to help fight viruses. The Acuitas LNP delivery system is being used in several Covid-19 vaccines including the BioNTech-Pfizer vaccine.
In his interview with Bob McDonald from CBC Radio’s Quirks & Quarks, Cullis explained how the technology he pioneered is essential to RNA vaccines:
The RNA vaccines have a fundamental problem that requires a delivery system to enable the mRNA to get into cells. What we’ve been working on is our so-called lipid nanoparticles that encase the RNA and protect it from degradation, but also enable the mRNA to be taken up into a cell and to be released into the cytoplasm – that’s the inside of a cell – where it can actually be translated to form any protein you want. In case of vaccines, it’s a protein that corresponds to one of the proteins associated with the virus.
Lipid nanoparticles are made of fats, your body has a lot of fat and not just the normal kinds of fats one normally thinks of. These are lipids that constitute the membrane that goes around all the cells in your body. You have a few trillion cells in your body, and all of them have a membrane around the outside. We use the same lipids in some cases as are present in those cell membranes, with a couple of extra additions.
Figure 4: Dr. Pieter Cullis, one of Acuitas‘s founders.
How the world of mRNA changed late in 2019
Shortly before midnight, on December 30, 2020, the International Society for Infectious Diseases, a Massachusetts-based nonprofit, posted an alarming report online. A number of people in Wuhan, a city of more than 11 million people in central China, had been diagnosed with “unexplained pneumonia”. Chinese researchers soon identified 41 hospitalized patients with the disease. Most had visited the Wuhan South China Seafood Market. Vendors sold live wild animals, from bamboo rats to ostriches, in crowded stalls. That raised concerns that the virus might have leaped from an animal, possibly a bat, to humans. After isolating the virus from patients, Chinese scientists on January 10, 2020 posted online its genetic sequence.
Because companies that work with mRNA don’t need the virus itself to create a vaccine, just a computer that tells scientists what chemicals to put together and in what order, researchers at BioNTech, Moderna, and other companies got to work. A pandemic loomed. The companies’ focus on vaccines could not have been more fortuitous.
The mRNA’s story likely will not end with Covid-19. Its potential stretches far beyond this pandemic. This year, a team at Yale patented a similar RNA-based technology to vaccinate against malaria, perhaps the world’s most devastating disease. Because mRNA is so easy to edit, Pfizer says that it is planning to use it against seasonal flu, which mutates constantly and kills hundreds of thousands of people around the world every year. BioNTech is developing individualized therapies that would create on-demand proteins associated with specific tumors to teach the body to fight off advanced cancer. In mouse trials, synthetic-mRNA therapies have been shown to slow and reverse the effects of multiple sclerosis.
“I’m fully convinced now even more than before that mRNA can be broadly transformational”, Özlem Türeci said. “In principle, everything you can do with protein can be substituted by mRNA”.
Final thoughts
The mRNA technology was born of many seeds, has been validated and is now subject to multi billion-dollar efforts. Its triumph, from backwater research to breakthrough technology, is not a hero’s journey, but a heroes’ journey. Without Robert Malone‘s genial idea and Katalin Karikó and Drew Weissman‘s grueling efforts to make mRNA technology work, the world would have neither BioNTech nor Moderna. Without government funding and philanthropy, both companies might have gone bankrupt before their 2020 vaccines. Without the failures in HIV-vaccine research forcing scientists to trailblaze in strange new fields, we might still be in the dark about how to make the technology work. Without an international team of scientists unlocking the secrets of the coronavirus’s spike protein several years ago, we might not have known enough about this pathogen to design a vaccine to defeat it last year.
1. Nucleosides are structural subunits of nucleic acids such as DNA and RNA. They are glycosylamines that can be thought of as nucleotides without a phosphate group. A nucleoside consists simply of a nitrogenous base and a five-carbon sugar (ribose or 2′-deoxyribose) whereas a nucleotide is composed of a nitrogenous base, a five-carbon sugar, and one or more phosphate groups.
References:
- https://www.nature.com/articles/d41586-021-02483-w
- https://www.sciencedirect.com/science/article/pii/S1074761305002116
- Verbeke, Rein, et al. “Three decades of messenger RNA vaccine development.” Nano Today 28 (2019): 100766.
- Garde D, Saltzman J. – The story of mRNA: How a once-dismissed idea became a leading technology in the Covid vaccine race. STAT. November 10, 2020.
- Derek Thompson – How mRNA Technology Could Change the World. The Atlantic. March 29, 2021.
- Christina Frangou – Researchers looking for mRNA were ridiculed by colleagues. Luckily, that didn’t stop them. Maclean’s. February 18, 2021.
- Canadian Institutes of Health Research – The long road to mRNA vaccines.
- https://en.wikipedia.org/wiki/BioNTech.
- https://en.wikipedia.org/wiki/Moderna.