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Explained: Why RNA vaccines for Covid-19 raced to the front of the pack

Many years of research have enabled scientists to quickly synthesize RNA vaccines and deliver them inside cells.

Anne Trafton | MIT News Office
December 11, 2020

Developing and testing a new vaccine typically takes at least 12 to 18 months. However, just over 10 months after the genetic sequence of the SARS-CoV-2 virus was published, two pharmaceutical companies applied for FDA emergency use authorization of vaccines that appear to be highly effective against the virus.

Both vaccines are made from messenger RNA, the molecule that cells naturally use to carry DNA’s instructions to cells’ protein-building machinery. A vaccine based on mRNA has never been approved by the FDA before. However, many years of research have gone into RNA vaccines, which is one reason why scientists were able to start testing such vaccines against Covid-19 so quickly. Once the viral sequences were revealed in January, it took just days for pharmaceutical companies Moderna and Pfizer, along with its German partner BioNTech, to generate mRNA vaccine candidates.

“What’s particularly unique to mRNA is the ability to rapidly generate vaccines against new diseases. That I think is one of the most exciting stories behind this technology,” says Daniel Anderson, a professor of chemical engineering at MIT and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science.

Most traditional vaccines consist of either killed or weakened forms of a virus or bacterium. These provoke an immune response that allows the body to fight off the actual pathogen later on.

Instead of delivering a virus or a viral protein, RNA vaccines deliver genetic information that allows the body’s own cells to produce a viral protein. Synthetic mRNA that encodes a viral protein can borrow this machinery to produce many copies of the protein. These proteins stimulate the immune system to mount a response, without posing any risk of infection.

A key advantage of mRNA is that it is very easy to synthesize once researchers know the sequence of the viral protein they want to target. Most vaccines for SARS-CoV-2 provoke an immune response that targets the coronavirus spike protein, which is found on the surface of the virus and gives the virus its characteristic spiky shape. Messenger RNA vaccines encode segments of the spike protein, and those mRNA sequences are much easier to generate in the lab than the spike protein itself.

“With traditional vaccines, you have to do a lot of development. You need a big factory to make the protein, or the virus, and it takes a long time to grow them,” says Robert Langer, the David H. Koch Institute Professor at MIT, a member of the Koch Institute, and one of the founders of Moderna. “The beauty of mRNA is that you don’t need that. If you inject nanoencapsulated mRNA into a person, it goes into the cells, and then the body is your factory. The body takes care of everything else from there.”

Langer has spent decades developing novel ways to deliver medicines, including therapeutic nucleic acids such as RNA and DNA. In the 1970s, he published the first study showing that it was possible to encapsulate nucleic acids, as well as other large molecules, in tiny particles and deliver them into the body. (Work by MIT Institute Professor Phillip Sharp and others on RNA splicing, which also laid groundwork for today’s mRNA vaccines, began in the ’70s as well.)

“It was very controversial at the time,” Langer recalls. “Everybody told us it was impossible, and my first nine grants were rejected. I spent about two years working on it, and I found over 200 ways to get it to not work. But then eventually I did find a way to get it to work.”

That paper, which appeared in Nature in 1976, showed that tiny particles made of synthetic polymers could safely carry and slowly release large molecules such as proteins and nucleic acids. Later, Langer and others showed that when polyethylene glycol (PEG) was added to the surface of nanoparticles, they could last in the body for much longer, instead of being destroyed almost immediately.

In subsequent years, Langer, Anderson, and others have developed fatty molecules called lipid nanoparticles that are also very effective at delivering nucleic acids. These carriers protect RNA from being broken down in the body and help to ferry it through cell membranes. Both the Moderna and Pfizer RNA vaccines are carried by lipid nanoparticles with PEG.

“Messenger RNA is a large hydrophilic molecule. It doesn’t naturally enter cells by itself, and so these vaccines are wrapped up in nanoparticles that facilitate their delivery inside of cells. This allows the RNA to be delivered inside of cells, and then translated into proteins,” Anderson says.

In 2018, the FDA approved the first lipid nanoparticle carrier for RNA, which was developed by Alnylam Pharmaceuticals to deliver a type of RNA called siRNA. Unlike mRNA, siRNA silences its target genes, which can benefit patients by turning off mutated genes that cause disease.

One drawback to mRNA vaccines is that they can break down at high temperatures, which is why the current vaccines are stored at such cold temperatures.  Pfizer’s SARS-CoV-2 vaccine has to be stored at -70 degrees Celsius (-94 degrees Fahrenheit), and the Moderna vaccine at -20 C (-4 F). One way to make RNA vaccines more stable, Anderson points out, is to add stabilizers and remove water from the vaccine through a process called lyophilization, which has been shown to allow some mRNA vaccines to be stored in a refrigerator instead of a freezer.

The striking effectiveness of both of these Covid-19 vaccines in phase 3 clinical trials (roughly 95 percent) offers hope that not only will those vaccines help to end the current pandemic, but also that in the future, RNA vaccines may help in the fight against other diseases such as HIV and cancer, Anderson says.

“People in the field, including myself, saw a lot of promise in the technology, but you don’t really know until you get human data. So to see that level of protection, not just with the Pfizer vaccine but also with Moderna, really validates the potential of the technology — not only for Covid, but also for all these other diseases that people are working on,” he says. “I think it’s an important moment for the field.”

3 Questions: Phillip Sharp on the discoveries that enabled RNA vaccines for Covid-19

Curiosity-driven basic science in the 1970s laid the groundwork for today’s leading vaccines against the novel coronavirus.

School of Science
December 11, 2020

Some of the most promising vaccines developed to combat Covid-19 rely on messenger RNA (mRNA) — a template cells use to carry genetic instructions for producing proteins. The mRNA vaccines take advantage of this cellular process to make proteins that then trigger an immune response that targets SARS-CoV-2, the virus that causes Covid-19.

Compared to other types of vaccines, recently developed technologies allow mRNA vaccines to be rapidly created and deployed on a large-scale — crucial aspects in the fight against Covid-19. Within the year since the identification and sequencing of the SARS-CoV-2 virus, companies such as Pfizer and Moderna have developed mRNA vaccines and run large-scale trials in the race to have a vaccine approved by the U.S. Food and Drug Administration — a feat unheard of with traditional vaccines using live attenuated or inactive viruses. These vaccines appear to have a greater than 90 percent efficacy in protecting against infection.

The fact that these vaccines could be rapidly developed within these last 10 months rests on more than four decades of study of mRNA. This success story begins with Institute Professor Phillip A. Sharp’s discovery of split genes and spliced RNA that took place at MIT in the 1970s — a discovery that would earn him the 1993 Nobel Prize in Physiology or Medicine.

Sharp, a professor within the Department of Biology and member of the Koch Institute for Integrative Cancer Research at MIT, commented on the long arc of scientific research that has led to this groundbreaking, rapid vaccine development — and looked ahead to what the future might hold for mRNA technology.

Q: Professor Sharp, take us back to the fifth floor of the MIT Center for Cancer Research in the 1970s. Were you and your colleagues thinking about vaccines when you studied viruses that caused cancer?

A: Not RNA vaccines! There was a hope in the ’70s that viruses were the cause of many cancers and could possibly be treated by conventional vaccination with inactivated virus. This is not the case, except for a few cancers such as HPV causing cervical cancer.

Also, not all groups at the MIT Center for Cancer Research (CCR) focused directly on cancer. We knew so little about the causes of cancer that Professor Salvador Luria, director of the CCR, recruited faculty to study cells and cancer at the most fundamental level. The center’s three focuses were virus and genetics, cell biology, and immunology. These were great choices.

Our research was initially funded by the American Cancer Society, and we later received federal funding from the National Cancer Institute, part of the National Institutes of Health and the National Science Foundation — as well as support from MIT through the CCR, of course.

At Cold Spring Harbor Laboratory in collaboration with colleagues, we had mapped the parts of the adenovirus genome responsible for tumor development. While doing so, I became intrigued by the report that adenovirus RNA in the nucleus was longer than the RNA found outside the nucleus in the cytoplasm where the messenger RNA was being translated into proteins. Other scientists had also described longer-than-expected nuclear RNA from cellular genes, and this seemed to be a fundamental puzzle to solve.

Susan Berget, a postdoc in my lab, and Claire Moore, a technician who ran MIT’s electron microscopy facility for the cancer center and would later be a postdoc in my lab, were instrumental in designing the experiments that would lead to the iconic electron micrograph that was the key to unlocking the mystery of this “heterogeneous” nuclear RNA. Since those days, Sue and Claire have had successful careers as professors at Baylor College of Medicine and Tufts Medical School, respectively.

The micrograph showed loops that would later be called “introns” — unnecessary extra material in between the relevant segments of mRNA, or “exons.” These exons would be joined together, or spliced, to create the final, shorter message for the translation to proteins in the cytoplasm of the cell.

This data was first presented at the Cancer Center fifth floor group meeting that included Bob Weinberg, David Baltimore, David Housman, and Nancy Hopkins. Their comments, particularly those of David Baltimore, were catalysts in our discovery. Our curiosity to understand this basic cellular mechanism drove us to learn more, to design the experiments that could elucidate the RNA splicing process. The collaborative environment of the MIT Cancer Center allowed us to share ideas and push each other to see problems in a new way.

Q: Your discovery of RNA splicing was a turning point, opening up new avenues that led to new applications. What did this foundation allow you to do that you couldn’t do before?

A: Our discovery in 1977 occurred just as biotechnology appeared with the objective of introducing complex human proteins as therapeutic agents, for example interferons and antibodies. Engineering genes to express these proteins in industrial tanks was dependent on this discovery of gene structure. The same is true of the RNA vaccines for Covid-19: By harnessing new technology for synthesis of RNA, researchers have developed vaccines whose chemical structure mimics that of cytoplasmic mRNA.

In the early 1980s, following isolation of many human mutant disease genes, we recognized that about one-fifth of these were defective for accurate RNA splicing. Further, we also found that different isoforms of mRNAs encoding different proteins can be generated from a single gene. This is “alternative RNA splicing” and may explain the puzzle that humans have fewer genes — 21,000 to 23,000 — than many less complex organisms, but these genes are expressed in more complex protein isoforms. This is just speculation, but there are so many things about biology yet to be discovered.

I liken RNA splicing to discovering the Rosetta Stone. We understood how the same letters of the alphabet could be written and rewritten to form new words, new meaning, and new languages. The new “language” of mRNA vaccines can be developed in a laboratory using a DNA template and readily available materials. Knowing the genetic code of the SARS-CoV-2 is the first step in generating the mRNA vaccine. The effective delivery of vaccines into the body based on our fundamental understanding of mRNA took decades more work and ingenuity to figure out how to evade other cellular mechanisms perfected over hundreds of millions of years of evolution to destroy foreign genetic material.

Q: Looking ahead 40 more years, where do you think mRNA technology might be?

A: In the future, mRNA vaccine technology may allow for one vaccine to target multiple diseases. We could also create personalized vaccines based on individuals’ genomes.

Messenger RNA vaccines have several benefits compared to other types of vaccines, including the use of noninfectious elements and shorter manufacturing times. The process can scaled up, making vaccine development faster than traditional methods. RNA vaccines can also be moved rapidly into clinical trials, which is critical for the next pandemic.

It is impossible to predict the future of RNA therapies, such as the new vaccines, but there are some signs that new advancements could happen very quickly. A few years ago, the first RNA-based therapy was approved for treatment of lethal genetic disease. This treatment was designed through the discovery of RNA interference. Messenger RNA-based therapies will also likely be used to treat genetic diseases, vaccinate against cancer, and generate transplantable organs. It is another tool at the forefront of modern medical care.

But keep in mind that all mRNAs in human cells are encoded by only 2 percent of the total genome sequence. Most of the other 98 percent is transcribed into cellular RNAs whose activities remain to be discovered. There could be many future RNA-based therapies.

MIT labs win top recognition for sustainable practices in cold storage management

Whitehead Institute and MIT named 2020 Organizational Winners in the fourth annual International Institute for Sustainable Laboratories International Laboratory Freezer Challenge.

Environment, Health and Safety Office
December 9, 2020

In its fourth year, the International Institute for Sustainable Laboratories (I2SL) International Laboratory Freezer Challenge drew 218 laboratory participants from around the world, from 88 research institutions. Three MIT laboratories participated in the challenge: the Department of Biology’s Barbara Imperiali Lab, Department of Biological Engineering’s Jacquin Niles Lab, and Department of Biology/Whitehead Institute for Biomedical Research’s David Sabatini Lab. MIT and the Whitehead Institute together received the Top Academic Organization Award. The Niles lab and the Imperiali lab are MIT Environment, Health & Safety (EHS) Green Lab Certified.

The Freezer Challenge, which is run by the nonprofit organizations My Green Labs and I2SL, is aimed at promoting efficient, effective sample storage for laboratories around the world, and using a spirit of friendly competition to increase sample accessibility, sample integrity, reduced costs, and energy efficiency.

Over a five-month period, challenge contestants implement optimal cold storage management practices, such as defrosting and removing dust from freezer intake or coils, regular cleanouts, organization of inventory on file, and high-density storage. Winners are then chosen based on the amount of energy saved. Additionally, in the spirit of friendly competition and collaboration that pervades the challenge, contestants can earn points for sharing tips about their own cold storage best practices.

This year, the 218 laboratory participants saved an estimated total of 3.2 million kilowatt-hours (kWh) per year, up from 2.4 million in 2019. The savings represents the equivalent of reducing carbon emissions by 2,260 metric tons per year, or removing 360 passenger vehicles from the road for a year. According to Christina Greever, operations manager at My Green Labs, the three participating MIT and Whitehead Institute labs saved an estimated 520 kWh/year.

Two of the three labs — Niles and Imperiali — have previously participated in MIT EHS’ Green Labs Freezer Challenge, and have consequently instituted good management practices surrounding cold storage. The Sabatini lab hasn’t previously participated in EHS’ challenge, but had also already implemented many of the practices the challenge encourages and rewards.

Edith Valeri, of the Sabatini lab, said that while her lab didn’t face any major difficulties, the challenge encouraged lab management staff to be “more aware of freezer usage” and “more mindful of wattage usage, turning down temperatures to a sustainable level, and defrosting the freezers.”

Similarly, both Sebastian Smick, a technical associate in the Niles lab, and Christine Arbour, an NIH postdoc in the Imperiali lab, found that participating in the challenge was not disruptive to operations, and the only difficulties they ran into came as a result of the Covid response. Because of their previous participation in  the MIT EHS’ Green Labs Freezer Challenge, efficient energy usage is already routine for the three labs.

Smick described the challenge as “a good incentive” for the Niles lab to practice regular thawing, and “a nice way to quantify what it means to the University’s power consumption.” He credits MIT Custodial Services for the invaluable support they provide on a regular basis. “Custodial Services is always there for us during our thaws to provide mopping and absorbent barriers while we thaw. Most of the ice is captured as a solid, but spillover is unavoidable. They’ve saved us thousands of paper towels!”

The Imperiali lab upgraded its cold storage in March, replacing its minus-80 degrees Celsius freezer with a newer, more energy efficient model, and entered the challenge ready to focus on maximizing that investment. “Our lab consistently cleans our freezer filters, -80 degree C freezer in particular, to prevent the compressor from overworking,” says Arbour. “We are also vigilant with appropriate chemical storage. We store chemicals at the temperature that the supplier/company recommends and nothing colder. This prevents overcrowding in –20 and –80 degree C freezers, which can start to add up!”

For Smick, a key takeaway from the challenge was the quantification of the power consumption of his lab’s cold storage. “I was so surprised when I first learned about the power consumption of our -80 C and -20 freezers,” he recalls. “It’s easy to see the impact of changing to a cheaper reagent or eliminating a wasteful process when it is something that comes directly out of your pocket, but electricity is something we take for granted; it should be conserved like any natural resource, and this challenge really shines an environmentally friendly, zero-energy consumption light on how easy it is to make a huge impact.”

Smick credits the challenge with inspiring his lab to conduct regular thaws, a major energy-saving practice. “I know for a fact that, prior to our regular freezer thaws which we started doing because of this competition, we were throwing away thousands of dollars of reagents away each year because they were lost in the glaciers that we were maintaining in our freezers.”

Similarly, Arbour says the Imperiali lab will continue to implement the practices recognized in the challenge. “Our lab practices will continue to evolve with new green practices,” she says. “Our entire lab is invested in doing better for the environment.”

“My hope is that competitions like this inspire MIT and the entire world to take a more serious look about how we deal with the resources available to us: from electricity to recyclable waste,” says Smick. “Science generates a huge amount of waste, and there is so much more that we can do to reduce environmental impact, and to offset the cost of generating meaningful data.”

MIT EHS has plans in the works for the enhancement and expansion of the Institute’s Green Labs program, and will be implementing them in the upcoming year. Labs interested in learning more about the Green Labs program, its benefits, and details on how to participate should contact environment@mit.edu.

A good environment for sustainable research
Whitehead Institute
December 3, 2020

From floods to forest fires to droughts, the consequences of climate change are affecting people and ecosystems around the globe, and these events will only grow more abundant in the coming decades. Researchers in many scientific fields are studying this complex problem from different angles. Whitehead Institute primarily focuses on biomedical research, and yet in recent years researchers in several labs here have discovered ways in which their work might contribute to climate resilience and sustainability. Scientists here are applying their skills to problems of climate change and sustainability in medicine, agriculture, and beyond. Learn more about their work in the stories below:

FEEDING A CHANGING WORLD

Researchers in Whitehead Institute Member Mary Gehring’s lab hope to help address the problem of global food security as the human population grows and the effects of climate change threaten agriculture. They are exploring new ways to engineer crops so they will thrive in the conditions created by climate change. Read about them here.

NATURE’S LIBRARY: THE VALUE OF BIODIVERSITY TO BIOLOGICAL RESEARCH

Climate change and other human activities have endangered many species and driven some to extinction. Protecting our remaining biodiversity benefits fundamental biology research, because important biological discoveries can come from the most unexpected species. In this video, discover more about the variety of species that Whitehead Institute researchers use and what they hope to learn from them.

MAKING GREEN DRUGS: TAPPING INTO NATURE WITHOUT TAPPING IT OUT

Whitehead Institute Member Jing-Ke Weng’s lab has developed a system to discover medicines in nature and produce them more sustainably, reducing the negative environmental impacts of pharmaceutical research and production. Read about it here.

AUDIOHELICASE SPECIAL: HOW RESEARCHERS AT WHITEHEAD INSTITUTE ARE BUILDING A MORE SUSTAINABLE FUTURE

Many graduate students and postdoctoral researchers at Whitehead Institute are passionate about how their research could help to tackle climate change and other threats to the environment. To hear from some of these early-career researchers directly, click here.

DESIGNING PLANTS THAT DON’T DECAY

Multiple labs at Whitehead Institute have recently joined forces, along with a lab at the Massachusetts Institute of Technology, in the hopes of developing a method for carbon capture to fight greenhouse gas emissions. Read more here.

BIONOOK

Inviting kids to explore the natural world scientifically is a great way to build a foundation for understanding climate change and making eco-conscious decisions. To learn more about Whitehead Institute’s educational offerings, explore BioNook, the Institute’s online biology resource center for students, parents, and teachers.

November 26, 2020
The bull Y chromosome has evolved to bully its way into gametes
Whitehead Institute
November 18, 2020

In a new study, published Nov. 18 in the journal Genome Research, scientists in the lab of Whitehead Institute Member David Page present the first ever full, high-resolution sequence of the Y chromosome of a Hereford bull. The research, more than a decade in the making, suggests that bulls’ Y chromosomes have evolved dozens of copies of the same genes in a selfish attempt to make more males — a move that is countered in the female-determining X chromosome.

“When you have an X and a Y chromosome, it’s a setup for conflict,” said Page, who is also a professor of biology at the Massachusetts Institute of Technology and investigator with the Howard Hughes Medical Institute. “Seeing this full blown competition between the cattle X and Y means we have to think more deeply about this conflict as a constant and general feature of sex chromosomes in mammals.”

This insight into the forces that govern sex chromosome behavior and evolution will help scientists in Page’s lab study genetic differences between males and females and how they play out in health and disease across every part of the body, Page added.

Of mice, men and cattle 

Sex chromosomes — the X and the Y — evolved from a regular pair of symmetrical chromosomes some 200 million years ago. Those born biologically female have two X chromosomes. Those born biologically male have one X and one Y.

Page’s lab successfully sequenced the human Y chromosome in 2003, and afterwards the researchers wanted to be able to compare the sequence to its counterparts in other animals in order to help understand how they have evolved and diverged over time.

To make these comparisons, researchers in Page’s lab laid out a list of several mammals — including chimps, opossums, and mice — that occupied different branches of the mammalian family tree. One after another, the scientists began sequencing these creatures’ Ys, using a high-resolution sequencing method called SHIMS — short for Single-Haplotype Iterative Mapping and Sequencing — to obtain a level of detail that other techniques, like shotgun sequencing, can’t.

This powerful sequencing technology allowed the researchers to observe a strange peculiarity of Y chromosomes: in some species, nearly all of the genetic material on the Y is made up of sequences of DNA that have been amplified dozens or hundreds of times over — “like a hall of mirrors,” Page said.

In mice, for example, repeats of just a few testis-specific genes make up nearly 98 percent of the Y chromosome. In humans, however, repeats make up only about 45 percent. “We wanted to know if this was just a peculiarity of rodents, or if other Y chromosomes might come close,” Page said.

That’s where the bull came in. “Outside of primates and rodents, the next branch off the mammalian tree includes bull,” said Jennifer Hughes, a researcher in Page’s lab and the first author of the paper. “We didn’t know if the bull’s Y chromosome would look like a mouse Y or a human Y or something else entirely.”

The running of the bull’s (sequencing data) 

It took the Page Lab and collaborators at Baylor College of Medicine’s Human Genome Sequencing Center, the McDonnell Genome Institute at Washington University, Texas A&M University, and other institutions more than a decade to tease apart the complexities of the bull Y chromosome. In fact, it turned out to be the most gene-dense of any Y chromosome ever mapped — largely due to the fact that 96 percent of its genetic material was made up of repetitive sequences.

As in the mouse, most of the bull’s “hall of mirrors” repeats appeared to be expressed in the testis. But the question remained: Why? “What drives it can’t just be purely making more sperm, because that’s just overkill, right?” Hughes said. “You don’t really need hundreds of copies of a gene to accomplish that task.”

The researchers found a clue when they took a closer look at the bovine X chromosome: the female-determining sex chromosome also had a few copies of these testis-specific genes. “We don’t really know the mechanism in the bull, but the thought is that somehow the amplification of these genes in the Y has to do with helping the Y get passed on — and the X copies are amplified to compete against that tendency and help the X,” Hughes said.

A selfish pursuit

This X-Y arms race has been proven to happen in mice: somehow, repetitive genes on the Y chromosome give it an extra edge when it comes to ending up in the sperm during gamete formation. In a 2012 study, researchers knocked out the Y-chromosome repeats. Without the extra genes, more X chromosomes than Ys ended up in sperm cells, and the sex ratio of offspring skewed female. Over years of evolution, the X has developed repeats as well — its own way to get a leg up in the race.

Competition between X and Y chromosomes is selfish, Hughes said, because it’s not a good thing for the species to have a skewed sex ratio. Thus, these alterations benefit only the lucky chromosome that ends up in the fertilized egg. The fact that a selfish — and even detrimental — mechanism would continue for millions of years in disparate branches of the evolutionary tree suggests that these conflicts may be an inevitable side effect of having a pair of asymmetrical sex chromosomes. “These X-Y arms races have probably been around for as long as mammals have been around,” Page said.

Evolutionary theory aside, knowing the mechanisms controlling the sex ratios of cattle could be of practical use in the coming years. “It could be of great interest to breeders, because they would love to be able to manipulate the sex of cattle offspring,” Hughes said. “For example, dairy farmers would prefer more females and meat farmers would prefer more males.”

Right now, the lab is working on leafing out the branches of their Y chromosome evolutionary tree. The bull’s is the seventh sex chromosome to be completely sequenced using the SHIMS method. Hughes, Page and the lab are also eyeing members of other animal groups, including reptiles.

“Our lab is focused on sex differences across the human body, and all of that work really is inspired by lessons that we’ve learned by comparing the Y chromosomes of different animals with our own,” Page said. “It’s like when you go to an art gallery and just sit on a bench and look and feel inspired — these sequences are an infinite source of inspiration in the work we are doing. And we can now add the bull to our gallery.”

***

Hughes, J. et al. “Sequence analysis in Bos taurus reveals pervasiveness of X-Y arms races in mammalian lineages.” Genome Research, Nov. 18, 2020. DOI: 10.1101/gr.269902.120