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MRNA TECHNOLOGY: FOUR DECADES IN THE MAKING  
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Jess Steier
December 23, 2024
Unbiased Science
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_ mRNA technology took 40 years to perfect. Here's the story,
briefly. So if you’re sitting around the holiday table and someone
tells you the mRNA technology is “too new” to trust, you now have
the “receipts” to explain why that’s not accurate. _

Crystal structure of the histone mRNA stem-loop, Tan Dazhi (GNU Free
Documentation License)

 

When mRNA vaccines emerged as heroes during the COVID-19 pandemic,
headlines heralded them as a revolutionary new technology. Many people
wondered: How could a new technology be safe enough to give to
millions of people? The answer reveals a surprising truth: mRNA
technology isn't new _at all_. Scientists have been developing and
testing it since 1978
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proving its safety through decades of careful research.

Few people realize that mRNA vaccines existed long before COVID-19,
but they hadn't gained widespread use for a simple reason: while they
consistently proved safe in trials spanning decades, they often fell
short of the high efficacy standards required for regulatory approval.
In other words, the vaccines were safe but not effective enough at
preventing disease to justify widespread use. Then came COVID-19, and
something extraordinary happened.

THE SCIENTIFIC JOURNEY: 1978-1990

The story of mRNA technology began in 1978 when scientists made a
groundbreaking discovery that would lay the foundation for future
vaccine development. They found that they could successfully
deliver mRNA into cells using liposomes
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droplets of fat that could carry genetic material. This wasn't just a
theoretical breakthrough; researchers demonstrated practical success
by introducing rabbit mRNA into mouse spleen lymphocytes and observing
protein production.

By 1990, the field had advanced significantly. Scientists successfully
demonstrated that liposome-delivered mRNA could work in living
organisms, not just in laboratory cell cultures. Using mice as test
subjects, they showed that the delivered mRNA could produce proteins
for up to 60 days after injection
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hinted at the technology's potential for therapeutic applications.
Importantly, these early studies helped establish that cells could
process external mRNA safely, without disrupting their normal
functions.

UNDERSTANDING THE TECHNOLOGY

To understand why mRNA vaccines have proven so safe, it helps to
understand how they work
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Unlike traditional vaccines that introduce inactivated pathogens or
protein fragments, mRNA vaccines work more like an instruction manual
for your cells:

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The mRNA molecule carries temporary instructions for making a specific
protein

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The instructions stay in the cell's cytoplasm (outer area) and never
enter the nucleus where DNA is kept

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The cell reads these instructions and produces the protein

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The cell's natural processes break down the mRNA within days

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The immune system recognizes the protein and builds defenses against
it

This process mimics natural viral infection but with a key difference:
the mRNA only provides instructions for making a single, harmless
protein—not the whole virus. _This makes it impossible for mRNA
vaccines to cause the disease they protect against._

KEY INNOVATIONS: 1995-2005

The path to viable mRNA vaccines required solving two major
challenges, each teaching valuable lessons about vaccine safety:

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The Inflammation Challenge (1997): During HIV vaccine research,
scientists discovered that synthetic mRNA could trigger unwanted
inflammatory responses
[[link removed]]. This might sound
alarming, but it led to a critical breakthrough: researchers developed
modified nucleosides, including a compound called pseudouridine, that
allowed mRNA to deliver its message without triggering inflammation
[[link removed](05)00211-6]. This
modification is now used in COVID-19 vaccines
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they don't cause the inflammatory problems seen in early research.
It's a perfect example of how identifying a safety concern led to
making the technology even safer.

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The Delivery Challenge (Early 2000s): Scientists needed a way
to protect the mRNA
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safely to cells. The development of Lipid Nanoparticles
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this problem. Think of LNPs as tiny protective bubbles made of fats
similar to those in our cell membranes. These particles:

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Shield the mRNA from breaking down too quickly

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Help cells absorb the mRNA efficiently

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Break down naturally in the body

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Have been extensively tested for safety

PRE-COVID CLINICAL TRIALS: BUILDING THE SAFETY RECORD

FIRST CANCER VACCINE TRIALS (1995)
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Goal: Test mRNA vaccines against tumors

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Results: Successfully demonstrated immune response against cancer
markers

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Safety Profile: Well-tolerated with no significant adverse events

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Why It Didn't Go Mainstream: While safe, the immune response wasn't
strong enough to effectively fight tumors. This trial exemplified a
pattern we'd see repeatedly: the technology was safe but needed
refinement to be effective enough for approval.

FIRST HUMAN INFECTIOUS DISEASE TRIAL: RABIES (2012)
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Participants: 101 healthy volunteers

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Goal: Prevent rabies infection

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Safety Results: Mostly mild reactions, no serious safety concerns

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Efficacy Results: Only 71% achieved protective antibody levels

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Key Takeaway: While the vaccine proved remarkably safe, it didn't
consistently reach the high protection levels needed to replace
existing rabies vaccines. The safety record was excellent, but
efficacy wasn't competitive with traditional vaccines.

MODERNA'S INFLUENZA TRIALS (2015)
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H10N8 Study (201 participants)

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Safety Profile: Excellent, with mostly mild reactions

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Efficacy: Variable immune responses

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Conclusion: Another example where safety was confirmed but
effectiveness couldn't match existing flu vaccines

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H7N9 Study (156 participants)

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Safety Record: Well-tolerated, no serious concerns

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Efficacy: Stronger immune response but still not consistent enough

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Outcome: While safety was again confirmed, the vaccines didn't offer
clear advantages over traditional flu shots

In each of these trials, safety was consistently demonstrated. The
technology didn't go mainstream not because of safety concerns, but
because it hadn't yet found a disease target where it could
demonstrate superior effectiveness compared to existing vaccines.

THE COVID-19 "LUCKY BREAK"

What made COVID-19 different? The SARS-CoV-2 virus proved to be an
ideal target for mRNA vaccination, primarily because of its spike
protein. Unlike previous targets, this protein had three
characteristics that aligned perfectly with mRNA technology:

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Accessibility: The spike protein sits exposed on the virus surface,
making it an easy target

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Stability: It maintains its shape consistently, allowing antibodies to
recognize it reliably

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Vulnerability: Antibodies targeting this protein effectively
neutralize the virus

This combination of factors created the perfect scenario
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vaccines to demonstrate their full potential
[[link removed]]. THE TECHNOLOGY
DIDN'T SUDDENLY BECOME SAFE—IT HAD BEEN SAFE FOR YEARS. Instead, it
finally found a target where it could also be remarkably effective.

LOOKING FORWARD

The success of mRNA vaccines against COVID-19 has opened new
possibilities, all building on decades of safety data:

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Cancer immunotherapy
[[link removed](23)02268-7/fulltext&sa=D&]

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Autoimmune disease treatment

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Protection against other infectious diseases

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Personalized medicine applications
[[link removed](23)02268-7/fulltext&sa=D&]

Each new application benefits from over 40 years of safety research
and understanding.

CONCLUSION

The story of mRNA technology teaches us an important lesson about
medical innovation: true breakthroughs often come not from sudden
discoveries but from decades of careful research and refinement. While
COVID-19 may have introduced the world to mRNA vaccines, their safety
was established through years of rigorous testing long before the
pandemic.

Understanding this history helps explain why scientists were so
confident in the safety of COVID-19 mRNA vaccines: they weren't
working with a new, untested technology, but rather with one whose
safety profile had been repeatedly demonstrated over decades
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What changed with COVID-19 wasn't the safety of the technology—that
was already well established. What changed was finding the right
target to demonstrate its effectiveness
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This long view of mRNA technology's development should reassure those
with concerns about its safety. The technology didn't rush to market;
it waited decades until it could prove both safe AND effective. This
patient, methodical approach to development is exactly what we want to
see in medical innovation.

So when you’re sitting around the holiday table and your uncle tells
you the mRNA technology is “too new”— you now have the
“receipts” to explain why that’s not accurate.

Stay curious,

Unbiased Science

_Unbiased Science is a science communication hub. We create and deploy
weekly podcast episodes, daily infographics via social media, and
bi-weekly newsletters here with the occasional added content. Our goal
is to provide science-based and objective appraisal of the available
evidence on science and health-related topics relevant to listeners’
daily lives._

_Dr. Jessica Steier is a public health scientist with expertise in
public health policy, biostatistics, and advanced analytics. Dr. Sarah
Scheinman is a Chicago-based neurobiologist with expertise in basic
science, preclinical, and translational biomedical research. Her
primary focus is on the molecular mechanisms of aging and
neurodegenerative diseases, but she also has subject-matter expertise
in cell biology, genetics, epigenetics, and psychology._

_SUBSCRIBE [[link removed]]. CONTACT THE
UNBIASED SCIENCE TEAM AT [email protected]._

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