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ALL CHILDHOOD VACCINES WERE TESTED AGAINST PLACEBOS – HERE’S THE
EVIDENCE  
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Jess Steier
January 17, 2025
Unbiased Science
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_ Yes, ALL childhood vaccines have been tested against placebos, and
most have been tested against inert placebos (when they aren't,
there's a very good reason why). We'll walk through the history, and
explore why trial designs have evolved. _

Child receiving vaccination, Heather Hazzan, SELF Magazine (via
American Academy of Pediatrics)

 

Last Monday’s newsletter
[[link removed]] about
randomized controlled trials in vaccine development generated
fascinating discussion and important questions from our readers. Many
of you reached out with specific concerns that deserve a thorough
response. Let's address the main points of feedback:

YOUR COMMENTS:

*
"Vaccines aren't always compared to saline placebos – they're
sometimes compared to other vaccines. This seems problematic."

*
"The COVID vaccine trials were unblinded after just a few months.
Doesn't this invalidate the results?"

*
"Where's the evidence that childhood vaccines went through proper
RCTs? Show us the historical data."

*
"Vaccine inserts state they weren't tested for cancer risks and other
long-term outcomes. How can you claim proper safety testing?"

These are excellent questions that get to the heart of how vaccine
trials are designed and conducted. Let's break down each one.

UNDERSTANDING PLACEBOS AND CONTROLS IN VACCINE TRIALS

Not all placebos are created equal – and for good reason. In vaccine
trials, researchers use three main types of control groups:

*
_Inert (True) Placebos_- These are typically saline solutions
containing no active ingredients. They're the gold standard for
testing completely new vaccines or vaccine technologies. When the
first mRNA COVID vaccines were tested, they used saline controls
because this was a novel technology requiring the clearest possible
safety data.

*
_Active Placebos_- These contain some vaccine components (like
aluminum adjuvants) but not the actual antigen that creates immunity.
They help researchers understand whether side effects come from the
antigen itself or other vaccine ingredients. Think of it as isolating
variables in a scientific experiment.

*
_Comparator Vaccines_- Here's where it gets interesting – and where
some of you expressed concern. Sometimes researchers use existing
licensed vaccines as comparators instead of placebos. But this only
happens in specific circumstances where there is already a
standard-of-care option, and after initial safety is established.

Understanding these different control groups is essential because they
each serve distinct scientific purposes. While saline placebos show us
the total effect of a vaccine compared to no intervention, active
placebos and comparator vaccines help us answer more specific
questions: Is this new component safe? Is this new vaccine at least as
good as what we already have? The choice of control group
[[link removed]] reflects
both our existing scientific knowledge and our ethical obligations to
study participants.

WHY USE COMPARATOR VACCINES?

The reason comes down to medical ethics. Once a safe and effective
vaccine exists for a disease, it becomes ethically questionable to
give study participants a placebo, effectively leaving them
unprotected. This principle is outlined in the Declaration of
Helsinki
[[link removed]],
which sets ethical guidelines for medical research. In such cases
[[link removed]],
scientists can propose alternative controls—such as another approved
vaccine—which regulatory authorities then evaluate for suitability.
These studies are still rigorously scrutinized by regulators and
designed to be statistically robust, ensuring reliable results
regardless of the type of control used.

For example: If we're testing a new measles vaccine, giving half the
children a saline placebo would leave them vulnerable to a potentially
deadly disease when a proven vaccine already exists. Instead,
researchers compare the new vaccine to the current standard to prove
it's at least as safe and effective (i.e. demonstrate noninferiority).

An expert panel from the World Health Organization notes that there
are specific circumstances 
[[link removed]]where using a
saline placebo in a vaccine trial is ethically and scientifically
sound, even if an effective vaccine already exists:

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When determining the local burden of disease

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When an existing vaccine is not appropriate locally (as determined by
epidemiologic or demographic factors, such as the cost of a vaccine)

*
When developing a vaccine that is locally affordable

*
When investigating the local safety and efficacy of an existing
vaccine

THE DEVELOPMENT AND TESTING OF HPV VACCINES - UNDERSTANDING COMPARATOR
CHOICE

A systematic review of 24 clinical study reports
[[link removed]] reveals
how and why modern vaccine trials use comparator vaccines instead of
saline placebos. The HPV vaccine trials, which included 95,670
participants, made specific choices about control groups for
scientific and ethical reasons:

Nearly all control participants (48,289 of 48,595, 99%) received
active comparators rather than saline placebo. This design choice
reflects several key scientific and ethical principles:

*
The aluminum adjuvant system was already proven safe and necessary for
the vaccine to work, so testing focused on the HPV-specific components

*
Using similar adjuvants in the control group allowed researchers to
isolate the effects of the HPV components while controlling for known
adjuvant effects

*
Using comparator vaccines like hepatitis vaccines provided a rigorous
control group (similar injection schedule, known safety profile) while
giving participants protection against another disease

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This design maintained proper blinding through similar injection site
reactions, ensuring reliable data collection

The key point is that using comparator vaccines doesn't reduce safety
monitoring - it actually helps researchers better understand the
specific effects of the new vaccine components while building on
established safety data.

THE COVID TRIAL UNBLINDING DISCUSSION

Several readers expressed concern about the unblinding of COVID-19
vaccine trials. This decision, while controversial,
followed established ethical principles
[[link removed]]. Once clear
statistical evidence showed the vaccines were both safe and effective,
researchers faced an ethical imperative to offer the vaccine to
placebo group participants – many of whom were healthcare workers at
high risk.

This follows the principle of "equipoise" in medical research: once we
have clear evidence that one treatment is superior, we have an ethical
obligation to offer it to all participants, especially those at the
highest risk of poor outcomes.

Concluding that every evaluation of a vaccine must contain a saline
placebo opens the door for unnecessarily risking the health and safety
of those participating in a clinical trial. Leaving patients
intentionally untreated or undertreated when there is a known
treatment or vaccine to compare against is unethical. As Dr. David
Gorski puts it
[[link removed]]:

_“THE ONLY TIME THAT A PLACEBO-CONTROLLED RCT OF A VACCINE CAN BE
ETHICALLY JUSTIFIED IS WHEN THERE CURRENTLY DOES NOT EXIST A SAFE AND
EFFECTIVE VACCINE AGAINST THE DISEASE FOR WHICH THE EXPERIMENTAL
VACCINE HAS BEEN DESIGNED.”_

As such, there are _many_ cases where this criteria is not met, and
the ethical conduct of research requires that we not leave research
participants completely untreated when it is not absolutely necessary.

When unblinding is a consideration, we must strike an ethical balance
in vaccine trials by prioritizing vaccination for those at the highest
risk while maintaining opportunities for lower-risk participants to
remain in placebo groups. During the COVID-19 vaccine trials, once the
vaccine was authorized for emergency use, participants in the placebo
group who were at high risk were offered the opportunity to receive
the vaccine outside of the trial. This approach addressed the ethical
obligation to provide access to a potentially life-saving intervention
for vulnerable populations, ensuring that no participant was denied
timely protection against a serious disease.

To preserve the integrity of the trial, many studies implemented a
"crossover" design, allowing placebo participants to receive the
vaccine while still being monitored under the same study protocol.
This ensured that researchers could continue collecting valuable data
on long-term safety and efficacy across both groups. In balancing
these ethical and scientific considerations, COVID-19 vaccine trials
not only protected high-risk individuals but were also able to
continue investigating the vaccine's performance.

This crossover design raised some challenges for the continued
assessment of the efficacy and safety of the vaccines while
maintaining the integrity of the study in the absence of a true
placebo, but this was overcome in several ways:

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Crossover was blinded
[[link removed]] so that vaccine
durability and long-term efficacy could continue to be measured
against a valid control, with sophisticated statistical modeling
accounting for the timing of crossover and vaccination status.

*
Trials were subject to continued efficacy and safety monitoring by
independent Data and Safety Monitoring Boards (DSMBs) and a
combination of active
[[link removed]] and passive
[[link removed]] surveillance
systems.

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The combination of real-world evidence
[[link removed]] and data
from immunological assays
[[link removed]] allows
researchers to continue to understand long-term efficacy in the
absence of placebo groups.

*
Large sample sizes (>30,000 participants in major trials) maintained
statistical power above 90% even after accounting for crossover
effects.

HISTORICAL EVIDENCE OF CHILDHOOD VACCINE RCTS

Many readers asked for evidence that childhood vaccines underwent
proper randomized controlled trials (RCTs). Here's the historical
data, tracking how vaccine testing evolved from early saline-placebo
studies to modern trial designs:

POLIO VACCINE (1954
[[link removed]])
- SETTING THE STANDARD

Participants:

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623,972 [[link removed]] children
received vaccine or saline placebo

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Additional 1+ million children as "observed controls"

Design: True double-blind RCT with saline placebo

Results:

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80-90% effective against paralytic polio

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No unexpected side effects

Impact
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Cases dropped from 58,000 (1957) to 161 (1961)

MEASLES VACCINE (1968
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- MULTIPLE VACCINE COMPARISON

Participants: 444 children total

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Children in the vaccine group were divided into four subgroups, each
receiving one of the four different vaccines.

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The remaining children were assigned a saline placebo

Design: RCT comparing four vaccines against saline placebo

Results:

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Strong immune response in vaccine groups

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Low adverse event rates

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Safe and effective compared to placebo

Impact
[[link removed]] (2000-2003):
prevented 60 million deaths globally.

ROTAVIRUS VACCINE - MODERN TRIAL DESIGN

_2009
[[link removed]] ROTAVIRUS
EFFICACY AND SAFETY TRIAL (REST)_

The development of rotavirus vaccines has been backed by large-scale
controlled trials that demonstrated both their safety and efficacy.
One of the most extensive and thorough trials was published in 2009.

Participants: 69,589 infants were assigned a pentavalent
human–bovine reassortant oral rotavirus vaccine or placebo (matching
liquid formulation without the active vaccine components)

Design: Blinded, placebo-controlled RCT

Results:

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Strongly effective against rotavirus

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No difference in adverse reactions between placebo and vaccine groups

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Safe and effective compared to placebo

Impact
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143 million children vaccinated

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Prevented 18.7 million severe cases

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Avoided 153,000 deaths

_2020 [[link removed]] P2-VP8
SUBUNIT ROTAVIRUS VACCINE TRIAL - MODERN USE OF SALINE PLACEBO_

A recent trial with saline placebo demonstrated the continued value of
true placebo controls when ethically appropriate:

Participants: 30 adults, 30 toddlers and 557 infants were assigned a
trivalent P2-VP8 subunit rotavirus vaccine or saline placebo

Design: True double-blind RCT with saline placebo

Results:

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Strong immune response in vaccine group

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No difference in adverse reactions between placebo and vaccine groups

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Safe and effective compared to placebo

EARLY DEVELOPMENT AND LICENSURE OF PERTUSSIS VACCINES

The history of pertussis vaccination provides important context for
understanding how vaccine testing and licensure requirements have
evolved. The first pertussis vaccines were licensed in 1914, in an era
with very different regulatory standards than today. Initial licensure
was based primarily on basic safety monitoring and evidence of immune
response, rather than the comprehensive clinical trials we now
require.

In the 1940s, controlled efficacy trials demonstrated that 4 doses of
whole-cell DTP vaccine were 70-90% effective at preventing serious
pertussis disease. The vaccine's impact was dramatic: cases dropped
from over 200,000 annually in the pre-vaccine era to just 15,000 by
1960. By 1970, annual incidence had fallen to fewer than 5,000 cases.

However, concerns about side effects from whole-cell vaccines led to
the development of more purified acellular pertussis vaccines in the
1990s. This development was informed by two pivotal Swedish trials
described below.

PERTUSSIS VACCINE DEVELOPMENT AND EVIDENCE

HISTORICAL CONTEXT (1914-1945):

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Pre-vaccine era: Over 200,000 cases reported annually

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1914: First whole-cell pertussis vaccine licensed

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1940-1945: More than 1 million cases reported (averaging over
170,000 cases per year
[[link removed]])

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Disease burden: ~150 cases per 100,000 population
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EARLY EFFICACY EVIDENCE (1940S-1960S) AND FURTHER DEVELOPMENTS
(1970S-1990S):

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1948: Combined DTP vaccine introduced

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Controlled efficacy trials showed 70-90% effectiveness with 4-dose
series

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By 1960: Cases dropped to 15,000 (8 per 100,000 population)

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By 1970: Further reduced to <5,000 cases annually

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1980-1990: Average of 2,900 cases per year (1 per 100,000)

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1991: The DTaP vaccine, which is acellular and causes fewer side
effects than DTP, is licensed
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MODERN CLINICAL TRIALS (1988 Swedish Trial
[[link removed]?]):

The first major trial of acellular pertussis vaccines used a placebo*
control group, as the vaccine technology was new:

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3,801 children randomized

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954 received placebo (vaccine solvent)

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1,419 received two-component vaccine

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1,428 received LPF-toxoid vaccine

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Results: Both vaccines ~80% effective

*_While it's reasonable to infer that the "vaccine solvent" mentioned
in the 1988 pertussis trials refers to a saline solution, without
direct access to the trial protocols or detailed reports, this cannot
be confirmed with absolute certainty._

The transition from whole-cell to acellular pertussis vaccines
illustrates how vaccine trials adapt to advancing science. The 1988
Swedish trial used a placebo because the acellular technology was
completely new. Once that trial established basic safety, later
studies could focus on comparing the new acellular vaccines to
existing whole-cell vaccines - allowing researchers to determine if
the new technology provided similar protection with fewer side
effects. This shows how trial design evolves to answer the most
relevant scientific questions at each stage of vaccine development.

SWEDISH COMPARATIVE TRIAL
[[link removed]]:

Following the success of the first trial, subsequent studies compared
the new acellular vaccines to existing whole-cell vaccines rather than
placebos - an ethical necessity since withholding proven vaccination
would have left participants vulnerable to a serious disease:

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9,829 children total

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7,255 received acellular DTP

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2,574 received whole-cell DTP

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Results: Five-component acellular vaccine showed 77.9% efficacy

Recent innovations continue to be evaluated with true saline placebos
when ethically appropriate. For example, in 2014, the first
placebo-controlled trial of BPZE1, a novel live attenuated intranasal
pertussis vaccine, demonstrated both safety and immunogenicity in
healthy adults.

RECENT INNOVATION (2014): BPZE1 Live Attenuated Vaccine Trial
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First saline placebo-controlled trial of new pertussis vaccine
technology

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Double-blind study design

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Demonstrated safety and successful colonization in a dose-dependent
manner

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100% seroconversion in colonized participants

From the groundbreaking polio trials of the 1950s to modern pertussis
innovations, this historical evidence demonstrates that childhood
vaccines have consistently been tested through rigorous controlled
trials - using saline placebos when ethically appropriate, and equally
rigorous comparative controls when existing vaccines made placebos
unethical.

ADDRESSING THE PACKAGE INSERT ARGUMENT

Many readers pointed out that vaccine package inserts don't list
testing for cancer risks and other long-term outcomes. This reflects a
misunderstanding of how safety monitoring works. This is because
vaccine trials aren't designed to directly test for cancer risk
because the biological mechanism of vaccines doesn't support plausible
carcinogenic effects

Here's why: Vaccines work by introducing specific protein antigens or
inactivated pathogens that are cleared from the body within weeks.
Unlike chemical carcinogens that can cause DNA mutations or persistent
biological changes, vaccine components don't remain in the body
long-term or interact with cellular DNA. The immune response they
generate is similar to what occurs during natural infection, but in a
controlled, less dangerous way. Furthermore, the aluminum adjuvants
used in some vaccines are largely eliminated from the body within
weeks
[[link removed]] and
have been extensively studied for long-term safety. A few other
reasons include:

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Cancer typically takes decades to develop, making it impractical for
pre-approval trials

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Instead, we have robust post-market surveillance systems (VAERS and
VSD to name just a couple!) that monitor for any unusual patterns of
disease, including cancers

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Population studies have repeatedly shown no increased cancer risk in
vaccinated populations

The aluminum adjuvants used in vaccines have been extensively studied
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clearance from the body. Research has shown that although aluminum is
a ubiquitous element in the environment, the small amounts used in
vaccines as adjuvants (frequently aluminum hydroxide or aluminum
phosphate) are well understood pharmacologically. Studies demonstrate
that aluminum from vaccines and diet throughout an infant's first year
of life is significantly less than corresponding safe body burden
levels established by regulatory agencies. The aluminum is eliminated
from the body through normal processes - primarily in the urine, with
small amounts being incorporated into bone formation during rapid
growth and development. The half-life of aluminum in soft tissues like
the liver is short (<2 days), indicating very little accumulation in
these organs.

It's important to understand that vaccine package inserts are
primarily legal documents required by regulatory authorities, not
comprehensive scientific reviews. Their primary purpose is to provide
prescribing information and document what was specifically tested in
pre-licensure trials, rather than to summarize all available safety
evidence. Post-marketing surveillance and epidemiological studies
often provide much broader evidence about long-term safety outcomes.

This evolution in vaccine testing reflects growing scientific
sophistication. While early vaccine trials relied on simple saline
comparisons because everything about the vaccines was novel, modern
trials build upon established safety data about components like
aluminum adjuvants. This allows researchers to focus their
investigations more precisely on new elements while maintaining
rigorous safety standards. Far from lowering standards, this
progression represents increasingly sophisticated scientific questions
backed by accumulating evidence.

THE TESTING PROGRESSION

To put it all together, here's how vaccine testing typically
progresses:

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_New Vaccine Technology:_

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Starts with true saline placebo trials

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Must establish basic safety before any other comparisons

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_Iterations of Proven Technology:_

*
May use active placebos or comparator vaccines

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Only after the platform's basic safety is established

*
_Competing Products:_

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Often compared to existing licensed vaccines

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Must first demonstrate basic safety or have done so in previous
studies

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Focus on proving "non-inferiority" to existing options

This systematic approach to vaccine testing has evolved over 70 years,
with each new vaccine benefiting from previous research. Understanding
this progression reveals how modern vaccine trials make evidence-based
choices about control groups while ensuring thorough safety testing.
The key principles remain constant:

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New technologies start with the most basic comparisons (saline
placebos)

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Proven platforms build on established safety data

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Ethics and science work together to protect both study participants
and future vaccine recipients

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Multiple layers of safety monitoring continue long after approval

This careful balance of scientific rigor and ethical responsibility
has given us vaccines that are among the most thoroughly tested
medical interventions in history.

Stay curious,

Unbiased Science

_You're reading Unbiased Science, where we take time to explain
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_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._

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