Full text
United States Government Accountability Office
Science, Technology Assessment, and Analytics
Report to Congressional Requesters
TECHNOLOGY ASSESSMENT
Pandemic Origins
Technologies and Challenges for Biological
Investigations
January 2023
GAO-23-105406
The cover image displays examples of possible pandemic origin scenarios. These scenarios include natural origin—such
as the accidental infection of one or more individuals by a pathogen transmitted from animals, including via insects or
other sources such as the environment. Scenarios also include laboratory origin that begins with either the infection of
individuals by a pathogen in a laboratory setting, or infections outside the laboratory caused by an accidental or
intentional release of the pathogen from a laboratory.
Cover source: GAO. | GAO-23-105406
United States Government Accountability Office
Highlights of GAO-23-105406, a report to
congressional requesters
January 2023
TECHNOLOGY ASSESSMENT
Pandemic Origins
Technologies and Challenges for
Biological Investigations
What GAO found
Determining the likely origin of pandemics is challenging. Researchers may use several
technologies to investigate a pandemic’s origin. For example, researchers use
technologies such as genomic sequencing, bioinformatics analysis, and genetic
databases to generate, analyze, and compare a pathogen’s genetic makeup against that
of other pathogens. A key limitation of these technologies is that some laboratory-based
genetic modifications may be indistinguishable from natural variations. Access to
samples is critical for conducting genetic sequence analysis, which allows researchers to
generate and analyze the data needed to support the likely origin of a pandemic.
Examples of technologies for pandemic origin investigations
Researchers also use technologies such as serology (i.e., blood analysis) and
epidemiological surveillance—tracking a disease as it moves through a population—to
monitor pathogen infection and disease occurrence in human and animal populations.
The resulting data can support pandemic origin investigations. However, for these
technologies to be effective in determining a pandemic’s likely origin, investigators need
access to samples and data from infected or exposed individuals from early in an
outbreak to reliably trace the disease back to the first human infection(s). Further,
researchers may conduct laboratory-based pathogen studies to generate data to
support known natural patterns or unusual patterns of spread indicative of a possible
laboratory-related origin. However, some pathogens cannot be easily cultured in a
laboratory setting, and some pathogens may require enhanced biosafety-level facilities.
However, experts told GAO that technologies are not the limiting factor for determining
the likely origin of a pandemic. GAO identified three cross-cutting challenges that hinder
pandemic origin investigations. These include a lack of sufficient access to samples and
genetic sequence data; a lack of standardized processes for submitting, accessing, and
using genetic sequence data stored in databases around the world; and a lack of a
sufficient and skilled interdisciplinary workforce.
View GAO-23-105406. For more information,
contact Karen L. Howard at (202) 512-6888,
howardk@gao.gov.
Why GAO did this study
Pandemics are global disease
outbreaks that can greatly increase
morbidity and mortality and cause
significant economic and social
disruptions. According to the
scientific literature, most pandemics
where the origin is known were
caused by the natural transmission of
a virus through animal-to-human
contact; however, there is potential
for a pandemic to originate from
laboratory research.
GAO was asked to conduct a
technology assessment on pandemic
origins. This report describes: (1) key
technologies available for pandemic
origin investigations, (2) strengths
and limitations of these tools and
how researchers use them to
investigate pandemic origins, and (3)
cross-cutting challenges researchers
face in trying to determine a
pandemic’s origin.
GAO reviewed peer-reviewed
scientific literature and other
documents, including reports from
the Centers for Disease Control and
Prevention, Office of the Director of
National Intelligence, the Johns
Hopkins Center for Health Security,
World Health Organization, and select
national laboratories; interviewed
government, industry, and academic
representatives; and convened a
meeting of 27 experts in March 2022
with assistance from the National
Academies of Sciences, Engineering,
and Medicine.
GAO is identifying policy options in
this report.
GAO identified five policy options that may help address the cross-cutting challenges. These policy options represent possible
actions that policymakers—who may include Congress, federal agencies, state and local governments, academia, industry, and
international organizations—could consider taking. See below for a summary of the policy options and relevant opportunities and
considerations.
Policy Options to Address Three Cross-Cutting Challenges in Pandemic Origin Investigations
Policy Option
Opportunities
Considerations
Establish multilateral agreements for
accessing and sharing samples and
genetic sequence data (report p. 21)
Federal policymakers and others could
encourage international preparedness in
advance of future outbreaks by establishing
multilateral agreements for accessing and
sharing samples and genetic sequence data.
• Ensuring timely access to genetic information
and samples in the critical beginning stages of a
pandemic as well as throughout an origin
investigation may help in the determination of
a pandemic’s origin.
• Establishing standing agreements between
nations before a pandemic occurs could assist
in the determination of a pandemic’s origin.
• Countries may be unwilling to participate
in multilateral, international agreements
because of concerns related to national
sovereignty, among other reasons.
• Identifying an appropriate responsible
entity to determine and monitor
whether countries are following agreed-
upon standard processes may be time
consuming and challenging.
Develop standardized processes for
genetic sequence database use (report
p. 22)
Federal policymakers and others could
empower or establish a working group to
develop standardized processes for
database use to support pandemic origin
investigations.
• Developing standardized processes for
database use could help ensure consistency of
submitted data and metadata across multiple
databases, improve researchers’ access, and
help researchers comprehensively compare
genetic sequences.
• Implementing leading practices for genetic
data integrity and associated metadata could
help improve the quality of data in genetic
sequence databases.
• Standardized processes may be difficult
to develop as there are risk-benefit
trade-offs. For example, access to certain
novel pathogen sequences should be
limited to trusted and credentialed
individuals with a need to access those
sequences.
• It may be challenging for multiple
stakeholders to agree on what data are
important.
Improve current, or develop new,
genetic sequence database tools
(report p. 23)
Policymakers could encourage the
improvement of current, or development of
new, genetic sequence database tools.
• Improved or new database interfaces could
streamline researchers’ data submission,
access, and use as well as improve data quality.
• Improved or new database interfaces could
help address the projected future growth in
genetic sequence data.
• Building new, or retooling current,
database interfaces could be time- and
labor-intensive.
• It may be challenging for groups of users
to agree on what database interface
features are important.
Encourage the development, retention,
and growth of a workforce with the
critical skills needed for pandemic
origin investigations (report p. 24)
Policymakers could encourage mechanisms
to provide training, workforce development,
and capacity-building, including in areas
considered hot spots of emerging infectious
disease.
• Encouraging development of expertise in
geographic areas where novel pathogens are
likely to emerge could increase the overall
global supply of skilled workers and help to
ensure the workforce is not concentrated in
any geographic region.
• A trained workforce skilled in origin
investigations could contribute to other areas
such as public health, or other types of related
activities.
• Pandemic origin investigations tend to be
episodic. As a result, it may be difficult to
adequately plan for and consistently
fund staffing in science fields related to
pandemic origin investigations.
• Researchers may experience unwanted
attention or pressure because of their
involvement in pandemic origin
investigations and leave the field or
refuse to participate.
Augment or develop a national
strategy to better coordinate and
collaborate domestically and
internationally on pandemic origin
investigations (report p. 25)
Federal policymakers could better
coordinate and collaborate with domestic
and international partners by augmenting or
developing a national strategy for pandemic
origin investigations. This could be a
standalone strategy or a component of
existing strategies such as the National
Biodefense Strategy.
• A national strategy could help address the
challenges that hinder pandemic origin
investigations.
• Federal coordination and collaboration
leadership, guided by a national strategy, could
increase preparedness for future pandemic
origin investigations.
• Understanding pandemic origins could help
mitigate health and economic costs associated
with pandemics by, for example, facilitating
surveillance that could identify future
pandemics more quickly.
• Allocating resources and defining how
federal agencies and others will
collaborate may be challenging because
of the number and types of entities with
relevant expertise.
• During nonpandemic periods, other
priorities and needs may arise and make
it challenging to provide sustained
resources and support needed for
maintaining a national strategy.
Source: GAO. | GAO-23-105406
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Pandemic Origins GAO-23-105406 i
Table of Contents
Introduction ........................................................................................................................ 1
1 Background ...................................................................................................................... 3
1.1 Natural origin ..................................................................................................................... 3
1.2 Laboratory origin ............................................................................................................... 5
1.3 Investigating pandemic origin ........................................................................................... 6
2 Technologies for Investigating Pandemic Origin ............................................................. 7
2.1 Genetic sequence analysis ................................................................................................. 7
2.2 Infectious disease surveillance .......................................................................................... 9
2.3 Laboratory-based pathogen studies ................................................................................ 10
3 Researchers Have Used a Variety of Technologies for Pandemic
Origin Investigations ......................................................................................................... 11
3.1 Researchers used genetic sequence analysis to determine the likely origin of
several pandemics ........................................................................................................ 11
3.2 Researchers used serology and epidemiological surveillance for pandemic origin
investigations ................................................................................................................ 13
3.3 Researchers used laboratory-based pathogen studies for pandemic origin
investigations ................................................................................................................ 15
4 Researchers Face Three Key Challenges When Investigating Pandemic Origin ............ 17
4.1 Researchers lack sufficient access to critical samples and data ...................................... 17
4.2 Lack of standardized processes for genetic sequence databases prevents
researchers from analyzing data effectively ................................................................ 18
4.3 The global research community lacks a sufficient skilled,
interdisciplinary workforce ........................................................................................... 19
5 Selected Policy Options to Help Address Three Cross-Cutting Key Challenges for
Investigating Pandemic Origin .......................................................................................... 21
6 Agency and Expert Comments ....................................................................................... 28
Appendix I: Objectives, Scope, and Methodology ............................................................ 31
Appendix II: Expert Participation ...................................................................................... 34
Appendix III: GAO Contact and Staff Acknowledgments .................................................. 37
Pandemic Origins GAO-23-105406 ii
Figures
Figure 1: Examples of pandemic origin scenarios ............................................................... 4
Figure 2: Genetic sequence analysis for pandemic origin investigations ........................... 8
Pandemic Origins GAO-23-105406 iii
Abbreviations
API
application programming interface
CDC
Centers for Disease Control and Prevention
MERS
Middle East respiratory syndrome
MERS-CoV
MERS coronavirus
SARS
severe acute respiratory syndrome
SARS-CoV
SARS-associated coronavirus
Pandemic Origins GAO-23-105406 1
441 G St. N.W.
Washington, DC 20548
Introduction
January 27, 2023
Congressional Requesters
Pandemics and epidemics—such as plague, cholera, influenza, severe acute respiratory
syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19—have afflicted
humanity throughout history, causing millions of deaths and costing trillions of dollars.1 For
example, prior to a successful vaccination campaign that eradicated smallpox in 1980, the
disease killed approximately 300 million people globally between 1900 and 1980.2
The COVID-19 pandemic has highlighted how infectious diseases continue to have a devastating
impact. As of the week ending January 7, 2023, the U.S. had about 1,090,000 reported deaths
attributed to COVID-19.3 A recent assessment estimated the human and economic cost of the
COVID-19 pandemic to the U.S. totaled more than $10 trillion.4
Given the magnitude of the health and economic costs of pandemics, policymakers—which
include Congress, federal agencies, state and local governments, academic and research
institutions, industry, and international organizations—have a need to better understand how
and where they originate.5 This understanding could help inform preparation and response to
future epidemics and pandemics. However, determining the origin of a pathogen—a bacterium,
virus, or other microorganism that can cause disease—requires evidence that may, in some
cases, take decades of research to acquire. The accumulated data from these investigations may
lay the foundation for future pandemic origin-tracing. For example, it took approximately 13
years to determine the origin of the SARS-associated coronavirus (SARS-CoV) pathogen that
1The Centers for Disease Control and Prevention (CDC) describes a pandemic as an epidemic that has spread over several countries
or continents; an epidemic as an increase in the number of cases of a disease above what is normally expected in an area; and an
outbreak as an epidemic, but in a more limited geographic area. However, these terms are not always consistently used for every
disease. For example, while some researchers describe MERS as a pandemic, others describe it as an epidemic or outbreak.
2K.K. Thomas, “40 Years in a Post-Smallpox World,” Johns Hopkins Bloomberg School of Public Health, May 8, 2020
(https://publichealth.jhu.edu/2020/40-years-in-a-post-smallpox-world).
3CDC’s National Center for Health Statistics COVID-19 death counts in the U.S. are based on provisional counts from death certificate
data, which do not distinguish between laboratory-confirmed and probable COVID-19 deaths. Provisional counts are incomplete
because of an average delay of 2 weeks (a range of 1–8 weeks or longer) for death certificate processing. See CDC, National Center
for Health Statistics, “Provisional Death Counts for Coronavirus Disease 2019 (COVID-19),” accessed January 10, 2023,
https://www.cdc.gov/nchs/nvss/vsrr/covid19/index.htm.
4R. Bruns and N. Teran, “Weighing the Cost of the Pandemic,” Institute for Progress, April 21, 2022: 1-7
(https://progress.institute/weighing-the-cost-of-the-pandemic/).
5Determination of a pandemic’s origin has some level of inherent scientific uncertainty. For this report, we use the term “origin” to
mean “likely origin,” acknowledging this uncertainty.
Pandemic Origins GAO-23-105406 2
caused the 2002-2003 SARS pandemic.6 However, the knowledge gained from those
investigations helped researchers more quickly determine the origin of the MERS outbreak of
2012, according to literature we reviewed.
You asked us to conduct a technology assessment to understand how the U.S. can be better
prepared to predict, prevent, detect, assess, and effectively respond to future pandemics, with a
focus on determining the origins of pandemics. In this technology assessment, we describe
•
key technologies available for pandemic origin investigations;
•
strengths and limitations of these tools and how researchers use them to investigate
pandemic origins;
•
cross-cutting challenges researchers face in trying to determine a pandemic’s origin; and
•
policy options that may help address the cross-cutting challenges of using these key
technologies to determine the likely origin of a pandemic.7
To address our objectives, we conducted literature searches and reviewed selected scholarly
articles and other documents, including reports from the Centers for Disease Control and
Prevention (CDC), Office of the Director of National Intelligence, the Johns Hopkins Center for
Health Security, World Health Organization, and select national laboratories, describing
technologies for pandemic pathogen characterization. Additionally, we interviewed
stakeholders and experts with a diverse set of perspectives on the science and application of
these technologies. This included holding an expert meeting with assistance from the National
Academies of Sciences, Engineering, and Medicine. See appendix I for more information on our
scope and methodology and appendix II for a list of participants in our expert meeting.
We conducted our work from August 2021 through January 2023 in accordance with all sections
of GAO’s Quality Assurance Framework relevant to technology assessments. The framework
requires that we plan and perform the engagement to obtain sufficient and appropriate
evidence to meet our stated objectives and to discuss any limitations to our work. We believe
the information and data obtained, and the analysis conducted, provide a reasonable basis for
any findings and conclusions in this product.
6Initial evidences showed the civet cat to be the primary animal origin of the SARS-associated coronavirus (SARS-CoV). Later studies
suggested that Chinese horseshoe bats were natural reservoirs—locations where the pathogen circulates among people and animals
between outbreaks—and that the civet cat most likely served as an intermediate host. However, the study identifying the closest
ancestor to SARS-CoV in a single bat colony in the Kunming, Yunnan Province in China was not published until December 2015.
7For the purposes of this report, the term “technologies” includes the instruments, techniques, skills, methods, and processes used
in pathogen characterization.
Pandemic Origins GAO-23-105406 3
1 Background
Pandemics are global infectious disease
outbreaks that can greatly increase morbidity
and mortality in people, and cause significant
economic and social disruptions. According to
the scientific literature, most pandemics
where the origin is known were caused by the
natural transmission of a virus through
animal-to-human contact. Outbreaks have
also been reported as a result of laboratory
accidents, and research suggests the 1977-
1978 H1N1 influenza pandemic may have
been the result of a laboratory accident or
other cause (see fig. 1).8 Determining the
likely origin of pandemics is challenging and
requires information gathered from
established methods for the investigation of
disease outbreaks.
1.1 Natural origin
A pandemic with a natural origin scenario
could initiate with the accidental infection of
one or more individuals by a pathogen
transmitted from animals, including via
insects or other sources such as the
environment. Pandemics are often the result
of zoonotic pathogens being naturally
transmitted between animals and humans.9
8Examples of known laboratory accidents involving pathogens
include the unintended release of smallpox virus from a
laboratory in the United Kingdom in 1978, which resulted in
one death and over 300 vaccinations and surveillance of the
researcher’s close contacts; the accidental self-injection of the
Ebola virus by a Russian scientist in 2004 that resulted in her
death; and the unintended release of Brucella bacteria from a
vaccine facility in China that began in 2019, continued in 2020,
and caused over 10,000 infections. Other causes suggested for
the 1977-1978 H1N1 influenza pandemic include deliberate
release of the virus or a vaccine trial mishap. See M. Rozo and
G.K. Gronvall, “The Reemergent 1977 H1N1 Strain and the
Gain-of-Function Debate,” mBio, vol. 6 (2015):e01013-15.
Zoonotic diseases can have several potential
outcomes:
•
the pathogen infects animals or humans,
where it may or may not cause disease;
•
the pathogen adapts so that it can be
transmitted to humans without sustained
human-to-human transmission, resulting
in only small outbreaks among people; or
•
the pathogen adapts for sustained
transmission among humans, resulting in
outbreaks, epidemics, pandemics, or
becoming endemic in the human
population.10
9Zoonotic “spillover” refers to the transmission of a pathogen
from animals to humans. Zoonotic “spillback” refers to the
transmission of a pathogen from humans to animals and is
sometimes referred to as “reverse zoonosis.”
10CDC describes endemic as the constant presence or the usual
prevalence of a disease or infectious agent in a population
within a geographic area. Adaptation of a pathogen to a new
host is not an absolute requirement for transmissibility among
humans.
Pandemic Origins GAO-23-105406 4
Note: These pandemic origin scenarios are not meant to be exhaustive. Other scenarios may be possible. For
example, researchers could be accidently infected from the environment during sample collection or during sample
packaging or shipment. In the laboratory origin scenario depicted in the right column, the “first person(s) infected”
may occur during sample collection, in the laboratory, or in the general public.
We identified three main factors that affect
the risk of zoonotic transmission: the animals
that harbor the pathogen, the nature of
human interaction with those animals, and
the frequency of those interactions. Scientific
literature suggests that the likelihood of
zoonotic disease spillover has increased in
recent decades likely because of factors such
Pandemic Origins GAO-23-105406 5
as increases in human-animal interactions
through farming practices, wildlife trade,
habitat loss, and climate change. These
interactions facilitate the repeated exchange
of pathogens between animals and humans.11
However, most pathogens that infect humans
through zoonotic transmission do not result in
significant human-to-human transmission.
The exact processes by which some
pathogens adapt to infect humans and then
maintain long-term human-to-human
transmission are not well understood, limiting
our ability to quickly or definitively establish
the origin of a pandemic. For example, the
origins of the Ebola virus and SARS-CoV-2,
which causes COVID-19, remain inconclusive.
Even established, well-understood pathogens
may adapt to expand beyond their typical
disease geography, become more
transmissible, or cause more severe disease.
Although most pathogens could evolve or be
manipulated in ways that may cause a human
pandemic, viruses—especially RNA viruses—
are the most likely to have this ability.12
Further, the location of the first reported
human disease case—also known as the index
case—might differ from where the pathogen
naturally resides, making it difficult for
11The repeated exchange of pathogens between animals and
humans is also known as “viral chatter.” The frequency of viral
chatter is high on farms where wild and domesticated animals
are housed and bred together as well as in live animal and wet
markets. Live animal and wet markets sell perishable items—
such as fresh meat and produce—and sometimes live animals
which are often slaughtered on-site.
12A. Adalja et al., “Characteristics of Microbes Most Likely to
Cause Pandemics and Global Catastrophes,” Current Topics in
Microbiology and Immunology, vol. 424 (2019):1-20.
researchers to identify a pandemic’s actual
origin.
1.2 Laboratory origin
A pandemic with a laboratory origin scenario
could initiate with either the accidental
infection of an individual or individuals by a
pathogen in a laboratory setting, or infections
caused by an accidental or intentional release
of the pathogen from a laboratory. For
example, such an infection could occur when
a researcher collects a sample containing a
pathogen and transfers it to a laboratory.13
During the course of handling the pathogen,
the researcher may accidently be exposed to
the pathogen and become infected.
Alternatively, laboratory containment may
break down, resulting in the accidental
release of the pathogen into the surrounding
environment and infection of individuals
outside the laboratory.14 Further, some
infections with a laboratory origin could
involve the intentional modifications of
13A sample may be obtained from human or animal sources
(e.g., blood, saliva, or tissues), the environment (e.g., water,
soil, or air), food, or other sources. The sample may contain the
pathogen or markers—such as antibodies—indicating
pathogen exposure or infection.
14For example, in 1979, anthrax spores were accidentally
released from a facility in the Soviet city of Sverdlovsk. The
cloud of spores produced a 50-kilometer trail of disease and
death in animals and humans—at least 66 people died. J.W.
Sahl et al., “A Bacillus anthracis genome sequence from the
Sverdlovsk 1979 autopsy specimens” mBio (2016) 7(5): e01501-
16.
Pandemic Origins GAO-23-105406 6
pathogens created using techniques such as
genetic engineering or serial passaging.15
1.3 Investigating pandemic origin
Several key technologies and approaches can
help inform a pandemic’s origin. Researchers
typically rely on samples and data obtained
from infected people, animals, and the
environment. For example, researchers may
collect clinical samples from infected
individuals or samples from animals in or
around outbreak areas such as farms or live
animal or wet markets. Researchers may also
collect environmental samples—such as
water, soil, or insects—in or around outbreak
areas. Data may consist of information about
the infected individuals collected during case
investigation activities—including travel
history and prior contacts with other infected
people—to help determine disease spread.
Data may also include pathogen genetic
sequence information and how the pathogen
infects or transmits between hosts.16
Chapters 2 and 3 of this report describe the
key technologies—including their strengths
and limitations—used to characterize
pathogens and assist in pandemic origin
investigations. Chapter 4 discusses the cross-
cutting challenges researchers face when
investigating the origin of a pandemic.
15Genetic engineering uses laboratory-based technologies to
alter the genetic makeup of a pathogen. For example, genetic
engineering may involve adding a gene from one species to an
organism from a different species to produce a desired trait.
Serial passaging involves iteratively growing a pathogen in
animals or cell cultures in a laboratory. Over time, the
pathogen could acquire mutations similar to those that arise in
natural environments. Cell culture involves isolating and
growing animal or plant cells in a laboratory environment.
Some pathogens, such as viruses, infect and replicate inside the
cells. GAO has work underway examining the Department of
Health and Human Services' oversight of research involving
enhanced potential pandemic pathogens.
Chapter 5 presents five policy options that
may help address these challenges and
improve the ability of researchers to respond
more quickly and effectively to future
pandemics.
16A pathogen’s genetic sequence—also known as the
genome—comprises the order of the chemical "letters" of a
pathogen’s genetic material—DNA or RNA (genomes of some
viruses only contain RNA). DNA and RNA contain all of the
pathogen’s genetic information. For the purposes of this
report, the term “sequence” refers to “genetic sequence,” and
the term “genetic databases” refers to “genetic sequence
databases.”
Pandemic Origins GAO-23-105406 7
2 Technologies for Investigating Pandemic Origin
Several key technologies can help inform a
pandemic’s origin. Drawing on information
from experts, stakeholders, and scientific
literature, we identified the following
categories of such technologies:
•
genetic sequence analysis;
•
pathogen exposure monitoring and
disease tracking; and
•
laboratory-based pathogen studies.
2.1 Genetic sequence analysis
Genetic sequence analysis involves the
combination of pathogen genomic
sequencing, bioinformatics analysis, and
genetic databases. These technologies allow
researchers to generate, analyze, and
compare a pathogen’s genetic makeup—its
sequence—against other pathogen sequences
(see fig. 2).17
17Bioinformatics is an interdisciplinary field that uses
computational algorithms for the analysis of biological data—in
this case, genetic sequences.
18Each of the four letters—A, C, G, and T (or U in the case of
RNA)—represents a chemical unit of DNA or RNA called a base.
After generating the sequence of the
pathogen, researchers use different
bioinformatics tools to piece together and
analyze the compiled sequences. While many
analyses compare the sequences against
those in genetic databases, other analyses
can be performed independent of the
databases.
Genomic sequencing. Genomic sequencing
identifies the order—or sequence—of the
chemical "letters" of a pathogen’s genetic
material.18 One traditional sequencing
method—Sanger sequencing—copies specific
segments of the pathogen’s genetic material
repeatedly, marks the copies with fluorescent
molecules, sorts them, and then reads the
individual letters.19 Sanger sequencing
produces accurate data. Reconstructing
complete pathogen genomes, which are
thousands to millions of letters in length,
letter by letter is slow and expensive.
19See GAO, Science & Tech Spotlight: Genomic Sequencing of
Infectious Pathogens, GAO-21-426sp (Washington, D.C.: Mar.
30, 2021).
Pandemic Origins GAO-23-105406 8
Next-generation sequencing technologies can
process hundreds of genomes simultaneously,
enabling researchers to generate large
amounts of pathogen sequence data more
quickly than Sanger sequencing. Most next-
generation sequencing technologies use a
“massively parallel” approach to generate
many short sequences of letters from
different parts of the pathogen’s genome at
the same time. Assembling the short
sequences then produces the entire sequence
of the pathogen’s genome.
Another next-generation sequencing
technology—nanopore sequencing—uses an
electrical current to thread single DNA or RNA
strands through tiny pores of a membrane. As
the DNA or RNA strand passes through the
pore, the electrical field varies based on the
specific sequence passing through the pore.
By measuring and analyzing variations in the
electrical field, the technology can sequence
long stretches of the DNA or RNA strand.
Pandemic Origins GAO-23-105406 9
Bioinformatics. Researchers use many types
of bioinformatics tools to analyze genomic
sequences. One type assembles the stretches
of DNA or RNA generated by next-generation
sequencing instruments to reconstruct the
pathogen’s genome. A second type compares
the pathogen’s genetic sequence to
sequences stored in genetic databases.20
Some of these tools allow researchers to
analyze the structural and functional
information of a gene or protein from the
sequences. These tools may also identify
mutations in the sequences and potential
genetically-engineered sequences. A third
kind of tool analyzes genetic sequences to
identify likely evolutionary relationships
between pathogens and their nearest
relatives. This process is known as
phylogenetic analysis.
Genetic databases. Researchers use genetic
databases to organize the biological
information gathered from many different
types of pathogens.21 Many of these genetic
databases contain millions of sequences from
thousands of pathogens, allowing users to
compare genetic sequences of a given
20Bioinformatics tools, such as the National Center for
Biotechnology Information’s (NCBI) Basic Local Alignment
Search Tool (BLAST), identify similarities between nucleic acid
or amino acid sequences. BLAST also scores the statistical
degree of similarities between the sequences. Higher scores
indicate a higher degree of similarity—or likely relatedness—
between sequences. For more information, see S.F. Altschul et
al., "Basic Local Alignment Search Tool," Journal of Molecular
Biology, vol. 215 (1990): 403-410.
21This information includes DNA, RNA, and amino acid
sequences from organisms collected from the environment and
research conducted in laboratories. Amino acids are the
fundamental building blocks of proteins.
22Examples of genetic databases include GenBank®, European
Nucleotide Archive (ENA), DNA Data Bank of Japan (DDBJ), and
Global Initiative on Sharing All Influenza Data (GISAID).
pathogen against many other pathogens that
were previously catalogued.22
2.2 Infectious disease surveillance
Other tools can help researchers understand
the path of the disease. The study of the
presence of antibodies in the blood in
response to pathogens, serology, enables the
characterization and monitoring of pathogen
infections in human and animal populations.23
Serology can help establish whether a human
or animal has been infected by a pathogen,
sometimes long after the initial infection.
Examples of technologies used for serology
include biological and chemical tests.24
Epidemiology—the study of disease
occurrence in humans and animal
populations—provides information about the
timing and geographic spread of the disease.
Epidemiological surveillance tracks disease in
populations to try to determine when and
where the disease originated, among other
things.25 For example, epidemiology may help
identify the source of the pathogen, its
possible spread, and possible “reservoirs”
23An antibody is a protein component of the immune system
that circulates in the blood, recognizes foreign substances like
bacteria and viruses, and neutralizes them. The percentage of
individuals in a population whose blood contains antibodies to
a pathogen is called seroprevalence.
24For example, an enzyme-linked immunosorbent assay (ELISA)
detects host antibodies by binding to pathogen proteins—
called antigens—coated in wells on test plates. The presence or
absence of these antibody-antigen complexes can then be
determined using enzymes. A chemiluminescent immunoassay
(CLIA) uses chemical probes that detect and label antibodies by
generating light emissions (i.e., luminescence) through a
chemical reaction.
25According to CDC, epidemiological surveillance is the ongoing
and systematic collection, analysis, and interpretation of health
data in the process of describing and monitoring a health
event.
Pandemic Origins GAO-23-105406 10
where the pathogen circulates among people
and animals between outbreaks.
2.3 Laboratory-based pathogen
studies
Laboratory-based pathogen studies examine
interactions between the pathogen and the
host animal or person infected with the
pathogen. Such studies can reveal how
pathogens infect hosts and are transmitted
from one host to another. The results of these
studies help researchers understand the
distribution and spread—epidemiology—of
the disease caused by the pathogen.
Researchers also study the degree to which a
pathogen can infect and transmit between
hosts using animals known as in vivo studies,
or cell cultures known as in vitro studies. For
example, laboratory-based pathogen studies
may use animals and cell cultures to
determine a pathogen’s transmission rate
between infected and uninfected animals and
cells as well as the pathogen’s infectious
dose.
Experts told us that other laboratory-based
technologies may enable researchers to
identify modifications to nucleic acids or
proteins. These technologies include
proteomics, the study of host and pathogen
proteins; glycomics, the study of sugar
molecules occurring on proteins; and
epigenetics, the study of chemical
modifications to host or pathogen nucleic
acids—see text box for further explanation.
The information gained from these
technologies could help researchers in
pandemic origin investigations; however,
these technologies are not fully developed for
such use.
Epigenetics
Researchers use epigenetics to study how behavior and
the environment may cause changes in DNA and RNA that
affect genes and proteins. For example, DNA and RNA may
be modified through the addition of chemical groups.
Typically, these chemical groups occur at specific places
on the DNA and RNA. The modifications affect the ability
of enzymes to “read” the DNA and RNA and produce
proteins, resulting in cellular changes.
Experts and literature note that certain pathogens can
cause epigenetic changes in infected people; some
ongoing research is focused on detecting whether
exposure to certain biological agents can be identified by
examining such epigenetic changes. Further, one expert
noted that it is not yet possible to detect laboratory
manipulation-based epigenetic changes, but epigenetics
may offer this capability for future origins investigations.
Source: GAO review of literature and the March 2022 expert meeting. |
GAO-23-105406
Pandemic Origins GAO-23-105406 11
3 Researchers Have Used a Variety of Technologies for Pandemic
Origin Investigations
Researchers have used a variety of
technologies for pandemic origin
investigations. For example, researchers have
generated pathogen sequence data using
genomic sequencing, then used
bioinformatics tools to analyze and compare
the sequence to reference sequences stored
in genetic databases. Three outcomes can
result from these comparisons:
•
If a pathogen’s sequence matches
sequences from naturally-occurring
organisms, this could provide support for
a natural origin. Further, phylogenetic
analyses may be conducted to identify
the pathogen’s closest relatives or its
most recent common ancestor.26
•
If a pathogen’s sequence, or parts of its
sequence, matches known, laboratory-
generated sequences, this could provide
support that a pathogen may have a
laboratory origin.
•
If a pathogen’s sequence does not closely
match any sequences in the genetic
databases, this could indicate a novel
26The most recent common ancestor of any set of individuals—
such as viruses—is the most recent individual virus from which
all of the other individual viruses in the group are directly
descended. This definition is adapted from the International
Society of Genetic Genealogy.
pathogen. This could also indicate the
genetic databases lack the diversity of
sequences needed to accurately compare
the pathogen’s sequence.
Other approaches, such as serology,
epidemiology, and laboratory-based
pathogen studies, have also been used to
support such pandemic origin investigations.
However, multiple lines of evidence are often
needed to establish a pandemic’s likely origin.
Further, experts told us technologies are not
the limiting factor for investigating the likely
origin of a pandemic.
3.1 Researchers used genetic
sequence analysis to determine the
likely origin of several pandemics
Researchers used genetic sequence analysis
to help establish the likely natural origins of
several pandemics and outbreaks, including
the 2002-2003 SARS pandemic, the 2009
H1N1 influenza pandemic, and the initial
MERS outbreak in 2012.27 Researchers also
27Genetic sequence analysis of samples from civet cats and a
raccoon dog from a live animal market showed that the animal
SARS-CoV strains were 99.8 percent identical to the SARS-CoV
strains isolated from infected humans. See L.-F. Wang and B.T.
Eaton, “Bats, civets and the emergence of SARS,” Current
Topics in Microbiology and Immunology, vol. 315 (2007):325-
344. Genetic sequence analysis also showed that MERS-CoV
strains isolated from camels were almost identical to those
isolated from humans and were phylogenetically related to bat
coronaviruses. See J. Cui et al., “Origin and evolution of
pathogenic coronaviruses,” Nature Reviews Microbiology, vol.
17 (2019): 181-192. Genetic sequence analysis of samples from
humans and pigs established the origin of the H1N1 influenza
virus in central Mexico, where it jumped from pigs to humans.
See I. Mena et al., “Origins of the 2009 H1N1 influenza
pandemic in swine in Mexico,” eLife (2016)
10.7554/eLife.16777.
Pandemic Origins GAO-23-105406 12
used phylogenetic analysis to trace the
transmission of HIV-1 from Africa to Haiti,
followed by its subsequent transmission from
Haiti to North American populations around
the 1960s. Researchers continue to use
genetic sequence analysis to investigate the
origin of other pandemics, including the
COVID-19 pandemic caused by SARS-CoV-2.28
The increasing speed and accuracy and
decreasing cost of genomic sequencing
technologies, such as next-generation
sequencing, allow researchers to
simultaneously process hundreds of pathogen
genomes. Researchers are thus able to quickly
generate pathogen sequence data necessary
for investigating potential origin. Experts told
us that because of these strengths, they
consider genomic sequencing a key
technology for pandemic origin investigations.
A key limitation of genetic sequence analysis
is that some laboratory-based genetic
modifications may be indistinguishable from
natural variations. For example:
•
Some traditional genetic engineering
techniques and newer genome editing
tools—such as CRISPR-Cas9—may leave
no detectable trace of genetic
modification.29 Some bioinformatics tools
that use artificial intelligence (AI) may
help researchers detect patterns
28J.E. Pekar et al., “The molecular epidemiology of multiple
zoonotic origins of SARS-CoV-2,” Science (2022)
10.1126/science.abp8337; M. Worobey et al., “The Huanan
Seafood Wholesale Market in Wuhan was the early epicenter
of the COVID-19 pandemic,” Science (2022)
10.1126/science.abp8715.
29Clustered Regularly Interspaced Palindromic Repeats
(CRISPR)-associated protein number 9 (Cas9) is one type of
genome editing technology that allows scientists to precisely
modify a pathogen’s genome, potentially leading to changes in
a pathogen’s characteristics.
indicative of genome editing.30 However,
these are currently limited by a lack of
large sequence datasets on which to train
the algorithms.
•
One agency official described a 2011 large
foodborne outbreak in Germany that was
caused by a strain of Escherichia coli (E.
coli) bacteria. Genetic sequence analysis
showed the strain contained genetic
sequences from two strains of E. coli. This
unusual genetic makeup potentially
supported a laboratory origin. However,
researchers later determined, through
additional research, that a natural origin
was more likely.
•
Sequence changes (i.e., mutations)
resulting from laboratory adaptation
experiments—such as serial passaging—
may be more difficult to detect than
genome editing because the laboratory
adaptation more closely mimics aspects
of natural processes of evolution. For
example, some researchers argue that
serial passaging may explain certain
features of the SARS-CoV-2 genome,
while others argue that a zoonotic origin
is the more likely explanation for those
features.31
Some phylogenetics software tools are
limited in their utility for assessing pathogen
origins because of technical limitations of the
30E.C. Alley et al., “A machine learning toolkit for genetic
engineering attribution to facilitate biosecurity,” Nature
Communications (2020) 10.1038/s41467-020-19612-0.
31K.G. Andersen et al., “The proximal origin of SARS-CoV-2,”
Nature Medicine, vol. 26 (2020): 450-455.
Pandemic Origins GAO-23-105406 13
analysis programs and deficiencies in
databases used for sequence comparisons.
For example, some phylogenetic tools use a
certain pattern of pathogen evolution from
other organisms when comparing sequences.
However, many pathogens do not follow the
types of evolutionary patterns that other
organisms follow. As a result, conclusions
based on the use of these tools should be
confirmed with other methods. More
recently, network-based approaches have
been used to reconstruct virus evolution
more realistically.
Additionally, some phylogenetic tools are not
capable of analyzing the millions of sequences
currently being generated. For example, one
expert told us that the volume and complexity
of SARS-CoV-2 data crashed a commonly used
phylogenetics program. The lack of reference
sequences and metadata in databases also
impacts researchers’ ability to conduct
meaningful phylogenetic analyses.32
Further, multiple experts told us that it can be
problematic when databases have sequences
overrepresented by specific countries. For
example, the SARS-CoV-2 sequences in the
Global Initiative on Sharing All Influenza Data
(GISAID) database are dominated by data
from the U.S. and U.K., whereas data from
relevant locations elsewhere in the world are
scarcer. This underrepresentation negatively
affects the ability to determine where a
pathogen may have originated.
32In this report, we refer to information about genetic
sequences, such as when and where a sample was collected, as
metadata.
3.2 Researchers used serology and
epidemiological surveillance for
pandemic origin investigations
Researchers have also used serology and
epidemiological surveillance to monitor
pathogen infection and disease occurrence in
human and animal populations to support
pandemic origin investigations. Serology and
epidemiological surveillance can provide
information regarding the timing and
geographic spread of the pathogen and
disease. For example, if serology studies
detect antibodies in animal populations near
a suspected disease outbreak in humans
where the disease is not normally present or
expected, this could lend support to a natural
origin. Further, epidemiological surveillance
can be used to generate models to predict
how a pathogen spreads. These models can
also be run in reverse to trace the spread of
the disease back to the early stages of a
pandemic. However, for serology and
epidemiological surveillance to be effective in
determining a pandemic’s origin, investigators
need access to samples and data from
infected or exposed individuals from early in
an outbreak and as close to index cases as
possible to reliably trace the disease back to
the first human infection(s).
Serology surveillance in people and camels
provided two key pieces of information that
contributed to the determination that camels
were direct sources of human infection with
MERS-CoV. First, researchers detected MERS-
CoV antibodies from archived camel blood
samples dating back to 1983. Second,
Pandemic Origins GAO-23-105406 14
serology surveillance showed a higher
prevalence of MERS-CoV antibodies in
humans exposed to camels relative to the
general population. Together with other
studies, this information led researchers to
conclude that MERS-CoV was likely
transmitted to people from camels.
Epidemiological studies of the first SARS cases
in Guangdong Province, China in 2002-2003
suggested a zoonotic origin of the virus. For
example, several of the early cases were
associated with occupations that involved
contact with wildlife, including handling,
killing, and selling wild animals as well as
preparing and serving wildlife animal meat in
restaurants. Subsequent serology surveillance
found a higher than normal seroprevalence of
SARS-CoV antibodies among wild animal
traders as compared to vegetable traders
from the same Guangdong market. Further,
serology surveillance of animal traders in
three different live animal markets found that
13 percent had SARS-CoV antibodies, whereas
72 percent of traders of civet cats had SARS-
CoV antibodies.33
Researchers also used epidemiological data,
among other types of data, to investigate the
hypothesis that the COVID-19 epidemic in
Wuhan began at the Huanan market. Based
on the geographic and timing patterns of
reported cases within the city and the specific
locations of cases within the Huanan market,
recent studies assessed that this market was
33L.-F. Wang and B.T. Eaton, "Bats, Civets and the Emergence
of SARS," Current Topics in Microbiology and Immunology, vol.
315 (2007): 325–344.
34E.C. Holmes et al., “The Origins of SARS-CoV-2: A Critical
Review,” Cell, vol. 184 (2021): ep. 1-9.
35Office of the Director of National Intelligence, National
Intelligence Council, “Updated Assessment on COVID-19
Origins” (2021): ep. 1-18.
“an early and major epicenter” of COVID-19
emergence.34 However, researchers and
agency analysts reported that uncertainty still
exists about where the first SARS-CoV-2
infections occurred because of a lack of
clinical samples available for serological and
genetic analyses as well as a lack of
epidemiological data from the earliest
cases.35
Serology and epidemiological surveillance
may be limited by the ability to collect and
analyze samples from infected humans and
animal populations. For example, certain
countries may refuse or limit researchers’
access to field sites, facilities, data, or people.
Further, researchers conducting field-based
sample collections may encounter logistical
and operational barriers to accessing remote
field sites, including personal protective
equipment constraints.36 Sensitive and
specific serology tests may also take time to
develop and validate.
Researchers may also face technical
challenges for collecting, preserving, and
transporting samples. For example, many
viruses, such as SARS-CoV-2, only contain
RNA, which is less chemically stable than
DNA, and may require specialized
preservatives. Samples may also require cold
storage and shipment—known as cold
chains—to maintain their integrity. In remote
parts of the world, cold chain infrastructure
36Collecting animal samples can be dangerous both to the
individual researchers collecting the samples as well as the
public. To collect samples, researchers typically need to make
personal contact with animals. One expert told us about a
project that uses drones or robots to collect guano samples
from bat caves, mitigating the possibility of researchers
contracting viruses by eliminating the need to enter the caves
themselves.
Pandemic Origins GAO-23-105406 15
may be lacking. Further, samples collected
from humans or animals have high amounts
of host genetic material, making it difficult or
more time-consuming to extract, isolate, and
analyze a pathogen’s genome.
Finally, even comprehensive field-based
sampling aimed at investigating the origins of
pandemic pathogens may be inconclusive. For
example, researchers recently reported a
sampling effort in China aimed at tracing the
origin of two pandemic pathogens, SARS-CoV
and SARS-CoV-2.37 Despite generating a
database of over 17,500 animal samples,
researchers did not find any closely related
coronaviruses.
3.3 Researchers used laboratory-
based pathogen studies for pandemic
origin investigations
Laboratory-based pathogen studies using cell
cultures or animals have generated
information about a pathogen’s ability to
infect, mutate, adapt to, and spread between
hosts. Results from these laboratory studies
provided evidence supporting known natural
patterns of spread or unusual patterns of
spread indicative of a possible laboratory-
related origin. For example, researchers
studying pandemic H1N1 influenza virus in
ferrets identified the viral genes, proteins of
transmission, and host receptor sites that
drive different routes of transmission.38 The
results of these studies supported the
conclusion that this virus likely originated
from animal-to-human transmission.
37Z. Wu et al., “A Comprehensive Survey of Bat Sarbecoviruses
across China for the Origin Tracing of SARS-CoV and SARS-CoV-
2,” Research Square (2021): ep. 1-37.
Several cell culture and animal studies have
also been used for studying SARS-CoV-2
infection and spread. For example,
researchers used cell cultures to isolate and
study the virus samples from some of the first
COVID-19 patients and to identify host factors
required for SARS-CoV-2 replication.
Researchers also used cell cultures to study
genetic changes in the virus during serial
passaging, including confirming the ability of
the virus to adapt quickly to the host. Further,
researchers used different animal studies to
determine the ability of the virus to transfer
to and infect healthy animals, which may
provide evidence for the virus reservoir and
intermediate hosts.
Laboratory-based pathogen studies are useful
for studying pathogen biology under highly
controlled conditions. Cell culture studies and
animal studies each have strengths. Cell
culture studies comply with the ethical desire
for reducing the use of animals, and they are
less expensive, faster, and allow for the study
of specific pathogen-host targets, which could
not be assessed in humans or animals. Animal
studies help researchers better understand
pathogen infection and transmission, and
they have the potential to elucidate the
natural history of the disease.
Key limitations of laboratory-based pathogen
studies are that some pathogens cannot be
easily cultured in a laboratory setting, and
some pathogens require enhanced biosafety-
level facilities. Results from controlled
laboratory transmission studies also may not
accurately represent the natural
environment, making it difficult for
38J.S. Long et al., “Host and viral determinants of influenza A
virus species specificity,” Nature Reviews Microbiology (2019)
10.1038/s41579-018-0115-z.
Pandemic Origins GAO-23-105406 16
researchers to clearly distinguish between
natural versus laboratory-controlled
transmission patterns. For example, cell
culture studies do not resemble the
complexity of a human or animal host, and
translating cell culture-generated data to
animal models can be particularly challenging.
Further, animal studies are costly and raise
ethical concerns.
Pandemic Origins GAO-23-105406 17
4 Researchers Face Three Key Challenges When Investigating
Pandemic Origin
In addition to the specific technology
limitations discussed earlier, researchers also
encounter three challenges at various stages
in the pandemic origin investigation process,
according to experts. Specifically,
•
Lack of sufficient access to samples and
genetic sequence data,
•
Lack of standardized processes for
submitting, accessing, and using genetic
sequence data stored in databases
around the world, and
•
Lack of a sufficient and skilled
interdisciplinary workforce.39
4.1 Researchers lack sufficient access
to critical samples and data
We found that access to samples from index
cases and other primary and secondary cases
or genetic sequence data derived from those
samples may be restricted in two broad ways.
•
Local concerns may limit access to
samples and data. For example, primary
care physicians may not collaborate with
public health officials. Therefore, data
from medical testing and patient care
may not be available for pathogen
surveillance. Privacy concerns, general
39Sufficient and prompt access to initial outbreak samples
enables actions to prevent current disease spread (e.g., via
travel restrictions, testing programs, vaccine development).
However, for pandemic origin investigations, which may occur
months or years after the initial outbreak, sufficient and timely
access to such samples is important to maximize the chances of
a reliable result.
mistrust, perceived infringements on a
country’s sovereignty, or fear of negative
consequences can also result in restricted
access.
•
Even if researchers have access to
samples and data, their ability to extract
suitable information may be limited by a
lack of standardized processes. For
example, health officials may collect
samples for a purpose other than
pathogen surveillance or store and
process the data obtained from the
samples in a way that precludes
investigations into the origin of the
pandemic. Further, no one entity is
responsible for determining and enforcing
standardized processes.
Experts told us that multilateral agreements
on sample and data sharing are necessary
because pandemics can originate from
anywhere and rapidly spread internationally.
They also said that negotiating or modifying
agreements each time a pandemic occurs is
not effective.
Pandemic Origins GAO-23-105406 18
4.2 Lack of standardized processes for
genetic sequence databases prevents
researchers from analyzing data
effectively
Some genetic sequence databases used by
researchers may lack standardized processes
for data submission, access, and use. To
investigate the origin of a pandemic,
researchers need access to genetic sequence
data, which may be stored in multiple
databases, such as the National Center for
Biotechnology Information’s (NCBI)
GenBank®, GISAID, and the European
Molecular Biology Laboratory-European
Bioinformatics Institute (EMBL-EBI).40 Experts
cited three main challenges to working across
multiple databases:
•
Each genetic sequence database may
have different processes for submitting,
accessing, and using the data. GenBank,
which is one of the most widely used
databases, is open access, places no
restrictions on the distribution of data,
and provides multiple submission tools
depending on the type of sequence data
to be submitted. GISAID, on the other
hand, requires personal access
credentials, prohibits any re-distribution
of data, and provides a web portal for
submissions. As a result, gathering all of
40GenBank is part of the International Nucleotide Sequence
Database Collaboration, which includes the DNA DataBank of
Japan (DDBJ), the European Nucleotide Archive (ENA), and
GenBank. These three databases exchange data on a daily
basis.
41For example, experts told us that GenBank allows only the
original author to edit a submission. This could be problematic
if an error to the record exists and the original author is no
longer active in research. In this case, the error may become
permanent. However, the National Institutes of Health noted a
record cannot be publicly released in GenBank until it has a
the data necessary to investigate the
origin of a pandemic can be challenging.
•
Genetic sequence databases generally
lack standardized user interfaces for data
submission and access, and some existing
user interfaces can be cumbersome. For
example, experts told us that submission
processes for some major genetic
sequences databases are not user-
friendly, and previous submissions can be
difficult to edit.41 Similarly, interfaces for
accessing data are not standardized. For
example, some major databases lack
application programming interfaces (API)
that would provide access to the data
from other applications.42 Because
researchers lack standardized submission
and access interfaces, they may have to
use different procedures to submit and
retrieve needed data from relevant
databases, which can be time-consuming
and inefficient.
•
Metadata are crucial for investigating the
origin of a pathogen, but their availability
and quality may vary. For example,
GenBank’s submission process allows
researchers to submit information in
distinct metadata fields with few
constraints on content. One record that
we examined lists “Japan” as the country
where the sample was collected and
“2020-07” as the collection date. Another
valid scientific classification. Further, if an organism’s valid
scientific classification is revised by an international standards
group, then the record can be updated accordingly without
requiring a submitter request.
42An application programming interface (API) enables
machine-to-machine communication, allowing users to obtain
real-time data updates. GAO, Open Data: Treasury Could Better
Align USAspending.gov with Key Practices and Search
Requirements, GAO-19-72 (Washington, D.C.: Dec. 13, 2018).
Pandemic Origins GAO-23-105406 19
record of a different genetic sequence
lists a more specific location, “Canada:
Toronto,” as the country where the
sample was collected, but no collection
date. Although GenBank allows users to
report the latitude and longitude where
samples were collected, a 2017 study
estimated that 99 percent of records do
not include that information.43
These challenges may be exacerbated by the
immense scale and continued growth of
genetic sequence data. (See text box for a
prediction on the future growth of genomic
data.) As the amount of data in each database
grows, and as more databases are added,
standardized processes are crucial to ensure
that researchers can compile, analyze, and
share all the genetic sequence data necessary
to investigate the origin of a pandemic.
However, it is unclear if the existing
infrastructure of multiple independent
databases worldwide can support the growth
of genomic data.
43T. Tahsin et al., “Named Entity Linking of Geospatial and Host
Metadata in GenBank for Advancing Biomedical Research,”
Database (2017): https://doi.org/10.1093/database/bax093.
National Institutes of Health officials told us they have since
made concerted efforts to increase collection and
harmonization of sample collection location and date
4.3 The global research community
lacks a sufficient and skilled
interdisciplinary workforce
Pandemic origin investigations require a
highly skilled workforce with expertise in
multiple fields. We identified four main
challenges to developing and retaining such a
workforce based on information we gathered
from experts and literature:
•
Demand for workers in relevant fields
tends to increase when pandemics occur
and decrease when pandemics end.
Likewise, funding for relevant research
tends to fluctuate. This makes it
challenging to keep the workforce
“warm” (i.e., available and proficient) to
conduct investigations promptly when
pandemics occur.
•
Pandemic origin investigations require
expertise in multiple fields such as
biology, virology, microbiology,
immunology, epidemiology, ecology,
genomics, bioinformatics, and computer
science. However, the current workforce
is siloed because of factors such as
academic structures, funding priorities,
and grant processes, according to experts
we interviewed.44 This makes it
challenging to build and maintain the
multidisciplinary workforce necessary to
conduct investigations.
•
The current uneven global distribution of
the workforce leads to political and
information. They also noted that in some cases, such data may
be unavailable due to privacy or ethical concerns.
44The term “academic structure” is defined as the components
of academic institutions and how they relate to each other.
Components include academic careers, departments, plans,
and subplans.
Rapid growth of big data
A 2015 study predicted that, by 2025, genomics research
worldwide will generate between 2 and 40 exabytes of
data annually. (For reference, 1 exabyte equals 1 billion
gigabytes.) This would make genomics one of the most
challenging domains of Big Data in terms of data
acquisition, storage, distribution, and analysis.
Accommodating the expected growth of genomic data will
require advancements in computational speed and power,
as well as algorithms optimized for Big Data.
Source: GAO review of literature. | GAO-23-105406
Pandemic Origins GAO-23-105406 20
logistical challenges during a pandemic.
For example, a 2021 study concluded that
inadequate sequencing capacity because
of limited skillsets, among other factors,
hindered biosurveillance during the
COVID-19 pandemic.45
•
Some researchers told us that they faced
criticism because of their involvement in
investigating the origin of a pandemic,
particularly when their conclusions were
considered controversial. These
researchers said they and others may be
reluctant to participate in further
investigations because of personal and
professional risks.
45M. Dzobo et al., “Inadequate SARS-CoV-2 Genetic
Sequencing Capacity in Zimbabwe: A Call to Urgently Address
this Key Gap to Control Current and Future Waves,” IJID
Regions, vol. 1 (2021): ep. 3-4.
https://doi.org/10.1016/j.ijregi.2021.09.004.
We found that a national strategy could help
to address these challenges. National
strategies are “whole of nation” efforts that
frequently include international components.
They may be part of a structure of
overlapping or supporting national strategies
and typically involve sectors, organizations,
entities, and resources outside the control of
the federal government.46
46See GAO, Combating Terrorism: Evaluation of Selected
Characteristics in National Strategies Related to
Terrorism, GAO-04-408T (Washington, D.C.: Feb. 3, 2004).
Pandemic Origins GAO-23-105406 21
5 Selected Policy Options to Help Address Three Cross-Cutting Key
Challenges for Investigating Pandemic Origin
Chapter 4 described three cross-cutting
challenges that hinder researchers trying to
investigate the origin of a pandemic:
•
Lack of sufficient access to samples and
genetic sequence data,
•
Lack of standardized processes for
genetic databases, and
•
Lack of a sufficient and skilled
interdisciplinary workforce.
GAO identified five policy options that may
help address these challenges. These policy
options are not mutually exclusive and
represent possible actions that
policymakers—who may include Congress,
federal agencies, state and local
governments, academic and research
institutions, industry, and international
organizations—could consider taking.
Addressing the three broad challenges with
these policy options could also help
improve the ability of researchers to
respond more quickly and effectively to
potential future pandemics.
Policy Option: Federal policymakers and
others could encourage international
preparedness in advance of future
outbreaks by supporting the development
of multilateral agreements for accessing
and sharing samples and genetic sequence
data.
Challenge Addressed: Access to samples and
genetic sequence data
Federal policymakers and others could help
establish comprehensive multilateral,
international agreements for accessing and
sharing genetic sequence samples and data
in advance of future outbreaks. These
proactive agreements could include
definitions of the roles and responsibilities
of international investigation teams and
incentives for adherence, helping ensure
more timely access to critical information.
Potential implementation approaches
•
Develop multilateral sample and data-
sharing agreements—for example, to
include expectations of timely access to
samples and detailed standards for
sample collection, sample storage, and
metadata that countries will supply—as
an objective in national pandemic origin
investigation strategies.
•
Work with international health
organizations, such as the World Health
Organization, to identify and address
barriers to establishing multilateral,
international agreements for ensuring
access to genetic sequence samples and
data, and support the development of
such agreements.
•
Seek agreement with stakeholders on
incentives for participation, such as
equitable access to vaccines and
therapeutics. These incentives could
also include economic assistance and
assurances to mitigate stigmatization
when promptly sharing samples and
genetic sequence data.
Pandemic Origins GAO-23-105406 22
Opportunities
•
Ensuring timely access to genetic
information and samples in the critical
beginning stages of a pandemic as well
as throughout an origin investigation
may help in the determination of a
pandemic’s origin.
•
Establishing standing agreements
between nations before a pandemic
occurs could assist in determination of a
pandemic’s origin.
•
Incentives may help encourage
reluctant countries to participate.
Considerations
•
Countries may be unwilling to
participate in such multilateral,
international agreements because of
concerns related to national
sovereignty.
•
Identifying an appropriate responsible
entity to determine and monitor
whether countries are following agreed-
upon standard processes and their
implementation may be time-
consuming and challenging.47
Policy Option: Federal policymakers and
others could empower or establish a
working group to develop standardized
47For example, it took 6 years for the Secretariat of the
Convention on Biological Diversity’s Nagoya Protocol on
Access to Genetic Resources and the Fair and Equitable
Sharing of Benefits Arising from their Utilization to the
Convention on Biological Diversity (an international
agreement which aims at sharing the benefits arising from
the use of genetic resources in a fair and equitable way) to
develop and implement the agreement. However, the
protocol still lacks a strong plan for compliance. The U.S. is
not a signatory to the Nagoya Protocol or the Convention on
Biological Diversity.
processes for database use to support
pandemic origin investigations.
Challenge Addressed: Lack of standardized
processes for data submission, access, and
use
A working group could develop
standardized processes for submission of
and access to data in databases such as
GenBank.48 Standardized processes could
help ensure that all users submit and access
the same kinds of data used for pandemic
origin investigations.
Potential implementation approach
Federal policymakers and others—such as
state and local policymakers, current
database providers, developers, and
users—could collaborate to identify and
develop standardized processes for using
genetic sequence databases. This could
include updating documentation
processes—such as clear instructions for
types of sample metadata—for using
GenBank and other databases and
encouraging those database providers to
implement these standardized processes.
48Other databases may be operated by other countries or
nongovernmental organizations.
Pandemic Origins GAO-23-105406 23
Opportunities
•
Developing standardized processes for
databases could help ensure
consistency of submitted data and
metadata across multiple databases,
improve researchers’ access, and help
researchers comprehensively compare
genetic sequences. For example,
standardized processes for recording
geographic details of sample collections
could help researchers who use the
database examine information to better
understand where a pathogen resides
naturally.
•
Implementing leading practices for
genetic data integrity and associated
metadata could help improve the
quality of data in genetic sequence
databases. For example, as discussed
previously, we heard from researchers
that some databases would only allow
the researcher who entered a genetic
sequence to change any of that
information or to delete the sequence.
Database governance practices that
give database administrators a greater
role in performing quality control could
help ensure more data can be used to
comprehensively compare genetic
sequences to determine a pathogen’s
evolutionary ancestry and origin.
Considerations
•
Standardized processes may be difficult
to develop as there are risk-benefit
trade-offs. For example, it is critical that
access to certain novel pathogen
sequences in databases be limited to
trusted and credentialed individuals
with a need to access those sequences.
The working group would therefore
need to balance the security of the
databases with ensuring that
researchers can access novel pathogen
sequences, as needed, for critical work.
•
Universities and industry researchers
may have existing policies governing
metadata to ensure privacy. For
example, the benefits of including
specific geographic information with
biological samples must be weighed
against any privacy concerns of the
people and communities from which
those samples were collected.
•
It may be challenging for multiple
stakeholders to agree on what data are
important. For example, stakeholders
may have different perspectives on
what metadata should be required
versus optional.
Policy Option: Policymakers could
encourage the improvement of current, or
development of new, genetic sequence
database tools.
Challenge Addressed: Lack of standard user
and application programming interfaces
Improving current genetic sequence
database tools or developing new ones may
help investigators determine a pandemic’s
origin more effectively. For example,
redesigning current or creating new
database user interfaces or APIs could help
researchers perform genetic sequence
comparisons more efficiently and aid in
phylogenetic analyses.
Pandemic Origins GAO-23-105406 24
Potential implementation approaches
•
Policymakers could encourage
improvements to sequence database
tools—such as user interfaces or APIs—
of current databases.
•
Policymakers could incentivize—for
example, via funding—the creation of
new database user interfaces or APIs.
Opportunities
•
Improved or new database user
interfaces and APIs—as agreed upon by
groups of end users and in conjunction
with standard processes— could, for
example, streamline researchers’ data
submission, access, and use and
improve data quality.
•
Improved or new database user
interfaces and APIs could assist in
addressing the projected future growth
in genetic sequence data by, for
example, enabling the analysis of large
datasets stored in distributed cloud-
based systems.49
Considerations
•
Building new, or retooling current,
database user interfaces and APIs could
be time- and labor- intensive.
•
It may be challenging for groups of
users to agree on what database user
interfaces and APIs features are
important. For example, users may
49Additional technological needs to address the future
growth in genetic sequence data may include data centers
with fast, tiered storage systems, improved algorithms, data
streaming approaches, and large-scale machine learning
systems.
have different opinions on what is
important to include in the user
interfaces to make the databases more
user-friendly or what applications need
to communicate with the databases.
Policy Option: Policymakers could
incentivize the development, retention,
and growth of a workforce with the critical
skills needed to conduct or support the
work of characterizing the likely origin of a
pandemic.
Challenge Addressed: Lack of a sufficient
and skilled interdisciplinary workforce
Incentivizing the development of the
workforce could increase the availability of
skilled workers by creating international
partnerships, among other things, and
leveraging or creating training programs to
encourage workforce growth and retention.
Potential implementation approaches
•
Policymakers could encourage
mechanisms to provide training,
workforce development, and capacity
building, including in areas considered
hot spots of emerging infectious
disease. Focusing on recruitment and
consistent investment in global as well
as domestic programs may increase the
available workforce by increasing the
number of skilled workers and retaining
those workers.
Pandemic Origins GAO-23-105406 25
•
Policymakers could leverage or enhance
existing programs to provide incentives
for students and research professionals
to pursue careers in fields with skills
necessary for pandemic origin
investigations.
Opportunities
•
Encouraging development of expertise
in geographic areas where novel
pathogens are likely to emerge would
not only increase the overall global
supply of skilled workers but also help
to ensure the workforce is not
concentrated in any one particular
geographic region.
•
Increased and improved educational
initiatives could foster a generation of
students and professionals with the
multidisciplinary qualifications and skills
needed to support pandemic origin
investigations. For example, the
National Science Foundation currently
invests in numerous graduate student
educational activities through a
program that provides activities and
training opportunities to augment
students’ research assistantships with
non-academic research internships.
Policymakers could continue to
leverage or expand these types of
programs by, for example, encouraging
investment in multidisciplinary scientific
fields that may support pandemic origin
investigations.
•
A sufficient and trained workforce
skilled in origin investigations could
contribute to other areas such as public
health, biotechnology, infectious
diseases, or other types of related
biological research and development.
Considerations
•
Pandemic origin investigations tend to
be episodic and irregular. As a result, it
may be difficult to adequately plan for
and consistently fund staffing in science
fields related to pandemic
investigations.
•
The scientific community may resist any
alteration to current academic
structures, and it may be challenging to
adapt priorities, processes, and funding
in a sufficiently timely manner needed
to respond to a pandemic. As a result,
attracting qualified people into the
necessary workforce fields may be
challenging if those fields are
marginalized and underfunded.
•
Researchers may experience unwanted
attention, pressure, harassment, or
influence because of their involvement
in pandemic origin investigations. As a
result, increasing the size of the
workforce may not lead to sustained
expertise if experienced researchers
leave the field or refuse to participate in
pandemic origin investigations.
Policy Option: Federal policymakers could
augment or develop a national strategy to
better coordinate and collaborate
domestically and internationally on
pandemic origin investigations.
Challenges Addressed: All
The 2022 National Biodefense Strategy and
Implementation Plan may assist in
addressing the cross-cutting challenges we
identified. For example, the 2022 Strategy
includes an Early Warning priority area that
encompasses targets and corresponding
Pandemic Origins GAO-23-105406 26
actions related to determining the origin of
biological events, including infectious
disease outbreaks.50 However, the 2022
Strategy does not specifically outline how
the lead and support departments and
agencies will coordinate and collaborate to
address origin determination. Augmenting
the 2022 Strategy or developing a separate
strategy with these specifics could better
position the nation to play a leading role in
pandemic origin investigations.
Potential implementation approaches
•
Federal policymakers could augment
the National Biodefense Strategy to
specify how lead and support
departments and agencies will
coordinate and collaborate with
domestic and international partners to
address pandemic origin investigations.
•
Federal policymakers could develop a
new, standalone, national strategy
focused on pandemic origin
investigations that describes how
federal entities will coordinate and
collaborate with domestic and
international partners on such
investigations.
Opportunities
50This priority area includes characterizing biological
material to support investigations, origin determination, and
attribution as well as supporting United Nations
investigations of outbreaks of unknown origin. See Office of
Science and Technology Policy, National Biodefense Strategy
and Implementation Plan for Countering Biological Threats,
Enhancing Pandemic Preparedness, and Achieving Global
Health Security (Washington, D.C.: October 2022).
•
A national strategy could help address
the challenges that hinder pandemic
origin investigations.
•
Federal coordination and collaboration
leadership, guided by a national
strategy, could increase preparedness
for future pandemic origin
investigations.
•
Understanding pandemic origins could
help mitigate health and economic
costs associated with pandemics by, for
example, facilitating surveillance that
could identify future pandemics more
quickly.
•
A national strategy that includes
pandemic origin investigations could
help identify and quickly deploy
resources needed for timely
investigation of a pandemic's origin.
Considerations
•
Allocating resources and defining how
federal agencies and others will
collaborate may be challenging because
of the number and types of entities
with relevant expertise that would be
involved.
•
During nonpandemic periods, other
priorities and needs may arise and
make it challenging to provide
sustained resources and support
Pandemic Origins GAO-23-105406 27
needed for maintaining a national
strategy.
•
Augmenting or developing a new
strategy would require careful
consideration to avoid duplication,
overlap, or fragmentation with existing
related strategies, such as those for
biodefense.
•
Integrating a goal of pandemic origin
investigations into existing strategies
could dilute the focus and resources of
the existing strategies.
Pandemic Origins GAO-23-105406 28
6 Agency and Expert Comments
We provided a draft of this product to the Department of State, Department of Defense,
Department of Homeland Security, Department of Energy’s Office of Science and National
Nuclear Security Administration Laboratories, Office of the Director of National Security’s
Intelligence Advanced Research Projects Activity, Office of Science and Technology Policy,
Department of Health and Human Services’ Centers for Disease Control and Prevention and
National Institutes of Health, Department of Justice’s Federal Bureau of Investigation, National
Institute of Standards and Technology, National Science Foundation, and United States Agency
for International Development for review. Six agencies provided technical comments on the
draft report, which we incorporated as appropriate.
We also invited the participants from our expert meeting to review our draft report. Of the 27
experts, 17 agreed to receive the draft for review and 10 provided technical comments. We
incorporated their technical comments as appropriate.
As agreed with your offices, unless you publicly announce the contents of this report earlier, we
plan no further distribution until 5 days from the report date. At that time, we will send copies
of this report to the appropriate congressional committees and other interested parties. In
addition, the report is available at no charge on the GAO website at https://www.gao.gov.
If you or your staff have any questions about this report, please contact me at (202) 512-6888 or
howardk@gao.gov. Contact points for our Offices of Congressional Relations and Public Affairs
may be found on the last page of this report. GAO staff who made key contributions to this
report are listed in appendix III.
Karen L. Howard, PhD
Director
Science, Technology Assessment, and Analytics
Pandemic Origins GAO-23-105406 29
List of Requesters
The Honorable Cathy McMorris Rodgers
Chair
Committee on Energy and Commerce
House of Representatives
The Honorable Bob Latta
Chair
Subcommittee on Communications and
Technology
Committee on Energy and Commerce
House of Representatives
The Honorable Jeff Duncan
Chair
Subcommittee on Energy, Climate, and Grid
Security
Committee on Energy and Commerce
House of Representatives
The Honorable Bill Johnson
Chair
Subcommittee on Environment,
Manufacturing, and Critical Minerals
Committee on Energy and Commerce
House of Representatives
The Honorable Brett Guthrie
Chair
Subcommittee on Health
Committee on Energy and Commerce
House of Representatives
The Honorable Gus Bilirakis
Chair
Subcommittee on Innovation, Data, and
Commerce
Committee on Energy and Commerce
House of Representatives
The Honorable H. Morgan Griffith
Chair
Subcommittee on Oversight and
Investigations
Committee on Energy and Commerce
House of Representatives
The Honorable Markwayne Mullin
United States Senate
The Honorable Kelly Armstrong
House of Representatives
The Honorable Larry Bucshon, MD
House of Representatives
The Honorable Michael Burgess, MD
House of Representatives
The Honorable Earl L. “Buddy” Carter
House of Representatives
The Honorable Dan Crenshaw
House of Representatives
The Honorable John Curtis
House of Representatives
The Honorable Neal P. Dunn, MD
House of Representatives
The Honorable Richard Hudson
House of Representatives
The Honorable John Joyce, MD
House of Representatives
The Honorable Debbie Lesko
House of Representatives
The Honorable Gary Palmer
House of Representatives
The Honorable Greg Pence
House of Representatives
Pandemic Origins GAO-23-105406 30
The Honorable Steve Scalise
House of Representatives
The Honorable Tim Walberg
House of Representatives
Pandemic Origins GAO-23-105406 31
Appendix I: Objectives, Scope, and Methodology
Objectives
This report identifies and discusses:
1. key technologies available for pandemic
origin investigations;
2. strengths and limitations of these tools
and how researchers use them to
investigate pandemic origins;
3. cross-cutting challenges researchers face
in trying to determine a pandemic’s
origin; and
4. policy options that may help address the
limitations and cross-cutting challenges of
using these key technologies to
determine the origin of a pandemic.
Scope and methodology
To address our first three objectives, we
assessed available and developing
technologies and approaches that are
currently used in pandemic origin
investigations. For all of our objectives we
reviewed peer-reviewed scientific literature
and other documents describing current and
developing tools, including reports from the
Centers for Disease Control and Prevention,
Office of the Director of National Intelligence,
the Johns Hopkins Center for Health Security,
World Health Organization, and select
national laboratories; interviewed federal
agency officials and experts from
government, academia, industry, and the
nonprofit sector; and convened a 3-day
51For the purposes of this report, the term “technologies”
includes the instruments, techniques, skills, methods, and
processes used in pathogen characterization.
expert meeting with assistance from the
National Academies of Sciences, Engineering,
and Medicine to discuss the objective topics.
We also reviewed federal agency guidance on
the development and deployment of these
technologies for pandemic origin
investigations.
Limitations to scope
The list of key technologies for pandemic
origin investigations discussed in this report is
not intended to be exhaustive. Based on our
review of the literature and discussions with
federal agency officials and other experts, we
selected technologies currently in use or
under development by researchers to
investigate a pandemic’s origin. We did not
include all possible types of pathogens; we
focused on those that are likely to lead to
direct human-human transmission. For
example, we did not include pathogens that
cause foodborne outbreaks. We also did not
review or include classified data or
intelligence. Since pandemics pose a global
threat, the policy options we identified
represent possible actions U.S. policymakers
and international stakeholders could take.
Literature search
In the course of our review, we worked with a
GAO research librarian to conduct a literature
search of key technologies for identifying and
characterizing pandemic pathogens.51 The
librarian conducted literature searches with
Pandemic Origins GAO-23-105406 32
Scopus using search terms including
“pandemic origins,” “biosurveillance,” “SARS-
CoV-2,” and “bioinformatics,” among other
keywords relevant to technologies for
characterizing pathogens. We conducted a
broad search of materials published within
the last 10 years, including scholarly articles
and government reports. From these
searches, we identified and selected relevant
articles to include in our review. We used the
results of our literature review to inform our
findings as well as identify experts to
interview or invite to participate in our expert
meeting.
Interviews
We interviewed federal agency officials and
researchers as well as nonfederal experts with
a diverse set of perspectives on the science
and application of these technologies. These
experts included individuals from 11 relevant
federal agencies: the Department of State,
Department of Defense, Department of
Homeland Security, Department of Energy’s
Office of Science and National Nuclear
Security Administration Laboratories, Office
of the Director of National Security’s
Intelligence Advanced Research Projects
Activity, Office of Science and Technology
Policy, Department of Health and Human
Services’ Centers for Disease Control and
Prevention and National Institutes of Health,
Department of Justice’s Federal Bureau of
Investigation, National Institute of Standards
and Technology, National Science Foundation,
and United States Agency for International
Development. We also interviewed experts
52This meeting of experts was planned and convened with
assistance from the National Academies of Sciences,
Engineering, and Medicine to better ensure that a breadth of
expertise was brought to bear in its preparation. However, all
final decisions regarding meeting substance and expert
participation are the responsibility of GAO.
from technology companies, universities, and
research institutes that use or develop
genome sequencing, proteomics
technologies, and laboratory characterization
methods for pathogen characterization;
representatives from national and
international health organizations (e.g., the
Association of Public Health Laboratories,
Association of State and Territorial Health
Officials, EcoHealth Alliance, and World
Health Organization); and other individuals
with expertise with technologies used for
pandemic origin investigations.
Expert meeting
To address all of our objectives, we also held
an expert meeting March 22-24, 2022. This
meeting was held with assistance from the
National Academies of Sciences, Engineering,
and Medicine and was divided into six
sessions: (1) genomic technologies for
determining pathogen sequences; (2)
genomic technologies for characterizing
pathogen sequences to inform origin; (3)
genomic technologies for determining
analytical confidence and reproducibility; (4)
non-genomic technologies for characterizing
pathogens; (5) surveillance technologies that
would inform pandemic pathogen origin; and
(6) potential policy options that could help
address technology limitations and other
challenges.52
We selected meeting participants based on
their expertise in at least one area related to
our four objectives. We provided the National
Pandemic Origins GAO-23-105406 33
Academies of Sciences, Engineering, and
Medicine with descriptions of the expertise
needed by expert meeting participants. From
this information, the National Academies of
Sciences, Engineering, and Medicine provided
an initial list of potential participants for the
expert meeting. We reviewed the list and
provided an additional list of experts based
on our review of the literature.
In addition to evaluating experts on the basis
of their expertise, we evaluated them for any
conflicts of interest. A conflict of interest was
considered to be any current financial or
other interest, such as an organizational
position, that might conflict with the service
of an individual because it could (1) impair
objectivity or (2) create an unfair competitive
advantage for any person or organization. Of
the 27 experts who participated in the expert
meeting, some were affiliated with
companies, government, or research-funding
entities. We took these affiliations into
consideration as potential conflicts of interest
when conducting our analysis and preparing
our report. We determined that these
experts’ affiliations were unlikely to bias our
overall reporting.
Policy options
Based on our research, we developed a series
of policy options. Policy options are not
formal recommendations for federal
agencies, or matters for congressional
consideration, but they are intended to
represent possible options policymakers can
take to address a policy objective. For each
policy option, we discussed potential
opportunities and considerations. These are
not listed in any particular order, nor are they
inclusive of all possible policy options. Based
on the goal of improving U.S. pandemic
preparedness, we decided on an objective
designed to identify options that could help
improve capabilities for pandemic origin
investigations. We limited policy options to
those that fit the objective and fell within the
report scope.
To develop our policy options, we compiled a
list of possible options over the course of our
work based on review of the literature,
interviews with experts, and our expert
meeting held March 22–24, 2022. We further
refined and assessed these options to ensure
they were adequately supported by the
evidence we collected, could be feasibly
implemented, and fit into the overall scope of
our work. We then analyzed the information
we collected to identify potential benefits and
considerations of implementing each policy
option. The policy options and analyses were
supported by documentary and testimonial
evidence.
We conducted our work from August 2021 to
January 2023 in accordance with all sections
of GAO’s Quality Assurance Framework that
are relevant to technology assessments. The
framework requires that we plan and perform
the engagement to obtain sufficient and
appropriate evidence to meet our stated
objectives and to discuss any limitations to
our work. Consistent with our quality
assurance framework, we provided the
relevant agencies and experts with a draft of
our report and solicited their feedback, which
we incorporated as appropriate. We believe
that the information and data obtained, and
the analysis conducted, provide a reasonable
basis for any findings and conclusions in this
product.
Pandemic Origins GAO-23-105406 34
Appendix II: Expert Participation
We convened a 3-day meeting of 27 experts with assistance from the National Academies of
Sciences, Engineering, and Medicine to inform our work on technologies for determining
pandemic origin; the meeting was held virtually March 22–24, 2022. The experts who
participated in this meeting are listed below. Some of these experts gave us additional
assistance throughout our work, including four experts who provided additional assistance
during our study by sending material for review or participating in interviews and 10 experts
who reviewed our draft report for accuracy and provided technical comments.
David B. Allison, PhD
Dean, Distinguished Professor and Provost
Professor
Indiana University–Bloomington School of
Public Health
Jesse Bloom, PhD
Professor, Basic Sciences Division
Professor, Herbold Computational Biology
Program, Public Health Sciences Division
Fred Hutchinson Cancer Research Center
Roger Brent, PhD
Professor, Basic Sciences Division
Professor, Public Health Sciences Division
Fred Hutchinson Cancer Research Center
James Diggans, PhD
Distinguished Scientist, Bioinformatics and
Biosecurity
Twist Bioscience
Joshua Dunn, PhD
Head of Design
Ginkgo Bioworks, Inc.
Livia Schiavinato Eberlin, PhD
Associate Professor, Department of Surgery
Baylor College of Medicine
Patrick Fitch, PhD
Associate Director of Chemical, Earth and
Life Sciences
Los Alamos National Laboratory
A. Oveta Fuller, PhD
Associate Professor of Microbiology and
Immunology
Medical School at University of Michigan
Gigi Kwik Gronvall, PhD
Senior Scholar
Johns Hopkins Center for Health Security
Associate Professor, Department of
Environmental Health and Engineering
Johns Hopkins Bloomberg School of Public
Health
India Hook-Barnard, PhD
Executive Director
Engineering Biology Research Consortium
(EBRC)
Katrina Kalantar, PhD
Computational Biology Lead, Infectious
Diseases
Chan Zuckerberg Initiative
Pandemic Origins GAO-23-105406 35
Ali S. Khan, MD, MPH, MBA
Dean, College of Public Health
University of Nebraska Medical Center
(UNMC)
Former Assistant Surgeon General
U.S. Public Health Service
Andy Kilianski, PhD
Senior Director for Emerging Infectious
Diseases
International AIDS Vaccine Initiative (IAVI)
Adjunct Professor, Schar School of Policy and
Government
George Mason University
Sergios-Orestis Kolokotronis, PhD, MPhil,
MA
Assistant Professor, Department of
Epidemiology and Biostatistics. School of
Public Health
The State University of New York (SUNY)
Downstate Health Sciences University
Suresh Kuchipudi, BVSc, MVSc, PhD,
PGCHE, FHEA, Dip. ACVM, MBA
Professor and Endowed Chair in Emerging
Infectious Diseases
Pennsylvania State University
Associate Director
Penn State Animal Diagnostic Laboratory
(ADL)
Jacob Lemieux, MD, DPhil
NIH-funded Physician/Scientist, Division of
Infectious Disease
Massachusetts General Hospital (MGH) and
Harvard Medical School (HMS)
Bronwyn MacInnis, PhD
Director of Pathogen Genomic Surveillance,
Infectious Disease and Microbiome
Program
Broad Institute of Massachusetts Institute of
Technology (MIT) and Harvard
Alemka Markotić, MD, PhD
Director
University Hospital for Infectious Diseases,
Zagreb, Croatia
Head of Department for Research and Head
of Clinical Department for Urinary Tract
Infections and Full Professor
Medical School, University of Rijeka and
Catholic University Zagreb
Associate Member, Croatian Academy
Jonna Mazet, DVM, MPVM, PhD
Vice Provost – Grand Challenges
University of California (UC) Davis
Chancellor’s Leadership Professor of
Epidemiology and Disease Ecology and
Founder, One Health Institute
UC Davis School of Veterinary Medicine
Folker Meyer, PhD
Professor of Data Science
University Hospital, University of Duisburg-
Essen
Tara O'Toole, MD, MPH
Senior Fellow
In-Q-Tel
Director, IQT Lab
BiologyNext
Pandemic Origins GAO-23-105406 36
Rushika Perera, PhD
Associate Professor, Department of Anatomy
University of California (UC) San Francisco
Brian Plew
Director, Public Health Solutions
Thermo Fisher Scientific
David Relman, MD
Thomas C. and Joan M. Merigan Professor in
Medicine
Professor of Microbiology & Immunology
Senior Fellow, Center for International
Security and Cooperation
Stanford University
Chief of Infectious Diseases
Veterans Affairs Palo Alto Health Care
System
Aaron Streets, PhD
Assistant Professor in Bioengineering
University of California (UC) Berkeley
Core Member, Biophysics Program and
Center for Computational Biology
Investigator, Chan Zuckerberg Biohub
David Walt, PhD
Hansjörg Wyss Professor of Bioinspired
Engineering
Harvard Medical School
Professor of Pathology
Brigham and Women’s Hospital
Core Faculty Member
Wyss Institute at Harvard University
Susan Weiss, PhD
Professor and Vice Chair, Department of
Microbiology and Co-Director
Penn Center for Research on Coronaviruses
and Other Emerging Pathogens,
Perelman School of Medicine
University of Pennsylvania
Governor
American Academy of Microbiology
Pandemic Origins GAO-23-105406 37
Appendix III: GAO Contact and Staff Acknowledgments
GAO contact
Karen L. Howard, PhD, Director, Science, Technology Assessment, and Analytics (STAA), at
(202) 512-6888 or howardk@gao.gov
Staff acknowledgments
In addition to the contact named above, the following STAA staff made key contributions to
this report:
Hayden Huang, PhD, Assistant Director and Senior Engineer
Michael Dickens, PhD, Analyst-in-Charge and Senior Biological Scientist
Calaera Powroznik, MS, Analyst
Craig Starger, PhD, Biological Scientist
Adam Wells, PhD, Data Scientist
These staff also contributed to this work:
Nora Adkins, JD, Senior Attorney
Virginia Chanley, PhD, Senior Design Methodologist
Louise Fickel, Communications Analyst
Anika McMillon, Visual Communications Analyst
Matthew Metz, Senior Electrical Engineer
Cindy Korir-Morrison, PhD, Senior Biological Scientist
Robert Rivas, MS, Senior Analyst
Sushil Sharma, PhD, DrPH, Assistant Director
Amber Sinclair, PhD, Senior Design Methodologist
Walter Vance, PhD, Assistant Director
(105406)
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