STUDENT CASE STUDY—MANSKE
THE (FERRET) SNEEZE HEARD AROUND THE WORLD: THE CASE OF THE
BIOENGINEERED BIRD FLU
CASE STUDY FOR AAC&U STIRS PROJECT
Jill M. Manske, Professor of Biology, University of St. Thomas, St. Paul, MN
STUDENT CASE
Learning Objectives
Part One: Understanding the Issues
 Describe the basic biology and epidemiology of influenza
 Describe how research is defined as Dual Use Research of Concern
Part Two: What’s All the Fuss About? Understanding the Experiments
 Describe experimental set-up
 Interpret and evaluate findings from experimental study data
Part Three: The Controversy
 Describe how surveillance of disease in animal and human populations is conducted
 Describe how case-fatality, relative risk, and other epidemiological measures are
calculated and interpreted
 Discuss how risk is calculated and communicated
 Discuss the potential harms and benefits of research that could be Dual Use Research of
Concern
 Explain vaccine effectiveness
Part Four: Should Science Be Censored?
 Synthesize and assess scientific evidence to inform policy
 Explore and articulate ethical principals involved in making science policy decisions
 Consider the evidence and make recommendations
Preparatory Materials
Before coming to class, please read carefully through the portion of the case study assigned by
your instructor as well as the associated materials:
For Part One: Understanding the Issues
 Study the PowerPoint “Introduction to Influenza”
 Watch Staying Safe in a Biology Revolution, with Laurie Garrett, up to 4:37 minutes.
https://www.youtube.com/watch?v=aPgHIbsbGDw
 Prepare questions for class discussion
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STUDENT CASE STUDY—MANSKE
For Part Two: Understanding the Experiments
 Read “Summary of the Avian H5N1 Airborne Transmission Experiments.”
For Part Three: The Controversy
 Watch “Dual Use Research: A Dialogue,”
http://www.youtube.com/watch?v=0yS1ur24j40.
 Watch “H5N1 Influenza Virus and Beyond: Panel Discussion Part One,”
http://www.nyas.org/MediaPlayer.aspx?mid=b9d67798-3fab-423b-b446-5aa5212d8bef.
 Read “What Will the Next Influenza Pandemic Look Like?”
http://www.scientificamerican.com/article/next-influenza-pandemic/.
For Part Four: Should Science Be Censored?
 Read “Your Guide to the Final Debate: Should Science Be Censored?”
You may find it useful to bring your laptop or tablet to class. Your instructor will let you know
which parts of the case to prepare before coming to class.
Introduction
“The packages that started arriving by FedEx on 12 October last year
came with strict instructions: protect the information within and destroy
it after review. Inside were two manuscripts showing how the deadly
H5N1 avian influenza virus could be made to transmit between
mammals. The recipients of these packages—eight members of the US
National Science Advisory Board for Biosecurity (NSABB)—faced the
unenviable task of deciding whether the research was safe to publish”
(Maher 2012).
The Story Begins: Two Guys, Ten Ferrets, and One Nasty Virus
Yoshihiro Kawaoka and Ronald Fouchier
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http://2015people.com/yoshihiro-kawaoka.html
On September 12, 2011, Ronald Fouchier from Erasmus Medical Center in the Netherlands
announced that his research group had induced genetic mutations into H5N1 avian influenza
(“bird flu”) to produce a virus that was capable of airborne transmission between ferrets.
Ferrets respond to influenza similarly to humans, so the studies suggested that this
bioengineered virus was likely transmissible human-to-human as well.
The following day The Influenza Times published:
“This virus is airborne and as efficiently transmitted as the seasonal virus,” said
Fouchier. His research team found that only five mutations, three by reverse
genetics and two by repeated transmission, were enough to produce this result.
“This is very bad news, indeed,” said Fouchier.
While the September 19, 2011, issue of Scientific American reported:
Ron Fouchier and his team "mutated the hell out of H5N1" and looked at how
readily it would bind with cells in the respiratory tract. What they found is that
with as few as five single mutations it gained the ability to latch onto cells in the
nasal and tracheal passageways, which, Fouchier added as understated
emphasis, "seemed to be very bad news." The variety that they had created,
however, when tested in ferrets (the best animal model for influenza research)
still did not transmit very easily just through close contact. It wasn't until
"someone finally convinced me to do something really, really stupid," Fouchier
said, that they observed the deadly H5N1 become a viable aerosol virus. In the
derided experiment, they let the virus itself evolve to gain that killer capacity. To
do that, they put the mutated virus in the nose of one ferret; after that ferret got
sick, they put infected material from the first ferret into the nose of a second.
After repeating this 10 times, H5N1 became as easily transmissible as the
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seasonal flu.
On the heels of Fouchier’s announcement, it later became known that a second research group,
led by University of Tokyo and University of Wisconsin professor Yoshihiro Kawaoka, similarly
had engineered a mammal-to-mammal transmissible form of H5N1.
Later that month, Fouchier and Kawaoka submitted papers describing their H5N1 research to
journals for publication. These two papers become the centerpiece of an unfolding controversy.
Stop the Presses!
In October 2011 The National Institutes of Health (NIH) asked the National Scientific Advisory
Board for Biosecurity (NSABB) to review the manuscripts submitted by Fouchier and Kawaoka,
and to make a recommendation as to how publication of the two papers should be handled.
Some governments and researchers had suggested that findings on the genetic factors that
cause H5N1’s high virulence and lethality should not be publicly disclosed (published in
scientific journals). A key figure of speech for this review was “dual-use”; the NSABB assessed
Fouchier’s and Kawaoka’s work in terms of the extent to which it constituted Dual-Use
Research of Concern (DURC).
The National Science Advisory Board for
Biosecurity (NSABB) has defined dual use
research of concern (DURC) as “research
that, based on current understanding, can
be reasonably anticipated to provide
knowledge, products, or technologies that
could be directly misapplied by others to
pose a threat to public health and safety,
agricultural crops and other plants,
animals, the environment, or material.”
National Research Council. 2004. Biotechnology Research in an Age of Terrorism. Washington,
DC: The National Academies Press.
The conduct of the work, the handling of its announcement, and the political turmoil set into
motion by the prospect of its publication raised serious questions about the limits of free
inquiry and the regulation of research with dangerous organisms. It also raised serious
questions about the terms under which such research should be organized, justified, and
critiqued.
Part One: Understanding the Issues
What is the issue?
Consider what you have just read.
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STUDENT CASE STUDY—MANSKE
Questions:
1) What might be the key arguments for and against publishing this work?
2) What are your initial thoughts about whether or not the work should be published?
3) What do you need to better understand to analyze the situation?
What is influenza?
Refer to the “Introduction to Influenza” PowerPoint to answer the following questions.
Answers will be turned in at the beginning of class.
Questions:
4) What is the structure of the influenza virus? What are its unique characteristics?
5) What is the difference between seasonal flu and influenza pandemics?
6) What are the epidemiological characteristics of infection with avian flu as compared to
yearly flu? What about these viruses causes such public concern?
7) Based on your understanding of influenza, summarize the concerns related to Fouchier
and Kawaoka’s experiments.
What is Dual Use Research of Concern (DURC)?
After watching the video by Laurie Garrett:
8) Write your own “tweetable” (140 character) description of DURC
9) Given your definition and the official definition, why was Fouchier’s and Kawaoka’s work
considered to be DURC?
Part Two: What’s All the Fuss About? Understanding the Experiments
The Scientific American article describes how the researchers
… let the virus itself evolve to gain that killer capacity. To do that, they put the mutated virus in
the nose of one ferret; after that ferret got sick, they put infected material from the first ferret
into the nose of a second.
A mutation in a gene that leads to addition of a function—in this case addition of ability for
airborne transfer from ferret-to-ferret is called “Gain-of-Function”
Gain-of-function mutation: A mutation that confers new
or enhanced activity on a protein.
http://www.medterms.com/script/main/art.asp?articlekey=39613
What did they do? The methods
The researchers conferred this function through transfer—referred to as “passing” or “passage”
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STUDENT CASE STUDY—MANSKE
—through ten different ferrets.
Question:
Refer to the “Summary of the Avian H5N1 Airborne Transmission Experiments.” Using this
summary,
10) Draw a flow chart or diagram illustrating the basic design of this experiment.
What happened? The results
A. Animals inoculated with wild
type H5N1. Virus titers in throat
(black bars) and nose (white
bars) are shown.
C. Animals inoculated with the
mutant H5N1 after it had been
passaged through ten previous
ferrets. Virus titers in throat
(black bars) and nose (white
bars) are shown.
(Herfst et al. 2012)
Questions:
11) What are the researchers measuring on the y-axis? What are they measuring on the xaxis?
12) What does Figure A tell you?
13) What does Figure C tell you?
14) What can you conclude from this experiment?
15) What can you infer from this experiment?
And then—the next part of the experiment:
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STUDENT CASE STUDY—MANSKE
?
http://news.sciencemag.org/sites/default/files/styles/thumb_article_l/public/media/sn-flu.jpg
Using your flow chart and the “Summary of the Avian H5N1 Airborne Transmission
Experiments”:
16) Add this experiment to the flow chart/diagram you drew for the first part of the
experiment.
17) What question are the researchers asking with this experiment?
Virus titer (log10 TCID/ml:
Axis numbers as in Figures A & C above
Results:
B. Ferrets housed next to
animals from A above. Virus
titers in throat (black bars) and
nose (white bars) are shown.
D. Ferrets housed next to
animals from C above. Virus
titers in throat (black bars) and
nose (white bars) are shown.
(Herfst et al. 2012)
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Questions:
18) What does Figure B tell you?
19) What does Figure D tell you?
20) What can you conclude from this experiment?
21) What can you infer from this experiment?
22) What is the take-home message?
Part Three: The Controversy
Before coming to class please:
 Watch “Dual Use Research: A Dialogue”
http://www.youtube.com/watch?v=0yS1ur24j40
 Watch “H5N1 Influenza Virus and Beyond: Panel Discussion Part One”
http://www.nyas.org/MediaPlayer.aspx?mid=b9d67798-3fab-423b-b446-5aa5212d8bef
(26.54–36.06)
 Read “What Will the Next Influenza Pandemic Look Like?”
http://www.scientificamerican.com/article/next-influenza-pandemic/
Make a list of the main arguments and issues raised. What information (evidence) will you
need to evaluate the arguments? Please bring your list to the next class period.
In-class discussion:
What are the main arguments and issues raised? What will you need to know to evaluate
them?
What was the big deal?
23) In the New York Academy of Science panel, Drs. Osterholm and Palese vigorously debate
the Case Fatality Rate (CFR) of H5N1 infection. Why is this important in understanding
the risks and benefits of the gain-of-function H5N1 influenza research?
The reported case fatality rate (CFR) is a
measure of the severity of a disease and is
defined as the proportion of reported cases
of a specified disease or condition which are
fatal within a specified time.
http://www.who.int/gho/epidemic_diseases/cholera/case_fatality_rate_text/en/
Specifically:
24) What is a case? How is this defined, and how does it affect data that are collected?
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STUDENT CASE STUDY—MANSKE
25) Why might it be difficult to establish CFR? List factors that might be obstacles in the
determination of CFR for different diseases.
26) What is disease surveillance? How is it done?
27) Why do these statistics and measures matter to the debate about whether or not this
research should be published?
Who cares?
You have been talking about this case with your roommate. She wonders why anyone would
care about this. “Don’t we have a vaccine for flu? If there was some safety problem with this
research, or this new flu somehow got out of the lab, couldn’t we just go get a shot?”
What might you say to her? Specifically,
28) What is influenza vaccine effectiveness and how is this measured and reported?
29) What is the process and timeline from initial recognition of an influenza outbreak to
introduction of a vaccine to the public?
In-class discussion: Given what you have learned about the influenza vaccine, how well will our
current vaccines protect us if a new, potentially dangerous, influenza virus were to escape from
a laboratory setting?
Part Four: The Final Debate: Should Science Be Censored?
We will debate whether or not gain-of-function (GOF) experiments on highly pathogenic agents
such as avian influenza should proceed and be published in full.
Prepare both sides of the argument (pro-GOF experimentation and publication and con-GOF
experimentation and publication).
Bring your written preparations—at least three well-supported bullet points from which you
could easily craft a three- to five-minute opening statement for either side.
On the day of the debate you will blind select your role from a hat at beginning of class. The
roles will be: opening statement, rebuttal, closing statements for either side of the issue.
References
Bennett, G. 2012. “H5N1 Timeline of Select Episodes and their Significance.”
https://labs.fhcrc.org/cbf/H5N1TimelineofEventsandEpisodesv3.docx.pdf.
Centers for Disease Control and Prevention. 2014. “Influenza—Flu Basics.” Last modified July
28, 2014. http://www.cdc.gov/flu/about/disease/index.htm.
CRS Report for Congress. 2007. “Oversight of Dual-Use Biological Research: The National
Science Advisory Board for Biosecurity.” http://fas.org/sgp/crs/natsec/RL33342.pdf.
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STUDENT CASE STUDY—MANSKE
European Scientists Working Group on Influenza (ESWI). 2011. “The Influenza Times Conference
Newspaper, September 2011.”
http://labs.fhcrc.org/cbf/Papers/H5N1_docs/FEIC_news_from_Malta.pdf.
Harmon, K. 2011. “What Will the Next Influenza Pandemic Look Like?” Scientific American,
September 19. http://www.scientificamerican.com/article/next-influenza-pandemic/.
Herfst, S., E. J. A. Schrauwen, M. Linster, S. Chutinimitkul, E. de Wit, V. J. Munster, E. M. Sorrell,
T. M. Bestebroer, D. F. Burke, D. J. Smith, G. F. Rimmelzwaan, A. D. M. E. Osterhaus, and Ron A.
M. Fouchier. 2012. “Airborne Transmission of Influenza A/H5N1 Virus Between Ferrets.”
Science, 336(6088): 1534–41. DOI: 10.1126/science.1213362.
Imai M, T. Watanabe, M. Hatta, S.C. Das, M. Ozawa, K. Shinya, G. Zhong, A. Hanson, H. Katsura,
S. Watanabe, C. Li, E. Kawakami, S. Yamada, M. Kiso, Y. Suzuki, E. A. Maher, G. Neumann, and Y.
Kawaoka. 2012. “Experimental Adaptation of an Influenza H5 HA Confers Respiratory Droplet
Transmission to a Reassortant H5 HA/H1N1 Virus in Ferrets.” Nature, 486(7403): 420–28. DOI:
10.1038/nature10831.
Maher, B. 2012. “Bird-flu Research: The Biosecurity Oversight.” Nature, 485(7399): 431–34.
DOI: 10.1038/485431a.
National Research Council. 2004. Biotechnology Research in an Age of Terrorism. Washington,
DC: The National Academies Press.
Osterholm M.T., N. S. Kelley, J. M. Manske, K. S. Ballering, T.R. Leighton, and K. A. Moore. 2012.
The Compelling Need for Game-Changing Influenza Vaccines: An Analysis of the Influenza
Vaccine Enterprise and Recommendations for the Future. Center for Infectious Disease Research
and Policy. http://www.cidrap.umn.edu/compelling-need-game-changing-influenza-vaccines.
About the Author
Jill Manske is a professor of biology at the University of St. Thomas. She earned a BA from the
College of St. Catherine, an MA from Southern Illinois University, and an MPH and PhD from the
University of Minnesota. She teaches courses in immunology, infectious disease, and women’s
health at all levels of the curriculum, introductory through senior seminars, for both majors and
non-majors. As this case illustrates, her teaching often draws students to questions at the
intersection of science and society to explore complex questions that cannot be answered
solely in the laboratory.
Professor Manske has extensive experience with curriculum development and assessment and
has been a peer-teaching mentor and consultant. Presently, she serves as chair of the College
of Arts and Science Faculty.
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Professor Manske’s research interest centers on the intersection between immunology,
infectious disease, and community health. Currently, she is working on projects related to
influenza, influenza vaccine, and science policy, as well as Lyme disease surveillance. She was
named an Association of American Colleges and Universities (AAC&U) STIRS Scholar in 2014.
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