Lessons learned from thirteen years of

gain-of-function research review

Richard Frothingham, MD, CBSP, FACP
richard.frothingham@duke.edu

I serve as co-chair of the Duke

IBC and IRE. The opinions
expressed here are my own,
not necessarily those of the
IBC or IRE.

NIAID Regional Biocontainment Laboratory at Duke

Richard Frothingham, Duke University, March 10, 2016

History of dual-use review

at Duke
Dual-use review at Duke began in 2003 with the NIH
funding for the Southeast Regional Center of Excellence
for Emerging Infections and Biodefense (SERCEB).
SERCEB included a Policy, Ethics, and Law Core. The
PEL core reviewed all SERCEB projects for dual use
potential. SERCEB reached out to IBCs to assist with
implementation of dual-use review for other protocols.
Most projects with significant dual-use potential were
GOF studies.

Richard Frothingham, Duke University, March 10, 2016

Davidson EM, Frothingham R, Cook-Deegan R. Science and security:

Practical experiences in dual-use review. Science 2007;316:1432-3.
Richard Frothingham, Duke University, March 10, 2016

GOF review
by Duke IBC
Seven questions were added to rDNA registration form
in 2005.
Duke IBC members were trained in 2006 using the
SERCEB module on dual-use research.
The IBC has reviewed all protocols since 2005 with no
specific dual-use definition or threshold.
IBC review has included rDNA, Select Agent, and BSL3
research. The IBC has reviewed other research upon
request.

Richard Frothingham, Duke University, March 10, 2016

How has GOF research

been identified at Duke?

NIH study section or program officer

PI completion of seven questions on rDNA
registration form
GOF concerns also identified by Duke IBC
members during the rDNA, Select Agent, or
BSL3 review process

Richard Frothingham, Duke University, March 10, 2016

Examples of GOF research at Duke

Cytokine expression by ectromelia (2004)
Dual use concerns raised by NIAID study section
Grant application withdrawn; PI did not pursue the research
Proposal submitted prior to Duke IBC dual-use review

Virulence factors in uropathogenic E. coli (2006)

Research approved with some limitations on antibiotic resistance
markers
Researchers received dual use training
PI agreed to suspend research and notify the IBC if major
increase in virulence is identified

Richard Frothingham, Duke University, March 10, 2016

Examples of GOF research at Duke

Adaptation of dengue virus for growth in Drosophila cell
lines (2007)
Duke IBC received external advice and concluded that risk was
minimal. Adaptation predicted to reduce virulence in humans.
Drosophila not a plausible transmission vector.
Project proceeded with dual-use training of research personnel.

HIV infectious molecular clone pseudotyped with VSV-G

for initial entry into renal cells (2015)
Duke IBC received external advice on risk assessment and
necessity for VSV-G pseudotyping to achieve research goals.
The project was approved under BSL3 containment in the NIAID
Regional Biocontainment Lab with administrative controls.
Richard Frothingham, Duke University, March 10, 2016

Lessons learned

The IBC regularly encounters GOF studies as part of the broad

category of dual-use research. We have not encountered GOF
studies of concern (GOF-SOC).
PIs have had challenges with the concept of dual-use research. We
have not yet trained specifically on GOF, but it may be easier to
understand.
The Duke IBC often reaches consensus that dual use potential is
typical for biomedical research. We have difficulty reaching
consensus on other dual-use categories (e.g., DURC). We have
reached consensus on risk mitigation strategies, and have not yet
rejected any GOF proposals.
The Duke IBC has received external expert advice on some GOF
studies as part of the review process.

Richard Frothingham, Duke University, March 10, 2016

Benefits of Duke review for

dual use research
Identified episodes of misuse of Duke research to harm public
health, agriculture, plants, animals, environment, or materiel

10
8

Duke IBC initiates dual

use review

6
4
2
0

Can we measure benefits from dual-use review?

Public trust in responsible science
Early review of GOF research may reduce wasted effort by
scientists and improve peer review and funding outcomes.
Richard Frothingham, Duke University, March 10, 2016

Perspectives on the NSABB

recommendations

GOF is easier to understand than dual use.

The proposed definition of GOF-SOC is much clearer than the current
DURC definition. It should be possible to reach consensus in determining
when GOF is GOF-SOC.
The GOF-SOC research world should be small and definable. There will be
substantial overlap with Select Agent programs. Institutional experience with
Select Agents will be valuable in implementing GOF review.
The current IBC or IRE mechanisms seem appropriate for institutional GOF
review. Institutions should have a low threshold for requesting external
expert advice.
Duke recently moved dual use review, including GOF review, out of the
public IBC space to a confidential Institutional Review Entity (IRE). The
process of GOF review should be transparent but the content is often
inappropriate for public disclosure.

Richard Frothingham, Duke University, March 10, 2016

10

People
Debra Hunt

IRE members

Select Agent program

Responsible Official (RO)
Biological Safety Officer
(BSO)

Wayne Thomann

IBC & IRE co-chair

Raphael Valdivia
Megan Davidson
Bob Cook-Deegan

Brian Letourneau*
Scott Alderman
Randall Reynolds
Pat Condreay*
Arlene Sena*
David Pickup
Carol Epling
Peg Hogan
Tai-Pong Sun

*community members
Richard Frothingham, Duke University, March 10, 2016

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