LSFMAGFALL2015-reduced

LSF MAGAZINEFall 2015 Telling the Story of Biotechnology
The
Microbiome
Ananda Chakrabarty | Environmental Metagenomics | Probiotic Philosophy

Departments
02 LSF News & Events
04 In Memoriam
Alan Walton
06 Biotech Bookshelf
Life’s Engines and The Microbiome
10 LSF Oral History Program
Immunex’s Founding Team
32 Educators’ Corner
René Dubos - Scientist, Humanist,
Environmentalist
36 In Conversation
Corey Goodman of Second Genome
58 Photo Finish
The Art of Joana Ricou
Features
08 Ian’s New Guinea Gut Experiment
18 The American Gut Project
20 Environmental Metagenomics
22 Probiotic Philosophy
A Brief History
40 Mr. Pseudomonas
Ananda Chakrabarty
50 Microbiome Innovation
AvidBiotics, Rebiotix, Vedanta Biosciences,
µBiome
60 LSF Annual Report 2015
Marie became seriously ill
and died of tuberculosis
in 1942. Her medical records
showed that she
had first had
tuberculosis as
a child. I came
I found other microbes
that secreted antibiotic
compounds.
In my personal
life, fate brought
both joy and
heartbreak
when I married
Marie-Louise.
Like me, she was
I discovered
gramicidin, the first
antibiotic used to
treat patients.
Using my methods,
scientists developed
many new drugs,
like penicillin and
streptomycin.
Some of them,
including my old
mentor Selman
Waksman, won
Nobel Prizes for
their discoveries.
The possibilities of this
induced enzyme are
tremendous!
... continued
fighting near
Paris.
40
32
5010
22
18

LSF Magazine 1
Executive Editor
Mark Jones
Editor
Marie Daghlian
Production Managers
Marie Daghlian
Kevin Vickery
Design/Layout
Zachary Rais-Norman
Contributors
Carol Collier
Marie Daghlian
Brian Dick
Paul Gabrielsen
Mark Jones
Meredith Knight
Daniel Levine
Funke Sangodeyi
Douglas Smith
Ramya Rajagopalan
Joana Ricou
Ian Signer
Kevin Vickery
On the cover
Other Self II (the human
microbiome), oil on
canvas, by Joana Ricou
© Copyright 2015
Life Sciences Foundation
All rights reserved
From the editor
In 1936, Harvard University Press published
The Great Chain of Being by Arthur O. Lovejoy,
a professor of philosophy at Johns Hopkins
University. “The Great Chain of Being” refers
to the natural hierarchical order of things as
imagined originally by Plato and Aristotle,
and subsequently many others in the Western
philosophical tradition. Lovejoy reviewed the
long history of the idea.
In late antiquity, the chain began with inert
matter and ascended through plants, animals,
and human beings, to the “pure absolute,”
a realm of spiritual perfection beyond the
vicissitudes and inconstancies of experience in
the material world.
In Europe during the Middle Ages, scholas-
tics imbued the idea with Christian theology.
The chain represented a divine order. The apex
was reserved for the one true God; next came
the angels and saints. Nearest to God among
earthly souls were kings, queens, and archbish-
ops, and further down, beneath shopkeepers
and shepherds, but still a notch above plants
and animals, were beggars, actors, thieves, and
gypsies.
As Lovejoy observed, formulations of the
great chain always reflected human values
and purposes, and with the rise of modern
science in the seventeenth and eighteenth
centuries, religion and spirituality were cast
off, and connections to philosophical idealism
and essentialism were diluted. But notions of
gradation and hierarchy persisted. The chain no
longer ascended toward perfection or divinity,
but it still privileged the greater complexity and
capabilities of “higher organisms.” Man replaced
god at the pinnacle.
Microbes never figured prominently in great
chain schemes. Their existence was unknown
until the seventeenth century, and later they
were usually positioned somewhere between
worms and dust, if mentioned at all. But
advances in DNA sequencing technology have
lately permitted scientists to survey microbial
populations and reassess their ecological
significance. And it turns out that they’re pretty
important.
By now, just about everybody has heard
the news about personal microbiomes: the
human body is a campus of invisible but vibrant
ecosystems, teeming with microbial diversity.
We all harbor trillions of bacteria. Some are
simply hitchhikers along for a ride, but many
are functional. They help us maintain good
health. We couldn’t survive without them.
We’ve learned that the human microbiome
is an organ, not an adjunct or an accessory, but
an integral, functional component of the human
body. We’re getting used to the idea that human
beings are superorganisms, human/bacterial
hybrids. And it’s not just us. Every living thing
is a hybrid, all swim in the same sea of life. This
is the end of the “Great Chain of Being.” We had
the wrong image. Now we see a vast network in
which everything is connected.
Knowledge of the microbiome will impact
many spheres of human action and enterprise,
medicine and healthcare perhaps most imme-
diately and broadly. Disturbances in the human
microbiome have been linked to a wide range
of serious ailments, including, in addition to
gastrointestinal problems, metabolic and auto-
immune disorders, cancers, and cardiovascular
and neurodegenerative diseases.
Little about the microbiome is currently
understood, but marketers and consumers are
already true believers. At Amazon.com, you can
find alongside titles on vegan and gluten-free
diets and methods for detoxing body and soul,
several new bestselling books on the microbi-
ome. Most are written by MDs. They promote
health claims that range from modest and
carefully qualified to quackish:
The Gut Balance Revolution (Boost Your Me-
tabolism, Restore Your Inner Ecology, and Lose
the Weight for Good!); The Microbiome Solution
(A Radical New Way to Heal Your Body from
the Inside Out!); The Microbiome Diet (The
Scientifically Proven Way to Restore Your Gut
Health and Achieve Permanent Weight Loss!).
Nothing has been “scientifically proven,”
but some of the advice might be sound anyway.
Who knows? In any event, this special issue of
LSF Magazine considers the past, present, and
future of the microbiome, and scientific efforts
currently underway to learn more about it.
Mark Jones

2 LSF Magazine
news & events
The Biotechnology Heritage Award
In June, the Chemical Heritage Foundation (CHF) bestowed
the 2015 Biotechnology Heritage Award on pioneering venture
capitalists Moshe Alafi and Bill Bowes, for their important
contributions to the growth of the biotechnology industry. The
Biotechnology Heritage Award is cosponsored by CHF and BIO,
the Biotechnology Industry Organization. It honors individuals
who have furthered biotech research and development through
discovery, innovation, commercialization, and/or public under-
standing. In partnership with CHF, LSF produced a video, a brief
tribute to the awardees, that was shown at the award ceremony. It
is available for viewing on the LSF website at biotechhistory.org.
LSF Partners with NHGRI
The Life Sciences Foundation and the National Human Genome
Research Institute (NHGRI) have entered into a formal research
partnership to document and publish the history of genomics,
including developments in DNA sequencing, bioinformatics,
human variation research, and precision and personalized med-
icine. LSF and NHGRI historians are working collaboratively to
collect oral histories from scientists, administrators, business-
persons, financiers, and others involved in the Human Genome
Project and subsequent genomics initiatives, in both public and
private sectors, and LSF research associate Brian Dick has been
granted NIH guest researcher access to the NHGRI archival
database, a unique collection containing more than 4 million
documents on genomics history.
LSF’s Ramya Rajagopalan on the Move
LSF research associate Ramya Rajagopalan spent the summer
serving as LSF’s ambassador to the academic community. In
mid-August, she attended the “Knowledge from the Margins”
conference at Michigan State University, and presented a paper
entitled “Difference in the Making: Biomedical Futures and
Health Equity.” She also attended the annual meeting of the
Science, Knowledge, and Technology section of the American
Sociological Association, held this year at Northwestern Uni-
versity in Evanston, Illinois. She spoke on “Precision Medicine
in the 21st Century: Big Data, Evidence, and Expertise.” Finally,
Ramya was invited to speak in Norway in early September at a
workshop on race and ethnicity organized by the Norsk Teknisk
Museum and the University of Oslo. She presented “Variations
on a Chip: SNPs and the Making of Populations in Human
Genetic Variation Studies.”
Legacy of the Orphan Drug Act
The Orphan Drug Act (ODA) of 1983 has had an enormous
impact on biopharmaceutical development and patient health
in the United States. It created economic incentives that allowed
private companies to pursue treatments for rare diseases
affecting fewer than 200,000 individuals. Since the ODA was
enacted, millions of patients have received treatments that would
not otherwise have been available.
On November 2 in San Francisco, LSF will host a moderator
and three pairs of expert guests who will discuss the history
of the ODA, its impact on the pharmaceutical industry, and
the ways in which it has facilitated patient involvement in the
development of new treatments for a host of rare diseases.
Please visit odalegacy.eventbrite.com for registration details.

LSF Magazine 3
Fall 2015
In July, an illustrious group of life scientists and technologists
joined historians and students at Cold Spring Harbor Laboratory
(CSHL) on Long Island for “The Evolution of Sequencing Tech-
nology: A Half-Century of Progress,” the latest CSHL Genentech
Center conference on the history of molecular biology and
biotechnology.
Presenters included many of the field’s leading pioneers—
Walter Gilbert, Leroy Hood, Clyde Hutchison, James Kent,
Tom Maniatis, Eugene Myers, Richard Myers, Melvin Simon,
Hamilton Smith, Lloyd Smith, Craig Venter, and Jim Watson
were all on hand. Others recounted the development of “next
generation” tools, including Shankar Balasubramanian,
cofounder (with David Klenerman) of Solexa and coinventor of
Illumina’s “sequencing by synthesis” technology.
The conference was organized by Mark Adams of the J. Craig
Venter Institute, Nigel Brown of the University of Edinburgh,
Robert Waterston of the University of Washington, and Mila
Pollock of the CSHL Library and Archives.
Cold Spring Harbor Laboratory History Conference:
The Evolution of Sequencing Technology
Walter Gilbert
Hamilton Smith and Eugene MyersShankar Balasubramanian
James Kent Tom Maniatis

4 LSF Magazine
Alan Walton (1936-2015)
in memoriam
Alan Walton, scientist, entrepreneur, venture capitalist, and
co-founder of Oxford Bioscience Partners, died at his home in
Westport, Connecticut on July 4, 2015, at the age of seventy-nine.
Alan Walton was born in 1936, in Kings Norton, a suburb
of Birmingham, England. During the war, his father worked as
an engineer at the Cadbury chocolate factory, which had been
refitted to manufacture tanks, munitions, and parachutes. Wal-
ton recalled enduring German bombing raids in underground
shelters:
“I’ll never forget hearing this bomb whistling down, and I
was absolutely sure we’d had it because it got louder and louder.
I don’t know exactly where it landed, but I couldn’t believe it
when we opened the bomb shelter door and our house was still
standing.”
Walton became fascinated with chemistry at an early age. His
parents encouraged the interest. He went on to earn a PhD in
chemistry and a DSc in biological chemistry from the University
of Nottingham, and then took a postdoctoral position in the
United States, at Indiana University. “I’d got the impression that
the streets of America were paved with gold,” he said. “I was
going to dig them up and bring them back to England.”
But he didn’t go back. After delivering a lecture at the Case
Institute of Technology in Cleveland, he was offered a permanent
faculty position in the Department of Chemistry. He accepted.
His first project as an assistant professor was a study of ice nucle-
ation. Every elementary school student knows that water freezes
at zero degrees Celsius, but Walton and a colleague showed that,
in fact, it can remain in liquid form down to nearly forty below.
Walton’s interest in phase transitions and a move into the
Institute’s Department of Macromolecular Science after a merger
with Western Reserve University led him next to a biological
problem: the chemistry of bone formation. As that work
proceeded, he noticed that much of the equipment in his new
department lay fallow. He asked the university if he and several
faculty colleagues could use it in their spare time for a commer-
cial operation and share the proceeds with the university.
It was an unusual request. When Walton was in the chemistry
department, the chairman had warned him: “‘If you do applied
work, we’ll fire you. This is an ivory tower.’” But times had
changed. The university gave its blessing, and in 1978, Walton
embarked on his first commercial enterprise, the BioPolymer
Corporation, which produced polypeptides and polysaccharides
for use in research and various industrial processes.
Three years later, Walton took a huge risk and left his tenured
position to join University Genetics (UGEN), a technology
transfer company that bought and sold intellectual property
rights. It soon became apparent that patent peddling wasn’t a
winning business formula, so Walton shifted gears. “Instead
of licensing,” he said, “we formed operating divisions to bring

LSF Magazine 5
Fall 2015
products to market, in order to control our own destiny.” UGEN
went public in 1983 and raised $5 million, enough to implement
the strategy. “We became venture capitalists, in effect,” said
Walton, “by seeding these operations.”
Walton’s creative maneuverings attracted the attention of
the venture capital community. Several firms, he said, “began
chasing me quite avidly.” Walton favored Oxford Partners, which
demonstrated serious interest in biotechnology. He joined in
1987, and enjoyed sensational success. “I was incredibly lucky,”
he said. “Everything I did turned to gold, and people around the
country started asking, ‘Who is this guy Walton who’s making
money out of biotech? Let’s try biotech.’”
One of Walton’s first investments was Martek Biosciences.
In the mid-1980s, powdered baby formulas lacked essential
nutrients—docosahexaenoic acid (DHA) and arachidonic acid
(ARA), for example—found in breast milk. Martek used algae to
add the missing nutrients to infant formula. Walton took great
pride in the product. He said, “It improved the cognition of
probably half a million premature babies, mainly in Africa.”
Walton also provided early funding for companies such as
Illumina, which started out with a DNA microarray technology,
and Geron, which was founded to develop cancer therapies from
advances in telomere biology. In 1993, he organized Oxford
Bioscience Partners, a firm dedicated exclusively to investments
in biotechnology. At that time, entrepreneurs and investors were
chasing new opportunities in genomics.
In 1991, Walton was invited by NIH patent officer Reid Adler
to give a lecture on the issue of patenting expressed sequence
tags, fragments of genes. Craig Venter attended and afterwards
told Walton of his plan to start an independent gene discovery
organization. Walton introduced him to financier Wally Stein-
berg of Healthcare Ventures.
Steinberg supplied Venter with $80 million to start The
Institute for Genome Research (TIGR) in exchange for access
to newly discovered genes. Rights to the genes were transferred
to Steinberg’s private venture, Human Genome Sciences (HGS).
Walton watched the deal unfold, and called it “the biggest
biotech home run of all time.” Oxford Bioscience Partners took a
stake in HGS.
Walton helped to establish a number of other important
companies in the field including Exelixis, the first functional
genomics company, Gene Logic, which identified cancer bio-
markers, and Psychiatric Genomics, which sought to understand
the genetics of mental illnesses and neurological disorders. He
was certain that genomics would make major contributions to
biomedicine, and was excited when the draft sequence of the
human genome was completed in June 2000. He was on a cruise
ship off the coast of Greenland. He went around sharing the
news, but found that few fellow passengers shared his enthusi-
asm: “80 percent said, ‘What’s a genome?’ 10 percent said, ‘That’s
the devils work.’ Another 10 percent said, ‘Oh that’s nice.’”
Walton did not retire from the venture capital business until
the end of 2013, but he had earlier formulated a plan “to squeeze
all the excitement I could out of my senior years.” He took time
off to indulge his taste for adventure and adrenaline rushes.
“When I kick the bucket,” he once said, “I want to have done
everything I could have.”
He traveled to the North Pole, made a trek up Kilimanjaro,
took a bungee jump off the Bloukrans Bridge in South Africa,
and sky dived from 30,000 feet over Mount Everest. He co-pi-
loted a Russian MiG-25, the world’s fastest jet, on a flight that
nearly ended in disaster when cracks appeared in the windshield
at 80,000 feet. And he almost made it into outer space—he pur-
chased a ticket on Richard Branson’s Virgin Galactic spaceship,
and, at the age of 71, went through extensive training as an
astronaut, but the flight was repeatedly delayed and still hasn’t
lifted off.
Alan Walton always considered himself “more a scientist
than a businessman.” He authored ten books and more than 120
scientific papers, and served on the boards of more than twenty
biotechnology companies. He received a host of honors, and in
2012, was awarded the Order of the British Empire by Queen
Elizabeth, for advancing knowledge in the life sciences and
financing the development of new medicines. His wife, E.J., three
children, and four grandchildren survive him. His daughter,
Kimm, preceded him in death in 2013.
opposite: Alan Walton receives the the Chemical Heritage Foundation’s
2013 Richard J. Bolte, Sr. Award for Supporting Industries.
below: Queen Elizabeth II admits Alan Walton to the Order of the
British Empire at Buckingham Palace on December 4, 2012.

6 LSF Magazine
biotech bookshelf
Paul G. Falkowski. Life’s
Engines: How Microbes
Made Earth Habitable.
Princeton: Princeton
University Press, 2015.
The origins of life on earth are a mystery. No one knows
exactly how the primordial soup gave rise to self-replicating
biological systems, but the fossil record shows clearly that by
2.6 billion years ago, long before the appearance and evolution
of plants and animals, and long before there was oxygen in the
atmosphere, microbial life had proliferated.
In Life’s Engines: How Microbes Made Earth Habitable,
oceanographer Paul Falkowski proposes that these ancient
microorganisms profoundly altered the chemistry and geology
of the planet, and established conditions of existence for all
subsequent forms of life. And, he says, biologists have largely
failed to appreciate their supreme importance in the grand story
of life on earth.
Of course, microbes have been studied intensively as causes
of disease, agents of fermentation, and model organisms in
genetics, but ever since the late eighteenth century when the
emergence of paleontology sparked scientific interest in natural
history and biological variation over time, evolutionary thought
has been concerned mainly with the natural selection of traits in
plants and animals. Until recently, scientists knew little about the
dynamics of microbial communities and the role of the global
microbiome in shaping the biosphere was almost wholly neglect-
ed as a topic of inquiry. In Falkowski’s opinion, “this oversight of
microbes…distorted our worldview of evolution.”
Classical evolutionary theory describes vertical hereditary
descent in branching lineages, but Falkowski points out that the
vast majority of the planet’s genetic, metabolic, and ecological
diversity resides in communities of symbiotic single-celled
organisms in which genes circulate by means of horizontal gene
transfer (through the processes of transformation, conjugation,
and transduction). Rather than the tall “tree of life,” the expan-
sive “network of life” is the better metaphor for evolutionary
change in the microbiome.
Life’s Engines describes how this mode of evolution was
responsible for creating biological “nanomachines,” molecular
constructs that have played crucial roles in sustaining all forms
of life on earth. Ribosomes are a prime example. As they exist
today, ribosomes are RNA/protein complexes found in the cells
of all organisms. They receive and translate genetic instructions
for ordering and assembling amino acids into peptide chains,
which cells then fold into enzymes and proteins involved in the
formation and maintenance of cellular structures and functions.
Ribosomes are indispensable, and they are microbial in origin.
Falkowski reviews the evidence for the claim. In the mid-
1970s, University of Illinois biochemist George Woese analyzed
ribosomal RNA sequences across a broad range of organisms—
bacteria, archaea (single-celled methanogenic microbes), and
eukaryotes (including fungi, plants, and animals)—and found
that certain regions are universally conserved. He concluded
that all life on earth is derived from a single common microbial
ancestor, the source of the original protein factory.
Other nanomachines established a “global electronic circuit
of life” that harnesses electrons in order to power chemical
reactions and sustain biological processes. “In effect,” Falkowski
writes, “all organisms are electricity-generating systems—they
work by moving ions, such as protons, across membranes to
generate their own electrical gradients.”
The sun is the ultimate source of all terrestrial energy. Early
microbial life tapped into it and found ways to distribute its
power across the biosphere. Photosynthesis first occurred in
anaerobic bacteria that split hydrogen sulfide to convert light
energy into chemical energy. Later microbes split water and
released oxygen into the atmosphere, an event that profoundly
altered the future of life on earth.
These microbial nanomachines were eventually engulfed by
plant cells, and are now called chloroplasts (and they continue to
replenish the planet’s supply of oxygen). Mitochondria, the pow-
er plants of eukaryotic cells that manufacture the energy-storing
and transporting molecule, ATP (adenosine triphosphate),
are also microbial in origin. But Falkowski points out that the
genomic repertoires borrowed by the planet’s higher (i.e., more
complex) forms of life represent but a miniscule fraction of the
metabolic pathways that have evolved in microorganisms.
The microbial sea of genes encodes an astonishingly diverse
inventory of life-sustaining molecular systems (many of which
are redundant). The microbiome is the guardian of the planet’s
metabolism. Horizontal gene transfer makes it remarkably
resilient and endlessly adaptable. Extinctions may occur, but
genes and metabolic capabilities will survive.
The message of Life’s Engines is that, contrary to human
conceits, single-celled organisms are the dominant form of
life on earth, and by far the most robust and most important.
They don’t need us, but we need them, as do all higher forms of
terrestrial life. For this reason, Falkowski considers microbes
the planet’s “true stewards.” For readers patient enough to walk
through the scientific explanations, Life’s Engines is a rewarding
source of insights.
Life’s Engines

LSF Magazine 7
Fall 2015
Edited by Rosamond
Rhodes, Nada Gligorov,
and Abraham Paul
Schwab. The Human
Microbiome: Ethical,
Legal and Social
Concerns. New York,
New York: Oxford
University Press, 2013.
In 2007, the US National Institutes of Health (NIH) gave
microbiomics research a huge boost when it funded and orga-
nized the Human Microbiome Project (HMP). Over the next
five years, the HMP awarded dozens of competitive grants that
enabled investigators around the country to begin characterizing
microbiota in and on the human body, and to learn how they
affect human health and disease.
At the same time, the NIH gathered a working group of
twenty-seven academic bioethicists, health policy analysts, legal
scholars, philosophers, physicians, and scientists to study the
ethical, legal, and social implications of microbiome research.
The task force evaluated policy options for managing antici-
pated consequences of expansion and progress in the field for
researchers, research institutions, research subjects, medical
professionals, healthcare providers and payers, state and federal
governments, and the general public.
The working group’s recommendations, which took shape
over two years of deliberation and discussion, are summarized
in The Human Microbiome: Ethical, Legal and Social Concerns.
Various group subcommittees penned the book’s seven chapters.
The authors are clearly impressed by the extent to which recent
research on human-microbe relations has eroded distinctions
between “us” and “them,” challenged conventional assumptions
about “individuality” and “humanity,” and in the process,
exposed the inadequacy of traditional ethical foundations in the
governance of research.
With some exceptions (discussed below) the book’s practical
policy recommendations are unremarkable. They are mostly
adaptations or extensions of established rules and oversight ar-
rangements. The authors continue to emphasize the importance
of communication and dialogue with the public, community
consultation, privacy and confidentiality safeguards, and the
restoration of public trust in research institutions.
Of greater interest, for their novelty, are the surprising con-
clusions the group draws about general assumptions and guiding
principles. After reviewing the philosophical underpinnings and
historical evolution of research oversight, the authors say, “The
microbiome introduces a radical shift in how we conceptualize
research ethics.” They go on to articulate first steps in a policy
reformation that will “liberate research ethics from its well-in-
tentioned ideology.”
The heart of this program is presented in chapter five. Its
most surprising feature is its willingness to relax commitments
to the doctrine of informed consent – the bedrock foundation
of research subject protection. Bioethicist Rosamund Rhodes is
the chapter’s lead author, the first of six. Rhodes et al. explain:
“Research ethics regulations and policies have primarily focused
on avoiding risks and providing benefits to research participants.
They should also give significant weight to advancing knowledge
and providing benefits to future patients.”
Striking a new balance between the interests of researchers
and the interests of research subjects will inevitably require
dilution of informed consent rules. What has led bioethicists to
make this startling move? The short answer is enthusiasm for
microbiomics.
The working group takes for granted that research in the
field will lead to important advances in medicine while posing
minimal physical risks to research subjects. At the same time,
the group recognizes that progress depends on the collection of
tissue samples from volunteer donors on unprecedented scales.
The Rhodes et al. policy revolution is designed to accelerate
scientific advancement by encouraging broad participation.
To facilitate access to samples, the authors propose a new
class of research—de minimis research, studies with negligible
risks—in which informed consent would not be required.
Implementation would require policymakers to view research
participants not as “vulnerable subjects who require paternalistic
protection” but as “capable people who can make choices that
reflect their own values.”
But when fully articulated, the new “liberated” research
ethics appear oddly collectivist and utopian, and not particularly
conducive to choice. The authors see microbiome research as “a
collective enterprise in which everyone cooperates to produce
new knowledge.” Emphasizing the great potential value to
society, they suggest that “now is the time to give up the view
that there is no duty to participate.”
The book stops short of calling for legislation, but the work-
ing group plainly wants to see service to biomedical research
become a universal obligation: “Without going so far as to make
participation mandatory,” the group writes in chapter five, “our
society should acknowledge the moral duty.”
The authors don’t formulate strategies for winning hearts and
minds or exerting moral pressure but, presumably, reformed
public dialogue and community outreach efforts would, in
addition to educating about risks, remind “liberated” people of
their civic obligations—much like a summons to jury duty. The
Human Microbiome is a singular document.
The Human Microbiome

8 LSF Magazine
Ian’s New Guinea
Gut Experiment
In August, Ian Signer, LSF’s Director of Education and Partner-
ships traveled to New Guinea, the world’s second largest island
(after Greenland), to hike in remote regions and photograph
wildlife. Because of its rugged topography and nutrient-poor soils,
New Guinea remains covered by lowland swamps and highland
rain forests and is home to hundreds of isolated tribes with
distinct cultures.
Since Ian planned to be in New Guinea for seventeen days,
and intended to subsist exclusively on local fare, we asked if he
would be willing to have his gut microbiome sequenced by the
non-profit American Gut Project for $99, and simultaneously by
a commercial outfit, µBiome, for $89. Both offer personal profiles
of gut microflora that participants can compare with the results
of anonymous others grouped by diet, lifestyle, and physical
condition. (Read more about the American Gut Project on page
18 and µBiome on page 56).
We proposed a before and after comparison to see whether
the exposure of a native Californian to Indonesian microflora
would register on a microbiome profile. Before leaving on his trip,
Ian sent samples to the American Gut Project and µBiome. He
repeated the exercise on the day of his return to the States. He will
receive two before and two after microbiome profiles for compari-
son. With the subject’s permission, we’ll publish the results.
Ian began his journey in the Cyclops Mountains outside of
Jayapura City, the provincial capital of Papua, Indonesia, and
made his way via plane, boat, and jeep to Sorong, at the tip of the
island’s westernmost peninsula, just over fifty nautical miles below
the equator at latitude 00º 52’ 46’ S. Along the way, he consumed
a variety of local foods, from Indonesian street staples like bakso
(a noodle soup with meatballs) and lalapan (chicken with fried
tempeh, tofu, chile and herbs) to Papuan specialties such as sago,
a mostly flavorless mucilaginous goo derived from the cooked
heart of the sago palm.
Did the experience of moving through a strange land and
consuming unfamiliar foods alter the ecological balance of Ian’s
intestinal tract? Did he acquire new companion microbes? Maybe
profiles from the American Gut Project and µBiome will provide
some clues.
We’re also interested in comparing the service providers.
Both rely on 16S ribosomal RNA sequencing to identify bacteria
in samples, but last year, Erika Engelhaupt, a reporter for
ScienceNews, was surprised to find large discrepancies in results
she received from the two groups.
She made inquiries and learned that variation or error can be
introduced at several stages in the process, from sample collec-
tion, handling, and preparation to data analysis, if labs employ
different computational estimation or data correction techniques
(corrections are made, for example, to compensate for expected
post-collection overgrowth of certain bacterial genera).
Mail order is not an ideal mode of sample collection and
submission, but researchers in the field believe that reproducibili-
ty can be improved enough to permit broad data pooling. Rashmi
Sinha, a senior investigator at the National Cancer Institute has
organized an effort to establish standards for microbiome testing
protocols—the Microbiome Quality Control Project. Twenty
leading national laboratories are participating in pilot studies.
Stay tuned for breaking news on Ian’s New Guinea gut
experiment.
An LSF staffer volunteers for microbiome
sequencing and spills his guts
Ian’s New Guinea Gut Experiment

LSF Magazine 9
Fall 2015
top left: Ian Signer with children in the village of Syoubri
bottom left: Ian samples fresh coconut
top right: Sago palm
middle right: Sago preparation
bottom right: betel nuts

10 LSF Magazine
Christopher Henney:
An Eye for Talent
In 1981, Christopher Henney left the security of academic tenure
for the uncertainty of a biotech startup. He may have been the
first senior life scientist to take the leap. He was forty years old,
chair of the department of immunology at the Fred Hutchison
Cancer Research Center in Seattle, and firmly established as a
world-class biomedical scientist. Leaving the institutional shelter
of the “Hutch” was a huge gamble, but the decision led to an
extraordinarily successful second career in industrial research and
development. Over the next twenty-five years, Henney’s work with
Immunex, Icos, and Dendreon helped put Seattle on the biotech
map.
Immunologist Christopher Henney entered the biotech
industry like a lottery winner—a pile of money fell into his
lap. In 1980, the Swiss pharmaceutical company Hoffman-La
Roche offered $1 million annually to fund all research in his
department at the “Hutch,” as the cancer center was known, in
exchange for commercial rights to new inventions.
Unfortunately, his faculty colleagues opposed the arrange-
ment. “The proposal,” Henney says, “was to make immunology
a hard money department. At the time, I was the only person
on hard money. But I could never sell the other departments on
it. They claimed it was unfair.” Henney’s scientific collaborator
Steve Gillis, an assistant professor at the Hutch, suggested that
they form their own company.
At first, Henney was reluctant. He was an internationally
recognized expert in cellular immunology. He had earned a PhD
at the University of Birmingham in England for investigations of
how antibodies become denatured in rheumatoid arthritis, and
before joining the Hutch, had held a professorship at the Johns
Hopkins University School of Medicine. Academia was home
and it was comfortable.
Gillis’ proposed plunge into business became palatable for
Henney when he hit on the idea of structuring the new venture
along academic lines: “I thought we could call it a company but
organize it as a research institute, which I knew how to run.”
Roche liked the idea, too, and increased its offer to two million
dollars a year.
Hutch administrators wanted Henney and Gillis to treat
their new venture, called Immunex (a contraction of immune
experiments), as a sideline, but the entrepreneurs realized that in
order to maximize chances for success, they needed to put skin
in the game. Henney says, “We saw that we really couldn’t do it
on the side, on a Wednesday, with our left hands.”
Meanwhile, the two had been introduced to local
businessman Steve Duzan. “He seemed to know his way around
the business community,” says Henney. Duzan joined them as
CEO, and helped to bring in a strong group of investors.
Immunex opened its doors on the Seattle industrial wa-
terfront in November 1981. Soon George Rathmann, CEO of
Amgen, another newly formed biotech startup, paid a visit.
He proposed a merger that would turn Immunex into “Amgen
North.” Henney now calls the idea premature: “We didn’t know
much about Amgen, and we wanted to do our own thing. It was
maybe five years too soon for that conversation.”
Henney and Gillis had connecting offices at Immunex. “At
that stage, we were a real team,” Henney recalls. “Steve liked to
go around the labs, reviewing experiments, and cracking the
whip. I became the recruiter.” Henney was superbly connected in
academic circles. He had a big name and an extensive network.
“When you have a certain reputation,” he says, “it’s a huge
advantage.”
He quickly expanded the company’s roster, but while he
found it easy to recruit talented immunologists, he had trouble
landing cloners. That changed when famed geneticist and Nobel
laureate Sydney Brenner visited as an investment scout for
Biotechnology Investments Ltd. (BIL), the Rothschild family life
science venture group. Henney says, “Not only did BIL invest in
Immunex, but Sydney helped us sign up molecular biologists.
oral history spotlights
Immunex’s Founding Team
Oral histories are narrative accounts of events and historical processes as told from the point of view of
eyewitnesses and participants. They preserve the experiences, recollections, and testimonies of history-makers.

LSF Magazine 11
After that, our credibility with the cloning crowd was never an
issue.”
In 1983, Immunex went public, and flourished. “The first five
years at Immunex were the most fulfilling of my life in every
way,” says Henney. “We had freedom. We made real progress.
It was extremely exciting. We created a company from our own
labs, and grew from six employees to over two hundred.”
The company expanded and enhanced its scientific ca-
pabilities with secondary stock offerings and revenues from
research and development deals with Roche, Behringwerke,
Syntex, Kodak, and SmithKline Beecham. “Fortunately,” Henney
says, “money was always available—but had we known in the
beginning how much it was going to take, we wouldn’t have gone
anywhere near it.”
Immunex struggled when it came time to transform itself
from a research operation into a full-fledged pharmaceutical
company. “Until clinical development projects began to mature,”
Henney says, “it was almost a badge of courage at Immunex that
no one had come from the pharmaceutical industry. We had
done research, development, manufacturing, and clinical trials
all on our own.”
When it came time to assemble a marketing team, the
Immunex executive group knew they needed to add pharmaceu-
tical industry experience, but Henney concedes, “The way we ap-
proached it was too much ‘by-the-book.’” The group first decided
what rank and salary a head of marketing should receive, relative
to others at Immunex. “Well,” says Henney, “against pharma-
ceutical marketing benchmarks, the figure we came up with was
nothing. And you get what you pay for.” In Henney’s opinion,
Immunex’s subsequent marketing efforts were subpar.
In the late 1980s, Henney and Duzan began to clash on
matters of strategy and control, as both acknowledge. Henney
became deeply frustrated. After nearly a decade at Immunex,
and before the company’s first pharmaceutical product reached
the market, he decided to leave.
Almost immediately, Seattle biotech pioneer Robert Nowinski
asked him to lead research at his new company, Icos. Henney once
again took charge of recruiting: “I soon had about sixty recruits
in helicopter-mode, waiting for us to secure funding.” Henney
also invited former Amgen CEO George Rathmann to serve as
Fall 2015
Immunex’s Chris Henney, Steve Gillis, and Steve Duzan

12 LSF Magazine
chairman. According to Henney, Rathmann looked at his list of
recruits and said, “If you deliver these sixty people, I’ll do it.”
The company had no proprietary technology, but collec-
tively Henney, Nowinski, and Rathmann had many decades of
scientific and general management experience. They were selling
know-how. The trio attracted Bill Gates as a major early investor
(and “diligent” board member). “He saw parallels,” says Henney,
“between biotech and software industry startups, and was very
interested in the technical side of the business.”
Icos opened in Bothell, Washington in 1989. Nowinski left
two years later, after falling out with Rathmann. Rathmann
became CEO, and Henney stayed on for several years. Icos
prospered. “I had very able scientific lieutenants,” says Henney,
“internationally known full professors, running our divisions.
They were so good I could have done my job standing on my
head. They were the best research group I ever had.”
The most important recruit was Ken Ferguson. Henney
persuaded him to bring his work on phosphodiesterase inhibi-
tors from Cold Spring Harbor Laboratory. That research led to
the development of a compound called tadalafil—which became
the erectile dysfunction drug Cialis.
Tadalafil was originally identified as a treatment for hyperten-
sion in a joint development deal with Glaxo. The initial devel-
opment plan stalled, but an intriguing side effect opened more
immediate commercial opportunities. Glaxo dismissed these as
small market, lifestyle niches, and surrendered all rights to the
compound. A short time later, Icos entered into a joint venture
with Eli Lilly to manufacture and commercialize it—a deal
worth $300 million. In 2006, Lilly paid $2.1 billion to acquire the
entire company.
Henney left Icos in 1995 when he was approached by the
founders of Activated Cell Therapy, a San Francisco Bay Area
company. Their main product was a device for isolating and
enriching stem cells in blood. “Scientifically, it was a sweet spot
for me,” Henney says. He joined as CEO.
The company was floundering and the investors were skittish,
but Henney saw opportunities. “I don’t like boxes with ribbons
on them,” he says. “People tell you to look after the box, and
don’t take the ribbon off, it’s perfect. Just watch it. I don’t like that
kind of project. Give me an ugly thing that needs fixing, I’ll do
that.”
Henney moved the company to Seattle and renamed it
Dendreon. “Raising early money for Dendreon was harder than
anything I’ve ever done,” he says. “There was so much prejudice
against cell therapies, and a widely held belief that the FDA
would never approve a cell-based therapeutic.”
With David Urdal, former head of biochemistry and presi-
dent of manufacturing at Immunex, Henney reinvigorated the
business with a technology that “teaches” patients’ dendritic
cells to trigger immune responses to prostate cancer (in 2010, it
became first FDA-approved cell therapy, marketed as Provenge).
He calls Dendreon “the most challenging and most scientifically
rewarding experience of my career.”
Henney left the company in 2004, and went on to serve as
chairman of several biotech companies. He continues to guide
startups as a board member, and encourages all to work for
multiple shots on goal. “None of us,” he says, “is smart enough to
know where the success will come from.”
Steve Gillis discusses a problem with Chris Henney

LSF Magazine 13
Steven Gillis:
Always Experimenting
In late 1980, patent attorney Jim Uhlir recommended to immu-
nologists Steve Gillis and Chris Henney what seemed obvious
to him, but had never occurred to them: that they should start
a company. Gillis recalls his initial gut reaction: “You’re nuts.
If we start a company, we’ll be academic pariahs. Nobody will
talk to us. We’ll be kicked off the good old boys club circuit. We’ll
be toast.” He ended up taking the leap anyway. He and Henney
founded Immunex in Seattle. The magnitude of the company’s
eventual success (a market cap of $16 billion by 2002) far
exceeded Gillis’ wildest dreams, and led him to a slew of further
opportunities in biopharmaceuticals and the venture capital
business.
Steven Gillis was born to be a scientist. “I’ve always liked
asking questions, doing experiments, and getting answers,” he
says, “and then moving on to the next puzzle.” He majored in
biology and English at Williams College, went to Dartmouth
for graduate studies in immunology, and quickly learned the
scientific trade: his first publication appeared in Nature during
his second year.
He earned a PhD in 1978 and began applying for academic
positions at top research institutions. He was confident about
his chances: “I was good at getting grants, I could write, I could
speak in public, and I could convey ideas to anybody, a PhD or
a guy selling doughnuts on the street.”
Gillis received a number of attractive offers, but chose the
Fred Hutchinson Cancer Center in Seattle (known locally
as the “Hutch”) because the recruiters emphasized scientific
freedom. He remembers the pitch: “They said, ‘come here, you
can do what you want.’ I could do virology or immunology if I
wanted to, or I could learn more about microbiology, because
the Hutch was hiring great people in that area.”
He arrived in the fall of 1979 as an assistant professor in
Chris Henney’s Department of Immunology. His laboratory
was next door to Henney’s and the pair began working togeth-
er on a molecule that turned out to be interleukin-2 (IL-2), an
immune signaling protein. They wanted to isolate, clone, and
express the gene that codes for IL-2, and produce enough of
the substance to test for therapeutic effects.
Hoffman-La Roche became interested and offered research
support in exchange for rights to future inventions. According
to Gillis, negotiations ground to a halt when a cabal of senior
faculty members told Roche that for every dollar for research,
they wanted another for administrative expenses, and a third
to build endowment. Roche’s reaction was that 200 percent
overhead was outlandish.
Gillis was unhappy. He and Henney needed to hire molecu-
lar biologists, but Hutch administrators told them they would
have to collaborate with personnel in other departments. The
suggestion was unsatisfactory—faculty members at the Hutch
worked on their own grants, and none could devote substantial
resources to cloning IL-2. Moreover, the administration told
them the cancer center had no money for filing patents. Gillis
felt the Hutch was squandering a prime opportunity: “I felt
boxed in. I couldn’t advance my work.”
He found Jim Uhlir, an intellectual property attorney who
was willing to file patents on spec. Uhlir told the scientists,
“You guys are nuts, these pharmaceutical companies are
interested in you. They’ll be just as interested in you if you start
your own company.”
Several rounds of deliberation ensued. As Gillis recalls,
“Chris would come to my office, and say, ‘Steve, you’re ten
years younger than I am. You can afford to make a mistake.
Why don’t you go to the company full-time, and I’ll be a con-
sultant?’ The next week, I’d say, ‘Chris, you’re well-established.
You can afford to make a mistake. Why don’t you go to the
company full-time, and I’ll stay here at the Hutch.’”
In the end, they decided that both would join the new
enterprise. They wanted to hire the best scientists available and
believed that if they didn’t make the move, they would have
trouble selling the opportunity. Gillis was afraid recruits would
ask, “‘if this is such a great idea, how come you’re still at the
Hutch five days a week?’”
They started looking for a CEO, because neither had
business experience. They found Steve Duzan, a successful
Seattle executive—a good fit, according to Gillis: “Chris and
I loved to joke and so did Steve. He didn’t know a T-cell from
a bowling bowl, but he knew business.” The three went off in
search of funding. Venture capitalist Tom Cable, of Cable &
Howse Ventures, put in $1 million, and promised $3 million
more if the company met certain milestones. “It was a huge
amount of money,” says Gillis, who was accustomed to drawing
Fall 2015

14 LSF Magazine
from grants on the order of $70,000.
In November 1981, the company rented space on the Seattle
waterfront. Henney gravitated toward recruiting and helping
Duzan to negotiate research partnerships. Gillis ran the labs.
He takes some credit for establishing Immunex’s storied work
culture: “It was a very critical place, but critical in a positive
way. I used to give out prizes for killing projects. We were
focused on the truth, and got to it as fast as we could.”
Immunex had a lot of competition—the company was vying
with Amgen, Cetus, Chiron, DNAX, and Genetics Institute to
be the first to turn IL-2 and other recombinant proteins into
drugs—but Gillis says he has never lost sleep over work: “I just
had this belief that if you surround yourself with bright people
and a problem arises, you can usually think your way out of
the box.” Of course, big problems did eventually arise, and
Gillis had chances to test his belief.
In 1993, Immunex merged with American Cyanamid’s
Lederle Oncology unit in a deal that gave American Cyanamid
53.5 percent ownership of Immunex. Gillis explains that it was
necessary to sustain the company: “We were twelve years old,
and in that entire span had booked only one profitable quarter.
We were no different than any other big biotech company at
that time. We needed a sugar daddy, too.”
Henney had already departed Immunex in 1990 to help
start Icos, and Duzan left after completing the merger. Gillis
became acting CEO. By this time, the company had taken a
molecule called etanercept into the clinic as a treatment for
rheumatoid arthritis, even though it had previously failed as an
experimental treatment for sepsis, and had been implicated in
some deaths.
Says Gillis: “We ran a randomized, placebo-controlled,
dose-escalating study with about a hundred sepsis patients, we
showed that the more drug we gave, the more people died. The
result was highly statistically significant. I’ve never done a trial
that gave a cleaner answer, but it was the wrong answer.”
American Cyanamid wanted Gillis to walk away from it.
He refused. The Phase 1 arthritis trials used lower doses, and
he had seen the data. The drug appeared to be safe and some
The floor plan of Immunex’s original waterfront location (from the company’s 1983 annual report).

LSF Magazine 15
severely arthritic patients had thrown away their crutches and
returned to work. Gillis stuck to his guns and negotiated a deal
that included development of etanercept—which eventually
became the blockbuster drug Enbrel.
In 1994, American Home Products (AHP) purchased
American Cyanamid. Gillis had enjoyed working with
Cyanamid, but he had trouble convincing AHP to build a
manufacturing plant for Enbrel. At that point, he had been at
Immunex for fourteen years. He was boxed in again, and ready
for a new challenge.
He found that he was in demand: he was recruited simul-
taneously to run R&D at a large pharmaceutical house and
to serve a new genomics company, Millennium, in Boston as
CEO. He took his time, however, and stayed in Seattle to help
two friends, microbiologist Steve Reed and Immunex’s director
of cellular immunology, Ken Grabstein, start a new company.
Reed and Grabstein were searching for startup funds, and had
approached the Silicon Valley venture capital firm Kleiner,
Perkins, Caufield and Byers (KPCB).
Gillis got a call from Joe Lacob, a partner at KPCB. Lacob
was impressed with the Seattle proposal, and also had a
promising technology on the line in California. He said to
Gillis, “Let’s start a new company with both.” Gillis calls it a
classic VC play: “I’ve got a dog, you’ve got a dog. Let’s put them
together and see if we have something that sits up and barks.”
A year later, Lacob asked Gillis to run the new company, which
was called Corixa. Gillis thought about it for about six months,
and then agreed to sign on. He built the firm on research
partnerships and took it public in 1997.
Corixa’s biggest product was a late stage cancer drug called
Bexxar. It saved lives, but almost killed the organization. “I
learned,” says Gillis, “that a great drug can be a horrible prod-
uct.” Bexxar was administered by radiologists, and only once.
“Oncologists lost control of their patients.” Gillis explains. “It
was a great drug for patients, but awful for physicians.”
Corixa was in trouble, but it had a vaccine adjuvant, MPL,
that was critical to GlaxoSmithKline’s vaccine pipeline. Gillis
brokered a $1.8 billion deal to manufacture MPL. When the
CFO at GSK looked at the deal, he decided it would be cheaper
to buy Corixa, and offered the company double its market
value in cash. Gillis accepted.
That was in 2005. Gillis subsequently moved into venture
capital as a managing director at Arch Venture Partners and
has remained, as he puts it, “on the dark side ever since.” He
enjoys keeping a hand in operations, however, and on several
occasions has served portfolio companies as acting CEO. “I
love the variety,” he says, “and being able to work in different
areas, on different programs, and different products.” He’s still
experimenting.
Stephen Duzan:
High Wire Act
Steve Duzan didn’t know anything about biotechnology, but he
knew how to run companies. In 1980, he was thirty-nine years
old and had acquired general management experience in three
different industries. After a fortuitous meeting late in the year with
two leading immunologists, Christopher Henney and Steven Gillis,
he became a co-founder and CEO of Immunex. The job description
was straightforward (raise money, impose fiscal discipline, and
focus the organization on commercial goals), but it was a new
industry in which progress—and often survival—depended on
creativity and improvisation. Duzan’s tenure at Immunex turned
into a thirteen-year high wire act.
Stephen Duzan comes from a long line of cattle ranchers.
His family settled in central Oregon’s Ochoco Valley in the late
1860s. He started riding a horse at the age of four, drove a tractor
at ten, and worked as a summertime ranch hand until seventeen,
but for all that, he never developed an abiding interest in the
family business. “As a young kid, Life Magazine convinced me
that there was more to life than you could find on a cattle ranch,”
he recalls. “I spent most of my youth plotting how not to become
a rancher.”
He went away to college, majored in history and political
science at the University of Washington (UW), and toyed with
the idea of becoming a lawyer. A year at the UW School of Law
soured him on that plan, and in the 1960s, he explains, the op-
tions for professional dropouts were limited: “Either you got an
MBA or you went to work in a management training program. I
did the latter.”
Fall 2015

16 LSF Magazine
Duzan went to work for a Seattle company that made
scrubbers to control industrial air pollution. He moved through
the ranks in the usual way, and in the mid-1970s was asked
by a group of local investors to become CEO of the Cello Bag
Company, a packaging manufacturer. He led the company for
five years and sold it to the Atlantic Richfield Company in 1980.
It was a good experience: “I learned how to run a company, how
to organize it, control its costs, and position it for success.”
His next assignment, which he took temporarily to help
out a friend, was reorganizing a company called North Star Ice
Equipment. North Star made machines that extruded large, thin
ice sheets to be added to mass concrete pours (building founda-
tions, dams, aqueducts, roads, and airport runways, for example)
in hot desert climes, to ensure uniform curing.
As Duzan prepared for the North Star project, a lawyer
involved in the Cello acquisition told him of two immunologists
at Seattle’s Fred Hutchinson Cancer Research Center who
were exploring starting a biotechnology company and needed
assistance in business matters. He asked if Duzan was interested.
Duzan didn’t know what to say. “I hadn’t come out of pharma-
ceuticals or academia,” he says. “I had never been involved in
biological research in any way.”
He agreed to meet the scientists, Christopher Henney and
Steven Gillis, if only to satisfy his curiosity. He learned that
Henney and Gillis had discovered tumor cells that made a
lymphokine—interleukin-2 (IL-2), an intercellular signaling
molecule. They hoped that IL-2 could be used to boost cell-me-
diated immune responses against cancers, and intended to use
recombinant DNA technology to manufacture it.
Duzan couldn’t assess the science, but believed he could
help the scientists with financing and organization. “In terms of
starting a business,” he says, “they were totally naïve. They were
academic guys.” Duzan agreed to work with them on a part-time
basis until the firm raised money. He wrote up a business plan
in early 1981, and helped the company obtain initial backing
from Cable & Howse, one of the few venture firms in the Pacific
Northwest.
Immunex was incorporated in July 1981 with Duzan as
part-time CEO. The startup’s remote location made it difficult to
attract capital from further afield, but Duzan managed to pull it
off. He secured investments from leading Silicon Valley and East
Coast firms, and closed a second financing round in July 1982.
In January 1983, he joined Immunex full-time as CEO,
wearing the hats of chief business strategist, operating officer,
Immunex’s Helix campus, twenty-nine acres on the Port of Seattle’s Pier 88. Construction began in 2001.

LSF Magazine 17
and public spokesperson, and guided the company to an initial
public offering of stock in July. By that time, he had negotiated
R&D partnerships with Hoffman La-Roche for the development
of IL-2, and Hoechst subsidiary Behringwerke for the devel-
opment of granulocyte-macrophage colony-stimulating factor
(GM-CSF), a molecule that stimulates the production of white
blood cells. Many other important deals followed.
Duzan enjoyed leading a public company, although he found
the 1980s market for biotech stocks incomprehensible: “It was
goofy. One company would do something wonderful and the
entire sector would soar. Then another company would have a
setback, and all stocks would plunge. This went on for years. But
going public provided capital and enabled us to draw a lot of
attention to what we were doing.”
Recognition was important: “We felt a little like the Rodney
Dangerfields of big time biotech, because we were up in Seattle
and nobody took us particularly seriously for a long, long time.
Every time there was a competition between us and somebody
else, the rest of the world assumed that somebody else was going
to win.”
In fact, research was the company’s strength. Everything
else—progress in the clinic, manufacturing, and marketing—
took longer than anticipated. Duzan attributes part of the trouble
to his lack of pharmaceutical experience, but adds, “To some
extent I can thank Chris and Steve for furthering my naiveté
because they didn’t understand either.”
Through it all, he says, his relationship with Gillis was easy:
“Our minds were alike in a number of ways, so we got along
really well.” It was different with Henney. Duzan and Henney
did not see eye-to-eye and battled regularly until Henney left
the company in August 1989. Henney’s departure coincided
with Duzan’s effort to reacquire marketing rights to a number of
previously licensed drug candidates and to push Immunex “from
focused research to focused selling,” as he put it in the company’s
1989 annual report.
In 1991, Immunex’s first pharmaceutical product reached
the market—Leukine, a recombinant version of GM-CSF. It
was developed in heated competition with Amgen, which had
a different molecule intended for the same medical indications.
Immunex had taken an early lead in the race, but Duzan asserts
that German partner, Behringwerke, neglected contractual
obligations and delayed manufacturing and marketing projects
until Immunex threatened to sue for nonperformance.
Immunex reclaimed US co-marketing rights and built its
own small manufacturing facility. In a rush to get to market,
Immunex pushed for FDA approval of Leukine in a narrow
indication—the restoration of white blood cell production in
bone marrow transplant patients. Amgen’s drug, Neupogen,
was approved in February for use in cancer patients receiving
chemotherapy. Leukine was approved in March. It had broader
therapeutic effects, but Neupogen grabbed a 90 percent share of
the market.
The disappointing result halved Immunex’s stock price. At the
end of 1992, Duzan negotiated a merger with Lederle Oncology,
a division of American Cyanamid with products to sell. For $1.1
billion, American Cyanamid took a majority ownership share,
but pledged that Immunex would continue to operate inde-
pendently. Duzan inked the deal and then retired because he felt
it was in Immunex’s best interests.
The company had development projects coming to maturity,
and Duzan believed it needed an expert in the drug trade. “I
wasn’t a pharmaceutical guy,” he says. “I didn’t think we would
achieve manufacturing and marketing goals until we involved
someone skilled in the general management of pharmaceutical
operations.” And, he says, “I was tired.” He had led an often
understaffed Immunex for thirteen years. It had been a tough
slog, but the organization had survived, and it had a chance to
prosper.
At the same time, Duzan was wrapping up important work as
chairman of the Industrial Biotechnology Association (IBA). At
that time, life science enterprises were represented in Wash-
ington, DC and various state capitals by two independent trade
organizations, the IBA and the Association of Biotechnology
Companies (ABC). The IBA membership included all the big
biotechs and most of the large pharmaceutical corporations. The
ABC had twice as many members, but most were small biotech
and biologics outfits.
The sector was fractured along multiple fault lines. The two
trade associations regularly adopted contradictory positions
on salient issues, negated each other’s arguments, and confused
policymakers. “We had a trade association nightmare on our
hands,” Duzan says. Both groups recognized the wisdom of a
unifying merger.
Duzan worked through difficult negotiations with Tom
Wiggans, president of the ABC, and assured him that smaller
companies would have equal representation on the board of a
unified organization. “That wasn’t universally popular,” he says,
“but it had to happen.”
At a meeting with Wiggans in Washington DC, Duzan took
out a legal pad and scribbled a letter of intent to effect a merger.
“Handwritten, no lawyers, no notebook. Nobody else there,” he
says. Duzan and Wiggans took the letter to their boards. Both
sides approved it and the Biotechnology Industry Organization
(BIO) was created. Duzan hired Carl Feldbaum to run it, and
served as chair of the new group “for about ten minutes” before
passing the baton to Kirk Raab of Genentech.
Looking back, Duzan sums up his adventures in biotechnol-
ogy: “Immunex was a great place to be. I don’t think anybody
could have gone through what we went through and not have
been touched by it. It was a unique experience. People genuinely
believed they were on an important mission. They believed the
company was doing good things for society. I was very fortunate
to have stumbled into the business the way I did, and of course,
I’m very pleased to have played a part in one of its success
stories.”
Fall 2015

18 LSF Magazine
In 2012, as biochemist Rob Knight’s involvement in the
Human Microbiome Project (HMP) was winding down, health
food enthusiast and promoter Jeff Leach approached him with a
question: “How much would it cost for a member of the public
to fund an analysis of their own gut microbiota?”
Leach argued that the service ought to be made available,
because citizen scientists and members of the general public
would benefit from direct, personal connections to microbiome
research, and the scientific community would gain a large, open
dataset—a portrait of what lives in American guts and how it
matters.
The question launched the American Gut Project (AGP),
which has since sequenced DNA from stool samples provided by
more than four thousand people of all ages with diverse lifestyles
and dietary habits. The data show the composition of partici-
pants’ gut microbiota and how they are alike or different from
others in the study.
Rob Knight first became interested in studying microbial
communities in 2001 as a postdoctoral scholar at the University
of Colorado-Boulder, home of metagenomics pioneer Norman
Pace. Pace had previously published a method for sequencing
highly conserved genes that code for ribosomal RNA. The tech-
nique enabled researchers to begin investigating phylogenetic
relationships among bacteria. Knight got hooked on the work,
and quickly made a name as a bug sequencer.
His timing was impeccable, because the multidisciplinary
field was exploding. There were soon projects galore to start or
join. Knight was a principal in the NIH-funded Human Microbi-
ome Project (HMP) from its outset in 2008. In August 2010, in
partnership with microbial ecologist Jack Gilbert of the Argonne
National Laboratory, he launched the Earth Microbiome Project
(EMP), an effort to “characterize global microbial taxonomic and
functional diversity for the benefit of the planet.”
When Leach proposed the AGP, Knight made some calcu-
lations and reported that a donation of $99 would be enough
to obtain, process, and analyze a single sample and produce a
microbial profile. The low cost of analysis was made possible by
late developments in automated DNA sequencing and bioinfor-
matics, which greatly accelerated the speed at which sequence
data could be generated and analyzed.
Knight brought Gilbert into the project, and the founders
turned to the public rather than government grants to obtain
startup funds. They launched a campaign on the IndieGoGo
crowdfunding platform on Thanksgiving Day, 2012. By the
following February, they had raised $339,000.
Participants in the project submit personal health histories
American Guts
American Gut Project cofounder Rob Knight
American Guts

LSF Magazine 19
and lifestyle information and receive swab kits for collecting
gut (and mouth and skin) samples, which are processed at
Knight’s lab in San Diego. After analysis, test subjects receive the
results—descriptions of the bacterial communities in their guts
and comparisons with others in the study grouped by age, sex,
diet, and other variables.
Personal records are then stripped of identifiers and added to
the open source Earth Microbiome Project database. The project
informs subjects about themselves as they help researchers
assemble a cross-sectional sample of variation in the population
at large.
The AGP’s promotional materials emphasize that individual
results do not serve as a basis for assessing health or diagnosing
illnesses. The composition of human microbiota is determined
by a complex interplay between genetics, diet, and a host of
environmental factors. As yet, much about it remains unknown.
A basic premise of the study is that relationships between
these variables will come into focus only as patterns emerge in
aggregated data. There is scientific strength in numbers—larger
sample sizes and more data on individuals with varied personal
histories and in varied states of health or illness will permit
finer-grained, more robust analyses.
Large-scale studies with high statistical resolution will
allow researchers to identify even subtle factors that regulate or
perturb human microbiomes and may be implicated in processes
of disease. “This is what we’re trying to bootstrap,” says Knight,
“with crowdsourcing and crowdfunding.” The goal is to generate
leads for further inquiries.
So far, few peer-reviewed studies have drawn on AGP data,
but one, published in 2014 by researchers at the National Cancer
Institute, exemplifies the state of research in the field. It reported
that gut profiles of adults born by cesarean section tend to share
certain unusual signatures. The authors could not explain these
patterned characteristics or speculate on health implications.
Knight’s goals for improvement include further reducing
costs of sampling, sequencing, and analysis until repeated profil-
ing becomes affordable. He wants “not just snapshots, but videos
of how microbiomes change.” A single sample, he explains, “is
like a photograph of your car sitting in the driveway.” Sampling
every day makes it possible to “track the route of your car as it
moves from place to place.”
Finally, he says, comparing personal data to the collective
profiles that the project generates “is like having a GPS to show
you how to get where you want to go.” He hopes that entices you
to participate.
Gut profile results of journalist and food activist Michael Pollan
Fall 2015
by Paul Gabrielsen

20 LSF Magazine
Environmental
Metagenomics
In the early 1670s, Anton van Leeuwenhoek, Dutch civil
servant, natural philosopher, and lens grinder, crafted the first
microscopes with sufficient resolving power to observe micro-
organisms. He called them “animicules.” Biologists ever since
have collected environmental samples and carried them off to
laboratories for further examination.
In 1881, German Robert Koch significantly bolstered micro-
biology’s technical capacities when he invented reliable methods
for establishing pure bacterial cultures on solid media. But he
also shifted the focus of research in the field from ecological
observation to experimentation on model organisms, and
today, microbiologists have grown less than 1 percent of known
bacterial species under artificial conditions.
In the past thirty years, however, researchers have devised
alternative means of studying the “uncultivated majority” and
learning about the composition and dynamics of bacterial
populations in their natural habitats. In the late 1980s, Indiana
University microbial geneticist Norman Pace developed 16S
ribosomal RNA (rRNA) gene sequencing, a method for reading
a specific bacterial gene that codes for ribosomal RNA.
The gene contains both highly conserved (highly stable) re-
gions that are found in every kind of bacteria and hypervariable
regions that serve as unique identifiers for individual species.
Researchers are able to compare 16S rRNA gene sequences from
environmental samples with sequences deposited in public or
private databases in order to identify known bugs. If unknown
organisms are found, the database sequences guide phylogenetic
analysis and taxonomic classification.
Pace’s innovation gave rise to a new scientific field: metage-
nomics, the collection and analysis of genetic information from
microbial populations, communities, and ecosystems wherever
they can be found, from deep in the earth’s crust to the upper
atmosphere at 33,000 feet.
Thousands of new bacterial species have been discovered,
and scientists are accumulating big data on ecosystem dynamics
that may help them improve natural resource management and
conservation across a range of industries, from agriculture to oil
recovery.
Lately, environmental microbiologists have turned their
attention to human habitats. They have sequenced microbial
DNA in homes, offices, daycare centers, subway stations, public
restrooms, football stadiums, and many other places, in order
to understand how microbes colonize built environments, and
how their presence affects the people who occupy these sites.
Studies of public and private spaces have shown that bugs
shed by human beings dominate indoor environments, but also
that the composition of microbial populations is affected by
a host of factors such as traffic patterns, architectural design,
surface materials, ventilation systems, lighting, and so on. Mi-
crobiologists hope metagenomic analyses will provide clues on
how to engineer healthier spaces for microbes and people alike.
Healthcare facilities have been much studied because they
are frequently unhealthy, and sometimes frighteningly danger-
ous. In the United States alone, hospital-acquired infections
caused by antibiotic-resistant “superbugs” kill 75,000 patients
and costs the system an estimated $9.8 billion annually. Solving
the problem is vitally important to patient health and the
containment of healthcare costs.
The tools of metagenomics have been recruited to the task.
In February 2013, a consortium of microbiome researchers
funded by the Alfred P. Sloan Foundation launched the Hospital
Microbiome Project (HMP). Investigators began collecting
microbial samples at a newly constructed University of Chicago
hospital pavilion.
The presence of bad bugs in hospitals is well documented,
but microbes work in concert. Jack Gilbert, one of the HMP’s
scientific leaders, says, “When a pathogen invades, it doesn’t do
this in isolation, it does this in the context of thousands of other
species. Very few studies have examined the rest of the commu-
nities that exist in hospitals.”
The goal of the Hospital Microbiome Project is to under-
stand how ecosystems support dangerous pathogens, and to
learn how to make interventions—not necessarily to eradicate
bad actors, but to create environments conducive to ecological
health and risk reduction for human beings. Understanding
how ecologies promote or suppress pathogens may lead to
solutions where previous efforts have failed.
By combining knowledge of microbial population dynamics
with know-how in materials science and environmental design,
researchers hope to create surfaces and spaces that encourage
the growth of beneficial or benign microbiota while inhibiting
virulent pathogens and helping to control the transmission of
infectious diseases.
In the past, biologists studied microorganisms one strain at a time, as isolates
in pure cultures. Now they have tools for studying heterogeneous microbial
communities “in the wild.” It’s serious business. Advances in the field could save
half a million human lives and tens of billions of dollars (US) worldwide, every year.
Environmental Metagenomics
by Meredith Knight

Probiotic Philosophy
A Brief History

LSF Magazine 23
Renowned microbiologist and Nobel laureate Joshua
Lederberg coined the term “microbiome” in 2001 to
represent “the ecological community of commensal,
symbiotic, and pathogenic microorganisms that
literally share our body space.’’ He added that these
companion microbes “have been all but ignored as
determinants of health and disease.” Clearly, with
the emergence of microbiomics as a large multidis-
ciplinary field of scientific inquiry, this is no longer
true, but Lederberg may have overstated the degree
of past neglect. An historical review shows that the
interdependence of human beings and microorgan-
isms has long been an important, albeit slighted, focus
of research in the life sciences and biomedicine, and
modern health practices have frequently taken the
form of microbial diplomacy.
On June 13, 2012, the National Institutes of
Health (NIH) announced the completion of the
Human Microbiome Project (HMP), a five-year
census of microbial communities living on and
inside human bodies. The next day, a series of pa-
pers reporting the project’s findings were published
simultaneously in Nature and several Public Library
of Science (PLOS) journals.
More than 200 investigators from more than
eighty top-flight research institutions had partici-
pated. They had sequenced DNA from more than
5,000 samples of microbial populations swabbed
from volunteers’ mouths, skin, and guts, and
identified and mapped the locations of more than
ten thousand bacterial species.
The results made headlines in scientific jour-
nals, newspapers, and popular magazines around
the world. Nature hailed the achievement as a
biomedical milestone, a huge step in understand-
ing “our microbial selves.” The Economist redrew
Leonardo da Vinci’s Vitruvian Man as a grotesque
human-microbe chimera and proclaimed “microbes
maketh man.”
Writing for The New Yorker, Michael Specter
provided a vivid description of early childhood
intended, obviously, to make readers question their
perceptions of the natural world and their ordinary
experiences within it: “We leave the womb without
a single microbe. As we pass through our mother’s
birth canal, we begin to attract entire colonies
of bacteria. By the time a child can crawl, he has
been blanketed by an enormous, unseen cloud of
microorganisms—a hundred trillion or more.”
Journalists reporting on the HMP emphasized
three messages: 1) Human beings are now obliged
to understand themselves as ecosystems; 2) the
invisible but teeming microbial hordes covering us
from head to toe, inside and out, are mostly friendly
and beneficial, important for the maintenance of
good health; and 3) as hosts, human beings have
behaved atrociously. At best, we have been thought-
less, ill mannered, and uncouth.
Some participating researchers portrayed the
HMP as a science-based challenge to the “war on
germs” that the medical profession has been waging
with chemical weapons for over a century. Julie
Segre, a senior investigator at the National Human
Genome Research Institute (NHGRI), told the New
York Times, “I would like to lose the language of
warfare. It does a disservice to all the bacteria that
have co-evolved with us and are maintaining the
health of our bodies.”
The metaphor’s persistence is understandable.
The principal business of doctors, from the middle
of nineteenth century through the first half of the

24 LSF Magazine
twentieth, was combating infectious diseases. By the 1940s,
physicians (and their allies, public health officials, bioscientists,
and pharmaceutical makers) had made significant progress.
Pneumonia and tuberculosis were no longer leading causes of
death in industrialized countries. Chronic diseases of age and
lifestyle—cardiovascular diseases and cancers—had supplanted
them.
The institutional power of the medical profession was tied to
its victory in the war against infectious diseases, and only in the
last twenty years have practitioners belatedly come to recognize
the severity of the problem of bacterial resistance caused by
the overuse of antibiotics. Yet, it is a mistake to call the warfare
metaphor entirely inapt or anachronistic, for at least two reasons.
One is that modern medicine continues to battle pathogenic
bacteria. The objective is to neutralize or destroy—that’s warfare.
Secondly, the warfare metaphor never represented the zeitgeist
of twentieth century biomedicine in its totality.
The rise of metagenomics has not engendered a conceptual
paradigm shift. The dominant philosophy of twentieth century
bioscience, biomedicine, and bioindustry may have been anti-
biotic, but it always coexisted with strands of probiotic theory,
research, and production. And now, while tremendous advances
in the speed, convenience, and economy of DNA sequencing
have permitted scientists to generate novel insights into the
composition and functions of human microbiota, the findings
of the HMP and related initiatives serve not as revelations of
human-microbe symbiosis but rather as enriching reminders.
Probiotic philosophy
Nothing exemplifies the recent probiotic renaissance in
science and medicine more than the acceptance of fecal trans-
plantation as a viable alternative to the use of antibiotics in
the treatment of gastrointestinal infections (and perhaps other
conditions as well—practitioners have reported salutary effects
on disorders ranging from rheumatoid arthritis to insomnia
and depression). Preparations of stool from healthy donors are
implanted in the intestines of patients. The idea is to displace
populations of pathogenic microbes by introducing friendly
bacteria capable of restoring ecological balance to the gut.
Fecal transplantation has a long history, dating back at least
to the Dong-jin dynasty in fourth century China. Ge Hong,
a traditional healer, wrote about using orally administered
fecal preparations to treat food poisoning and severe diarrhea.
He claimed to cure patients at death’s door. In the sixteenth
century, during the Ming dynasty, the Ben Cao Gang Mu, the
encyclopedia of traditional Chinese materia medica, described
the successful use of various fecal solutions, suspensions, and
powders in cases of acute gastrointestinal illness.
The first transplant in the United States was reported in 1958
in the journal Surgery. Four physicians at the University Colora-
do School of Medicine documented the successful treatment of
four patients with acute pseudomembranous colitis (PMC, now
known to be caused by Clostridium difficile). Three were desper-
ately ill with severe bloody diarrhea, extreme dehydration, and
high fever. After receiving fecal enemas, the patients’ symptoms
ceased abruptly. All made swift recoveries.
Over the next several decades, dozens of transplants were
performed annually in a handful of hospital and research insti-
tutions as experimental therapies. Despite consistently positive
results in trials, the procedure was never broadly adopted,
perhaps partly due to the “ick factor” and partly due to the fact
that the first large outbreaks of infections caused by new, highly
virulent, antibiotic resistant strains of C. difficile did not emerge
until 2004. But now it appears that because of the dire medical
need, physicians and patients alike are overcoming their aversion
to the procedure. It is being widely touted as a “miracle cure,” but
it’s not a new discovery.
The “probiotic philosophy” may have been overshadowed
by medical crusades to vanquish pathogens, but it has inspired
a lot of productive activity nonetheless. It serves as the basis
for a thriving industry. Revenues from global sales of probiotic
The Probiotic Philosophy
Ge Hong, fourth century
Chinese herbalist

LSF Magazine 25
products, including foods containing live microorganisms—
yogurt, kefir, various cheeses, sauerkraut, tempeh, miso soup,
sourdough bread, and sour pickles, for example—are projected
to surpass US$28 billion in 2015. There is also a growing market
for “prebiotic functional foods” containing fibers, soluble and in-
soluble, that “good” bacteria indigenous to the human digestive
tract can metabolize.
In the post-war era, US consumption of probiotic and prebi-
otic products lagged behind Europe and Japan in relative terms,
but the market began slowly to blossom after Congress passed
the Dietary Supplement Health and Education Act in 1994.
The act permitted unrestricted marketing and sales of natural
products in the absence of scientific evidence showing that they
pose health risks.
The peer-reviewed scientific evidence on the efficacy of probi-
otics in restoration or maintenance of health is mixed. The Yale
Workshop for Probiotics, an international group of physicians
and scientists from leading academic institutions, has met three
times since 2004 to review the available evidence and make
recommendations to clinicians. For certain strains of bacteria
and certain indications the evidence is strong. In most cases,
however, the results of meta-analyses are inconclusive.
But the lack of scientific support was never the industry’s
biggest problem. Efforts to increase sales in the United States
were hindered to a greater extent by the fact that the large
segments of the potential market were unaccustomed to (the
idea of) consuming bacteria as health foods. Consumers were
urged by marketers to buy products that kill bacteria, but not
advised by medical professionals or public health officials to
eat or drink bacteria. The passage of the Dietary Supplement
Health and Education Act permitted priobiotics manufacturers
to advertise safety and wholesomeness, if not to promote specific
health claims.
The tide was turning in the life sciences and biomedicine
as well. By 2001, the year Joshua Lederberg coined the term
microbiome, researchers had begun, in increasing numbers, to
entertain hypotheses inspired by the probiotic philosophy (for a
variety reasons, chief among them were technical advances that
made it possible to take broad surveys of microbial popula-
tions and the problem of drug resistant pathogens that made
it imperative to find alternatives to conventional antibiotic
therapies).
Investigators picked up guiding ideas formulated decades
earlier by respected researchers such as Elie Metchnikoff, René
Dubos, and Theodor Rosebury, pioneers who understood
microbes as Lederberg urged: as neighbors in shared ecosystems,
for good or ill. Like contemporary microbiome scientists, they
made bacterial communities objects of study, targets of therapy,
and subjects of popular discussion.
Good bacteria
Biologist Elie Metchnikoff was born in Russia in 1845, the
youngest son of a member of the Tsar’s Imperial Guard. He stud-
ied natural science at the University of Kharkov in the Ukraine,
and spent the first half of his scientific career as an itinerant
university professor in Russia, Germany, France, and Italy.
In 1883, while conducting experiments with starfish larvae
in Messina, Sicily, Metchnikoff discovered phagocytosis,
the process in which specialized immune cells swallow and
destroy infection-causing germs. Others later named the cells
phagocytes. The discovery was widely acclaimed. Metchnikoff
subsequently spent several years in Odessa before moving to the
Institut Pasteur in Paris, where he became director after Pasteur’s
death in 1895.
Today, Metchnikoff is best known for his many fundamental
contributions to immunology, but at the end of his career, he
achieved great fame for proposing that intestinal microbes have
health-giving properties. His idea presented a solution to a
common medical problem of the time.
In the late nineteenth-century, the leading explanation for all
manner of ailments was the presence of “putrefying” bacteria in
the gut that poisoned the body. In extreme cases, doctors advised
Fall 2015
1908 caricature of Metchnikoff entitled
“The Manufacture of Centenarians.”

26 LSF Magazine
removing the colon to rid the body of “intestinal toxemia.”
Metchnikoff subscribed to this general model of disease, and
theorized biological mechanisms at the cellular level.
He formulated a general model of senescence: putrefying
bacteria secrete toxins, which poison cells; compromised cells
then become targets for the body’s army of phagocytes, which
destroy them; the body is weakened, becomes progressively
infirm, and finally dies. But he also proposed that fortifying
healthful bacterial populations in the intestines could block this
process, sustain health, and extend life.
When in his fifties, he began to test his theories by treating
himself. Famously neurotic, he grew increasingly anxious
and depressed about aging. In an effort to increase his vitality
and prolong his life, he sought to rid his intestines of harmful
bacteria that hastened cellular breakdown by countering them
with friendly microbes.
The friendliest he found were in Bulgarian yogurt, a staple
food that he suspected was responsible for the astonishing
longevity of peasants in certain Bulgarian villages. Metchnikoff
theorized that the yogurt’s lactic-acid producing properties
established “useful” flora in the gut that promoted health.
He tried to find experimental evidence for his theory, but
the complexities of cultivating intestinal bacteria proved too
great for turn-of-the-century laboratories. Then, insisting that
“rational deductions from observation” were adequate proofs,
he began to experiment on himself, and systematically added
cultures of various lactic-acid producing bacteria in sour milk to
his diet.
He swore by the effects on his health, preached the benefits
of bugs, and laid out his ideas in two popular books, The Nature
of Man: Studies in Optimistic Philosophy, published in 1903, and
The Prolongation of Life: Optimistic Studies, which appeared in
1907 (a year before Metchnikoff was awarded a Nobel Prize for
his contributions to immunology).
The books presented arguments for the curative and restor-
ative properties of probiotics, foods that promote the health of
both gastrointestinal microflora and their human hosts. They
also proposed a new science of aging. Metchnikoff’s term for it is
still used today: gerontology.
Metchnikoff’s status as an eminent scientist helped spawn
a booming industry for commercial preparations of Bacillus
bulgaricus in Europe and the United States. By 1910, the “good”
microbe had, according to the Washington Post, “achieved a
notoriety hardly excelled by the most famous and dreaded of
the pathogenic bacteria whose names have become household
words.”
Bacterial boom-to-bust
Metchnikoff was not a model spokesperson for the efficacy
of the bacillus. He died in 1916 at the unremarkable age of
71, decades short of the Bulgarian centenarians he sought to
emulate. In 1924, the American Medical Association’s Council
on Pharmacy and Chemistry moved to discredit claims made for
B. bulgaricus therapies. Researchers had found that the bacte-
rium did not survive in the human gut. They concluded that it
was unlikely to be the magic aging tonic that Metchnikoff had
proposed.
But the idea of using intestinal microbiota to preserve or
recover health was not abandoned. In 1921, Harry Cheplin and
Leo Rettger of Yale University proved that Bacillus acidophilus,
a close relative of Metchnikoff’s Bacillus bulgaricus, could be
implanted successfully in the intestines. They published their
results as a monograph entitled A Treatise on the Transformation
of the Intestinal Flora. Like Metchnikoff, they saw potential
Advertising Acidophilus
Acidophilus milk was a peculiar product. An advertisement
in the June 1928 issue of the trade magazine Printer’s Ink read:
“It is not a drug, though it is sold in drug stores. It is scarcely a
medicine, though prescribed by physicians. It is simply a scientif-
ic means for re-implanting in the intestinal tract healthful bacilli
which nature intended to be there.”
Acidophilus products had two markets—it was sold first to
doctors, but dairy farms and distributors almost instantaneously
saw the potential to sell to the general public. Pitches to medical
professionals focused on the value of the product for treating
specific ailments. But when acidophilus milk took its place
beside a host of other popular health products available to the
consuming masses, the claims became much broader. Acidoph-
ilus was touted as a tonic and revitalizer for mind and body,
an antidote to the “rush of modern life,” and a remedy for “our
faulty diet” and “lack of proper exercise.”

LSF Magazine 27
commercial value in probiotics, but went further and sought
to capitalize on their finding. They applied for a patent on the
production of acidophilus milk.
In 1923, Cheplin went into business to make and sell the
preparation. He founded Cheplin Biological Laboratories and
put advertisements in the American Journal of Medical Sciences
and Journal of the American Medical Association to extoll the
healthful benefits of acidophilus milk—the regulation of bowel
movements, relief from intestinal gas and abdominal pain,
and the restoration of energy. The ads encouraged doctors to
prescribe the product to their patients.
Sensing an opportunity, dairy and pharmaceutical companies
followed suit. A host of acidophilus products soon flooded the
market. An advertisement for Lederle’s preparation encouraged
consumers to “Exchange the Germs of Decay for the Germs of
Health.” Consumers responded enthusiastically, and swallowed
acidophilus in copious amounts. And B. bulgaricus did not
disappear entirely. Diary products containing it were still sold
through the 1930s.
Consumer and medical demand for acidophilus declined
during World War II, as the federal government and the
pharmaceutical industry organized a massive effort to develop
penicillin. The drug promised to save millions of lives, including
American soldiers wounded while fighting overseas. In 1943,
Bristol Meyers purchased Cheplin Laboratories and converted
its factory into a penicillin plant, one of many private operations
working in this way to support the war effort.
Pharmaceutical grade penicillin made headlines when it
became available in 1944. It proceeded to transform the practice
of medicine, and society at large, as well. Antibiotics replaced
probiotics in the public imagination.
The great success of antibiotics opened up a new postwar
market for germicides—antibacterial agents promoted as
improved disinfectants, superior to those developed during
the Progressive Era as a part of the public health movement.
New chemicals such as hexachlorophene wiped out microbes
and could be added to cleaning products without introducing a
strong antiseptic smell.
Consumer demand for antibacterial soaps, detergents, and
air fresheners grew five-fold in the latter half of the 1950s, from
$200 million to $1 billion annually. Squeaky-clean became
an American ideal. By the mid-1960s, antibacterial products
took over the personal soap market, and accounted for over
50 percent of sales by the end of the decade. Dial’s hexachlo-
rophene-laced soap, the first to market in 1948, led the charge.
Americans became known as the greatest germophobes in the
history of human civilization, and the market for probiotics
shrank to a vanishing point.
Antibiotics and the indigenous flora
At this moment in history, René Dubos was moving in
exactly the opposite direction. Dubos is a towering figure in the
history of microbiology, the history of medicine, and the history
of ecology. Today, he is known as “the father of antibiotics,”
but as postwar America became increasingly germophobic,
he promoted a distinctly counter-cultural understanding of
Fall 2015
“Body Ecology” and the FDA
In 1972, the US Food and Drug Administration (FDA)
began a safety and efficacy review of over-the-counter
drugs. Products containing antibacterial additives, includ-
ing popular soaps, were caught in the net as well. The agen-
cy’s panel of expert dermatologists and skin bacteriologists
released its draft guidelines in 1974. The group was worried
that antibacterial soaps could harm normal protective skin
flora and encourage the growth of pathogens. The guide-
lines recommended a ban on additives in soaps intended
for everyday use. And if the FDA would not act, the panel
declared, then Congress should.
The rule change would have been a major blow to the
soap industry. David Duensing, CEO of Armour-Dial, the
first company to introduce an antibacterial product, sent a
telegram to FDA Commissioner Charles C. Edwards. He
protested the speculative nature of the panel’s claims and
the lack of controlled studies to support them. The agency
backed down. Forty years later, in December 2013, the FDA
shifted the burden of proof and required manufacturers
to provide data showing that their products prevented the
spread of germs and did not pose long-term safety risks.

28 LSF Magazine
human-microbe relationships.
Born in France and trained originally as an agricultural soil
scientist, Dubos moved to the United States in the 1920s and
earned a PhD in microbiology at Rutgers University under
Selman Waksman. Waksman was a soil microbiologist who
advocated studying bacteria in situ, in native environments, and
chided colleagues in medical bacteriology for experimenting
exclusively with pure, isolated cultures. Waksman’s bias had a
profound influence on Dubos’s approach to bacterial research.
In 1927, biochemist Oswald Avery invited Dubos to join his
laboratory at the Rockefeller Institute for Medical Research (now
Rockefeller University) in New York City. Avery was searching
for a way to attack Streptococcus pneumoniae, the bacterium that
causes pneumonia and host of other serious illnesses, including
meningitis, pericarditis, and osteomyelitis. He wanted to dissolve
the polysaccharide capsule that encloses the entire bacterial
cell and contributes to its virulence by protecting it from host
immune responses.
Dubos started mining soil samples for antibiotic compounds.
He understood soils as self-purifying environments naturally
equipped to maintain an ecological balance. He introduced
pieces of the capsule into soil samples and looked for “defensive”
or “restorative” chemical responses from native microbes. After
three long years, he found, in a sample from an acidic New
Jersey cranberry bog, an enzyme capable of breaking down the
capsule.
The enzyme could not easily be purified and detoxified, and
it didn’t work well in serum, but Dubos continued to refine his
methods. In 1937, he discovered a bacterium, Bacillus brevis,
that manufactures two compounds with antibiotic properties:
gramicidin and tyrocidine. Gramicidin became the first clinical-
ly administered antibiotic.
Selman Waksman called Dubos’s work “the stimulus which
flooded with bright light the whole previously unillumined field
of antibiotics.” He employed Dubos’s soil enrichment techniques
himself, to discover streptomycin, for which he was awarded the
Nobel Prize in Medicine in 1952.
As Dubos observed the adoption of antibiotics by physicians,
and the rush of the biomedical establishment into antibiotic
discovery programs, he criticized both groups for being too
narrowly concerned with discrete pathogenesis. He cautioned
against reckless efforts to hunt down and eradicate microbes re-
sponsible for illnesses with no regard for the impact of antibiotic
agents on normal bacterial flora, and he warned that bacterial
resistance to antibiotics should be expected.
In 1944, Dubos abandoned antibiotics and turned to the
study of tuberculosis, which afflicted his wife, Marie-Louise. The
condition was especially useful for investigating host-microbe
interactions because tubercular infections can be latent or
active. If exposure to a pathogen is not a sufficient condition for
disease, he reasoned, there must be other causal factors. In 1952,
he co-authored a book, entitled The White Plague: Tuberculosis,
Man and Society, which addressed the complexities of tubercu-
losis, including the social complexities of its transmission and it
association with urbanized industrial society.
Dubos argued that health and disease were adaptive respons-
es of organisms to environmental conditions, and that normal
and pathological states ought to be viewed as outcomes of com-
plex, interactive processes involving multitudes of living things.
He knew from his training in soil science that the microbial
world was immensely rich and diverse, far more, he believed,
than could be imagined by captives to monocausal etiology. He
began devising methods for the study of bacterial ecologies.
In 1961, he changed the name of his research unit from Bac-
teriology and Pathology to Environmental Medicine, and began
conducting comparative experimental studies with specific
pathogen-free and wild type strains of mice, observing how the
animals, intestinal flora, and environmental inputs interact to
shape life processes.
In this groundbreaking work, Dubos and collaborators cul-
tured samples taken from mice at every stage of development in
order to map out ecological succession in microbial populations.
They generated a great mass of empirical evidence to show that
naturally forming microbiota play important roles in shaping
and reshaping physiology, metabolism, and morphology, and are
implicated not only in disease but in states of health as well.
From his investigations on microscopic organisms, Dubos
developed big picture views. He argued that all organisms (and
René Dubos

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