Jan-Feb 2014 ASCB Newsletter - page 10-11

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ASCB
NEWSLETTER JANUARY/FEBRUARY 2014
JANUARY/FEBRUARY 2014
ASCB
NEWSLETTER
anywhere as a functional organism or even as a new
species.
As proof of principle, Venter described how the
JCVI synthesized the entire genome of a bacterium,
Mycoplasma mycoides
, by assembling
sections as DNA “cassettes,”
transplanting them into yeast, and
then inserting the entire synthesized
genome (with a synthesized centriole)
into a distantly related bacterium
that the genome took over, molecule
for molecule. In 2010, this labor-
intensive effort yielded what Venter
described as the first human-made
species.
We’re All Different and
We’re Not Alone
Venter told the Annual Meeting
audience that his institute’s advances
in rapid sequencing revealed many of
our earlier views of genomics to be
simplistic. The first human genome
sequenced was a haploid conglomerate of four
individuals (including Venter), and the common
wisdom at the time was that we, humans, would
all have a mostly common sequence with only a
few variants. This is not accurate, said Venter. As
the sequencing price has fallen and the number
of individual sequenced genomes piles up, it’s
become clear that every one of us has in our own
genomes a significant number of non-synonymous
substitutions. The first diploid genome to be
sequenced, in 2007, was Venter’s own, and it
showed significant variation within a single
human. We are all “compound heterozygotes,”
Venter declared. By sequencing individual sperm,
Venter’s lab found an average of one crossover
sequence per cell and the same holds true for
eggs. Increasingly, said Venter, the question has
become, what is a normal human phenotype?
Nor are we alone in our genomes
and our bodies, according to Venter.
Shotgun sequencing of the human
gut biome shows that while we all
have roughly 100 trillion human cells,
we are also joined by 200 trillion
bacteria. If we all have 20,000 or so
human genes, we also live with 10
million microbial genes. Our resident
microfauna affect us, Venter said,
pointing to new studies linking the
composition of the microbiome to
diseases such as obesity and diabetes.
Beyond the biome, said Venter, is the
human metabolome, which is the
mix of all chemicals circulating in
your blood. Human cells can produce
about 2,400 different chemical
compounds, but studies have shown
that about 500 compounds are circulating at
any one time. The bacterial residents of our
microbiome churn out a key portion of the
metabolome. Analysis of these compounds has
shown that about 60% are of human origin and
30% can be traced to the plants and animals
in our diet, but 10%, or 50 chemicals, are of
bacterial origin.
Life Forms by Email
Beyond the crowded human genome, Venter
took the audience into outer space with an
explanation of his Digital Biological Converter
(DBC), a bio-robot that would be able to
Shotgun
sequencing of
the human gut
biome shows
that while we
all have roughly
100 trillion
human cells,
we are also
joined by 200
trillion bacteria.
2014 President Jennifer Lippincott-Schwartz, ASCB Executive Director Stefano Bertuzzi, and Keynote Speakers Elaine Fuchs
and Craig Venter
investigator of stem cells, a term that was just
coming into the public consciousness in 2001,
Fuchs was about to move to the Rockefeller
University in New York City. In New Orleans
last month for the 2013 ASCB Annual Meeting,
Fuchs and Venter shared the keynote platform with
talks that showed just how much cell biology has
changed in 12 years. (Videos of both keynotes are
at
)
136 Years of Stem Cell Research
Fuchs spoke on the origins of the term stem cell,
tracing it back to the German biologist Ernst
Haeckel in 1877 and its popularization by the
American biologist E.B. Wilson in 1896 as a
synonym for what we would now call a germ
cell in developmental biology. The modern
meaning of stem cell as the pluripotent source
for all subsequent differentiated cells in a lineage
took decades to evolve, and it wasn’t until 1961
that James Till and Ernest McCulloch clearly
demonstrated the existence of hematopoietic stem
cells in bone marrow. The successful culturing
of adult stem cells took until the mid-1970s, by
which time Fuchs was already at the forefront
as a postdoc in the Massachusetts Institute of
Technology laboratory of Howard Green. The
Green lab discovered how epithelial stem cells
required an exquisitely tuned niche to protect
their “stemness.” The stem cell niche controls
the stem cell’s decision to remain quiescent, to
make tissue, or to stop making tissue. Fuchs said
that understanding in detail how that decision is
regulated has been her single research objective
from her earliest days in the Green lab through to
the present.
Stem cells and the tissues they generate turn
over at different rates in response to different
events, Fuchs explained. The epithelial cells that
line the intestines have a life span of three to five
days from their differentiation in the crypts of
Lieberkühn to being sloughed off. In contrast,
the stem cells that generate sweat gland tissue are
quiescent for decades, responding only to deep
wounding. Her favorite system, though, is the
hair follicle, where the stem cells move through
“cyclical bouts” of growth and rest. “Unfortunately
the resting stages get longer and longer as we age,”
she added. But the follicle’s nuanced response
to external and internal signals makes it an ideal
model system to understand what drives stem cells
from quiescence to activation and back. Using the
hair follicle as a model system, the Fuchs lab has
thrown light on a variety of basic biology questions
from signaling pathways to epigenetic labeling and
most recently on what Fuchs described as “so-
called cancer stem cells.”
Not Normal Stem Cells
The mechanisms that control a hair follicle stem
cell’s decision to make tissue or remain quiescent
are closely related to those that drive cancer stem
cells. “In fact, when we began to study the basic
mechanism by which stem cells sit in quiescence
or begin to make tissue, when we over-activated
that system, we got mice that were tumor prone
and when we under-activated that system we
got mice that were tumor resistant,” Fuchs said.
“That began to tell us that cancer, effectively
cancer stem cells, have hijacked the basic
mechanisms that stem cells utilize in order to
activate and make tissue.”
Squamous cell carcinomas arise in the same
epidermal population as normal hair follicle
stem cells, Fuchs explained. By fractionating
tissue samples of squamous cell tumors and
analyzing gene expression patterns, her lab came
up with a few common features—squamous
tumors have their own “stem” niches and express
high levels of self-renewal genes characteristic of
stem cells—but hundreds of differences between
cancer stem cells and their normal counterparts.
The differences include “everybody’s favorite list
of cancer genes,” said Fuchs. “This is not what
normal stem cells look like.” The concept that
cancer cells behave as stem cells glosses over the
vast differences between them.
To home in on those critical differences, the
Fuchs lab has painstakingly developed a novel
genomic screen. It targets the single cell layer
of epidermal progenitors that develops in the
mouse embryo right after gastrulation. Using
lentiviral transfection and short hairpin RNA
interference, the Fuchs lab is working through
the entire mouse genome. “This has opened
up the pathway for us to understand more
about cancer stem cells and the [niche] tumor
initiating cells and their behavior.”
Creating a Digital Biology
Venter was happy once again to follow Fuchs
to the podium. “I learned tonight that I’m not
bald,” Venter declared. “I just have quiescent
stem cells.” And with that, Venter plunged into
a dizzying account of his post-Celera career.
Now the head of his own J. Craig Venter
Institute (JCVI), Venter has steadily pursued his
goal of creating a pure “digital biology,” a new
kind of synthetic biology where the nucleotide
bases of DNA can be read out rapidly as binary
software, re-engineered, and then recreated
Keynote, continued from p.1
[Fuchs’] lab
came up with
a few common
features—
squamous tumors
have their own
“stem” niches
and express high
levels of self-
renewal genes
characteristic
of stem cells—
but hundreds
of differences
between cancer
stem cells and
their normal
counterparts.
[Fuchs’]
favorite
system…
is the hair
follicle, where
the stem cells
move through
“cyclical bouts”
of growth
and rest.
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