IncyteGenomics
Featured Scientist Series
Testing the Boundaries
Mina
J. Bissell, Ph.D.
Director,
Life Sciences Division
Lawrence
Berkeley National Laboratory
Mina J. Bissell,
Ph.D., likes taking risks. Whether moving to
the United States from
Iran when she was barely 18 or
broadening scientists' conceptions of cell
behavior and
gene regulation, she
has consistently tested the
boundaries of
science—and of life. Driven by her
exceptional intellect,
energy, and compassion, Bissell is a
progressive and
outspoken thinker whose ideas have had
a significant impact
on cellular research. Bissell currently
serves as director of
the Life Sciences Division at
Lawrence Berkeley
National Laboratory, where she has
been working since
1976.
Bissell has always
been interested in understanding the
essence and impact of the environment around her. As a
young girl, Bissell
was encouraged, and inclined, to ask
questions and pursue
their answers. As an adult,
intellectual curiosity
directed her first toward literature
and then chemistry as
an undergraduate at Bryn Mawr
College (where she
studied for two years) and Radcliffe
College, from which
she graduated cum laude. Bissell went
on to study bacterial
genetics at Harvard University for
her Ph.D., but began
focusing on the cells—and their
surroundings—of higher
organisms during her postdoctoral
work at the University
of California at Berkeley.
Bissell's willingness
to think outside the box—or, in this
case, the
cell—prompted her to ask questions about cell
morphology and behavior. Her research led to her
hypothesis that the
extracellular matrix (ECM) was much
more than simply
cellular scaffolding. Bissell, her research
group, and other
collaborators began working with breast
cells, demonstrating
that when normal and cancerous
breast cells are grown
in culture (in the absence of the
ECM), each type grows
at the same rate and looks like
the other. When the
ECM is added to the culture,
however, both kinds of
cells change behavior: The normal
cells organize
themselves, stop growing, and become
differentiated, while
the cancerous cells grow rapidly in a
tumorous mass.
Bissell's group later showed that by
manipulating signals
from the ECM, they could get cancer
cells to behave normally.
Bissell's
three-dimensional approach revealed a crucial
social interaction—or
"dynamic reciprocity"—between ECM
molecules and the
nucleus: The ECM affects the pattern
of gene expression,
and the nucleus affects the makeup
of the ECM. Thus,
Bissell found that the nature of tissue
and organ specificity
cannot be known unless the
microenvironments of
the proteins within the tissues are
understood.
Grateful for her
upbringing; the support of local, national,
and international colleagues;
and the role of national labs
in fostering
scientific and technological advances, Bissell's
integrity and
scientific insight have earned her many
honors and awards,
including the U.S. Department of
Energy's Ernest
Orlando Lawrence Memorial Award and
election to the
Institute of Medicine of the National
Academy of Sciences.
Bissell is a past president of the
American Society of
Cell Biology and the recipient of an
honorary doctorate
from Pierre & Marie Curie University,
Paris (2001).
Incyte Genomics is
proud to present an in-depth
conversation with Mina
Bissell as part of an ongoing series
of discussions with
the dedicated, passionate scientists
who are shaping the
world of genomics and the life
sciences.
Mina Bissell was
interviewed by Christopher Vaughan, a
writer who lives in
Menlo Park, California. Vaughan is the
author or coauthor of
three popular books on science:
How Life Begins (Dell
Publishing 1997); The Promise of
Sleep (with William C.
Dement, Delacorte Press 1999); and
The Prenatal
Prescription (with Peter Nathanielsz, July
2001).
Q: Many of your
concepts were at first considered
radical. Do you think
you're naturally inclined toward bold
ideas?
DR. BISSELL: Yes, and I think that it comes from the
way I was raised.
Trust me—I'm a great believer in
genetics. I, like
others, am a creature both of my genes
and of how I was born
and raised. I come from a very
educated family and
was encouraged to express myself
from an early age. I
don't have any brothers, and I was
kind of like the son
in the family. I am also the youngest.
Whether I would have
been the same person had I not
had the same genetic
material, I don't know. I do have a
sister and cousins;
half of them are as outspoken as I
am, and half are not.
I grew up having
political debates with my father, and I
performed on stage
early on. I was raised to question
things, and it always
fascinated me to ask, "Why?" When
I look back on my
career, I realize that I have always
gotten myself into a
bit of trouble by doing things that
aren't quite
predictable. It's not because I go looking for
those things. I
honestly don't. I'm given a problem and I
start asking
questions, like the kid asking about the
emperor's clothes. The
question is, Why do I do this more
than most? It could be
partly cultural, partly genetic, and
partly the way I was
raised.
But believe me, I get
myself into more trouble than I
need! [Laughs.] People
say to me, "Mina, you are so
direct. How did you
ever get to be a division director?"
Sometimes I wonder. I
think that it takes other people
around me who appreciate
directness, are not afraid of
challenges, and allow
me to lead. In that respect, I give a
lot of credit to some
of the men and women with whom I
have worked—people who
are able to tolerate this kind of
boldness. But I'm
afraid I take the same kind of position in
many other aspects of
my life. I am very interested in
human rights, and I'm
one of these people who get very
upset about injustice
in science and in society. I have
always had very strong
opinions. At times, therefore, I
can come across as
being self-righteous, which is not a
good thing!
The success I've had
in saying unconventional things and
moving those ideas
forward has to do with the context I
was in. Initially,
being in a national lab was a necessity
because I was not
doing mainstream science and had to
stay in the [San
Francisco] Bay Area. In the beginning, it
wasn't as if I had ten
job offers at universities. But it
allowed me to be bold
and to survive.
Q: Describe the process of
your early breast cancer and
cell work.
DR. BISSELL: I used
breast cells as a model for how
normal behavior of a tissue comes to pass. Breast is one
of the few tissues in
the body that changes during adult
life. After women go
through puberty, the breast
develops. When an
animal becomes pregnant, the breast
develops further and
produces milk. When you take the
babies away, the
breast involutes. It changes constantly
as a function of the
hormones and the microenvironment,
so it appeared to be a
good model.
One of my earliest
fellows, Joanne Emerman, brought the
technique of culturing
mouse breast cells to my
laboratory.
Interestingly, when you put breast cells in
tissue-culture
plastic, they change shape, won't make
milk, and completely
forget where they came from. We
realized that something
had to be missing. We gave the
cells hormones; we
gave them all the nutrients they
need. They grew but
did not differentiate. What could be
missing? It appeared
to be the material of the
extracellular matrix.
Up to that point, people had thought
that the ECM was just
like scaffolding, but I thought that
maybe this material
actually contained the important
information. When we isolated the right kind of
ECM for
breast cell—called
basement membrane—put it in a dish,
and put the cells on
the top, it was miraculous: The cells
came together and reorganized. Now we know
that ECM
molecules and this
gelatinous basement membrane have
information. The ECM
is involved in signaling in the liver,
prostate, breast—you
name it. The ECM is involved in
every single tissue of
the body, including the lymphatic
and blood tissues as
well as the cells in the brain.
In 1980 I wrote a
theoretical article with two of the
fellows in my
laboratory, Glenn Hall and Gordon Parry,
posing the question,
"How does the extracellular matrix
direct gene
expression?" I took the concept of "dynamic
reciprocity" (a
term that one of my colleagues had used
to address how a
receptor may interact with the interior
of the cell), and I
applied it to this broader concept. I
theorized that the ECM—which of course is the product
of the genes—can
itself influence the genes, once it gets
out and reorganizes.
Cells make three-dimensional
organizations that are
not necessarily specified by the
genome but by what is
surrounding them.
Next I said,
"These things have information. They must
have receptors so that
they can send the information."
At the time, the
receptors for the ECM molecules had not
really been discovered
or at least appreciated. I thought,
"How would this
receptor work? It would have to be
attached to the scaffolding cytoskeleton inside
the cell."
I theorized that it is
then attached indirectly to the
nuclear matrix, which
at that time people didn't even
believe existed. Then I postulated—again, by reading
some literature and
thinking in 3-D—that the chromatin,
the structures into
which DNA is packed, is probably
attached to the nuclear
matrix. If something from the
outside behaves like a
pulley and it is pushed and pulled,
it sends information
all the way to the nucleus. Some
people think that it
is either all biochemical or all
mechanical, but I
suggested that the control is both
mechanical and
biochemical. If you destroy this unit of
control at any given
point, then dynamic reciprocity is
lost and the cells
could go awry.
This made a lot of
sense to me and to some of my
colleagues. So we set
out to show, step by step, how it
happens and where the
process can go wrong in disease
and, specifically, in
cancer.
Q: How did the broader
scientific world respond to your
theory about the
extracellular matrix?
DR. BISSELL: The theory was supported by a small
minority in the United
States who were thinking along the
same lines. But it had
enthusiastic support from a few
prominent scientists
in Russia and Eastern European
countries. I think
that's partly because back then those
people had very few
technological gadgets but a good
deal of intelligence
and time to think. I used to get
wonderful letters from
people in the Soviet Union and a
few other countries
saying, "Wow, this is so exciting. We
believe that this is
true." But in the United States,
scientists basically didn't take the idea
seriously.
Molecular biology and
gene-cloning were very
exciting—there was not
much enthusiasm for complexity!
Q: What might be the
advantages of having cell behavior
regulated partly by
something outside the cell?
DR. BISSELL: Once
again it relates to the fact that the
information inside
every cell's genome is the same. If you
have everything
regulated from the inside, how do you
bring about local and
rapid regulation of gene expression
in a way that is
tissue specific? It's a very difficult thing
to do. On the other
hand, if you have a marriage, if you
will, between the
outside and the inside, the outside
factors could very
quickly and locally change the
regulation of the gene inside, and vice
versa. They could
create a
microenvironment that would allow tissue
specificity of cell
behavior. It's difficult to think that you
could always start with a fixed genome and have each
cell respond from
within in so many different
ways—imagine all these
organs, let alone memory, vision,
and smell. Over the
years, we as well as others have
shown that the
extracellular matrix is an important player
in regulating tissue
or organ specificity. It seems to be
one of the central
regulators.
Q: What constitutes
the designer microenvironments that
you talk about in your
research? Has that idea changed
over the years?
DR. BISSELL: When you
put the cells in a
microenvironment that
is malleable and permissive to a
certain tissue, the
cells have a memory of organization
and
three-dimensionality. They recognize it, and they
start behaving the way they're supposed to behave.
They begin laying down
their own ECM—basement
membrane—which is now
tissue-specific. In a sense, cells
make their own
designer microenvironments if you allow
them to.
In the case of the
breast, we use materials such as
basement membrane
isolated from an interesting mouse
tumor or gels made of
rat-tail collagen. We have defined
what is around the
breast cells in vivo, but this material is
hard to isolate and
gets denatured during the process of
isolation. When we put
cells together with these
gelatinous substrata
in three dimensions, the cells
remember what they are
supposed to do and they now
make their correct
ECM.
But my real ambition in the next five years or so—in
collaboration with my
colleague in Denmark, Olé
Petersen—is to make an
honest-to-goodness model of
the breast in 3-D.
That would require not only breast
epithelial cells but
also the other cell types that are
around the breast in
vivo. These cell types all talk to one
another, and they each
do different things. We have
already nearly
succeeded in making a replica of breast
tumors in 3-D and have
made recent advances with
putting epithelial and
myoepithelial cells of the breast
together in 3-D.
We have limited
ourselves to the study of the breast
because we don't have
the time to develop yet another
designer model. But
more and more, researchers are
creating different
models. I think that each tissue or
organ will require a
specific designer microenvironment,
probably developed
from different materials than we have
used.
Q: You're suggesting
that the extracellular matrix tells the
cell that it exists in
a social environment with other cells?
DR. BISSELL: Correct.
There is a social interaction
between the cells and
also in relation to the nucleus. The
outside tells the
nucleus what to do, and the nucleus
tells the outside what
to do. The signals go back and
forth and change very rapidly and
dynamically. That's
why I refer to the
concept as "dynamic reciprocity."
We need to understand
this interaction in relation to
