Experiments that point to a new understanding of cancer Mina Bissell
now I don’t usually like cartoons I
don’t think many of them are funny I
think find them weird but I love this
cartoon from The New Yorker so the guy
is telling the cat don’t you dare think
outside the box well I’m afraid I used
to be the cat I always wanted to be
outside the box and his portly because I
came to this field from a different
background chemist and a bacterial
geneticist so what people were saying to
me about the cause of cancer sources of
cancer all for that matter why you are
who you are didn’t make sense so let me
quickly try and tell you why I taught
that and how I went about it so to begin
with however I have to give you a very
very quick lesson in developmental
biology with apologies to those of you
who know some biology so when your mum
and dad met there is a fertilized egg
that round thing with that little blip
it grows and then it grows and then it
makes this handsome man so this guy with
all the cells in his body all have the
same genetic information so how did his
nose become his nose his elbow his elbow
and why doesn’t he get up one morning
and have his nose turn into his foot it
could it has the genetic information you
all remember dolly it came from a single
memory south so why doesn’t it do it so
have a guess of how many cells he has in
his body somewhere between 10 trillion
to 70 trillion cells in his body
trillion now how did these cells all be
the same genetic match
y’all made all those tissues and so the
question I raised before becomes even
more interesting if you taught about the
enormity of this in every one of your
bodies now the dominant cancer theory
would say that there is a single
oncogene in a single cancer cell and it
would make you a cancer victim well this
did not make sense to me do you even
know how a trillion looks now let’s look
at it there it comes these zeros after
zeros after zeros now if point 0 0 0 1
of this South got mutated and point 0 0
0 0 1 got canceled you’ll be a lump of
cancer you’ll have cancer all over you
and you’re not why not so I decided over
the years because of a series of
experiment that this is because of
context and architecture and let me
quickly tell you some crucial experiment
I was able to actually show this to
begin with I came to work with this
virus that causes that ugly tumor in the
chicken rouse discovered this in 1911 it
was the first cancer virus discovered
and when i call it oncogene meaning
cancer gene so he made a filtrate he
took this filter which was liquid after
he passed the tumor through a filter and
he injected it to another chicken and he
got another tumor so scientists were
very excited and they said the single
oncogene can do it all you need is a
single oncogene so they’d put the cells
in culture chicken cells dump the virus
on it and it would pile up and they
would say this is malignant and this is
normal and again this didn’t make sense
to me so for various reasons we took
this oncogene attached it to a blue
marker and the injected it into the
embryos now look at that there is that
Butte
tiful feather in the embryo every one of
those blue cells are a cancer gene
inside a cancer cell and they’re part of
the feather so when we dissociated the
feather and put it in a dish we got
massive blue cells so in the chicken you
get a tumor in the embryo you don’t you
dissociate you put it in a dish you get
another tumor what does that mean that
means that micro environment and the
context which surround ourselves
actually are telling the cancer gene and
the cancer cell what to do now let’s
take a normal example the normal example
let’s take the human mammary gland I
work on breast cancer so here is a
lovely human breast and many of you know
how it looks except that inside that
breast there are all these pretty
developing tree-like structures so we
decided that what we like to do is to
take just a bit of that mammary gland
which is called an asanas were there are
all these little things inside the
breast where the milk goes and the end
of the nipple comes through that little
tube when the baby sucks and we said
wonderful look at this pretty structure
we want to make this is structure and
ask the question how do the cells do
that so we took the red cells you see
the red cells are surrounded by blue
other cells that the squeeze them and
behind it is material that people
thought was mainly inert and it was just
having a structure to keep the shape and
so we first photographed it with the
electron microscope years and years ago
and you see the cell is actually quite
pretty it has a bottom it has a top it
is secreting gobs and gobs of milk
because he just came from an early
pregnant mouse you take these cells you
put them in a dish and within three days
is they look like that they completely
forget so you take them out you put them
in a dish they don’t make note they
completely forget for example here is a
lovely yellow droplet of milk on the
left there is nothing on the right look
at the nuclei the nuclei on the cell on
the left is in the animal the one on the
right is on a dish they are completely
different from each other so what does
this tell you this tells you that here
also context all the rights in different
contexts cells do different things but
harders contacts signal so Winston said
that for an idea that does not first
seem insane there is no hope so you can
imagine the amount of skepticism I
received couldn’t get money couldn’t do
a whole lot of other thing but I’m so
glad it all worked out so we made a
section of the mammary gland of the
mouse and all those lovely ass annoys
are there every one of those with the
red around them or an asst honest and we
said okay we are going to try and make
this and I said maybe that Redis stuff
around the asanas that people think
there is just a structural scaffold
maybe it has information maybe it tells
the cells what to do maybe it tells the
nucleus what to do so I said
extracellular matrix which is this stuff
called ECM signals and actually tells
the southward to do so we decided to
make things that would look like that we
found some gooey material that had the
right extracellular matrix in it we put
the cells in it and lo and behold in
about four days they got reorganized and
on the right is what we can make in
culture on the left is what’s inside the
animal we call it in vivo and the one in
culture was full of milk the lovely red
there is full of milk so we got milk for
the American audience all right
and here is this beautiful human cell
and you can imagine that here also the
context goes so what do we do now I made
a radical hypothesis I said if it’s true
that architecture is dominant
architecture restore to a cancer cell
should make the cancer cell think is
normal could this be done so we tried it
in order to do that however we needed to
have a method of distinguishing normal
from malignant and on the left is the
single normal cell human breast put in
three-dimensional gooey gel that has
extracellular matrix it makes all these
beautiful structure on the right you see
it looks very ugly the cells continue to
grow the normal ones stop and you see
here in higher magnification the normal
asanas and the ugly tumor so we said
what is on the surface of these oddly
tumors could we calmed them down they
were signaling like crazy and they have
pathways all messed up and make them to
the level of the normal well it was
wonderful boggles my mind this is what
we got we can revert the malignant
phenotype
and in order to show you that the
malignant phenotype I didn’t just choose
one here are little movies sort of fuzzy
but you see that on the left or the
malignant cells all of them are
malignant we add one single inhibitor at
the beginning and look what happens they
all look like that we inject them into
the mouse the ones on the right and none
of them would make tumors we inject the
other ones in the mouse hundred percent
tumors so the new way of thinking about
cancer is a hopeful way of thinking
about cancer we should be able to be
dealing with these things at this level
and these conclusions say that growth
and malignant behavior is regulated at
the level of tisch organization and that
the teacher organization is dependent on
the extracellular matrix and the micro
environment all right thus form and
function interact dynamically and
reciprocally and here is another
five-second of repose is why mantra form
and function and of course we now ask
where do we go now we like to take these
kind of thinking into the clinic but
before we do that I like you to think
that at any given time when you are
sitting there in your 70 trillion cells
the extracellular matrix signaling to
your nucleus the nucleus is signaling to
your extracellular matrix and that is
how your balance is kept and restored we
have made a lot of discoveries we have
shown that extracellular matrix talks to
chromatin we have shown that there are
little pieces of DNA on the specific
genes of the mammary gland that actually
respond to extracellular matrix it has
taken many years but it has been very
rewarding and before I get to their
necks aside I have to tell you that
there are so many additional discoveries
to be me
there is so much mystery we don’t know
and I always say to the student and
postdocs I lecture too don’t be arrogant
because arrogance kills curiosity
curiosity and passion you need to always
think what else is need to be discovered
and maybe my discovery needs to be added
to or maybe it needs to be changed so we
have now made an amazing discovery a
postdoc in the lab who is a physicist
asked me what did the cells do when you
put them in why did it what do they do
in the beginning when they they do i
said i don’t know we couldn’t look at
them we didn’t have high images in the
old days so she being an imager and
physicist did this incredible thing this
is a single human breath up in a tree
dimension look at it it’s constantly
doing this has a coherent movement you
put the cancer cells there and they do
go all over they do this they don’t do
this and when we revert the cancer cell
it again does this absolutely boggles my
mind so the cell acts like an embryo
what an exciting thing so I like to
finish with the poem but I used to love
English literature and I debated in
college which one should i do and
unfortunately or fortunately chemistry
one but here is a poem from yates i’ll
just read you the last two lines it’s
called among the schoolchildren or body
swayed to music or brightening glance
how do we tell the dancer from the dance
and here is Merce Cunningham I was
fortunate to dance with him when I was
younger and here he is a dancer and
while he’s dancing he’s both the dancer
and the dance the minute he stops we
have neither so is like form and
function now I like to show you a
current picture of my group I have been
fortunate to have had this magnificent
students and post doc who have taught me
so much and I have had many of these
scum angle they are the future and I try
to make them not be afraid of being the
cat and being told don’t think outside
the box and I’d like to leave you with
this thought on the left is water coming
through the shore taken from a NASA
satellite on the right there is a coral
now if you take the mammary gland and is
spread it and take the fat away on a
dish it looks like that do they look the
same do they have the same patterns why
is it that nature keeps doing that over
and over again and I’d like to submit to
you that we have sequence the human
genome we know everything about the
sequence of the gene the language of the
gene the alphabet of the gene but we
know nothing but nothing about the
language and alphabet of form so it’s a
wonderful new horizon it’s a wonderful
thing to discover for the young and the
passion as old and that’s me so go to it