Faculty Forum Online: Women’s Health Research at MIT with Professor Linda Griffith

Faculty Forum Online: Women’s Health Research at MIT with Professor Linda Griffith


Good afternoon. Welcome to the
Faculty Forum Online where alumni learn from MIT
faculty about their research and ask questions by
an interactive chat. I’m Judy Cole, the Executive
Vice President of the Alumni Association, and I will
serve as the moderator. To participate, input a user
name and a location, and type your question at the
bottom of your screen. We will do our best to answer
as many questions as possible, but we are not likely to get
to all of them, I imagine. Our guest today is
Professor Linda Griffith. She’s Professor of Biological
Engineering and Mechanical Engineering and Director of
the Center for Gynepathology Research at MIT. Our theme today is leading edge
women’s health research at MIT. Linda, can you
begin by giving us a little bit of an
overview of your work and the work of the center? So my own research has primarily
been in tissue engineering and biomaterials. And over the recent
10 or 15 years, we’ve been applying those
concepts more and more not just to
regenerative medicine, but also to developing
models of disease that would help us do
better drug development and understand both by
identifying better drugs as well as seeing that
they’re safe and effective. And what became apparent
over the past decade or so as I served on a lot
of advisory council at the National
Institutes of Health, but also became more involved
in research with my colleagues having to do with
chronic inflammation and engineering
of immune systems, is that there are many unmet
needs in the area of women’s health having to do with
immune system function, but also particularly
gynecology functions, where MIT had some unique approaches
and resources that might yield very, very exciting advances. What I should delineate,
we’re very, very active at MIT in cancer research
through the Koch Institute, and breast cancer is very
well represented there. A whole host of other
women’s diseases, though, are relatively
understudied. And that’s really where I
see an opportunity for MIT to make huge contributions. We thus started in
2009 a whole center to focus on
gynepathologies, or things that go wrong with
the reproductive tract below the waist in order
to bring new approaches both from the biology– biological
engineering, as well as the more traditional engineering
to study of these diseases. Fascinating. MIT is not usually associated
with women’s health issues. In what areas do you see your
Center for Gynepathology making contributions? So I will tell a little bit
about the academic landscape at MIT. As you know, there’s been
a tremendous revolution in modern molecular
life science dating back over 50 years at MIT. And naturally, the
School of Engineering has been very involved in
adapting advances in biology to practical use. So in fact, starting in
1998, we did an experiment to see if there was a new
discipline of doing engineering based in modern
molecular life science. In other words,
biological engineering. And it led to a
whole new department, a whole new undergraduate
major now known as Course 20. I led development of that. And the opportunity to
use engineering of biology to understand and treat
diseases is huge potential. So the intellectual
landscape is there. The opportunity to apply
this to women’s health came about in part
because there’s a fabulous gynecologist who’s
now at Newton Wellesley, was at Mass General. Very, very interested in working
with engineers to bring new approaches, particularly
to diseases of the uterus. And so he teamed up
with us and said, well, we can do more
than just surgery. Can’t we bring systems
biology and all of this ways of thinking
about biology quantitatively, can’t we bring this to clinical
practice and do something that you could not do anywhere
else in the country or probably the world? And so we founded a center to
gather with a foundation grant to try to bring
these systems biology forefront of
biological engineering into the study of inflammation
and women’s diseases, particularly gynecology. Well, as a woman, thank you. [LAUGH] What are some of the major
challenges to research on women’s health issues? So some of the challenges–
so I’ll talk about disease. The main disease that we focus
on right now– not exclusively. There’s preterm birth,
infectious diseases. But a major one is
endometriosis, a disease that afflicts
about 10% of women, starting typically
when they’re teenagers. It causes a lot of
pain and infertility, and it can even cause
internal organ damage. And the challenges are partly– one’s of federal funding. So there is not as
much attention paid, in part because there’s also,
even in the clinical community, not an appreciation about how
serious some of these diseases are and how dramatically
they impact women’s lives. Even if they’re
not killing women, they’re causing
them to miss work and miss all aspects
of their lives, because they’re very
debilitating diseases. So there’s not quite
the levels of funding that you have for
a lot of things like heart disease
and cancer, and so on. So we’re trying to bring
the forefront of engineering in, because this is leveraged
at MIT by other resources, and say, hey. Let’s have the very
first application of this fabulous new
software that people developed in CSAIL, the
very first application is in endometriosis. The very first systems biology
in vivo is for endometriosis. Let’s have first in some
big engineering advance be applied to this disease. And it raises
awareness all around, and then people get
excited about that disease, because they see people have
blazed a trail to study it. So a challenge, I think,
is one of just lack of awareness of how
important these things are. We’re trying to raise awareness. I have to ask this question,
and it’s a little bit delicate. But is that because in the
past, you hear so much about how research is done on men’s– the studies are done
with men, because they have less volatile hormonal
structures, or something like that? And if the researcher
is a man, it might be easier to
study men than women. And how does that impact the
funding for women’s health research? So I’m not an expert
on those past events. I can say that there are a lot
of sexual dimorphisms, things that play out
differently in women. Heart attacks, symptoms
of heart attacks, heart disease, and so on. They play out differently
in women than men. There is appreciation
that these– now there’s growing appreciation
that they’re different. But even so, studies of
new drugs and so on, there still needs to be
constant vigilance to have this included as
a factor in developing drugs for any disorder. And I think we’re really
still at the beginning stages of understanding
the interplay of hormones with everything
else in physiology. And again, it’s very striking
that a lot of the immune system disorders more prominently
influence women. Chronic pain disorders often are
more commonly found in women. Things like temporomandibular
joint syndrome, the kind of pain you get. So a lot of these things
are very strongly skewed toward female, and
we don’t understand the relationship between
hormones and immune system. Fabulous engineering problem
with modern biological engineering where
we think about, how do we use
information sciences to understand human physiology
and develop treatments? Well, and I have to imagine that
taking some of the engineering innovations and applying them
first to a woman’s disease does exactly that,
raise the visibility and help people
understand it better. So we’re starting to
get questions here, so I will move right to
the viewer questions. Christine at Yale
University asks, what is the current thinking
on the causes of endometriosis? And will your research
clarifying the subpopulations improve clinical
management and move us toward establishing the cause? So the question probably
refers to a paper we recently published in Science
Translational Medicine, which has received some
press, in which we took endometriosis patients who
had all different stages of the disease, I through
IV, and examined the fluid that we get out of
their abdominal area, their pelvic fluid. And we classified the
immune networks there using an unbiased approach. And we found that there
was, in about a third of the patients, a particular
signature of an immune network that we could then go
in and find a place to cripple that
using a drug that’s in development for other
inflammatory diseases. So it was a nice demonstration,
that if you took an approach where you said, you know, the
surgeons classify the patients as stage I, II, III, IV
based on disease morphology, and that had some
utility for them, but it’s not clear
that that really is going to get us
toward mechanisms that help us decide which
patients will benefit from different kinds of drugs,
which now don’t even exist. Because 10% of women
have this disease. You expect they might
have different mechanisms. So we found a mechanism. We don’t think
it’s the only one, and we have to see
that it plays out in larger patient populations. How does that get us back– so
that opens a window to saying, we may be now able to start
finding mechanisms that would let this group
of patients be treated, or this group or this group. How does that get back to
the origins of the disease? I’m still not sure. I think there are
hypotheses that it’s menstrual tissue that refluxes
into the abdominal cavity. All women have flow
through the fallopian tubes of menstrual tissue. A hypothesis about
endometriosis is that that tissue
survives and grows in the abdominal cavity in
women who get the disease. There’s evidence
to support that. There’s also evidence
that stem cells that are present at birth, and
just don’t make it correctly to the uterus, are stimulated
to grow at the time of puberty. There’s evidence that newborns
have a tiny little period right after they’re born, and
maybe the menstrual fluid is going into the abdominal
cavity at that stage, or even before the
babies are born. What I could say is maybe
all of these mechanisms are partially true,
and that there’s some that are more
operative in some patients than in other patients. Our work, I hope, can help
us figure this out, in part by– we’re doing a
very detailed analysis of the abdominal fluid. And once we establish that
our methods have validity in adult populations, we
hope to implement them in younger patient
populations to try to test to see the environment
around the time of puberty. So we don’t have
answers, but we do have ideas about how we can take
the approaches we’ve developed and use them to eliminate
this very, very challenging and still mysterious question
of what causes endometriosis. It’s a much more complex
disease than I had realized, because you sort of think
of it as monolithic. And I’ve had friends
who’ve had it, and I didn’t realize
that there were all these different
variations and subpopulations. It’s really interesting. Yeah. The key thing I forgot
to say is that we found that patients with all
surgical stages of the disease had the signature of
the immune networks. So that there were
patients with stage I who had this immune signature,
and patients with stage I who didn’t have it,
and all throughout. So it was a molecular
classification of the patients that complements
the surgical classification. Like breast cancer, two
tumors that look very similar could have very
different prognosis and need very
different treatments when you look at their
molecular profiles. And I myself had breast
cancer, and so appreciate this kind of classification as
being very helpful to patients. Yeah. Allison in Syracuse asks, in
a recent New Yorker article– you were just mentioning
that earlier– you note that your recent
research takes an engineering approach to endometriosis. What does that mean? So engineers are used to
taking big, complicated, messy problems and breaking them down
into smaller parts, and asking, what can we do today in the
absence of complete information to try to make
progress on a problem? And in particular, how can
we use all different kind of mathematics to tease out
patterns and see where things might be going by understanding
something about mechanism and taking a
semi-empirical approach? So here what we did
is say, you know, if we look at information flow
in the cell and in our bodies, it goes from DNA to RNA to
proteins, protein activity states, and so on. And as you move up
that information flow, you’re integrating information
from the previous method. So there’s tremendous,
tremendous efforts in genomic studies and
in transcriptomics, all of that lower end. And so far, it hasn’t really
helped us move forward very far for a lot of reasons. What we said is, gee. There may be a
lot of information here at the other end where
if we measure the proteins, they integrate all this. They integrate what
your genes are. They integrate, were
you exposed to dioxin? That’s another hypothesis,
that environmental chemicals contribute. But that may change
your epigenetic state. Well, your proteins and
protein network states are going to be a
readout of that. So that’s an
information-rich area. But you’ve got to know
something about mechanism. You have to frame the problem. So engineers think, hmm. Where could I get really
useful information? So it’s an insight using some
of the mechanism we know, figuring out, where can you
make a few measurements that would open up a new direction? So it’s an engineering approach. We used a lot of math. But we also used intuition
and mechanism-based approaches to try to get us information
where we didn’t have it. So it’s being agnostic
to the kinds of math, and looking at an end of the
spectrum that hadn’t really been probed very deeply before. So moving right along,
Danielle in Austin asks, your research focuses
on the independence of biological systems. Interdependence, excuse me. Interdependence of
biological systems. Is this indicative
of a larger trend? So I’m going to
interpret interdependence of biological systems
to mean perhaps a– because that could
mean a lot of things– to mean networks. That immune cells, there’s all
different kind of immune cells, and then there’s
the endometrium, and they use signals to
communicate with each other. And then when a cell receives
a signal, a molecule that came from a macrophage, then it
has an information processing system with inside that we
call the signal transduction network, and then it
decides what to do. So I will use– or I will interpret
the interdependence to mean that these cells are
in a network communicating. And if somebody over
here changes something, everybody else hears about
it, and responds accordingly. So yes, we are trying
to get more people to appreciate that you can
use very powerful mathematics coupled with very strategic,
multiplex measurements to get into and listen in
to those networks, understand them, and understand
how you could perturb them in a positive way rather
than a negative way. So this idea of
systems biology which, arguably, Doug
Lauffenburger, the Department Head of Biological
Engineering at MIT, he’s one of the
fathers of this field, and was recruited to
MIT, in fact, to help develop this field. Many people in our Department
of Biological Engineering are very involved in this
network, interdependent, systems biology approach. Mike Yaffe, Forest White,
Ernest Fraenkel, and so on. And so trying to bring
measurements and computation together to understand how
all these cells are talking to each other is, I think,
a really, really powerful approach that will be
used for lots of diseases, and is being used
for Alzheimer’s and inflammatory bowel
disease and other diseases, kind of building on what
we did in endometriosis. So my colleagues are using
it for these diseases. Even though I don’t
participate, they’re using these same
kind of approaches we describe here now for
Alzheimer’s and other diseases. So was endometriosis
the first disease to which this particular
approach was applied? So certainly, this was one of
the very first in vivo systems biology in people. So I’d say, this particular
approach has been appreciated for other diseases, and this
would be the first time this exact approach has
been applied. . But it is being applied
to other diseases now, and there is in the
whole systems biology community an appreciation that
this can yield strong insights. Marta asks– well,
first she says, thank you for your
research on endometriosis. Could you speak to what’s
known about the effectiveness of alternative therapies? E.g., chiropractic care
for treating endometriosis. So we have a deficit of
very well-controlled trials, in part because the metrics
for what was effective or how effective something is
are still a little bit squishy. You have a visual analog
score for pain, for example. You have outcomes of fertility. And unless someone runs a
very well-controlled trial with very
well-documented metrics, it’s very hard to interpret,
because there’s often placebo effects. All of that said,
there are a number of people in the field
who are trying to document the effects of these. And I really admire
these approaches, because I believe that
lifestyle and diet really can make an influence, but
you do need to have data. So for example, Kevin
Osteen at Vanderbilt is really doing
some pioneering work on how dietary
changes can influence the severity of endometriosis. I don’t know about
chiropractic or acupuncture, or any of these other things. And I think one confounding
issue for endometriosis goes back to this very problem
that our research addressed. It’s probably not one
disease in every patient. So there’s probably
subsets of patients who will benefit from
certain interventions that are alternative health,
just as there are subsets who might benefit from drugs. And how we figure out
how to assess this to me is a huge challenge,
and I think where MIT could have fabulous
impact by bringing in the people in
computer science and in mobile health, where we
can start to get hard data on, what are metrics? How much mobility do you gain? How much better are
you really feeling by using software programs
and by using things like these fabulous
new little Bluetooth pulse and activity
meters that would let us get hard data to do trials? And so we’re working
with people in CSAIL and so on to develop
software and so on that would help us get data
from patients to let us really be driven by the data
on who this would help and what the interventions do. So I think that’s a barrier. We’re lacking data. I think it’s a really exciting
thing to be thinking about, and we just need more data
to guide actual actions. Terrific. Christina in Norfolk
asks, you led development of the biological
engineering undergrad program, MIT’s first
new undergraduate major in more than 40 years. How important will
biological engineering be in the future of
medical research? So of course, my bias
is that it’s going to be tremendously impactful. And when you think about it,
most the major engineering disciplines were developed
at MIT and changed the world. Chemical engineering
was developed when the science
of chemistry went from being alchemy to being
a predictable, quantitative, molecular science. And then engineering came along
and translated those advances into things that people
use, and still do that. So every few decades, there’s
a revolution in science. MIT figures out how to
take that and translate it through the prism of engineering
into practical applications. So I think that the molecular
to systems-level analysis where you build models
of how systems work, very complex systems, is essential
to both understanding and manipulating both
small-scale and large-scale biological systems. So I think that many of
the revolutions in health will come from this biological
engineering approach, because it organizes this
very complicated landscape and helps us understand the
important influences or not. So I think MIT has
tremendous potential through this academic
endeavor, which, of course, gets
applied to many areas in ways you can’t predict. Because the kids we educate–
a really important thing about MIT– and I know I’m going long– MIT educates the
leaders of the future. So any individual– you
know, my research program, it has impact. But the real impact are
the students that I teach, because they’re going to
be the ones who go out and change the world. And I see that every day,
interacting with alumni. I can’t tell you
how fantastic it is to see what students
do when they leave MIT. With a little bit
of knowledge and way of thinking we give
to them, they go out, and they really do
change the world. So our impact in MIT is through
creating this discipline and having it multiply when
the students leave and take it. This is our way of
implementing mens et manus. Yes, it is. It is. Peter in Taos, New
Mexico asks, why did you choose to work
with patient tissue rather than cultured cells? So patient tissue gives
us the fresh information. So we have to understand,
what is actually happening in the patient? When we got into this
project, I thought that we would build a model
of how endometrium invades in the peritoneal cavity. You know, how does the
endometrium invade the bladder? And I work in
tissue engineering. I said, oh, well, we’ll build
a tissue-engineered model, and then we’ll put
endometrium on. And then I realized,
you know, it’s a lot more complicated in
the body than I anticipated. We need to understand, what
are the important facets in the peritoneal fluid,
in that pelvic fluid? What’s even there? We really don’t know. Thousands of papers
are published on individual
components, but we didn’t have a picture in
groups of patients who were very well care–
where we looked at everything. So we have other work– not just that one paper– but
other related papers where we’re looking at other
facets of that environment to put together a story of, how
do these inflammatory molecules then influence things that
we know can lead to invasion? So in fact, we do work
with cultured cells in other facets of our
program, because we can say, how do these cytokines then
drive a model of invasion? Because we can’t watch
invasion in a person. But we can actually take
the patient’s cells now and make them undergo
an invasive process. So we have other work
that’s now eliminating that. But I think you really do need
to start with the patient, because that’s where there’s
so much information of what the important variables are. Is the center working to improve
the diagnosis of endometriosis? And what are the indications
for medical therapy versus surgical intervention? So two things. The diagnosis– we would love to
improve the diagnosis, and some of the work that we’re doing
hopefully will lead to that. I think we’re also trying to
enable other people working on imaging, and so on. I think our software
program could help do that. Because part of the
whole diagnosis, some women will respond
to hormonal therapies. And that’s wonderful
when it happens, or they’ll respond for
some period of time. So one of the things
we’re trying to do is build software programs that
let you smoothly or enhance the patient communication
with a doctor to let the doctor and patient
realize when the therapies that are available now
are working and when they’re not so that she can have
surgery as soon as possible. Right now, surgery really
is the definitive treatment to reduce pain and reduce
some of the symptoms. It often doesn’t– it’s
not a cure, though. Some patients may have one
surgery and it’s controlled. They get pregnant and
they don’t have symptoms. Other patients may
need 10 surgeries to control the pain and
other kinds of suffering. So I think right
now, we’re still in a landscape that’s
very complicated. Heterogeneous
patients, most of them will need some kind of surgical
intervention eventually, and some of them may need
many surgical interventions. So Daniel in Cambridge
asks, you have said menstrual issues
are the third rail, even in the scientific community. What can the scientific
community and general public do to get rid of this stigma? So it’s interesting. And this is where I
have an opinion that’s not shared by everyone. It’s just an impression, being
in the environment at MIT. I’ve been a faculty member
here for over 20 years now, and I love MIT. I think MIT is a tremendously
liberating place for women. It’s a place you get to do
all kinds of cool science. And it’s never– I’ve never
experienced any issues with being a woman
in this environment. Except it actually is
a squeamish topic to– if you have menstrual-related
health problems, it is something that is just
difficult to talk about. So when I had breast
cancer, everyone immediately understood this problem. The dean gave me a term of leave
so I could have chemotherapy. No one was at all squeamish
about the consequences of breast cancer. And plenty of
people do research. There’s a scientific language. But the fact that a lot of the
menstrual problems are very debilitating and
underdiagnosed– women are told, it’s in your
head, or you’re normal– and it can be very complicated
in a professional life to manage some of the symptoms
if you have a lot of bleeding. A lot of women in their
40s have fibroids. They may bleed so
excessively they can’t even attend a meeting. And so I think there’s
no way to really manage conversations about this
in a professional setting, or no good ways. People at MIT are
very understanding. It’s not like
people are resent– you know, it’s just that it’s
a squeamish kind of topic. So we chose a name for
our center, Gynepathology. The surgeon I work with
said, that’s not a word. We can’t call our center that. And there’s only
three Google hits, and they weren’t even
from places in the US. So we actually chose that
name, because we can make it– we can brand it. We can say, OK. Here’s a scientific
language to start talking about these processes. And they’re fascinating from
an engineering standpoint. So let’s move it into
a realm of science. Everybody can be
fascinated with it. And then you can talk about, oh. Somebody has a gynepathology. They can’t come to
the meeting today. And then it’s not,
they’re using tampons. You make it a little bit less
personal and a little bit– Yes. It’s a science thing. Oh, they have this science– you know, this scientifically
documented problem that they can’t come to the meeting. Not, they’re using
10 tampons today. Yeah. Do you know if
endometriosis is associated with women that are
taking hormones directly or pregnant or breast feeding? That was asked by
Jasmine in New York. All kinds of women
get endometriosis. An enduring mystery
is why some women with very serious
endometriosis– meaning lots of lesions, lots of
internal organ distortion– can easily become
pregnant, and some women with very minimal,
surgically stage disease can never become pregnant. So I think we really
don’t understand the relationships between
fertility and pregnancy and this disease,
in part because it’s an inflammatory disease. And when we think about it
as an inflammatory disease, it starts to make sense. Many other autoimmune disorders
wax and wane with pregnancy. So anyone who’s
been pregnant may have had their allergies become
worse or not during pregnancy. Mm-hmm. So Kenneth in Philadelphia
asks, you co-founded the center with a surgeon. How has Dr. Isaacson’s
nonacademic, hospital-focused perspective shaped the
vision of the center? He is an academic. He’s actually a professor
at Harvard Medical School. He’s very highly published. He’s created all kinds
of surgery approaches. He actually has
scientific publications from his fellowship years. But he’s the President of
the American Association of Gynecologic Laparoscopy. Just finished being president. He’s really the
leader in developing the frontiers of academic
surgical medicine, and he very much appreciates
the molecular approach. So he is an academic, and yet
he’s a fabulous clinician. So it’s really both
together that, you know, he treats patients, but he
comes to MIT nights and weekends and does research with us. That’s a great combination. One last question. Mark in Cambridge asks,
does your modeling suggest that superficial
removal of endometrial tissue actually improves a
patient’s prognosis? Our modeling doesn’t
suggest that. And I’d be happy
to answer questions if other people have them and
want to email me with them. So there is a whole literature
on the removal of endometriosis that we can refer you to. Excellent. Thank you so much. On behalf of the MIT
Alumni Association, we really appreciate
you sharing– Thank you for having me. I really enjoy alumni,
and look forward to interacting with you more. And thank you to our viewing
audience for joining us. We encourage you to continue
discussing these issues on our blog, the Slice of MIT. You could go there too and
talk about it with the alumni. By following the link that
will appear on your screen, you can also view an archive
of past Faculty Forums Online by visiting the Learn section of
the Alumni Association website. Please join us in April for
the next session of the Faculty Forum Online. Thank you. Thank you.

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