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- Incyte Genomics Interview

- Nature Medicine Interview

IncyteGenomics

Featured Scientist Series

www.incyte.com/insidegenomics/int/bio/int_bio_0001/int_bio_0001_1.shtml

 

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

                        every organ and tissue in the body. My colleagues and I

                        know just a little about that interaction in the breast.

                        Some people know a bit about skin, and others know a bit

                        about brain, but really we all know very little. There is so

                        much to learn, and the sequencing of the genome is just

                        the very beginning.

 

                       

                        Q: What other disorders may be tied to change in the

                        extracellular matrix?

 

                        DR. BISSELL: Generally, people think about the ECM in

                        relation to cancer because it's easier to see how

                        disorganization leads to cancer. But I believe that many

                        kinds of disorders and diseases may be tied to

                        misregulation of the ECM. There is, for example, a skin

                        problem called epidermolysis bullosa. One type of this

                        disease results from a mutation in one of the three genes

                        for laminin, which is an important basement membrane

                        component in various tissues. Mutation in these ECM

                        genes can wreak havoc in different kinds of tissues and

                        cause a variety of diseases.

 

                       

                        Q: Might that make the extracellular matrix a more

                        advantageous target for cancer therapies?

 

                        DR. BISSELL: I wouldn't say that it makes it a more

                        advantageous target, but I think that it is a very good

                        additional way to attack cancer.

 

                        The ECM is not just one molecule; it is a collection of

                        molecules that talk to their receptors, and the receptors

                        in turn talk to the cytoskeleton and the nucleus to

                        change the cell. Any of those molecules involved in signal

                        transduction by the ECM are every bit as good a target

                        for a therapy. In the past we have paid tremendous

                        attention to growth factors and growth regulation, but

                        we need to pay equal attention to those genes that

                        determine organ specificity and structural specificity. The

                        ECM is one part of cell regulation, and thinking about how

                        the ECM can be part of therapy is very good. We now

                        know that many growth factors need ECM signaling to

                        function, so we must understand both kinds of signaling.

 

                        Let me make an additional point: We concentrate too

                        much on the cancer cell itself. Often it's what is outside

                        these cells that leads to genomic instability and mutation.

                        For example, when your cells have the BRCA 1 and BRCA

                        2 mutations, why do you get only breast cancer and

                        ovarian cancer? Why don't you get cancer of the skin?

                        Why don't you get cancer of the gut? These mutations

                        are in every one of your cells but cause only very specific

                        types of cancer. Even with the breast cancer genes, not

                        everybody who has a BRCA 1 or 2 mutation gets breast

                        cancer. And even if you do get breast cancer, you get it

                        in only a few cells.

 

                        What happens to the rest of the breast cells that are just

                        sitting there? The breast cells, I think, are all poised to

                        become cancerous sooner or later. Even if you don't have

                        a primary mutation like BRCA 1 or 2, a drastic change in

                        microenvironment can lead to mutation in the epithelial

                        cells. In collaboration with Zena Werb at the University of

                        California at San Francisco, we made transgenic mice

                        that overexpress metalloproteinases in the breast to

                        destroy the ECM. Those mice eventually got breast

                        cancer.

 

                        Remember that there is a significant correlation between

                        cancer and aging. Aging is an organismic-level

                        phenomenon. As you get older, one of the most important

                        things in your body that changes is the ECM's and cells'

                        microenvironment. We get wrinkles because the ECM that

                        is normally supple and allows correct signaling starts to

                        dissolve. Matrix metalloproteinases, which dissolve the

                        ECM, get up-regulated as you age. They disrupt dynamic

                        reciprocity and create a situation in which the epithelial

                        cells are poised to become unstable.

 

                        I argue that we should also be directing cancer therapy

                        toward the field outside the cell. Is there a way to

                        change the whole-field-effect of a tissue? Could we

                        change the microenvironment so that another tumor

                        doesn't develop? In terms of gene therapy, I think these

                        are additional challenges. We have shown that we can

                        revert malignant breast cells by manipulating ECM

                        receptors on the surface of the cells.

 

                       

                        Q: Is there something fundamental about the role of the

                        ECM, like the p53 gene, in causing cancer?

 

                        DR. BISSELL: I would say that the extracellular matrix

                        and its interaction with its receptor could regulate genes

                        like p53; in fact, there is some evidence for this from

                        other labs. I think that everything is absolutely

                        interconnected. When we do 2-D studies (on plastic) as

                        opposed to 3-D, we find that a lot of genes get changed.

                        The cells in 2-D express some genes that are not

                        expressed in 3-D, and vice versa. We also find that many

                        genes are modified when cells are grown in 3-D as

                        opposed to 2-D. We have data to show that the ECM and

                        its receptor affect cell-cell interaction—which in turn

                        impacts the ECM and its receptor. Both of these things

                        affect important genes within the nucleus, such as p53.

                        They all work in concert.

 

                        I believe that cancer may be caused by a mutation of

                        classical tumor suppressors, by a disorganization of the

                        cytoskeleton, and/or by messing up the extracellular

                        matrix. The result is similar, but the pathways by which

                        someone gets cancer are different.

 

                       

                        Q: In other words, once a person gets cancer, the

                        extracellular matrix may be tied to metastasis by allowing

                        cancer cells to exist in microenvironments that differ from

                        those in which they originated?

 

                        DR. BISSELL: Exactly. But I am saying more than that.

                        Cancer can start by messing up the ECM and structure,

                        but loss or change of the ECM is also involved in

                        metastasis. For these cells to get out of their tissue,

                        they have to travel out of their ECM, so extracellular

                        matrix-degrading enzymes get produced. They eat up the

                        ECM, and then the cells are able to move. This doesn't

                        mean that tumor cells can't make extracellular matrix.

                        Sometimes they make gobs of it, but they don't assemble

                        it correctly. They make piles of it, but it doesn't know

                        how to get organized. The process messes up the

                        balance that determines tissue and organ specificity.

 

                       

                        Q: How does genomic science affect the work that you

                        do?

 

                        DR. BISSELL: I use all the tools that genomic researchers

                        are developing. All of the genes that are expressed by

                        the mammary gland need to be cloned, need to be

                        known. I didn't discover the metalloproteinases—other

                        people discovered (and continue to discover) them and

                        have cloned and sequenced them—but I use them as

                        markers and tools.

 

                        As far as the study of the genome goes, I think of a

                        lovely slide that I usually show at the end of my talks. It

                        says, "Science is built of facts, as a house is built with

                        stones. But a collection of facts is no more science than

                        a heap of stones is a house." I say that a collection of

                        genes doesn't define a particular tissue or organ, in the

                        same way that a lot of bricks do not define a house.

 

                        Clearly, we need those collections of genes; we need to

                        understand the proteins that are being expressed and the

                        regulatory sequences that make those proteins carry out

                        their function. My work is just another facet of the

                        biology we need to do. The reason I've been perhaps a

                        little too loud in the last 15 years is that 98 percent of

                        the researchers are working to understand genes, and

                        maybe 2 percent are trying to understand the

                        extracellular regulation of cells. It needs to be 50-50

                        because both sides are important. We ought to be

                        working together to understand the whole complexity of

                        tissue specificity.

 

                        The imbalance is somewhat understandable because

                        science, by its nature, needs to simplify. I do argue,

                        though, that some of the ideas my laboratory is putting

                        forward are not as complicated as they sound. If you

                        isolate genes and then study them in isolation or under

                        unnatural conditions, you make life a lot more complicated

                        because isolated cells can give you misleading

                        information. But if you put them in the right context, they

                        give you the information that you want to know: how

                        those genes and cells may behave when they are in your

                        body. But, of course, in the final analysis you also want

                        to study these regulations in vivo.

 

                       

                        Q: Are you worried about the ethical implications of

                        human genome research? For example, once we have the

                        power to test for the presence of genes like BRCA 1 and

                        BRCA 2, how do you advise whether or not to be tested?

 

                        DR. BISSELL: At the same time that I'm a great

                        advocate for human rights, I'm also a great advocate for

                        freedom to seek information. No one should muzzle

                        science. Knowledge is a one-way process, and you can't

                        stop it. If people do decide they want genetic tests, then

                        they should have genetic tests. If they don't want to

                        have them, they shouldn't. As scientists, we need to

                        educate as we discover. It's the same way I feel about

                        abortion issues or fetal research. If we're not doing

                        anything that infringes on the basic rights of another

                        human being, we ought to be able to do it.

 

                        On the other hand, I do think that we need certain laws

                        and regulations to prevent powerful people from taking

                        advantage of this information. We also need to educate

                        people about the pros and cons of genetic testing. Do

                        you want to know whether you have a BRCA 1 or 2

                        mutation? If I had a mother and a grandmother and/or a

                        sister who had breast cancer, I would get tested.

                        Admittedly, the test is not always accurate. I would

                        remind everyone that a number of people who have BRCA

                        1 or 2 do not get breast cancer—and even if you do get

                        it, you can take care of it if you find out early.

 

                        I'm all for genetic engineering, but we need to make sure

                        that it doesn't harm the environment. I'm all for finding

                        out what kind of genes people have but at the same time

                        educating them about what this information means. I'm

                        also all for diversity. In other words, I think it's very

                        important for people to realize that the implications of

                        these things are not simple. We must preserve our

                        creativity, diversity, and three-dimensional way of

                        thinking.

 

                       

                        Q: Can laws to control the use of genetic information be

                        effective?

 

                        DR. BISSELL: I don't see why not. If laws are created in

                        consultation with scientists and the scientific societies,

                        they could make sense and could work. If we end up with

                        politicians telling scientists and society what to do, it's

                        not good.

 

                        I'm not saying that scientists should run amok. They are

                        like anybody else: They need to police themselves, and

                        they need to exercise a certain degree of control.

                        Science, like all other professions, has its portion of

                        crooks, yet I don't think that scientists are unscrupulous.

                        A lot of scientists are arrogant, and we are susceptible to

                        the same kinds of problems as anyone else. It's just that

                        if you're a scientist, in the same way as if you're a

                        doctor, you have an additional obligation to try to uphold

                        the truth, whatever that may be.

 

                       

                        Q: How does the funding system for a national laboratory

                        impact your research?

 

                        DR. BISSELL: The way that biology is funded in national

                        labs is different from how scientists get funded at the

                        National Institutes of Health [NIH] in-house laboratories.

                        The latter have their funding and salaries provided. This

                        was never the case in national labs for biology. People

                        don't understand that all of our funding, including the

                        scientists' salaries, are on "soft money," so we have to

                        constantly compete.

 

                        Also, most people don't realize that researchers

                        supported by the Department of Energy [DOE] have

                        contributed tremendously to some of the boldest ideas in

                        biology in the United States. They are the ones who

                        started the Human Genome Project. They are the ones

                        who supported the first studies on DNA repair, which now

                        has become a huge field. They are the ones who

                        supported Bruce Ames when he developed the Ames

                        Test. At the time, he couldn't get money from the NIH.

 

                        In addition, the DOE has developed a huge amount of

                        technology that has come out of national labs. It has

                        allowed individual scientists a degree of freedom to do

                        what they like. I was fortunate enough to have run into a

                        few men in the DOE who appreciated that I was

                        passionate about what I was doing, and they felt that I

                        was an original thinker. They gave me enough freedom to

                        move a little in other directions. I am totally indebted to

                        the Office of Biological and Environmental Research and

                        to the DOE. I think the NIH is a magnificent and well-run

                        system, but people don't appreciate how important it is in

                        science to have multiple sources of funding. Without

                        funding for bold research, creativity really gets stifled.

                        Scientists and artists have a lot in common: Good

                        scientists have an artistic streak, and requiring them to

                        accept the conventional wisdom would stifle their

                        creativity. Scientists should be encouraged to push the

                        envelope.

 

                        Funding organizations ought to allow scientists some

                        freedom to be able to explore things that are not

                        fashionable. One of the worries I have about how

                        biotechnology and biology get developed these days is

                        that we kind of clone ourselves: You go to a study

                        section and they say, "Oh, but you don't have the

                        background," or "Your ideas don't agree with what's

                        published. How could your ideas be true?" That's one of

                        the reasons we should support the NIH as well as the

                        National Science Foundation [NSF]. We should support

                        the DOE's Office of Biological and Environmental Science,

                        but also NASA's biological office. It's crucial in a free

                        society that we don't rely on just one giant organization,

                        even when it works so very well. I'm a passionate

                        advocate of multiple funding sources. It's important for

                        originality, and I'm delighted to see that the NIH now

                        includes originality as a criterion for supporting research.

                        Also, it is wonderful that people as prominent as Harold

                        Varmus—the very successful and brilliant past director of

                        the NIH—are now calling for doubling the funding also for

                        the NSF and for the Office of Science of the DOE.

 

                       

                        Q: Let's turn to your own "developmental matrix." How did

                        growing up in Iran shape your perspective about your

                        career?

 

                        DR. BISSELL: People often ask me how a woman from

                        the Middle East has been able to come to this country,

                        go to Harvard, and be successful in creating and directing

                        a huge division. I remind them that hundreds of

                        thousands of women are out there who have done the

                        most amazing things. The United States is full of such

                        immigrants, but I think I have done what I have done

                        precisely because I come from Iran.

 

                        When I was growing up, Iran was a class-divided society,

                        very much like the old England. In fact, class was more

                        important than gender. I was fortunate enough to come

                        from a well-to-do and educated family and to have a

                        stable background. Basically, I grew up telling people

                        what to do and was encouraged to express myself. I was

                        encouraged by my mother especially, although my father

                        also expected us to have higher education and to

                        achieve. Women of my family's class did exactly as they

                        pleased because they had a "room of their own"! Women

                        had children, but they also had servants, so they were

                        more free to pursue careers and their own interests.

 

                        My sister does not buy this explanation. She says, "But

                        you also were the top high school student in the country.

                        You were number one in most or all subjects." But I think

                        that thousands of kids out there could be top students if

                        they had the same opportunities.

 

                        It didn't occur to me that I—or anyone—couldn't do what

                        I did. I came to the United States all by myself, when I

                        was barely 18. I had won a big scholarship and landed in

                        New York. I went to college, got married, and had a child

                        the first year of graduate school. This was 35 years ago,

                        when only 3 of the 200 students at Harvard Medical

                        School were women. Everybody immediately assumed I

                        would quit. Maybe I was being naive, because I didn't

                        realize how difficult things could be: I didn't have

                        servants; I didn't have my mother next door; we were

                        living on student salaries. But it didn't occur to me even

                        once to quit.

 

                        People would say, "Of course you are quitting. What is

                        your mother going to say?" You know what my mother

                        said? She called from Iran and said, "You're not quitting,

                        are you?" and she came to help for a few months. Now

                        how many American mothers, 35 years ago, would say

                        this to their daughters? They would make you feel

                        guilty—they would say, "You have to stay home and take

                        care of your kid." I'm not saying that people shouldn't do

                        that. People should stay home and take care of their kids

                        full-time, if they want to. But with my energy level when

                        I was that young, if somebody had forced me to stay

                        home I probably would have jumped off the roof. I

                        probably would have driven my kids crazy. (I'm sure they

                        thought I drove them crazy anyway!) I have a wonderful

                        daughter and a wonderful son. Both are well educated

                        and in good shape. They're now both married, and I'm a

                        grandmother.

 

                        I had my daughter during my first year of graduate

                        school, and my son the second year of postdoc, and I

                        just continued to work. I never stopped. Now I look back

                        and realize how difficult it was. I keep thinking, "How on

                        earth did I do it?" But in the end it was worth it.

 

                       

                        Q: Even with all your energy, it must have been

                        challenging to raise a family, earn your degree, and work

                        all at the same time. How did you manage to give

                        appropriate time and energy to each commitment?

 

                        DR. BISSELL: It was even harder because I was doing

                        very unconventional science. That didn't help. I didn't

                        have a regular mentor; I didn't have a club to which I

                        belonged. At the time, I didn't know that what I was

                        doing was so hard; I just didn't see it that way. Again,

                        that's part of this whole background situation. People

                        don't realize how much our background shapes us. Some

                        very powerful men in science think I'm a little too

                        outspoken, or that I say inappropriate things. Sometimes

                        I wish I wouldn't say certain things to my colleagues, but

                        it comes from my background. I was never punished for

                        speaking my mind; I was encouraged. If I had been

                        punished, I probably would have gotten so depressed

                        that I would not have developed the same way. But

                        cultural backgrounds play a big role in how people

                        behave.

 

                       

                        Q: How has being a woman scientist in the United States

                        affected you? Has it been a detriment?

 

                        DR. BISSELL: Oh, it has. In my generation, being a

                        woman really was a handicap in science. But believe it or

                        not, I didn't recognize that until after graduate school.

                        After my postdoc I got my first job here at Berkeley. I

                        realized when I started the job that a male colleague of

                        mine—who was younger, had fewer publications, and

                        hadn't done half as much as I—had been hired into a

                        better position with a much higher salary: He was my

                        boss. I wasn't used to that kind of discrimination. I

                        couldn't understand it, and the injustice of it really

                        affected me. I looked at the situation and thought,

                        "Huh?" Of course it made me angry and caused problems,

                        because I can't be as creative when I'm dealing with

                        anger. Nevertheless, I managed to move on. As I moved

                        higher and higher up, things became more and more

                        difficult. In retrospect, it could have been partly my

                        fault—I may have appeared to feel entitled, which isn't

                        right. But part of it was simply frustration.

 

                        But I think I lucked out in many different ways, partly

                        because of sheer force of energy. Now I feel very

                        grateful, and I'm sure I could have done things differently

                        had I realized the cultural differences. I'm grateful to

                        many people, including my current director at the

                        Lawrence Berkeley National Laboratory, Chuck Shank; the

                        people in the Department of Energy's Office of Biological

                        and Environmental Research; and a few other colleagues

                        across the United States who have been very supportive.

                        Unfortunately, even though younger women may not

                        have as much trouble, I do think that a lot of

                        discrimination still goes on, even though people think it

                        has been eliminated.

 

                        I'm pleased to see how many gains women have made in

                        science, but I still see the difference between being a

                        man and being a woman in the field. Very often, I'm the

                        only woman in the room. In a lot of cases, I'm the only

                        one who speaks up. And often, when I speak up too

                        much, it causes trouble. Of course, men can also get

                        themselves in trouble if they speak up, yet there is still a

                        big difference.

 

                       

                        Q: Do you think that any of the relatively new areas of

                        genomic research are "friendlier" to women?

 

                        DR. BISSELL: Yes and no. People say, for example, "We

                        have enough women in biology because it is the study of

                        nature and is intuitive for women. We don't have enough

                        women in physics because women don't think that way." I

                        was surprised to notice years ago that some of the best

                        physicists in this country are women of Italian origin, and

                        I always wondered why so many brilliant female physicists

                        come from Italy. Then I found out that in Italy, physics is

                        considered a fine art. Men go into politics and finance,

                        and women are encouraged to do math and physics along

                        with painting and music!

 

                        I think our family's expectations as we are growing up

                        have a lot to do with the career we end up in. It is my

                        hope that the genomic sciences will remain more open to

                        women. Diversity and different points of view are good for

                        science. It's not just because 50 percent of this society

                        is made up of women—I think that women do bring

                        different insights to science.

 

                       

                        Q: You've said that you had difficulty choosing between

                        pursuing chemistry or literature. Do you feel that you

                        made the right decision?

 

                        DR. BISSELL: I think I did, although literature—and

                        having taken what I believe was one of the best English

                        classes this country had to offer, at Bryn Mawr

                        College—has stood me in terrific stead. I still read a

                        tremendous amount of literature. Colleagues ask where I

                        find the time, but I read just before I go to bed. I love

                        good writing. It's such a pleasure.

 

                        I eventually chose chemistry because I figured that I can

                        read on my own but I can't study chemistry on my own.

                        I'm glad I did science. I absolutely love what I do. My

                        enthusiasm and love of science is what has carried me

                        through all these years. It is like doing jigsaw puzzles and

                        getting paid for it!

 

                       

                        Q: Is it important for scientists to study literature and

                        take other courses not related to science?

 

                        DR. BISSELL: Absolutely; I think so. Scientists are not

                        being taught enough social sciences or enough literature.

                        These are very important subjects, and I think that a

                        liberal-arts education is a very good background for

                        scientists. Too many people are being trained to be

                        straight-A premed students. They cram, but they don't

                        become full human beings.

 

                        From time to time, we have scientific geniuses who are

                        really weird and are social misfits. What we also want are

                        creative scientists who can also be nice human beings

                        and interact with society. This is one of the problems

                        that scientists have: Often, they are not articulate

                        enough to express themselves or speak to the public, or

                        they don't care to do so. I'm delighted to see scientists

                        involved in politics. Bruce Alberts, who is the president of

                        the National Academy of Sciences and an inspiration in

                        many areas, including science education, recently

                        returned from Iran with the other two National Academy

                        presidents. They went to Isfahan, where 6 out of the 12

                        members of the city council apparently were medical

                        doctors. He said that this would never happen in the

                        United States.

 

                        In societies like Iran's, scientists are revered. This year,

                        even under the Islamic regime, Iranian women make up 60

                        percent of the medical school class, and the figures are

                        similar in science, engineering, and architecture. We need

                        more of that in this country. We need a marriage

                        between politics and science, and we need multifaceted

                        scientists. Fine arts, literature, and the rest of the

                        liberal-arts curriculum should be introduced into science.

                        It would help shape scientists' ways of thinking and allow

                        us to better understand biology. The reverse is also true:

                        Society needs scientific education. We must encourage

                        our children not to be afraid of science.

 

                       

                        Q: Has your liberal-arts background made you more open

                        to an "environmental" view of cells and their regulation?

 

                        DR. BISSELL: Absolutely. But at the same time, it's

                        important not to be afraid of physics, math, and

                        computers. It's crucial that we educate minorities and

                        women in those areas, because it's easy to be scared of

                        math, science, and physics. People need to overcome

                        their fear of these subjects. But they need teachers who

                        encourage them. I had wonderful math and physics

                        teachers in high school, and some were bright and

                        inspiring women.

 

                        Ultimately, society needs to create multifaceted

                        individuals to think in multifaceted ways. But, we have to

                        study science to understand the complexity of what we

                        face in the new millennium.

 

                       

                        Q: The existing intense collaboration between industry

                        and academia represents a huge change in the research

                        environment since the early 1970s. Has the change been

                        good for biology?

 

                        DR. BISSELL: In general, it's been good. In any case, we

                        can't stop it. The part that worries me is what worries

                        everybody else—that patent laws and secrecy affect

                        researchers' ability to talk about their work. A lot of

                        scientists say, "I won't talk about it until I can patent it,"

                        and they aren't as willing to share their research material.

                        It's difficult to get information from companies. These

                        attitudes can be harmful.

 

                        The good news, of course, is that [industrial-academic

                        collaboration] has brought a lot of very intelligent and

                        capable people into research. They realize they don't

                        have to go to the stock market to make money: They

                        can go into biology to make money! [Chuckles.] It also

                        has created a bigger job market for biologists. We need

                        to watch for the dangers and increase the benefits.

                        Cooperation and interaction with industry is good, as long

                        as it doesn't muzzle us too much.

 

                       

                        Q: Looking to the future, what areas of biology and

                        genomic research should researchers be focusing on?

 

                        DR. BISSELL: Opinions vary, and some areas are rather

                        obvious, but something I really would like to see

                        emphasized more in biology—and in combination with

                        genomics—is the science of imaging. It's important for

                        people to really think about where genes are expressed. I

                        want to see companies and universities paying a lot more

                        attention to imaging because we will not understand the

                        nature of tissue and organ specificity unless we know

                        exactly the microenvironments of these proteins within

                        the cells and tissues. I would like to see a combination of

                        genomics and imaging being developed. That's another

                        reason I'm in a national lab—it allows a multifacetedness

                        that until recently didn't exist in universities.

 

                        I'd also like to see larger and more equal teams of people

                        collaborating and bringing different disciplines together.

                        At the national laboratories, biologists are working next to

                        informatics experts, engineers, and physicists. We

                        encourage multiteam investigations. This is the way of

                        the future in biology.


JOHN FITZGERALD KENNEDY
35TH PRESIDENT OF THE UNITED STATES

UNDELIVERED REMARKS PREPARED FOR DELIVERY
AT THE TRADE MART, DALLAS, TEXAS
NOVEMBER 22, 196

 

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