In her 23 years as a scientist, Valerie M. Weaver, PhD, has overcome countless challenges – lack of funding, dismissive colleagues, and breaking ground in a new field. Recognized for her contributions, Weaver continues to show the scientific community a thing or two.
In late 2021, Weaver, professor of Surgery; director of the Center for the UCSF Bioengineering and Tissue Regeneration; and co-director Bay Area Center for Physical Sciences and Oncology, received the 2022 Shu Chien Award from the Biomedical Engineering Society (BMES).
Weaver is the first women to receive the award which recognizes an individual who has made exceptional contributions to the field of cellular and molecular bioengineering. These contributions include groundbreaking scientific advances, the development of programs to support this emerging field, the mentoring and training of the next generation of scientists, and the advancement of diversity and inclusivity.
Below, Weaver talks about her life in science, the importance of working across disciplines, and her commitment to training the next generation.
Q. The BMES 2022 Shu Chien Award is the most prestigious of its kind for the field. Congratulations! You are the first woman to receive it. Would you share your thoughts on being recognized by peers for groundbreaking work, and on being the first woman to receive the award? Does that say anything about a glass ceiling for women in science?
A. My first response when I heard that I received the award was delight quickly followed by “Wow, why me?” I would be lying if I did not admit that I felt quite humbled, especially given the impressive accomplishments and credentials of past awardees, and my knowledge of the qualifications and contributions of many of my well deserving colleagues in the field. However, when I realized that I was the first woman to receive the award I also felt quite honored because I do appreciate the impact of mentoring, and how important representation is for inspiring the next generation of female scientists.
Yes, there remains a glass ceiling for women in science – probably more so in the field of physical sciences – however I do believe that this is changing. As the field of biomedical engineering matures, I have every reason to believe that more women will rise into senior roles, and an increasing number of qualified women will be recognized for their important contributions.
I learn every day working with others and realize all too well that the mentoring relationship goes both ways."
Q. What drew you to the physical sciences? Was there an event, class, or person from your childhood or adolescence that influenced your path?
A. I don’t believe that there was a single event, class or person that drew me to the field of the physical sciences. Rather it was a slow evolution. During my postdoctoral training with Mina J. Bissell at Lawrence Berkeley National laboratories in Berkeley, California, interdisciplinary research was emphasized at the institutional level, and this certainly had a profound impact on how I viewed my science.
My interest in interdisciplinary research was further stimulated at the University of Pennsylvania, where I began my independent academic career, and where my first laboratory was located at the Institute for Medicine and Engineering (IME). At the IME my office and group were situated adjacent to the engineering labs, and we were literally surrounded by research labs run by engineers and physicists. I recall attending lectures on assorted engineering and biophysics topics and being incredibly stimulated and excited by the concepts that I was learning. These experiences and my own curious nature and belief in studying scientific questions with as many different perspectives as possible served to nurture my lifelong desire to study biology from a physical sciences perspective.
Q. Tell us how you chose bioengineering and tissue regeneration – with regard to oncology? Can you characterize where the field is and where it is headed?
A. When I joined the University of Pennsylvania and started my laboratory at the Institute for Medicine and Engineering (IME), it was incredibly challenging to attract cell and molecular biology or pharmacology graduate students to even consider doing a research rotation in my laboratory. IME is located across the campus from the medical sciences and cancer research center at University of Pennsylvania and students like to “cluster.” Moreover, cell biology students are intimidated by the physical sciences. This left me the option of mentoring engineering students.
The field of mechanobiology was confined to the study of cardiovascular disease where perturbed blood flow has been implicated in vascular plaques or in the study of orthopedics or even lung ventilation. Yet, my research focused on the role of the tissue microenvironment and the extracellular matrix in breast cancer. Rather than changing my research focus, I decided to examine whether mechanics had any relevance for breast cancer. I admit that I had more skeptics than supporters at this point in time, and I was unable to obtain even modest pilot project funding to support my research from any of the internal and external agencies I applied to.
However, I have never been dissuaded from doing what I set out to do by a lack of morale or financial support. Instead, I managed to recruit my first bioengineering graduate student, and then we set about to design a research program addressing the potential role of tissue mechanics in breast cancer risk and progression that would encompass quantitative and engineering concepts combined with cell and molecular biology to fulfill her program requirements.
A mechano-engineering colleague had a postdoctoral fellow with time on his hands, and he agreed to teach us how to conduct unconfined compression analysis on mouse mammary tumor tissue. Together, we wrote a small animal protocol that allowed us to use discard murine tumor tissues and we bargained with graduate students over in the cancer center to allow us to sacrifice their extra mice with mammary tumors, so we could harvest the tumor tissue. The measurements we obtained from these studies were incorporated into our first mechanics of cancer article that was published back in 2005 in Cancer Cell – which has already been cited close to 4,000 times.
These early studies stimulated a lifelong interest in clarifying the role of tissue mechanics in malignancy, and I have never looked back. Since our first sets of cancer mechanics studies back in 2002, my group has expanded our breast cancer work to include work on pancreatic adenocarcinoma and glioblastoma. We have also been exploring the role of tissue tension in adult stem cell expansion and differentiation as well as embryonic development. Fortunately, our engineering and biophysics colleagues as well as cell biologists and developmental biologists have also embraced this exciting area of research which has helped enormously with fruitful collaborations.
Sadly, cancer clinicians and biologists, for the most part, have either ignored this type of work or have been quite dismissive or skeptical and have yet to embrace this field. My current goal is to continue to generate ever more compelling data to illustrate the importance of mechanics to cancer to try to convince my cancer research colleagues, and to develop methods and approaches that will make conducting this research easier for them to embrace.
For instance, given the importance of tumor genetics, we have published several articles demonstrating how the genotype of the tumor can increase tumor tissue tension to drive its aggression. Our more recent work revealed the importance of tissue tension in breast cancer risk and how tension can also modulate tumor treatment efficacy. However, until such time as we and others can illustrate how modulating tissue mechanics can improve chemo or immune therapy, it is doubtful whether cancer biologists will fully embrace this area of inquiry.
Nevertheless, our current work is now directed towards studies examining the impact of tissue tension on anti-tumor immunity and our more exciting work examines how tissue tension modulates the genome to initiate cancer. Time will tell whether or not we will be successful in this quest; and if so, whether at last the cancer community will finally begin to appreciate the importance of tissue mechanics and incorporate this concept into their perspective and work.
Martin Žídek, MD, far left, postdoctoral fellow, explains his cancer research to his PI Valerie Weaver, PhD, professor of Surgery, and Jeroen Roose, PhD, professor of Anatomy and director of a collaborative research grant from the Mark Foundation to study metastatic cancer. Photo by Susan Merrell
Q. You truly are an interdisciplinary scientist, perhaps more than some. What is behind this?
A. I have always been very curious and especially mindful of the fact that different perspectives yield a different understanding of a situation or problem. This is true of all things in life. Whether it be people with different socio economic, racial, ethnic, or religious backgrounds examining a social problem, we all view things with our unique perspective.
The same thing can be said of the different scientific disciplines. A cell and molecular biologist might focus more on the genetics of a disease, whereas a developmental biologist would examine things at a tissue level; a biophysicist would look at things from a single molecule level; a biochemist at protein structure/function; and a chemical engineer at kinetics; and a mechanical engineer at the physical context. Each discipline using different perspectives to understand the same scientific problem. I find this fascinating and quite a useful approach to incorporate into my research.
Diseases such as cancer are incredibly complex, and I am an enthusiastic believer that the only way we will truly understand cancer is if we apply an interdisciplinary approach and incorporate the best and brightest minds into our research programs. Each discipline brings a unique set of ideas and methods and examines the question with a specific bias. By combining different fields and perspectives and techniques, we slowly begin to clarify the question we are studying.
I have been constantly challenged, frequently surprised, and always pleased with the results I have obtained when I have used an interdisciplinary approach in my research. I heartily recommend this approach to all of my colleagues. It does mean, however, that you must leave your ego at behind and understand that you will often feel daunted by the nature of the work and humbled by the intelligence of your colleagues.
Q. In your time working as a scientist, what have been the most significant discoveries, including developing technology, that have advanced the field?
A. Back when I was a postdoctoral fellow working with Mina Bissell at LBNL, I was trying very hard to “kill” breast tumor cells by blocking beta 1 integrin adhesion activity. I inadvertently induced the phenotypic reversion of these tumor cells so that they recapitulated the acinar phenotype of nonmalignant mammary epithelial cells. When I did this experiment the first time, I was convinced that I had somehow mixed up my cell lines and embedded nonmalignant MECs into the matrigel culture hydrogel. So, I redid the experiment and once again induced a phenotypic reversion of those tumor cells. After repeating the experiment several times, I finally concluded that I had somehow normalized the tumor phenotype. Only then did I present my findings to Mina and the Bissell group at our weekly lab meeting. This discovery changed everything for me and stimulated a lifelong interest in studying the impact of the extracellular matrix (ECM) on tissue development and cancer.
Since that original discovery, I also discovered that ECM stiffness is a major regulator of tissue organogenesis and expression of the malignant phenotype, that many oncogenes drive cancer by “tuning” the actomyosin tension of the tumor cell, that tension modulates treatment responsiveness and anti-tumor immunity.
Each discovery is a surprise and is humbling and delightful, and each discovery stimulates ever more new ideas and avenues for research. I cannot know truly what impact my work has had on the research community, but I do like to believe that my discoveries have stimulated others to begin exploring the role of the ECM in tissue development and cancer and to examine the impact of tissue tension.
Over the years, to execute our work we have developed methods to manipulate and measure ECM stiffness and tissue tension. Though I do realize that other more talented scientists have been able to build ever more sophisticated approach and techniques than those we developed. I do hope that what we have been able to do has stimulated our colleagues to develop these more sophisticated techniques and approaches.
Q. With regard to your work, what are you most proud of so far? Where is your work headed? What else would you like to accomplish?
A. If I contributed to establishing the field of cancer mechanobiology and galvanized studies addressing the impact of tension on tissue development, then I am quite pleased. As mentioned above, it is quite difficult to appreciate just what impact one’s work has had on a field, but I do know that my group’s work has stimulated others, especially many young engineers. I believe that my role is to push the boundaries of what we know and can do in the area of cancer and tissue mechanics. My efforts include developing in vivo mouse models with which cellular mechanosignaling and ECM tension can be manipulated in vivo so that others can use these models for their work.
Our studies are also directed towards clarifying how cells and tissues “adapt” to chronically aberrant tension to try to understand how this could influence tumor aggression and metastasis. Our work is also directed towards clarifying if aberrant tissue tension can “initiate” cancer by inducing genomic alterations and defining how this could ensue. Finally, I am working with colleagues to determine how we might use the information and insights we have made regarding the role of force in tumorigenesis for more effective anti-tumor treatments including immune therapies.
Q. How different might your career look had you not come to UCSF? What drew you here?
A. UCSF has a long and strong track record of collaboration. The university also has on faculty many strong women leaders, including the late Zena Werb who inspired me and many others to take on leadership roles. The collaborative environment and female leadership drew me to UCSF. Had I not come to UCSF, I would still have done the research I managed to do thus far, but I believe it would have been more challenging and likely lonelier.
Q. The BMES award also recognizes you for mentorship. What is your philosophy for training the next generation? And paving the way for women in STEM, in particular?
A. I am a people person – and while I love ideas and doing science - pretty early on in my career I realized that I thoroughly enjoyed sharing my love of research with others. I find it so gratifying to mentor others and to watch my trainees confidence, technical competence and creativity grow and flourish. While I certainly recall the thrill of publishing my first article, I quickly learned that my enjoyment was amplified when I was able to share this achievement with my trainees. I learn every day working with others and realize all too well that the mentoring relationship goes both ways. I might be teaching a student or postdoctoral fellow or guiding a junior colleague, but engaging with them nurtures me as well.
Mentoring challenges me to be a better person on multiple levels and keeps me engaged in science and excited about the work and ideas. From my perspective, research is the practice of science and that involves inspiring, guiding, supporting and believing in others and sharing in their journey towards independence and success. Each person I have trained, and every independent scientist I have had the opportunity to mentor, is unique and so is my approach towards mentoring them. I truly believe that each individual has something special to contribute to science, and that it is my job as a mentor to identify their strengths, build their confidence, stimulate that fire inside them, and help them to achieve their goals.
Regarding STEM in particular, It is important as a mentor to support women in the physical sciences -- all women from all backgrounds, races, ethnicities and religious backgrounds. Part of my job as a senior scientist is to remain vigilant and to always appreciate that visibility is key here – and engagement with younger women. To support junior women and senior women and to build a vibrant community.
Q. Finally, how does someone who lives and breathes science and mentoring the way you do spend truly free time? Do you puzzle over scientific questions while walking your dogs?
In 2020, Dr. Weaver shared a slice of her pandemic life, which included daily hikes with her two dogs, in our feature How We're Working and Living During COVID.
A. Great question. Some of my best ideas have actually come while I have been hiking or cycling. I love the outdoors – and hiking and cycling are two of my favorite activities – and yes walking with our dogs is up there as a favorite activity as well. In addition to hiking and cycling, I also love kayaking and canoeing as well as camping. Other activities I enjoy include partaking in the visual arts, including drawing and painting and photography as well as reading.
I am a scientist which means that I don’t suddenly stop thinking about science once I stop focusing on work. I count myself as lucky in that I love what I do and I get to make a living doing it.