Breaking Barriers: In the Brain, between Science and Medicine, and in Life

By Joanna Sun, Leo Lansky, Larry To, Natasha Paranjapye

The blood-brain-barrier (BBB) is a protective membrane layer covering the brain that maintains a safe environment for the brain, regulating what passes to and from it. It acts as a guard wall for the most important organ of the body, but becomes a problem for accessing the brain for therapeutic drugs. Developing therapeutics that directly reach the brain would take a huge step towards treating diseases of the central nervous system (CNS) such as Alzheimer’s, Parkinson’s, cerebral palsy, and brain tumors. Historically, researchers have faced problems with dose and efficacy. That is, until transformative findings led by Dr. Elizabeth Nance demonstrated the first successful completely bio-inert drug delivery platform capable of penetrating the BBB and moving in the brain microenvironment [1].

This safe and biodegradable polymeric nanoparticle-based platform was shown to not only penetrate the BBB, but locally and specifically travel to the desired therapeutic area in living rat brains. Published in August 2012, this work represents enormous progress in the potential for sustained, targeted, and regulated delivery of drugs into the brain and brought Dr. Nance worldwide attention, including recognition in a ‘30 under 30’ list of young scientists changing the world by Forbes magazine [2]. Denatured Journal spent a morning meeting with Dr. Nance, now a Clare Boothe Luce Assistant Professor in Chemical Engineering and Adjunct Professor of Radiology at the University of Washington, to learn about her plans for her research and how her unique background and philosophy drives her passion for discovery.

Nance's Approach Innovates in Drug Delivery, Uptake, and Tunability
To develop their approach, Nance’s team first characterized the transport rates, chemical reactions, and effective pore size of nanoparticle transport in human and rat brains. Nance’s team discovered that 28% of spaces between cells in rat and human brains are greater than 100 nanometers (1 nm is 10-9 meters), enabling potential of larger drug delivery particles than previously assumed [1]. Diffusion distances and rates of polyethylene co-glycol (PEG)-coated nanoparticles of various sizes were evaluated in brain tissue.

Polymeric nanoparticles have several advantages, including stability in the bloodstream, greater drug loading, and controlled drug release over time.1 Nance and her team found that 60 and 75 nm particles were the optimal size for delivery in a sick brain, and particles even up to 114 nm in diameter penetrated successfully. Larger particles offer vast flexibility in drug delivery design and have higher drug holding capacity than other approaches. Additional PEG coatings enhance nanoparticle penetration and circulation, and are expected to lead to greater drug distribution in the brain. It was found that even much smaller nanoparticles (40 nm) are essentially immobile in the brain if uncoated.

Tracking particle movement via confocal microscopy, Nance’s team showed that nanoparticles that can penetrate travel safely and quickly to a desired area, while other areas are left untouched. The beauty of their platform lies in the ability to tailor delivery time and tune nanoparticle properties for specific drug delivery purposes in a variety of diseases, like cancer [3]  and newborn brain injury [4].  The team also confirmed minimal tissue damage through the experimental protocols, concluding that the in vivo rat brain tissue maintains physiological functioning during the experimental time frame.

The bottom line? Nance’s brain-penetrating nanoparticles allow localized drug delivery, can be patient- and disease-specific, and are deeper-penetrating than ever before. This research could mean targeted treatment for CNS disorders such as Parkinson’s, Alzheimer's, depression, and epilepsy.

Diverse Applications Mean a Bright Future for this Technology
Nance’s approach to developing this technology was to focus on overarching principles governing the system and use these to adapt to specific complexities, such as honing in on common aspects of disease that influence movement. Previous researchers focused their energies on getting drugs to the brain but not on what came after crossing the blood-brain barrier, Nance explained. “If you’re doing that, you’re not leveraging the technology and maximizing it to the best of its ability. This doesn’t serve diverse patient populations, because these are reasons why your technology doesn’t work.” This project arose from a previously-developed drug delivery platform in the lab of Justin Hanes based on overcoming mucosal barriers, the membrane protective layer that coats your lungs, gastrointestinal tract, and eyes, to name a few. This platform failed to work in the brain, and Nance adapted this technology and meticulously tailored it to its current use in the brain.

This brain-penetrating nanoparticle platform is currently being used in other research, not only in the brain but in other areas of the body for its power as a well-characterized, well-controlled, and bio-inert platform. Collaborators at the University of Virginia combined Nance’s platform with MRI-guided focused ultrasound to effectively visualize drug and nanoparticle movement in the brain, using contrast agents that enhance uptake by the BBB.5 As far as next steps for her, Nance would like to maximize the platform to leverage and control transport in the brain, and get real-time quantitative information about diseases that are not yet well-understood, such as autism. Projects in the Nance lab are currently trying to find out how the autistic brain differs from other brains and how that affects the way therapeutics are delivered. In yet another application, Nance’s lab uses this same technology to track and image the Zika virus (see page xx) in the brain to gain information on how to treat it based on the virus’s mechanism of movement.

The future of nanotechnology is bright, no doubt in part thanks to Nance’s contributions. Nance says that the field has a lot of potential, stating, “I believe nanotechnology will have the ability to provide real-time quantitative information about a disease state, will help reduce healthcare and patient costs, will provide effective and safe therapeutic interventions, and will help provide us with more in-depth understanding about our bodies and how they function.”

Nance Synthesized Motivation, Education, and Knowledge
Nance was inspired to pursue this field of study because of a personal connection. An undiagnosed neurodegenerative disease runs in her family, and witnessing her family members struggle gave her a firsthand view of the shortcomings of research in this field. Medicine could not diagnose the disease, science could not provide an explanation, and neither field could treat it.

Nance admitted that chemistry was not her best subject in high school, but her personal motivation combined with a passion for problem solving led her to pursue her undergraduate degree in Chemical Engineering, with minors in English and biotechnology. The major especially appealed to Nance because students learn broad fundamental principles that they can then apply towards applications that they are interested in. Going into her Ph.D., Nance knew that she wanted to pursue Chemical Engineering with some application to the brain.

From the moment she chose this field, Nance was sure she wanted to pursue a Ph.D. She described how it appealed to her independence, love of learning, and curiosity. She also enjoyed that the amount of “smart time”, intentional and focused time, could directly impact the outcome of her efforts.

While she knew that she wanted a Ph.D., it was not until months into her postdoctoral fellowship that she was set on pursuing academia. Nance’s reservations stemmed from insecurities about whether or not she could come up with enough original ideas to lead a research lab and to get funding. However, she worked through these insecurities using advice from mentors, and by using a problem-solving approach. She says, “I treat insecurities and uncertainties as points of opportunity to gain more information.”

Nance’s passion and excitement about the possibility to revolutionize the field and provide mentorship to students drove her to cast aside these insecurities and join academia. She started as a Clare Luce Booth Assistant Professor at UW in September 2015. Since then, she loves the field she chose to pursue. She was excited to talk to us about the many facets of her job- her research, her role as an instructor, and the mentorship she can offer a diverse body of students every day.

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A Philosophy of Open-Mindedness and Bridging Gaps
Nance’s underlying philosophy is to maintain openness and honesty, both with herself and the students she mentors. She carries this philosophy throughout every aspect in her life, and hopes to be as open as possible about her process of choosing academia and the insecurities that she had. Through this approach, she hopes to make herself more accessible and useful to the students that she mentors.

Nance’s openness to outside opportunities led her to pursue her post-doctoral fellowship at Johns Hopkins School of Medicine, working alongside neuroscientists. She believes that this experience was integral to her training as an engineer, saying, “People should be able to explore non-traditional paths. People should be able to step out of their expertise to get necessary information to allow that expertise to be applied in an efficient way”. She found that getting a post-doctoral position as a chemical engineer in neuroscience was difficult, as people are usually expected to specialize and work in their own field. She hopes that one day, it will be easier for students to gain diverse experience in different fields.

Nance’s lab at UW aims to bridge those gaps, and her mentorship philosophy includes encouraging students to not shut the door on any learning opportunities by the idea of specializing in only one area. One day people in the sciences will be more focused on how we form connections between different fields, and medical outcomes will be improved as a result of this greater scope of knowledge. Nance hopes to touch the lives of students so she can impart her philosophy to those she mentors and make a widespread impact in the culture of the field.

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Nance Creates Opportunities for Mentoring Relationships
Nance’s philosophy and approach make her a rather non-traditional chemical engineer. On top of that, she is one of few women in a male-dominated field. However, she is an ardent supporter of the mindset that she is a chemical engineer first, although she is still proud of the fact that she is a woman. As she said, “Science can be a very lonely road, especially if you feel like you have to work twice as hard for everything you want to achieve, and you want to do it differently than everyone else has done. It can be very difficult but also be very rewarding, and can allow you to have life experiences to share with students going through the same thing.”

This idea, and the realization that women in the chemical engineering department needed a way to connect with each other and share experiences, led Nance to found Women in Chemical Engineering at UW. She noticed how many people came to her seeking advice and perspective from a female faculty member, and decided to create a sustainable network of support for women in the field to find connections, advice, and leadership experience. After forming the initial framework for the group, the students have grown the organization, with undergraduates, graduate students, alumni, and faculty all involved.

Nance’s underlying goal of connectedness in science has also become an overarching theme in her life-- she stressed that she does not see anything as being mutually exclusive. An avid reader, photographer, and animal-lover, Nance maintains a crucial work-life balance by forming connections between everything that she does. She described how even when relaxing with a book, she always thinks about how she can use it in interactions with students or in her job as a professor. Through this, she makes the most of the time that she is at work, while still making time to read and take care of her rescue boxers.

Nance hopes to revolutionize the field of chemical engineering through her non-traditional approach, and to bridge the gaps that still exist between science and medicine. She shows a remarkable passion for connecting with and helping students, having an open door policy, and showing enthusiasm for the wide diversity of stories that she gets to hear every day. But more importantly, she is willing to share her experiences to help guide these students towards the same success that she has attained.

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