Advancing Drug Discovery through Structural Biology with Diane Joseph-McCarthy, Boston University

About the Interviewee (Sourced from Boston University – College of Engineering’s Official Website)

Dr. Diane Joseph-McCarthy is the Executive Director of the Bioengineering Technology & Entrepreneurship Center (BTEC) and Professor of the Practice in Biomedical Engineering at Boston University.

Before joining Boston University (BU), she was a senior life science executive with over 20 years of drug discovery, development, and leadership experience in the pharmaceutical and biotechnology sector. She was the Senior Vice President of Discovery & Early Development at EnBiotix, a BU spinout company focused on bioengineering novel antibacterials. She was an Associate Director in the Infection iMED at AstraZeneca, where she led an innovative group of scientists as well as a global team in Predictive Science. Prior to that at Wyeth, she held positions of increasing responsibility. She has been actively involved in the discovery of several compounds that have reached clinical trials.

Dr. Diane Joseph-McCarthy received her Bachelor of Arts in Chemistry with a minor in Computer Science from Boston University, her Ph.D. in Physical Chemistry from Massachusetts Institute of Technology (MIT), and was a postdoctoral fellow at Harvard University and Harvard Medical School. She has more than 75 publications/patents and has given numerous invited talks. She also has served as a member of the National Academy of Sciences Polio Antiviral Advisory Committee.

The Discussion

Banking on Early Phase Innovation in the Field of Drug Development to Enrich Patient Care

[Dex Marco]: It’s such a pleasure to have you here with us today, Dr. Diane. With over 2 decades of proven track record in leadership in pharmaceutical and biotechnological drug discovery and development and industrial and academic research, what would you say drove you towards this field, and what brought you to eventually accept the Directorship position at the Bioengineering Technology & Entrepreneurship Center (BTEC) and the Practice in Biomedical Engineering Professorship position at Boston University?

[Dr. Diane]: Well, that’s a far-reaching question. My journey through the pharmaceutical and biotechnological realms, and eventually to the Executive Director position at the Bioengineering Technology & Entrepreneurship Center (BTEC) and the Practice in Biomedical Engineering Professorship position at Boston University, is deeply rooted in a passion for innovative early-stage technologies and their application in drug discovery to enhance patient care.

I began as a computational chemist and biologist during my academic years, focusing on structure-based bioinformatics. That laid the foundation for my entrance into the pharmaceutical world. At Genetics Institute, which later became part of Wyeth‘s research division, I spent a decade working closely with medicinal chemists on diverse drug discovery projects. It was here I delved into various therapeutic areas, but I was particularly focused on inflammation research.

A new chapter unfolded at AstraZeneca, where I led an Infectious Disease computational sciences group. My team and I pioneered breakthroughs in antibacterial drug development which was an exhilarating challenge in its own right. I, then, ventured into the world of start-ups, as a founding member of a bioengineering company rooted in innovative antibacterials. This experience exposed me to all facets of business decision-making and steering science and technology directions.

Then, the opportunity at Boston University arose. I assumed the leadership role at BTEC, a center under construction, which provided an exceptional opportunity to shape its vision, build it from the ground up, and act as a bridge between academia and industry. This theme of building from the ground up is a recurring one in my career, and it’s been incredibly fulfilling.

At BU, I also co-teach the Biomedical Engineering senior design course, where students embark on year-long projects, often with industry advisors. This interaction with students and industry has been an enriching part of my role. In tandem with these responsibilities, I continue my own research, primarily focused on computational drug discovery, employing novel computational methodologies.

Throughout my journey, the emphasis has always been on continuous learning and growth. It’s an exciting cycle of starting afresh, building, and learning, no matter the position. This path has also always had a mentoring component, whether it’s guiding enthusiastic students or co-chairing the board of a peer-to-peer mentoring group called New England Women in Science Executives (NEWISE) Club, which comprises senior-level women in the field.

My career trajectory has been about unceasing curiosity, growth, and mentoring, and I’m thrilled to have the opportunity to contribute to both education and innovation at Boston University’s BTEC.

Magnifying Research Capabilities with Cryogenic Electron Microscopy and the Predictive Power of AI

[Dex Marco]: Considering the evolving landscape of structural biology and its implications for drug discovery, especially in the context of cryo-electron microscopy’s capabilities to elucidate intricate details of elusive drug targets, and the synergistic integration of artificial intelligence to expedite drug development, can you explain how your strategic leadership would navigate the intricate balance between investing in cutting-edge cryo-EM technologies and establishing a robust AI framework? Furthermore, how do you envision overcoming the multifaceted challenges that arise, spanning from optimizing cryo-EM protocols for diverse target classes to harnessing AI algorithms for predictive modeling of drug interactions, in order to position your organization at the forefront of innovative and effective drug discovery?

[Dr. Diane]: The landscape of structural biology is indeed evolving rapidly, and the integration of cutting-edge technologies like cryo-electron microscopy (cryo-EM) and artificial intelligence (AI) is profoundly reshaping drug discovery. It’s an exciting time to be at the forefront of this field.

Cryo-EM has enabled us to unlock the intricate details of elusive drug targets, and we’re witnessing a surge in high-resolution structures for a wide range of targets, including the recent breakthroughs in SARS-CoV-2 structures. These structures have opened doors for more precise structure-based drug design. Our work has benefited from these advancements by expanding the range of targets that computational hot spot mapping and fragment-based drug discovery approaches can be applied, aiding us in identifying druggable sites within proteins and, subsequently, potential drug targets.

In terms of differentiating between X-ray and cryo-EM structures, I believe that, with sufficient resolution, cryo-EM structures are indeed suitable for computational drug design. The resolution and quality of cryo-EM structures have reached a point where they are on par with X-ray structures in many cases.

Moving on to AI, it’s not just about predicting protein structures, although AlphaFold from DeepMind has certainly been a game-changer in that regard. AI is opening up a plethora of opportunities for structure-based drug discovery. With AI, we can generate models for proteins that were previously difficult to study through traditional means. This expands the scope of potential drug targets. Additionally, AI is helping us with generative chemistry, sparking new ideas for molecules. We’re making strides in incorporating AI into synthesis considerations, making previously unpractical ideas more viable. This trend is set to increase further in the coming years.

At Boston University, I am a co-PI on an NSF Predictive Intelligence for Pandemic Preparedness that involves a large multi-disciplinary team.  As part of that effort, we are applying structure-guided computational approaches to develop mitigation strategies for emerging pathogens.  We are, for example, utilizing large language models, like ChatGPT-4 with engineered prompts, to mine the literature for potential drug targets and then advanced hot spot mapping techniques for identifying druggable sites on these proteins of interest.  This work involves integrating X-ray and cryo-EM structural information with structural model predictions produced by AlphaFold.  If a druggable site can be determined with a reasonable confidence for a given target that information can then be used for drug repurposing efforts.  The synergy between AI and more traditional computational drug discovery approaches stands out as a formidable force in expanding the toolbox available for transforming drug discovery.

In essence, our approach is to leverage the synergistic potential of structural information and AI while keeping a close eye on innovations in the field. This will enable us to address multifaceted challenges. By constantly evolving with the field, we aim to position our research at the forefront of innovative and effective drug discovery.

Complementing Scientific Experimentation with Structure-Based Computation

[Dex Marco]: Drawing upon your wealth of experience in the biotechnology landscape, we recognize the pivotal role that structure-guided computational techniques play in modern drug development. Could you provide us with a comprehensive overview of a particularly intricate drug discovery endeavor where the amalgamation of structure-guided computational methods had seamlessly integrated with experimental efforts?

[Dr. Diane]: Over the years, my track through the biotechnology landscape has been a fascinating one, and I’ve had the privilege to be a part of various drug discovery endeavors that highlighted the importance of structure-guided computational methods seamlessly integrated with experimental efforts.

One significant chapter of this journey unfolded during my time at AstraZeneca. We adopted a holistic approach where structure-based techniques were not merely a supplement but an integral part of our drug discovery process. Our strategy was to apply these techniques right from the inception of target selection.

At AstraZeneca, we had a dedicated Target Evaluation Team, which meticulously analyzed the structural bioinformatics of potential drug targets. This process entailed a two-fold examination – first, we assessed the druggability of the target, and second, we evaluated its homology to human targets we needed to avoid. This was particularly critical in the context of developing antibacterials.

Virtual screening and high throughput screening went hand-in-hand in our workflow. They complemented each other, with virtual screening often offering us valuable, albeit sometimes weak, hits that served as early compounds or starting points for lead optimization.

As we progressed into lead optimization, structural data took center stage. We conducted extensive modeling, made the most of available structures, and worked closely with our team of medicinal chemists in an iterative fashion. The synergy between computational approaches and experimental chemistry was instrumental in refining our leads.

This approach allowed us to not only identify promising drug targets but also to efficiently optimize leads, ultimately moving us closer to developing effective medications. It’s important to emphasize that in drug discovery, this seamless integration of computational and experimental methods has become a bedrock for efficiency and success.

This experience underlines the pivotal role of structure-guided computational techniques in the dynamic and ever-evolving field of modern drug development. It’s a testament to the power of collaboration and innovation in our quest to address challenging healthcare issues.

Shaping Modern Drug Development in the Age of Data

[Dex Marco]: In the dynamic continuum between traditional drug development techniques and the modern arsenal of biophysics, chemical biology, computational science, and advanced tools, you’ve witnessed the evolution firsthand. Could you expound on a transformative drug development project you’ve been involved in, encompassing both eras? Highlight how this juxtaposition not only expedited target identification and validation but also orchestrated a seamless transition from lab bench to clinical promise.

[Dr. Diane]: When reflecting on the various aspects of drug development, it’s apparent that the intersection of traditional methodologies and cutting-edge approaches has been the catalyst for transformative breakthroughs. One project that vividly encapsulates this dynamic juxtaposition was a multidisciplinary endeavor to hasten target identification and validation, seamlessly guiding us from laboratory experimentation to the promise of clinical translation.

In this endeavor, we harnessed a diverse array of data streams, seamlessly integrating insights from high-content screening, omics data, and intricate structural details concerning the target in question. This multidimensional approach not only broadened our perspective but also allowed us to gain a more profound understanding of the intricacies surrounding the biological target.

In particular, we adopted a holistic view, fusing insights from systems biology modeling into our repertoire. By exploring the cellular system as an intricate, interconnected network, we could better discern the nuances of various pathways and their interplay. This holistic perspective empowered us to make more informed decisions throughout the drug development process.

Moreover, this integration not only expedited the pace of our work but also significantly improved the quality of our decision-making. It allowed us to pinpoint promising drug candidates more efficiently and mitigate the risks associated with clinical translation.

As we look ahead, I firmly believe that this fusion of knowledge domains and data streams will continue to shape the future of drug development. The potential for breakthroughs lies in the convergence of diverse disciplines, making the boundaries between traditional and modern techniques increasingly porous. By embracing this dynamic continuum, we’re poised to make even greater strides in the years to come, ultimately benefiting patients and healthcare as a whole.

Expediting the Bench to Bedside Process with Strong Collaboration

[Dex Marco]: Dr. Diane, your illustrious career journey vividly illustrates your adeptness at bridging the chasm between pioneering research and tangible clinical advancements. As we delve into the annals of your leadership roles and indelible contributions to diverse therapeutic domains, we are eager for your culminating insights on the strategic navigational compass that has steered your achievements. In the intricate tapestry woven by multidisciplinary cohorts, bleeding-edge technologies, and the high-stakes realm of clinical progression, we are intrigued to uncover the architectural blueprints behind your consistent triumphs. Can you explain in detail how you manage to bring together resources, knowledge, and innovation to create clinical candidates that merge scientific potential with patients’ needs?

[Dr. Diane]: Thank you for your question. Success in bridging the gap between pioneering research and clinical advancements requires a combination of tenacity and adaptability. One example that comes to mind is during my time at a startup. We pivoted to developing a late-stage asset through drug repurposing. The particular compound, Colistin, was approved for intravenous use everywhere but only in Europe for inhalation, we licensed the ex-European worldwide rights to ColiFin® for inhalation, targeting pseudomonas infections in cystic fibrosis patients.

Our focus was on navigating through regulatory processes and advancing the compound into Phase 3 clinical trials. It’s crucial in these instances to maintain open lines of communication and ensure that each functional unit understands the others’ actions and motivations. In a larger company, you have the advantage of well-defined departments, each responsible for specific functions, and the challenge is keeping them coordinated. In a smaller setting, like our startup, you often find yourself rolling up your sleeves and taking on various roles, working closely with partners and regulatory consultants to fill the expertise gaps.

Now, regarding your question about the speed of output in big companies versus smaller ones, it’s a matter of perspective. In larger organizations, you certainly have more resources at your disposal, but you might also encounter more layers of bureaucracy, which can slow down the decision-making process. In contrast, smaller teams are nimble and highly focused. You can rapidly pivot to address specific challenges.

In academia, such as at Boston University, I’m fortunate to work with brilliant collaborators across various departments. There’s a constant flow of innovative ideas, and it’s like having a treasure trove of expertise at your fingertips. Whether in a big or small setting, the key to success is a combination of resourcefulness, adaptability, and strong collaboration.

I hope this provides a more in-depth insight into how we merge scientific potential with patients’ needs and the diverse resources we utilize to achieve that goal.

Drug Discovery Legacy: From Good to Great, Great By Choice, Now Built to Last

[Dex Marco]: As a distinguished researcher in the realms of biophysics and chemical biology, your expertise bridges foundational principles with cutting-edge applications. Considering your profound understanding of identifying binding sites, deciphering ligand interactions, and crafting potent, selective drugs, how would you guide the next generation of scientists toward transcending the boundaries of traditional approaches? Perhaps, you may outline a visionary educational strategy that not only imparts the core techniques but also nurtures innovation by leveraging emerging technologies like AI, machine learning, and advanced structural analyses. Furthermore, detail how you would instill a deep appreciation for both the artistry and precision inherent in drug design, inspiring young minds to sculpt the future of therapeutic discovery.

[Dr. Diane]: In the ever-evolving landscape of biophysics and chemical biology, it’s paramount that we not only equip the next generation of scientists with a strong foundation but also inspire them to innovate using emerging technologies. To do this, we need to foster an environment that not only imparts core techniques but also nurtures creativity and a deep appreciation for the advanced technologies inherent in drug design.

At the Bioengineering Technology and Entrepreneurship Center (BTEC) that I have the privilege of leading, we’re all about the student experience. We believe in hands-on learning, and we know the value of working closely with faculty members and industry experts to tackle real-world problems. This collaboration enables students to apply cutting-edge technologies to complex issues, which is where the magic happens.

My advice to budding scientists is simple: Follow your passion, even when it leads you to challenging subjects. Often, that’s where the most growth occurs. Practical experience is invaluable. Don’t hesitate to roll up your sleeves and engage in research, especially when you confront difficult, unanswered questions. The beauty of research lies in its uncertainty. It’s the discovery of solutions to these unknowns that makes the process exhilarating and intellectually stimulating.

Don’t be afraid to explore uncharted territories. Dive in and work on problems that genuinely pique your interest, and seek guidance from mentors and collaborators who can offer insights and support. Education is the cornerstone, and you can pursue it at a university, through internships with companies, or during a postdoc – whether it’s in academia or industry. These diverse experiences will help you discover your true calling.

In our center, we focus on three critical areas: digital and predictive medicine, where my own research primarily lies, biosensors and instrumentation, and molecular, cellular, and tissue engineering. These fields represent the forefront of biomedical engineering, and I believe they will witness remarkable advances in the coming years.

So, to the next generation of scientists, embrace the unknown, stay curious, and be unafraid of challenges. It is in these moments of discomfort that you’ll find your true potential and, ultimately, sculpt the future of therapeutic discovery.

Engr. Dex Marco Tiu Guibelondo, B.Sc. Pharm, R.Ph., B.Sc. CpE

Editor-in-Chief, PharmaFEATURES

Join Proventa International’s 10th Annual Drug Discovery Biology Strategy Meeting at Le Meridien Boston Cambridge, Massachusetts this 7th of November 2023 to learn more about Structural Biology and Biophysics (Track 5) in the realm of drug development. Click on the photo below to download the brochure for the event.