2015 SRF Summer Scholar Profile: Katie Manescu

My degree and experience in the processing and manufacturing of biological systems for therapeutic purposes have greatly influenced my passion for regenerative medicine. I have completed a Bachelors of Engineering in Biochemical Engineering at University College London (UCL) where I will be returning to complete the final year of my Masters of Engineering in Bioprocess Management later this year. I am particularly interested in the development and application of biological processes for the treatment and prevention of disease. As a Project Engineer in the Technical Manufacturing Support team at GlaxoSmithKline, I worked on a number of process improvement projects. One of them was the installation and validation of process equipment which contributed to the timely production of Augmentin for global supply, in accordance with regulatory requirements. The plant, which abided by current Good Manufacturing Practices, showed me the types of regulatory challenges, which often inhibit the onset of technological and therapeutic progress.

Joining Prof. Andrea Streit’s research team during a summer internship at the Craniofacial Development and Stem Cell Biology Department at King’s College in London, further strengthened my understanding of the connection between research and clinical applications. Developmental programming exists in the genome, initially, in the form of coding and non-coding genes. Throughout development, specific genes are activated or repressed by various transcription factors which contribute to cellular differentiation. Although the specific components that govern these events have been identified, Prof. Streit realized the importance of defining the Gene Regulatory Networks (GRNs) in order to establish predictive differentiating models during normal development and disease. GRNs offer a systematic explanation of the developmental process, organogenesis and cellular differentiation and thus provide a representation of the cell fate decisions at molecular level.

During my internship, I assisted with the electroporation of small interference DNA at different stages of the chick embryo, a well-understood model system. This helped to evaluate the transcriptional factors and receptors influencing the network components during development. Prof. Streit’s lab devised an experimental workflow describing how to construct a GRN using the chick embryo as a model. The findings on the nature of cellular development as a result of the gene regulatory network were published in the article: “Experimental approaches for gene regulatory network construction: The chick as a model system” Streit A. et al, 2012.

This experience has brought to my attention the importance of bridging the gap between academic research and the application and commercialization of ideas as well as some as the challenges commonly faced by innovators en route to clinical progress. This is essential, particularly in the fast-moving field of regenerative medicine, and is one of the many characteristics of working in the Karp Lab that appeal to me. I am very passionate about the development of research concepts into therapeutic or technological products, particularly the evaluation and translation of an idea into its viable medical potential.

I will continue to foster my interest in regenerative medicine while I work under the guidance of Dr. Jeff Karp and Executive Director Brock Reeve at the Harvard Stem Cell Institute. The Karp Lab has established a multi-disciplinary environment to approach contemporary medical challenges, which has created a successful platform for numerous technologies. I feel both inspired by Dr. Karp’s work and motivated by SENS Research Foundation’s broad-based research to contribute to progress in the field of regenerative medicine.

Cell therapy has been heavily explored in recent years for its therapeutic potential. Increased attention has been given to naturally occurring cellular by-products, extracellular vesicles (EVs), which have been identified to play an important role in cellular communication, and the overall healing process. My project will evaluate the therapeutic potential of extracellular vesicles against established and developing therapies, in particular cell therapy, in order to yield a comparable and informative appraisal to guide research and clinical endeavors.

Systematic Review of the Therapeutic Potential of Extracellular Vesicles (EVs)

Research exploring the potential of EVs as therapeutic agents has exponentially increased in recent years, giving rise to a wide range of unsystematic and uncomparable results. During my time working for SRF at the Harvard Stem Cell Institute and the Karp Lab, I hope to compile a systematic review and meta-analysis of such studies to objectively evaluate the therapeutic potential of EVs. This report will attempt to normalize EV therapy such that researchers can compare it to the efficacy of existing and equivalent therapeutics, particularly cell-based ones.

Intercellular communication is an essential part of cellular development. Eukaryotic cells are able to produce and release membrane-derived vesicles to reach both neighboring and distant cells. These extracellular vesicles contain proteins, lipids, and nucleic acids and play an important role in the maintenance of stem cells, tissue repairs, and immune surveillance as well as a series of other underlying processes in the body. As a result, EVs have been increasingly evaluated for their potential as therapeutic agents in the treatment of such health problems as cerebrovascular and myocardial conditions, vascular diseases, pulmonary diseases, immune diseases, traumas and musculoskeletal disorders.

Figure 1. Extracellular vesicle formation and composition[3].

Eukaryotic cells give rise to EVs through a variety of ways: ectosomes and microparticles are produced via direct membrane budding while exosomes are released via internal multivesicular components. Although this can give rise to membrane vesicles of different sizes, they typically functionally resemble the parent cell. Microvesicles can exist in the range of 50 – 1000nm, while exosomes are much smaller in the range of 40 – 120nm [2]. Figure 1 shows an example of common EV contents and displays the process by which EVs are commonly released from the cell.

The outcome of this report will help to define the expectations and potential of EV therapeutics. I hope that through reconciling heterogeneity in EV research, results will become more comparable and informative and help guide this emerging field towards feasible endpoints.

Future Plans:

I am interested in developing my understanding of the body’s adaptability to disease and functional defects in order to identify ways in which we could replicate the process through regenerative medicine. I aim to remain deeply involved in the development and commercialization of clinical therapeutics, where I can contribute to the translation of scientific discoveries into viable medical applications.

References:

[1] “Experimental approaches for gene regulatory network construction: The chick as a model system”, Streit A., Tambalo M., Chen J., Grocott T., Anwar M., Sosinsky A., Stern C. D., 2012.

[2] “Exosomes: Current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials”, Vlassov A., Magdaleno S., Setterquist R., Conrad R., 2012.

[3] “Extracellular Vesicles Commercial Potential As Byproducts of Cell Manufacturing for Research and Therapeutic Use”, Smith J. A., Ng K. S., Mean B. E., Dopson S., Reeve B., Edwards J., Wood M. J. A., Carr A. J., Bure K., Karp J. M., Brindley D. A., 2015.

2015 SRF Summer Scholar Profile: Dee Luo

My name is Dee Luo, and I am a rising senior at the University of Pennsylvania working towards a degree in the Biological Basis of Behavior from the College of Arts and Sciences and a minor in Healthcare Management from the Wharton School of Business. This summer, I am working with Dr. David Brindley, Dr. David DiGiusto, Anthony Davies, and Kirk Trisler to investigate regulation strategies in regenerative medicine.

My past research encompasses both clinical and benchwork experience. As an independent student researcher under Dr. David Asch and Dr. Ben Roman at the Leonard Davis Institute of Health Economics under Dr. David Asch and Dr. Ben Roman, I was able to conduct an investigation on the effective use of Positron Emission Tomography combined with Computed Tomography (PET/CT) scans to detect reoccurring tumors as a patient management tool. In today’s medical climate, advancements in medical imaging technologies show great therapeutic promise, but the accompanying price tags pose an increasingly more difficult obstacle in the effort to reduce healthcare expenditures in the United States. One such costly new imaging modality, PET/CT scans, showed promise in detecting reoccurring tumors. However, at the time of discovery, there wasn’t enough data to either prove or disprove the efficacy of the scans. The Centers of Medicare and Medicaid Services (CMS) therefore conditionally covered the usage of such scans in an effort to accumulate data. However, when a formal evaluation two years later showed there is little evidence to support the effectiveness of PET/CT to detect reoccurring tumors, the technology was already widely incorporated into clinical practice and attempts to withdraw coverage for the procedure was met with so much physician backlash that CMS revised their decision to allow three PET/CT scans per cancer patient.1

We sought to determine whether physician rationaleeasons for supporting low value care could be explained by sufficient perceived benefit of PET/CT and/or loss aversion. Content analysis proceeded through several stages, resulting in the identification ofa 7 main reasons. The results are currently being analyzed, with prominent trends such as loss aversion promising some surprising results that could tie health economics more closely with business models.

The research I conducted on the inefficiencies in healthcare policy made me realize the crucial importance regulation has on the ability of medicine to help patients. If guiding policy is outdated or misinformed, a therapy might never pass regulations, and the patient population will continue to suffer. On the other hand, if a promising technology is released into market that doesn’t measure up, the entire healthcare economy has to shoulder that expense. This interest in regulation drew me to SENS Research Foundation, because the cutting edge research being conducted in regenerative medicine at SRF is exactly where regulatory science research is needed.

My benchwork stems from an acknowledgement that all policy suggestions should come from a background based in science. As a current assistant researcher under Dr. Gordon Barr at the Children’s Hospital of Pennsylvania Department of Anesthesiology and Critical Care Management, I study acute and chronic pain management from a developmental perspective. When infants are admitted into intensive care, they undergo painful tests and procedures that utilize anesthetic opiates such as morphine.2 Infant models for morphine withdrawal are currently unstudied. I am investigatinge the novel mechanisms for infant pain management through formalin-induced c-fos expression in areas associated with pain perception, namely the periaqueductal gray of the midbrain, of model rats.3 I have high hopes that this research will break grounds in the standard of care in the neonatal intensive care unit.

An Evaluation of Market Dynamics in Regenerative Medicine

My research with SRF at Stanford University, supervised by Dr. David Brindley and Dr. David DiGiusto, will focus on the regulatory environment for combinational therapies in regenerative medicine. Regulatory science is an interdisciplinary field that focuses on standardization and optimization of healthcare innovations. The recent advances in highly promising yet extraordinarily expensive stratified medicines offer unique challenges for developing regulation. There are groundbreaking combinational therapies that attack the root of previously incurable diseases, such as breast cancer, but regulations can often limit the innovation of such drugs or create such a high cost that the price is unsustainable for the healthcare economy. Therefore, my research investigating the areas of regulation that can be improved will have vast influence on the ability of the pharmaceutical industry to develop crucial therapies.

Figure 1. Companion diagnostic development and regulation concomitant with drug therapy development.

This is a basic overview of the regulatory approval pathway for co-developing a therapeutic and its companion diagnostic. The relationship and timeline between drug and diagnostic as shown by the purple double arrows is an approximation.

I plan to identify the regulatory barriers in regenerative medicine by examining the market dynamics of breakthrough combination therapies. Combinational therapies consist of a drug therapy and a diagnostic, a model that is similar to many regenerative medicine therapeutics, which require a cellular component and a device. By examining such criteria as the attrition rates, target population sizes, and prices, I hope to identify novelew relationships between the two components of combination therapies. Then, I plan to examine regenerative medicines on the market based on the same criteria and suggest improvements to the regenerative medicine regulatory process. Because the advent of regenerative medicine is relatively recent, and regulation of these therapeutics is still under development, this research is timely.

Through understanding the factors that influence the availability of combinational therapies currently on the market, I hope to construct a regulatory decision support tool that will help academic innovators improve or develop a regulatory strategy for regenerative medicine.

Future Plans:

I hope to continue conducting impactful research and apply to medical school an undecided number of years after I graduate. I believe that for medicine to improve, there has to be more interaction between the stakeholders in healthcare. Therefore, I hope to continue conducting research in clinical management, while gaining a solid understanding of the field from a physician’s perspective, and eventually use my background in the two perspectives to create innovative solutions. Along the way, I hope to continue developing my skills as an avid dancer and writer.

References:

1. “Proposed Decision Memo for Positron Emission Tomography (FDG) for Solid Tumors (CAG-00181R4”. The Centers for Medicare and Medicaid Services. Washington.

2. Barr, GA. “Formalin-induced c-fos expression in the brain of infant rats.” J Pain. (2011): 263-71.

3. Meadows, NA, Morrison, A, Brindley, DA. “An evaluation of regulatory and commercial barriers to stratified medicine development.” The Pharmacogenomics Journal. (2014): 1-7.

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