Improving Drug Discovery With Organoid-Based “Phase 0” Testing
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Technology Networks recently had the pleasure of speaking with Soumita Das, associate professor at the University of California San Diego, to learn more about her work with organoids and some of the research activities at the HUMANOID™ Center of Research Excellence, where she is chief scientific director.
Das also discusses HUMANOID’s approach to clinical trials, which aims to reduce the failure rate of drugs by testing candidates in multi-dimensional human organoid-based disease models as part of “Phase 0” trials.
Laura Lansdowne (LL): What area of research is your lab focused on? Can you tell us about the HUMANOID Center of Research Excellence (CoRE)?
Soumita Das (SD): My lab is interested in identifying the three-way crosstalk and interactions between gastrointestinal epithelial cells, immune cells and microbes (beneficial as well as pathogenic). The host gut barrier is disrupted after encountering microbes, toxins and/or microbial products linked to inflammation and chronic diseases. Inflammation following infection also leads to DNA damage, which predisposes the epithelium to neoplastic transformation and cancer progression. Our recently developed gut organoid/gut-on-a-dish model comprising epithelial cells, immune cells and microbes is helpful when investigating mechanisms related to gastrointestinal inflammatory diseases – both oncogenic and non-oncogenic. The model is particularly useful for identifying new diagnostic and therapeutic targets, identifying beneficial vs harmful microbes, nutritional components and screening the efficacy of drugs to combat inflammation-linked diseases. The lab's core expertise is biochemistry, molecular biology, cell biology, microbial pathogenesis and mucosal immunology.
In collaboration with Dr Pradipta Ghosh and other University of California San Diego faculty members/industry partners, we have initiated the HUMANOID project to develop the Organoid CoRE, where I work as the faculty director.
The following are the major focus of HUMANOID CoRE:
- HUMANOID is dedicated to building and validating preclinical human healthy and disease models as platforms for research and drug development by enabling early ex vivo testing for toxicity and efficacy.
- With few exceptions, all tissues from human, mouse, embryonic, adult, diseased, normal, iPSCs, can be developed into organoids and subsequently into disease models with a few network-guided tweaks.
- Our ex vivo models recreate in vivo complexity by making multi-dimensional organoids by exploiting co-culture techniques that capture the three-dimensional nature of organoid tissues plus the microbiome and immune or non-immune cells.
- In powerful synergy with the computational team under the guidance of Dr Debashish Sahoo, and through use of AI-assisted target discovery, HUMANOID can build personalized models with patient tissue – to enable “precisionalized” medicine.
- HUMANOID collaborates with an extensive network of clinicians, industry collaborators and basic scientists, both on and off-campus.
- HUMANOID enables the research community to access and experiment with primary human cells, organoids, organoid-derived monolayers, derivatives of organoids, support sponsored research projects, provide consultation, offer formal and informal education on organoid research and more. More information can be found here.
HUMANOID can successfully isolate, expand and biobank three-dimensional (3D) organoids from healthy and diseased human tissues, isolate and biobank primary cells, and develop models for studying organ physiology or human diseases. It also supports the collaboration for assay design and validation for the development of novel diagnostic and therapeutic avenues using human disease models. HUMANOID builds the disease model based on the computational lab's prediction data, translating the research from a potential target to an effective drug that is poised to enter clinical trials and much more likely to succeed. More importantly, patient-derived organoid models for all human diseases will help “weed out” ineffective drugs at an early stage in drug discovery, helping to reduce the financial burden and avoid false hope.
Anna MacDonald (AM): Can you explain what a “Phase 0” clinical trial is? What difference could they make to drug discovery?
SD: Generally, every drug goes through a pipeline of triphasic testing before the US Food and Drug Administration (FDA) can approve them. These stages include Phase 1 to primarily assess safety; Phase 2 to confirm safety and assess some efficacy; and Phase 3, the pivotal efficacy trial. Most drugs fail somewhere along this pipeline, many in the last phase because of a primary lack of efficacy. Companies must increase the price of their successful drugs to counteract the money lost from developing unsuccessful ones. Scientists and clinical trial specialists spend much of their careers pursuing failures, while unfortunately, patients standby awaiting treatment.
HUMANOID’s team of scientists has taken a new approach to human clinical trials by introducing “Phase 0”. Before a drug progresses to clinical testing in human participants, Phase 0 is introduced to test the candidate’s efficacy in multi-dimensional human organoid-based disease models-in-a-dish. This helps to identify and eliminate ineffective compounds earlier on in the process. Currently, most drugs are validated in two-dimensional (2D) cultured cells, which usually represent just one cell type. This simplistic model fails to recapitulate human tissues' multi-dimensional nature where multiple cell types (epithelial, stromal, immune) interact in three dimensions within the extracellular matrix, and some tissues have additional dimensions such as coexisting microbes. Using patient-derived stem cells to grow into organoids, HUMANOID is changing the game by reverse-engineering these complex multi-dimensional healthy and diseased human tissues, one cell at a time.
HUMANOID recreates this complexity with 3D (and more as needed) organoids derived from patient stem cells. These organoids contain many cell types and, because they are generated from a patient’s actual tissues, they better recapitulate the disease biology. If a given organ model or disease state demands the addition of microbes and immune or non-immune support cells, we add that too; in other words, we build up the complexity that is essential to study any given condition. Because these organoid-based models recapitulate key critical aspects of the human disease condition, they offer an efficient model to test a potential drug’s efficacy and ADME-Tox properties in real-time.
LL: How have advances in 3D cell culture technology impacted your research?
SD: My lab had an urgent need for an epithelial cell model that mimics in vivo human physiology. Stem-cell-based 3D cell culture has helped us to create human tissue specimens successfully in a culture dish. Each individuals’ genotype and phenotype is represented by the 3D cell line that is generated from each patient.
Soumita Das was speaking to Laura Elizabeth Lansdowne, Managing Editor, and Anna MacDonald, Science Writer for Technology Networks.
