The Need for Nuance in Preclinical R&D

Bryan Yoo
February 2024
5 min read

Bryan Yoo is co-founder and CEO of Nuanced Health. Bryan completed his PhD in Cellular and Molecular Neurobiology at Caltech in the Mazmanian Lab. Previously, he was a venture fellow at Flagship Pioneering and an operator at multiple early-stage startups. Bryan graduated from Stanford University with a B.S. in Biology and enjoys spending time with his daughter and following the 49ers.

Our Companions

We are never alone. Everywhere we go, from birth until death, we carry trillions of microscopic companions with us. On average, the human gut harbors 100,000,000,000,000 bacteria from hundreds of unique species, and scientists refer to this bacterial constellation as the gut microbiome. The gut microbiome acts as the interface between the outside world and our bodies, helping us process food, fight infections, and maintain homeostasis. Mammals have co-evolved with their intestinal bacteria for millions of years, and maintaining this symbiosis is critical for the survival of nearly all vertebrates today.

Intestinal bacteria affect the development and regulation of the immune and metabolic systems through direct interactions with our gastrointestinal system. However, the gut microbiome also has systemic impacts on human biology which reach far beyond the gut itself: 80% of the molecules circulating in human blood are significantly modulated by our gut microbiome. These small molecules in our bloodstream, collectively called the metabolome, reach tissues throughout the entire body via the circulatory system and have robust impacts on health and disease.

A New Frontier

From 2013 to 2023, there was a 20-fold increase in PubMed publications with the term “gut microbiome” in the title. This revolution in microbiology has yielded critical insights into the importance of a healthy gut microbiome, not only to prevent intestinal disease but also for systemic health.

Researchers and clinicians now know that dysbiosis of the gut microbiome is strongly associated with intestinal disorders like Crohn’s disease, ulcerative colitis, irritable bowel syndrome, and coeliac disease as well as extra-intestinal disorders like cancer, diabetes, cardiovascular disease, obesity, allergy, asthma, Parkinson’s disease, and autism spectrum disorder. This incredibly wide range of disease pathologies demonstrates the systemic impact that the microbiome has on our bodies through immunomodulation, metabolic control, large and small molecule synthesis, and many other mechanisms.

Additionally, recent research has revealed the essential role of the gut microbiome in clinical response to a wide range of therapeutic modalities. Commensal bacteria have been implicated in clinical response to immunotherapy, cell therapy, radiation, and chemotherapy for cancer, cardiometabolic therapeutics and statins for metabolic disorders, cytokine and integrin targeting antibodies and methotrexate for inflammatory disease, vaccines for infectious disease, and dopamine precursors for neurological disorders.

A Microbial Fingerprint

A healthy symbiosis between bacteria and host is essential for the health and wellbeing of all humans. At the same time, however, there is no singular “healthy” human gut microbiome. Instead, each of us has a unique fingerprint of bacterial species with varying abundances, highly dependent on our genetics and our environment. Significant differences in the gut microbiome are seen across regions, races, genders, and lifestyles.

Our microbiomes are unique, and they are also constantly evolving. As we adopt new diets, move to new cities, and share germs with our kids and pets, our microbiome flexibly adapts. Throughout our life, the bacterial species in our gut bloom and fade to accommodate our changing environment. Therefore, the gut microbiome can also be studied as an imprint of the environment on human biological systems.

The Environment's Imprint

While traditional drug development research has focused on genetic drivers of disease, 45% of global deaths are attributable to dietary and non-dietary environmental factors. These environmental drivers of disease often act subtly, complexly, and on long timescales, making them very difficult to study.

Until recently, the primary way to interrogate environmental disease burden has been through enormous, longitudinal cohort studies in humans. One such study, the Framingham Heart Study, followed over 14,000 participants for over 75 years to study cardiovascular outcomes. This herculean effort revealed actionable medical insights and led healthcare providers to begin to measure key biomarkers like blood pressure, cholesterol, and triglycerides in the clinic. Other massive cohort studies include the Seven Countries Study, which followed over 12,700 participants for over 65 years, the Nurses Health Study, which surveyed over 280,000 participants over 47 years, and the Harvard Study of Adult Development, which followed over 1,500 participants for over 85 years. These efforts have generated important biomedical findings and saved countless lives as a result. However, following tens of thousands of patients over many decades is neither an efficient nor a scalable way to interrogate the environmental and behavioral determinants of health.

For most other biological questions where human studies prove too lengthy, costly, and invasive, researchers turn to model organisms, especially rodents. Environmental drivers of health and disease including diet, air quality, location, and behavior, however, have been systematically treated as noise that should be reduced in preclinical animal studies. In hopes of achieving more controlled experiments, researchers intentionally hold these environmental variables, which we now know have massive impacts on human health, constant.

Poor Models

Mice are the workhorse of preclinical drug discovery and development, as they inhabit a sweet spot of relative similarity to human biology, manageable size, and fast growth. In all mouse studies, the goal is to represent human biology. However, current mouse models fail to do so in one key way: they have gut microbiomes that do not resemble our own whatsoever. These mice, usually sold to academic and industry research groups by commercial vendors, have been bred to all have the same, stable microbiome. While this reduces variability in experiments, these intentionally reductionist models cannot be effectively used to study the gut microbiome and the many environmental drivers of disease.

There are two important shortcomings with currently available commercial mouse models. First, the commercially available mice share few microbial species with humans. That is, most of the bacteria that profoundly shape our own biology are not present in the mice that researchers use to represent us. Second, and equally important, commercially available mice fail to represent the immense microbial diversity that is seen among humans; diversity that arises from each of our unique environmental and biological circumstances.

These traditional “n of 1” models reduce the enormous diversity of the human microbiome to one singular mouse – a mouse that also shares very few bacterial species with any humans at all.

Time for a Change

Nuanced Health solves this challenge by generating preclinical models that recreate the taxonomy and diversity of the human gut microbiome, providing novel ways to interrogate environmental drivers of disease. In the next post, we will outline why the time is now to fully integrate microbiology into biopharma workflows, how our groundbreaking technology can revolutionize preclinical research and development, and how you can join us on our mission to create therapeutics that work for everyone.

Click below to read the second post in this series, where we outline our unique approach to preclinical R&D. We’d also love to hear from you at

Led by Caltech co-founders Sarkis Mazmanian and Bryan Yoo, Nuanced Health uncovers the environment’s biological imprint on human health, fundamentally advancing our understanding of diseases and our ability to treat them. By systematically introducing microbial variability into preclinical models, we elucidate complex molecular, cellular, and physiological impact of the microbiome on health. These next-generation models recreate human biochemistry, physiology, disease progression, and drug response at never-before-seen fidelity and scale. By leveraging high-resolution, diverse multi-omic data, we develop therapeutics that are evolutionarily designed for humans, enhance the efficacy of existing therapeutic modalities, and maximize the efficiency of drug development paradigms. Nuanced was founded in 2021 with a transformative thesis backed by lead investment from 8VC and co-investors Freeflow, Gaingels, Open Field Capital, Heritage Group, Luma Bio-IT SPV, Presight Capital, Axial, January River, and other top investors, angels, and operators.

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