Roadmap to Precision Medicine: Role of Human In Vitro Translational Assays

Precision medicine is the personalized approach to human disease that considers individual people’s differences in genetics, environment, and lifestyle. The goal of precision medicine is the right medicine to the right patient at the right time.

Achieving this goal will require a deeper understanding of human disease biology than currently exists. While animal studies have long contributed to our knowledge about many fundamental aspects of biology, precision medicine requires human-specific approaches to address species differences.

Animals are missing human-specific regulatory mechanisms

Research animals are missing major swaths of regulatory mechanisms present in humans. These biological mechanisms reflect differences in size, lifespan, and environment. And they regulate important areas of biology such as cell proliferation, the cardiovascular system and immune biology, among others (see here).

Human-specific mechanisms impact our ability to accurately test for efficacy and safety. The lack of predictive models that reflect human-specific biology likely contributes to the high failure rate of new medicines in clinical trials (Scannell, 2022).

Precision medicine requires human-specific approaches

Precision medicine often refers to clinical outcome studies evaluating patient cohorts for genomic and other associations. These studies have led to breakthroughs in our understanding of disease biology, including the discovery of novel, human-specific targets.

Complementary approaches using in vitro studies with human cell-based assays and platforms also contribute to the goals of precision medicine. They support target confirmation and enable detailed investigation of patient-specific pathway mechanisms. In toxicology or safety testing, these in vitroapproaches are known as new approach methods (NAMs). In drug discovery, human in vitro translational assays are NAMs (also known as novel alternative methods) that can also be used to support efficacy testing.

Human in vitro translational assays are NAMs for drug discovery

Human in vitro translational assays are cell-based assays and platforms that can be used in drug discovery or product testing to inform on potential clinical effects. These include assays with human primary cells, stem-cell- or iPSC-derived cell types or human cell lines. Endpoints measured are clinically relevant and may include substances (e.g., proteins, metabolites, transcripts, etc.,) or outputs that inform on key biological processes (e.g., proliferation, morphology, impedance, etc.). Human in vitro translational assays may include one or more cell types and utilize 2D, 3D, spheroid, organoid, bioprinted tissue, precision slice or tissue chip-based formats (i.e., organs-on-a-chip or microphysiological systems, MPS).

The throughput and cost of these platforms range widely, and impact where these tools are applied during the drug discovery process. Higher throughput, more affordable systems are used in early discovery where large numbers of compounds or therapeutic candidates need to be tested. More complex systems such as tissue chips that capture organ level biology, are typically reserved for testing agents in late discovery, where lead candidate numbers are low.

Barriers to adoption need to be addressed

Despite the growing availability of human in vitro translational assays and NAMs, adoption of these tools in drug discovery and preclinical testing has been slow. Drug discovery researchers (and program funders!) continue to rely on animal models for efficacy and toxicity testing.

The advantages of human translational assays are clear: these assays and tools can expedite the identification of therapeutic candidates, address human-specific mechanisms, improve drug safety, reduce ethical concerns, and lower costs compared to in vivo animal studies.

So why the slow adoption? Human-based alternatives are difficult to find, understand and access. Assays are complicated and the assay provider landscape is diverse and fragmented. Also, these alternatives can seem expensive if their return on investment (time savings, unnecessary studies avoided) is ignored.

What can be done to promote adoption of NAMs?

Standardization of methods and qualification metrics will help make alternatives easier to understand and promote confidence. Tools such as searchable catalogs and accessible reference data will make these approaches easier to find and compare. Access to large reference data sets, useful for building predictive models and as inputs to large language models (LLMs) may also help drive adoption.

The NIH wants your input

The NIH is looking for input on “challenges and opportunities for further development and use of alternative methods (NAMs) in biomedical research” (see NOT-OD-23-140 Request for Information on Catalyzing the Development and Use of Novel Alternative Methods to Advance Biomedical Research).

Stay tuned for information on new projects that address the barriers to adoption of NAMs from Alto Predict. Promoting the increased use of these tools holds promise for improving drug discovery productivity and the achieving the vision of precision medicine.

Photo by Maria Orlova on Unsplash.