Ancestry of cells must be considered in bioengineering - Nature

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The biomedical engineering creed is to use engineer- ing to advance human health and improve well- being. The field has generated artificial heart valves, advanced joint replacements and mRNA-lipid nanoparticle vaccines, to name only a few achievements. However, the full potential of bioengineering will not be met until our engineering advances benefit all popula - tions. Discussions around diversity in sex and ancestry are occurring at the level of pharmacogenetics and in clinical trial design. Here, we would like to address the consideration of ancestry at the cellular level, as cells provide the foundation of many of our technologies.

Defining ancestry in biomedical research

Ancestry is defined as one's family origins or heritage, and typically refers to biological or genetic character- istics, although sociocultural factors, such as language and family history, also impact ancestry 1 . By contrast, race is a "culturally structured, systematic way of look- ing at, perceiving, and interpreting reality" that also has biological impacts, such as the effect of racism on health 2 . Genetic ancestry is defined by genetic markers, such as ancestry- informative markers, which show large frequency differences between populations and can be used to estimate genetic ancestry in populations or indivi duals. Studies that compare genetic and socio- cultural factors have found that sociocultural factors may better predict health outcomes2 . Self- identified ancestry combines biological factors with sociocultural components that can capture an individual's perception of their ancestry. To understand and treat diseases, espe - cially those that exhibit racial differences in prevalence, it is important to consider all aspects of ancestry includ - ing genetic ancestry and sociocultural factors, such as discrimination and socioeconomic status. Although ancestral factors are complicated to classify and measure, they clearly impact health at the popula- tion and individual level. Here, we define ancestry in its broadest sense to include genetic ancestry and socio- cultural factors. In biomedicine, it is important to study

and understand how the amalgam of ancestral factors, including sociocultural factors such as experiences of dis-crimination, contribute to differentiation among popula

- tions and how these differences can be interrogated to develop better therapeutics to improve patient outcomes3 . Health inequities are seen in many diseases, including cancers, cardiovascular diseases and mental health dis - orders. Accounting for an individual's ancestry improves the accuracy and effectiveness of precision medicine. The sociocultural experiences that contribute to ance - stry, such as racism, also influence cells at the mole cular level 4 . For example, experiences of racial discrimination have been associated with altered DNA methylation at multiple sites across the genome of peripheral blood mononuclear cells 5 . Moreover, racial discrimination exposure is correlated to elevated cytokine levels in the blood, lasting over 3 years following the discrimination event 6 . Thus, ancestry influences cell function and, as a result, bioengineering must consider ancestry of cells to fulfil the quest of improving human health.

Limitations of ancestry in biomedical research

The reluctance to report ancestry at the cellular level is historical and permeates the current biomedical science landscape. Race- based policies have often been used to exclude people from housing, education, employment and health care. Since the 1950s, race has been promoted as a social rather than a biological construct, which has had the positive effect of debunking race science. At the same time, this has resulted in the flattening of our understanding of genetic and sociocultural diver- sity, and has led to a supposed colour- blind approach to race in biomedical research, for example, the idea that studying only genomes from European ancestry would be sufficient to represent people from all backgrounds.

However, an assessment of genome projects, human

tissue banks and cell culture repositories revealed a dearth of ancestral diversity7 . The lack of ancestral diver- sity in genome- wide association studies led the National Institutes of Health to develop the All Of Us campaign, which focuses on the intersection of biology, including genetics, lifestyle and environment.

Ancestry of cells must be considered

in bioengineering

Erika Moore

1, Josephine B. Allen

1 , Connie J. Mulligan 2 and Elizabeth C. Wayne 3 Bioengineered platforms, intended to be used in the investigation of human health and disease, often incorporate cells of unknown ancestry or that lack diversity. To develop tools and platforms that benefit the entire human population, we must consider the ancestry of cells and intentionally diversify the cells we use in our designs. 1

Department of Materials

Science and Engineering,

University of Florida,

Gainesville, FL, USA.

2

Department of Anthropology,

Genetics Institute, University of

Florida, Gainesville, FL, USA.

3

Department of Chemical

Engineering, College of

Engineering, Carnegie

Mellon University, Pittsburgh,

PA, USA.

e- mail: moore.erika@ufl.edu https://doi.org/10.1038/ s41578-021-00397-72 | January 2022 | volume 7 nATURe ReVieWs | MATeriAls

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The importance of cell ancestry

Human cell lines, which are a key component of many bioengineered models, often lack ancestral diversity 8 . Therefore, our models may miss important differences in how cells respond to treatments, ultimately limiting our ability to develop therapeutics and interventions for diverse populations. Similarly, induced pluripotent stem cells (iPSCs) are used in multiple bioengineer- ing platforms to investigate disease. Interestingly, self- reported ancestry of individuals was associated with variation in iPSC transcripts related to reprogram - ming efficiency 9 ; thus, iPSC function and their subse - quent use in bioengineering platforms are informed by ancestry. Ancestry as well as the genetic diversity that exists between individuals have also been shown to influence cellular responses to drugs in vitro, supporting the inclu - sion of cellular ancestry in drug screening to improve the accuracy and effectiveness of precision medicine 10 . Cells with different ancestral origins respond divergently to chemical, mechanical and biological stimuli in vitro; for example, one- fifth of the 167 molecular entities sub- mitted to the US Food and Drug Administration (FDA) for approval between 2009 and 2015 showed diffe - rences in drug pharmacokinetics, safety and efficacy for different ancestral groups 10 .

A call for including ancestry

Excluding diverse ancestral backgrounds is a missed opportunity to explore new translational targets. As we design our platforms, we must ask ourselves, whose health will our work impact? The lack of sample collection from diverse ancestral backgrounds and lack of testing of cellular ancestry limit the development of new therapeutic targets for diseases that are known to affect diverse backgrounds. For example, the autoimmune disease systemic lupus erythematosus disproportionately affects women of African descent, a disease for which biomaterial platforms remain elusive thus far. To identify the ancestry of the primary cells we use in our models, we sought healthy control cells from com - mercial cell vendors. However, we were unable to readily access ancestral information, leading us to wonder how other biomedical engineers approach ancestry in their own studies. Although resources, such as

Cellosaurus, are avail-

able to classify ancestry of cell lines, acknowledgement and reporting of diverse cell lines remain limited. Resurging conversations about ancestry, race, and the impact of racist structures on science and medical inventions should also be reflected in bioengineering. Bioengineers should consider their roles in unknowingly propagating these plights through lack of cellular diver- sity in model platforms. Our past is littered with genera - tions of left- out populations and missed opportunities. Which discoveries may we miss if we do not include diverse backgrounds in our cellular designs? The more inclusive we are in our science, the more everyone bene - fits. We, as a community, need to ensure that our science is inclusive as well as conducted ethically and holistically.

Challenges and considerations

Including ancestry in bioengineering requires collabo - rations and crosstalk with experts across multiple fields, including genetics, anthropology and epidemiology, to ensure that we consider diverse populations in our studies (Fig. 1). This task is not trivial, as several challenges and considerations must be addressed. Of paramount importance is to protect the privacy of genetic informa - tion and donors from exploitation of that information, in particular, vulnerable populations.

We know that ancestry can influence cellular res

- ponses, and, therefore, we should at least report cellu - lar ancestry in our engineered platforms, including in publications, presentations and reports. Reporting of ancestry will provide a scaffolding to assess who is being included, for whom we design our model systems, and who we are not even considering. To deliver on the promise of biomedical engineering to improve human health, we must consider ancestry in patient samples and cells, in both basic science studies as well as preclinical and clinical research. Our call to include and report the ancestry of cells and to be inten - tional in cell selection may be challenging, but it is feasi - ble. As bioengineers, we must leverage our designs to consider and intentionally include ancestry.

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Bioengineered platformsPopulation epidemiology

Epidemiological

Environmental Public health Social research

Clinical trials

Patient participation

Tissues

Tissue repositoriesCellular Cellular therapies iPSCs

Genomic

PK/PD assessments

Fig. 1

| Ancestry should be included at all levels in biomedical research. iPSC, induced pluripotent stem cell; PD, pharmacodynamics; PK, pharmacokinetics. www.nature.com/natrevmats

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Acknowledgements

The authors express gratitude to K. Stevens, A. N. Koppes and S. Lindström for helpful discussions and framing.

Competing interests

The authors declare no competing interests.

Peer review information

Nature Reviews Materials

thanks Aylwyn Scally and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Re LAT e D L inks

Cellosaurus:

https://web.expasy.org/cellosaurus/

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