Implementing systems thinking and data science in the training of the regenerative medicine workforce | npj Regenerative Medicine - Nature.com

Regenerative Medicine and Advanced Therapies (RMAT) are analyzable products and often see “living” cellular materials. Every patient—and, for immoderate applications, each product—is unique, and merchandise manufacturing entails lengthy, analyzable processes. Intricate relationships beryllium betwixt the patient’s illness state, the donor starting material, the manufacturing process, supply-chain logistics, and the objective response. RMAT products are stimulating a paradigm displacement successful biopharma manufacturing due to the fact that it means knowing interrelated systems astatine aggregate scales—from molecular and cellular processes to optimization of the manufacturing parameters and workflow, supply-chain logistics, and diligent queuing. Therefore, the RMAT endeavor is well-suited to applications of systems thinking, i.e., the usage of systems mentation and strategy sciences to analyse relationships and make effectual enactment successful analyzable contexts. The next-generation workforce tin beryllium prepared for this situation with modern information tools and methods and a systems-thinking mindset to extract insights utilizing techniques similar information mining and instrumentality learning.

Cooperation betwixt biologists, engineers, and computational scientists is important to achieving the committedness of RMAT products arsenic personalized therapeutics. Systems reasoning leverages large, multifaceted datasets to found reliable manufacturing and organisation methods and to specify cellular identities that lucifer intended applications successful patients¹. Data science, data-driven models, and mathematics tin nexus assorted disciplines, specified arsenic stem compartment biology, physiology, immunology, and engineering, successful effectual transdisciplinary research². It would beryllium beneficial to hole a workforce of “integrators” who tin use blase computational approaches to regenerative medicine research, construe multidimensional information crossed sectors of the RMAT enterprise, and construe results of basal probe to manufacturing, effectual regulations, and the session (Fig. 1).

Fig. 1: Summary of the relation of information subject grooming successful the aboriginal of RMAT workforce development.

The relation of information subject grooming successful the aboriginal of RMAT workforce development. Like a puzzle portion joining parts of a whole, information subject tin assistance to link areas specified arsenic objective care, find science, and manufacturing successful the tract of RMAT. Training tin instrumentality galore forms, including some world paths and others. Systems-level reasoning could heighten the improvement of caller RMAT products.

Given the complexity of RMAT products, the Forum connected Regenerative Medicine of the National Academies of Sciences, Engineering, and Medicine (NASEM) held a store called Applying Systems Thinking to Regenerative Medicine³. The store examined long-standing challenges associated with characterizing patient-specific RMAT therapies to alteration palmy products, processes, analytics, and supply-chain logistics. Discussions made wide that this tract presents important data-related challenges. The information instrumentality galore forms, including multi-omics data, functional data, analytical information from processes and manufactured products, supply-chain and healthcare logistics, and diligent data. The assortment of information requires combining and harmonizing information crossed sources and formats, and the tiny size of immoderate first-in-human objective trials limits analytical powerfulness and augments the request for information sharing. These demands make method challenges similar handling, integrating, and interpreting a “system” of large, diverse, and analyzable datasets, arsenic good arsenic challenges associated with maintaining privacy, cybersecurity, and proprietary information.

Interpretation of information to qualify RMAT products and foretell objective occurrence involves precocious statistical methods and mechanistic models. Advanced quantitative methods whitethorn beryllium indispensable cognition for the modern method expert, yet these are not presently a halfway constituent of biologic probe training. Indeed, concepts specified arsenic entropy, stochasticity, and captious phenomena are comparatively caller to compartment biology applications⁴. Efforts to integrate process and merchandise analytics with prime power and to integrate manufacturing information with patient-queuing and supply-chain logistics could payment from systems-level reasoning that is presently unprecedented successful biopharma and bioengineering. Providing broad-based coursework, hands-on training, and real-life experiences to enactment the well-versed RMAT practitioner whitethorn beryllium challenging but could beryllium advantageous for the objective and commercialized occurrence of the industry. Although not everyone successful the RMAT workforce request beryllium a information subject and modeling expert, each workers whitethorn request a basal knowing of information handling, analytics, and interpretation.

A caller bid of NASEM meetings highlighted the intersection of information subject with accepted domain sciences and however this interplay impacts information subject teaching⁵. Rooted successful disciplines specified arsenic machine science, statistics, and mathematics, information subject is an interdisciplinary tract enriched by collaborations betwixt respective disciplines. In summation to the method aspects of information subject and applications to circumstantial technological domains, the societal considerations of information subject merit peculiar attraction for RMAT practitioners. Societal and ethical issues see however information and communities interact and the relation of inclusion and equity successful collection, interpretation, and exertion of data.

In this perspective, we sermon the challenges facing the next-generation RMAT workforce successful utilizing information encountered successful this field. We see a wide scope of information issues that volition beryllium captious for the divers tract of RMAT products. Our extremity is to rise consciousness of this captious facet of RMAT for educators and manufacture professionals. We judge that grooming the aboriginal workforce whitethorn hap successful accepted and nontraditional ways, and tin see 2-year colleges, probe universities, postgraduate and postdoctoral grooming arsenic good arsenic grooming opportunities for the existing biopharma workforce.

Areas of the RMAT improvement endeavor wherever information subject volition play an important relation see some technical, technological issues and related societal and ethical issues (Fig. 1).

Societal and ethical considerations successful information science

Artificial intelligence/machine learning (AI/ML) algorithms are progressively applied to analyse information and marque predictions successful regenerative medicine^6,7,8,9. As has been wide acknowledged, specified algorithms tin beryllium biased^6,10. Since AI/ML strategies incorporate proxies for existent variables of interest, label-choice bias tin exist. Recent studies applying AI/ML to healthcare are instructive for the regenerative medicine tract due to the fact that “health”—like “cell quality”—is inherently subjective, holistic, and multidimensional; determination is nary single, precise mode to measurement it. A caller survey successful healthcare, for example, recovered that bias occurs erstwhile an AI/ML algorithm uses wellness costs arsenic a proxy for wellness needs¹¹. Further, datasets whitethorn beryllium biased successful presumption of demographics similar race, gender, oregon socioeconomic status. Bias tin hap during labeling of grooming data, arsenic a effect of however information are collected, oregon owed to self-selection by members of the people populations. For instance, successful 1 study, 87% of patients were white, and astir were comparatively affluent¹². The preponderance of information from this demographic whitethorn not supply an capable grooming acceptable to use to non-white, non-affluent populations.

To statesman addressing these issues, guides were developed astir however to define, measure, and mitigate bias successful algorithms^10,13. Privacy, accountability, safety, transparency, fairness and non-discrimination, quality power of technology, nonrecreational responsibility, and effectiveness are among the cardinal elements¹⁴. These playbooks and principles could beryllium adapted for regenerative medicine contexts and incorporated into workforce training. Data subject grooming tin besides hole the workforce to enactment with ample datasets and leverage different efforts to alleviate wellness information disparities^15,16.

Cybersecurity

The RMAT workforce should beryllium prepared to code issues of cybersecurity. Biotech has been the people of cyberattacks, putting the wellness of patients successful jeopardy¹⁷. Protecting diligent and institution data, including intelligence spot and delicate wellness information, is captious and challenging. Cybersecurity is simply a captious diagnostic of establishing a robust RMAT proviso chain. The National Institute of Standards and Technology (NIST) defined a model for cybersecurity successful 2018 and has since updated guidance^18,19. The model provides wide guidance for assessing cybersecurity risk, managing cybersecurity wrong the proviso chain, and reducing hazard to captious infrastructure. Again, adapting this model for regenerative medicine could assistance guarantee unafraid RMAT proviso chains successful accord with national and organization standards.

Data sharing and information integration

A systems-based attack to solving the analyzable challenges faced successful regenerative medicine requires information sharing crossed stakeholders, and the up-and-coming workforce tin beryllium instrumental successful achieving that aim. Although encouraged by immoderate backing agencies, including the National Institutes of Health (NIH)^20,21,22, wide information sharing has been uncommon to-date successful compartment biology, objective research, and manufacturing. Data sharing tin beforehand regenerative medicine by enabling studies with greater statistical power, a wider scope of variables, and a much divers diligent basal than azygous studies tin achieve. Collaboration tin harness caller and existing information sources to beforehand data-driven technological find and innovation crossed the backstage and nationalist sectors globally^23,24. Incorporating FAIR Guiding Principles for technological information (Findability, Accessibility, Interoperability, Reuse of integer assets) successful probe practices and workforce grooming encourages unfastened entree and furthers the nationalist good²⁵. Such approaches tin supply advantages for RMAT akin to those from the Bermuda Principles, which enabled the Human Genome Project to stock information soon aft sequencing and strengthened planetary cooperation^26,27.

Data sharing besides facilitates comparability studies and the improvement of standards for RMAT products. Reproducibility remains a situation successful RMAT probe and merchandise improvement and is mostly attributable to analyzable and highly manual manufacturing processes, variability successful donor and diligent cells, reagent prime variability, and the deficiency of standards and comparability metrics. Data sharing and standardization could alleviate these issues and importantly amended outcomes successful trials with RMAT products. Finally, the regenerative medicine workforce should beryllium cognizant of the ineligible challenges of information sharing related to intelligence spot and however information sharing whitethorn interaction the information of diligent data^28,29. Data sharing could substantially beforehand the tract but remains contingent connected due information absorption and information practices; creating specified infrastructure is ongoing³⁰.

Education pathways indispensable proceed to germinate truthful that students are data-literate and prepared for careers successful domains similar regenerative medicine. Integration of information subject perspectives into data-intensive domain courses tin output transformative researchers and practitioners educated successful some the foundations and domain-specific applications of information science. Integrating information subject acquisition passim the RMAT grooming pipeline tin guarantee that students are versed successful the connection of information collection, analysis, interpretation, management, and security.

Implementation of information literacy programs ensures a captious wide of workforce talent. Indeed, galore universities person launched information subject institutes, programs, oregon schools. The 2018 Moore-Sloan Foundation’s report connected the presumption of information subject highlights approaches to information subject astatine universities. Approaches alteration crossed concern strategy (e.g., field and backstage funding), curricular accent (e.g., engineering, information/computer sciences, business, mathematics/statistics), and enactment (e.g., institute, school, department/division)³¹.

Undergraduate education

Many institutions admit the expanding relation of information successful the workplace and the commensurate value of information literacy for caller graduates. Attempts to conscionable the request for information subject grooming scope from specialized coursework housed successful existing statistic oregon machine subject departments to caller programs and majors, specified arsenic the Data Theory Major astatine the University of California, Los Angeles³². A 2018 NASEM study details assorted routes for information subject grooming astatine the undergraduate level³³, yet grooming opportunities could beryllium expanded.

Competencies for these programs comprise information subject foundations and applications and whitethorn incorporated ethics, ineligible and regulatory issues, and societal concerns. Flexibility and incentives for sharing courses, materials, and module would enactment nascent programs. A cardinal situation of incorporating further information subject courses successful undergraduate curricula is the constraint of not expanding the full recognition hours for grade programs—i.e., different people indispensable beryllium removed to accommodate the information subject course(s). Gaining statement among programs connected reallocating people contented would beryllium challenging, but doable, and advantageous. An alternate oregon complementary attack could beryllium adding information subject grooming and projects to existing courses with domain-specific examples.

Graduate education

Graduate acquisition could see innovative programs successful information science, delivered done modular and nontraditional methods, including applying asynchronous pedagogical strategies to residential and non-residential integer learning. Masters and doctoral students could enroll successful information subject programs oregon domain-specific programs with a information subject certificate. Possibilities see modular, stackable postgraduate certificate programs and 3 postgraduate degrees successful information science: (i) nonrecreational subject masters, (ii) masters, and (iii) doctoral.

Graduates of information subject programs enactment successful each occupation sectors and service successful galore roles. Although not everyone successful the RMAT workforce needs information subject expertise, astir workers—across each levels—should recognize the connection of information subject good capable to construe investigation of RMAT products and to pass with information subject specialists. Students volition get information subject literacy done vulnerability to information subject passim the postgraduate and undergraduate curriculum.

Complementary opportunities for information subject education

Complementary acquisition pathways could capable gaps successful the RMAT grooming pipeline. Community oregon method colleges are 1 avenue for providing information subject grooming and guiding individuals into regenerative medicine. Two-year colleges are already processing courses, certificates, and subordinate degrees successful information science, analytics, and information absorption to conscionable the request for a data-literate workforce⁵. For example, the Northeast Wisconsin Technical College offers a Data Analytics Associate’s Degree to hole students to enactment successful fields similar precocious manufacturing and healthcare. Through partnerships with 4-year colleges and nationalist oregon determination centers focused connected biomanufacturing oregon information sciences (e.g., BiofabUSA, BioMADE), biotechnology programs astatine 2-year colleges tin connection experiential, project-based learning and enhanced grooming opportunities for entry-level workforce. For example, the National Science Foundation Engineering Research Center for Cell Manufacturing Technologies (CMaT) offers hands-on probe and grooming opportunities for 2-year assemblage students successful Georgia and Wisconsin and works with 2-year assemblage instructors to make curriculum.

Data subject footwear camps, which are intensive skill-building programs, tin complement different world oregon manufacture acquisition and amended link participants with manufacture demands⁵. Internships tin besides supplement the acquisition of caller graduates from accepted world programs who whitethorn deficiency manufacture experience. Experienced employees mightiness payment from continuing acquisition programs that leverage and repurpose the on-the-job workforce^5,34. The aboriginal of workforce improvement volition besides see acquisition opportunities extracurricular of world institutions, and online workshops, webinars, and courses could beryllium further expanded and supported by assorted sectors of the regenerative medicine field. Moreover, virtual learning opportunities whitethorn beryllium accessed anyplace by individuals with varying levels of acquisition and education, and asynchronous options whitethorn beryllium accessed anytime, frankincense supporting diversity, equity, and inclusion successful the workforce. An illustration is simply a caller 12-lecture virtual and asynchronous people launched jointly by the International Society for Cell and Gene Therapy (ISCT) and CMaT; the people covers concepts successful regenerative medicine and compartment manufacturing, is unfastened to anyone astir the world, and is co-taught by world and manufacture leaders³⁵.

The request for a data-literate workforce creates a request for synergy betwixt stakeholders crossed sectors (e.g., industry, academia, and government) of the RMAT enterprise. In world settings, curricula to hole information scientists for enactment successful regenerative medicine fields mightiness see topics successful regulatory affairs, objective development, and manufacturing. These topics volition equip students to recognize the unsocial discourse of regenerative medicine and admit systems thinking. Academia tin besides bolster the RMAT ecosystem by expanding the cognition basal of educators and providing resources for students funny successful nonacademic careers. Synergy occurs from sectors moving unneurotic connected cardinal areas of involvement and providing some ceremonial and informal acquisition opportunities that span information subject and regenerative medicine. The organizations mentioned beneath are examples of beardown multisector activities that tin play an effectual relation successful processing the RMAT workforce.

Regulatory

Workforce improvement successful data-dependent regulatory issues warrants peculiar attention. Because RMAT products are highly adaptable and customizable, the regulatory scenery continually evolves, and the regulatory assemblage indispensable support gait with advancements. To facilitate crosstalk and opportunities to usage information subject for regulatory decision-making, the regulatory affairs workforce needs to recognize information subject fundamentals, and the information subject workforce needs a basal knowing of regulatory issues. Now is simply a cardinal clip to bid a information subject workforce to negociate the regulatory situation of a rapidly evolving merchandise and exertion space.

Regulatory grooming tin statesman done world courses and grade programs³⁶. The U.S. Food and Drug Administration (FDA) interfaces with respective world institutions wrong the Centers of Excellence successful Regulatory Science and Innovation (CERSI) programme to assistance bid students successful regulatory science³⁷. However, regulatory acquisition could besides beryllium incorporated into existing courses. Reallocating humble portions of curricula crossed aggregate world stages could amended hole students to interact with regulatory guidance and to hole documents for regulatory agencies. Statistics courses could bid students to analyse ample datasets with the extremity of introducing regulatory concepts specified arsenic captious prime attributes (CQAs), captious process parameters (CPPs), mean operating scope (NOR), and proven acceptable scope (PAR). Lab-based courses could thatch students to hole process descriptions successful accordance with FDA guidance documents and to picture theoretical process-characterization strategies based connected risk-assessment exercises conducted successful class. Advanced courses could promote students to sermon the applicability of information subject approaches (e.g., real-world data, integer transformation, AI/ML) for regulatory decision-making done answering questions specified as:

• How tin real-world information code regulatory filing requirements from clinical, preclinical, and manufacturing perspectives?

• How tin information subject tools assistance found the information and efficacy of a regenerative medicine product?

Clinical and translational science

Discoveries successful stem compartment biology and associated technologies often hap successful basal subject laboratories, but the committedness of regenerative medicine is realized successful the clinic. Academia tin hole students with involvement successful clinically oriented roles by emphasizing information subject and theoretical investigation successful programs similar the Institute for Clinical and Translational Research (ICTR) astatine the University of Wisconsin–Madison, which offers minors successful Clinical Investigation for PhD students, oregon the Georgia Clinical & Translational Science Alliance (CTSA), an NIH-funded programme crossed Georgia-based universities that connection a Master of Science successful Clinical Research and certificate programme successful translational probe for PhD trainees. Such programs promote students to see the quality interaction of technological discoveries and beforehand translational research.

Ranging from information acquisition and harmonization to diligent privacy, data-related challenges tin impede the translation of regenerative medicine discoveries to the clinic. Small illustration sizes often bounds probe successful the uncommon illness space, and information integration among probe groups and datasets tin hamper progress. To contend with these issues, respective institutions established their ain data-sharing capabilities, including Johns Hopkins, the Mayo Clinic³⁸, CMaT³⁹, and others. CMaT, for example, works to standardize methods crossed its eight-university ecosystem and partners with companies to grounds information successful a unified format via batch signaling software. Data tin beryllium stored successful the unreality for collaborators crossed spouse organizations to entree and analyze.

Started by 9 aesculapian probe organizations, different initiative, the National Center for Data to Health (CD2H), facilitates information sharing and collaboration crossed the assemblage of wellness informatics researchers³⁴. The National Heart, Lung, and Blood Institute (NHLBI), including the NIH-wide Regenerative Medicine Innovation Project (RMIP)⁴⁰, besides established a data-sharing level for NIH-funded projects—the Biodata Catalyst—which is intended to service arsenic a cardinal information repository for unfastened sharing among eligible researchers²⁰. Moreover, a workforce that tin manage, interpret, and deploy information subject efficiently and securely volition let the RMAT manufacture to capitalize connected imaginable benefits, some nationally and globally⁴¹.

Manufacturing

As the RMAT manufacture grows and new, progressively analyzable products participate the pipeline, highly trained and appropriately certified workers volition beryllium in-demand to manufacture high-quality products, astatine scale, with debased batch nonaccomplishment rates and maximal reproducibility—all portion ensuring efficacy and diligent information and maintaining strict regulatory standards. Biomanufacturing is progressively integer and truthful requires proficiency successful some quantitative methods and biology-based laboratory techniques. Moreover, a imaginable aboriginal exemplary of manufacturing is decentralized, distant manufacturing successful infirmary settings. To enactment this strategy and different distributed manufacturing approaches successful the future, knowing distant access, integer networks, and AI would payment the workforce.

Academia tin leverage guidance documents designed for manufacture to amended hole students for roles successful manufacturing regenerative medicines⁴². When designing curricula, world entities could integrate discussions with manufacture and objective manufacturers to amended recognize the skillsets needed for biomanufacturing. Manufacturing sciences arsenic a abstracted subject is lone disposable astatine a fewer world centers; rather, manufacturing is often taught done mechanical oregon chemic engineering departments. Collaboration betwixt experts successful manufacturing sciences and different specialized domains (e.g., compartment therapy, biofabrication) would assistance guarantee curricula and grooming materials bespeak domain cognition successful the discourse of broader manufacturing principles. This collaborative, transdisciplinary effort crossed engineering, compartment biology, objective translation, and concern manufacturing volition beryllium captious to hole the adjacent procreation of RMAT workforce.

Beyond acquisition efforts, world scientists tin amended coordinate with manufacture by considering manufacturing guidelines, specified arsenic Good Manufacturing Practice (GMP) regulations, successful their research. To facilitate translation from seat to bedside and summation uptake of innovations successful the clinic, world laboratories and researchers could purpose to make caller devices, tools, software, and technologies that are GMP-compatible, travel Quality-by-Design principles, incorporated standardized analytical tools and measurements, and instrumentality regulatory constraints.

Finally, cardinal exertion hubs and public-private partnerships play an important relation successful integrating information cognition into workforce development. Organizations focused connected RMAT manufacturing see the aforementioned CMaT, Marcus Center for Therapeutic Cell Characterization and Manufacturing (MC3M), National Institute for Innovation successful Manufacturing Biopharmaceuticals (NIIMBL), BioFabUSA by the Advanced Regenerative Manufacturing Institute (ARMI), the Catapult Network successful the UK, and the Centre for Commercialization of Regenerative Medicine (CCRM) successful Canada. Examples of important steps these organizations person taken to physique a dynamic workforce include:

• Collaborative people module improvement for some method and ethics/regulatory competencies.

• Collaborations with 2-year assemblage systems for hands-on grooming and program development.

• NSF-funded Future Manufacturing Network (FMNet) Consortium for “Building a Network to make the Workforce Foundation, Actionable Roadmap, and Infrastructure Design to Integrate Data Science, AI, and Predictive Analytics passim Biomanufacturing”.

Notably, astir of these efforts are successful the aboriginal stages and request concern to standard up nationally oregon internationally. Community-based, distributed workforce grooming programs that physique industry-identified skillsets and incorporated robust certification could importantly beforehand the palmy usage of large-scale information successful regenerative medicine.

The rapidly evolving tract of RMAT requires a workforce trained to instrumentality afloat vantage of information from antithetic sources and astatine scale. Addressing the challenges of the analyzable systems that specify the RMAT endeavor whitethorn entail forming large, unbiased datasets for statistically meaningful analysis. A workforce equipped with some the technological and method cognition and the collaboration skills to integrate expertise tin determination the tract guardant successful each aspects of regenerative medicine, including basal research, regulation, and manufacturing.

To present connected the committedness of regenerative medicine relies connected the tract to enactment unneurotic crossed sectors to bid the aboriginal workforce to leverage modern tools of information subject and facilitate the occurrence of RMAT products arsenic subject and exertion proceed to progress. This insubstantial is simply a telephone to bring attraction to the integration of information subject and the exertion of systems reasoning for addressing the challenges faced successful processing regenerative medicines.

References

Authors and Affiliations

1. Biosystems and Biomaterials Division, National Institute of Standards and Technology, Gaithersburg, MD, USA

   Anne L. Plant

2. CRISPR Therapeutics, Cambridge, MA, USA

   Nicole Piscopo

3. Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA

   Krishanu Saha

4. Akron Bio, Boca Raton, FL, USA

   Claudia Zylberberg

5. Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA

   Krishnendu Roy

6. Janssen Research and Development LLC, Spring House, PA, USA

   Katherine Tsokas

7. Health and Medicine Division, National Academies of Sciences, Engineering, and Medicine, Washington, DC, USA

   Samantha N. Schumm & Sarah H. Beachy

Contributions

Conceptualization—A.L.P., N.P., K.S., C.Z., K.R., K.T., and S.H.B.; writing—original draft: A.L.P., N.P., K.S., C.Z., K.R., K.T., and S.N.S.; writing— revision and editing: A.L.P., N.P., K.S., C.Z., K.R., K.T., S.N.S., and S.H.B. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Samantha N. Schumm oregon Sarah H. Beachy.

Competing interests

The authors state the pursuing competing interests: K.T. is an worker of Janssen Pharmaceutical Companies of Johnson & Johnson and a stockholder of Johnson & Johnson. K.S. receives sponsored probe enactment from Synthego and Spotlight Therapeutics. K.R. directs the NSF Engineering Research Center for Cell Manufacturing Technologies (CMaT), which has workforce grooming programs. The remaining authors state nary competing interests.

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