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What is Unique about Nanomedicine? The Significance of the Mesoscale

Published online by Cambridge University Press:  01 January 2021

George Khushf  and
Ronald A. Siegel
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In prominent funding and policy statements, a particle with at least one dimension in the 1-300 nm size range must have novel physicochemical properties to count as a “nanoparticle.” Size is thus only one factor. Novelty of a particle's properties is also essential to its “nano” classification. When particles in this size range are introduced into living systems, they often interact with their host in novel ways that require some modification of existing methods and models used by pharmaceutical scientists and toxicologists for assessing their efficacy and safety. It is not clear, however, whether the novelty of the intended physicochemical properties is in any way related to the novel behavior of those particles when their toxicity is evaluated. In fact, when considering toxicity, much of the concern about nanoparticles relates to the unanticipated or poorly understood interactions.

Type
Symposium
Information
Journal of Law, Medicine & Ethics , Volume 40 , Issue 4 , Winter 2012 , pp. 780 - 794
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Copyright © American Society of Law, Medicine and Ethics 2012

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References

The definition provided by the National Nanotechnology Initiative (NNI) is representative: “Nanotechnology is the understanding and control of matter at the nanoscale, at dimensions between approximately 1 and 100 nanometers, where unique phenomena enable novel applications. Encompassing nanoscale science, engineering, and technology, nanotechnology involves imaging, measuring, modeling, and manipulating matter at this length scale. Matter such as gases, liquids, and solids can exhibit unusual physical, chemical, and biological properties at the nanoscale, differing in important ways from the properties of bulk materials and single atoms or molecules.” This wording is from the NNI website (http://www.nano.gov/nanotech-101/what) (last visited November 1, 2012), and variants of it are in many NNI policy documents. Note how this definition concerns both the size (1–100 nm) and the novelty of phenomena/applications. The size range used by NNI is controversial. Ledet and Mandel argue that “[f]or most pharmaceutical applications, nanoparticles are defined as having a size up to 1,000 nm.” Ledet, G. and Mandal, T. K., “Nanomedicine: Emerging Therapeutics for the 21st century,” U.S. Pharmacist 37, no. 3, Oncology supp. (2012): 7–11. Many of the meso-level, biological phenomena we reference in this essay occur at roughly 1–300nm, so we will use this range. However, it should also be kept in mind that the properties of nanomaterials may extend to their aggregated forms, which may have larger dimensions. See Hamburg, M. A., “FDA's Approach to Regulation of Products of Nanotechnology,” Science 336, no. 6079 (2012): 299–300.Google Scholar
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Whether protein-based drugs and therapeutic uses of nucleic acids raise problems, and, if so, what these are, has always been controversial. The best studied example relates to “gene therapies,” with the special oversight associated with the Recombinant DNA Advisory Committee (RAC). When considering the things that make gene transfer novel from the perspectives of clinical trials, Nancy King highlights “those characteristics that produce decision-making challenges” (“RAC Oversight of Gene Transfer Research: A Model Worth Extending,” Journal of Law, Medicine & Ethics 30, no. 3 [2002]: 381–389). Among these are the complexity of gene therapies, the lack of good animal models, and the uncertainty engendered by these. When considering questions of “special scrutiny,” Carol Levine and colleagues highlight research projects which “are, in some morally relevant sense, ‘outliers,’ presenting novel or ethically challenging questions, situations, and strategies or a challenge to the status quo.” (Levine, C. et al., “‘Special Scrutiny‘: A Targeted Form of Research Protocol Review,” Annals of Internal Medicine 140, no. 3 [2004]: 220–223). Two of their three criteria focus on the problems we consider in this essay. Their first criterion relates to research that “involves initial experiences of translating new scientific advances to studies in humans, especially when the intervention is novel, irreversible, or both.” Their third criterion concerns research protocols that raise “ethical questions about research design or implementation for which there is no consensus or there are conflicting or ambiguous guidelines.” In the essays of King and Levine et al., the primary concern is with the issues we consider: Namely, with those kinds of interventions that require innovation/research related to the infrastructure that is used to evaluate the products. We have attempted to disentangle that primary element from the others, and make it the crucial one when considering what makes a therapeutic agent novel from a regulatory perspective. An extensive discussion of the questions of special oversight is found in the winter 2009 issue of Journal of Law, Medicine & Ethics, edited by Wolf, Susan Ramachandran, Gurumurthy Kuzma, Jennifer, and Paradise, Jordan.Google Scholar
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In a more detailed review, we would need to distinguish between general-, network-, and complexity-based accounts of the meso-scale and those accounts that are discipline specific. In discipline-specific definitions of the mesoscale, the etymological meaning of “meso” is prominent (deriving from the Greek word for “middle”). This scale is between two different scales of analysis, each with roughly independent logics of explanation. In condensed matter physics, for example, the mesoscale characterizes a region between the atomic scale, where quantum principles of explanation are needed, and a bulk level, classical scale. In meteorology, the meso-scale is between a microscale and storm-scale cumulus systems (on the low end) and synoptic scale systems (on the high end). So, in similar ways, we could find meso regions of importance in a host of other areas. Discipline specific accounts of meso thus are distinguished by the regions and logics of analysis that characterize their lower and upper scale. We will distinguish physicochemical and biological accounts of nanoscience by means of such discipline specific characterization of the upper and lower domains. Beyond these discipline specific accounts of the meso-scale, there are also general accounts that are informed by complexity and network analysis. In one prominent account that has informed nanoscience in many different disciplinary areas, George Whitesides and colleagues follows complexity theorists: “[t]he distinctive properties of meso-scale systems arise when the characteristic length of a process of interest, such as a ballistic movement of an electron, excitation of a collective resonance by light, diffusion of a redox-active molecule close to an electrode, or an attachment and spreading of a eukaryotic cell, is similar to a dimension of a structure in (or on) which it occurs. These processes involve interactions with small localized ensembles of atoms and molecules.” (Kumar, A. Abbott, N. Kim, E. Biebuyck, H., and Whitesides, G., “Patterned Self-Assembled Monolayers and Meso-Scale Phenomena,” Accounts of Chemical Research 28, no. 5 [1995]: 219–226. Even when highlighting this general definition, Whitesides et al. highlight the middle level, bridging character of this scale: “Meso-scale systems bridge the molecular and macroscopic.” As a result of the complexity and nonlinear character of the interactions that constitute this middle scale, research practices need to integrate theoretical and experimental techniques from high and low scales. Meso-scale work will thus involve a convergence of top-down and bottom-up strategies. For an example of how a general, network-based account of the meso-scale can work with a discipline specific account in ecology, see Estrada, E., “Characterization of Topological Keystone Species Local, Global and ‘Meso-Scale’ Centralities in Food Webs,” Ecological Complexity 4, nos. 1–2 (2007): 48–57.CrossRefGoogle Scholar
When characterizing the nanoscale as bridging the quantum and classical domains, we use a discipline specific account that is perhaps too dominated by the physics of the particle, especially as worked out in areas like condensed matter physics. In some areas of nano-chemistry, emphasis would still fall on the “intrinsic” novelty of the systems, but there is much greater interest in the kind of collective, multi-particle systems discussed by Whiteside and colleagues (see note 5). A good example of chemical meso-systems can be found in the self-assembly of lipid bilayers (for a representative early account, see Mouritsent, O. G. and Jorgensen, K., “Micro-, Nano- and Meso-Scale Heterogeneity of Lipid Bilayers and Its Influence on Macroscopic Membrane Properties,” Molecular Membrane Biology 12, no. 1 [1995]: 15–20). These structures provide a valuable bridgework between the physics of the meso-scale and a biological meso-scale. For an account of how these lipid assemblies may relate to higher order, functionally organized dynamics of cells, see Mayor, S. and Rao, M., “Rafts: Scale-Dependent and Active Lipid Organization at the Cell Surface,” Traffic 5 (2004): 231–240.CrossRefGoogle Scholar
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When considering nanomedicine and other areas of nanobio, it is difficult to find carefully developed definitions, and some definitions have odd characteristics that can only be understood in terms of disciplinary specific uses of language. The European Science Foundation (ESF) defined nanomedicine as “the science and technology of diagnosing, treating, and preventing disease and traumatic injury, of relieving, and of preserving and improving health, using molecular tools and molecular knowledge of the human body” (ESF, Nanomedicine An ESF – European Medical Research Councils (EMRC) Forward Look Report (2004), Strasbourg Cedex, France). In an editorial on how his journal will view nanomedicine, Thomas Webster observed that many medical researchers find the European definition odd, since they (and molecular biologists generally) have long been focusing on molecular interactions (Webster, T., “Nanomedicine: What's in a Definition?”, International Journal of Nanomedicine 1, no. 2 (2006): 115–116). But this criticism misses something important about medical history: Namely, that many view modern, scientific medicine as arising with an appreciation of anatomy and physiology at a gross scale, and they view progress as moving down scale from organ systems and organs to tissue, and from tissue to cellular functions and histology. The “molecular revolution” designates the final advance in precision and shift in the organization of medical knowledge, where disease processes are understood at their most basic, i.e., molecular level. Nanoscience is then viewed as enabling this advance in both the understanding and interface with biosystems at the sub-cellular level. Webster contrasts the ESF definition with the US NIH Roadmap definition, where nanomedicine is defined as “an offshoot of nanotechnology, [which] refers to highly specific medical interventions at the molecular scale for curing disease or repairing damaged tissues.” Following the U.S. NNI, Webster wishes to emphasize the novelty of properties. However, it is not clear how such novelty manifests in medicine. Webster tries get at this by emphasizing “significantly changed medical events,” but he tells us nothing about how such novelty is to be identified. Since this novelty is supposed to distinguish nanomedical approaches from other molecular approaches, the emphasis falls upon a middle range between conventional molecular approaches (such as one might find with development and use of a conventional drug) and a higher-scale, functional interface (such as one finds when understanding and interfacing with cells, tissues, and organs as one might find with a device).CrossRefGoogle Scholar
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We focus on novelty arising from complexity and the role this plays in thwarting rational drug design. The issues we consider are general and would apply to all drugs, whether they involve novel targets or not. But even within the conventional drug category, a distinction could be drawn between conventional and novel drug targets, and many of the challenges we consider with meso-level agents would also arise with drugs that target novel targets. For a discussion of these challenges associated with novel targets, see Ma, P. and Zemmel, R., “Value of Novelty?” Nature Reviews Drug Discovery 1, no. 8 (August 2002): 571–572; Butcher, E., “Can Cell Systems Biology Rescue Drug Discovery?” Nature Reviews Drug Discovery 4, no. 6 (June 2005): 461–467; and Hopkins, M. et al., “The Myth of the Biotech Revolution: An Assessment of Technological, Clinical and Organizational Change,” Research Policy 36, no. 4 (2007): 566–589. Each of these essays note that research oriented toward novel targets has not lead to expected returns and profit, and that the primary challenge associated with such novelty relates to health and safety.CrossRefGoogle Scholar
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“Inductive risk” concerns the risk of mistaken inference from a given knowledge base. Any science involves a complex weighting of evidence that is reflected in assumptions that inform any set of experimental practices. When non-epistemic consequences are managed by means of those practices, a qualitative transition in the background rates of unanticipated interactions/harms can lead to a reappraisal of the way uncertainty is managed. This reappraisal is motivated by both scientific and ethical considerations. For a nice review of the issues related to inductive risk, see Douglas, H., “Inductive Risk and Values in Science,” Philosophy of Science 67 (December 2000): 559–579.CrossRefGoogle Scholar
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An extensive literature now shows that nanoparticles are novel in just this way, i.e., they cannot be assessed by methods and instruments that are currently available, and thus require research efforts that are directed toward the QA/QC infrastructure itself. Representative essay documenting this need for infrastructure innovation include: Fischer, H. and Chan, W., “Nanotoxicity: The Growing Need for In Vivo Study,” Current Opinion in Biotechnology 18, no. 6 (2007): 565–571; Warheit, D., “How Meaningful Are the Results of Nanotoxicity Studies in the Absence of Adequate Material Characterization?” Toxicological Sciences 101, no. 2 (2008): 183–185; Oberdorster, G., “Safety Assessment for Nanotechnology and Nanomedicine: Concepts of Nanotoxicology,” Journal of Internal Medicine 267, no. 1 (2009): 89–105; Jones, C. F. and Grainger, D. W., “In Vitro Assessments of Nanomaterial Toxicity,” Advanced Drug Delivery 61, no. 6 (2009): 438–456; Gil, P. R. et al., “Correlating Physico-Chemical with Toxicological Properties of Nanoparticles: The Present and the Future,” ACS Nano 4, no. 10 (2010): 5527–5531.CrossRefGoogle Scholar
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