The elusive risks of nano-medicine

Photo ParisTech Review / Editors / October 31st, 2014

Nano-sciences and nano-technologies are opening up hitherto unmapped paths to our bodies and health. But nano-medicine does not avoid the heated debates associated to this new scale. Risk assessment cannot be limited to a cost-benefit analysis. So, where do we go from here?

The therapeutic arsenal of nano-medicine has a very wide range: medicinal drugs, of course, are the basis, but we should include vaccines, products from regenerative medicine, imaging and certain products used for in vitro diagnosis. Some of these items are already available in the therapeutic marketplace but the majority are still in the labs or in clinical development test phases.

The promises inherent in nano-medicine are countless. At this nano-world scale (one thousand millionth part of a meter), materials change and display new physical properties. The nano-scale allow medical scientists to design novel therapeutic devices and products that can be delivered directly inside living cells in situ. This radically changes the situation for a certain number of therapeutic protocols, notably in the field of oncology.

The promises of nano-medicine
Nano-scaled medicinal drugs are now considered as providing a particularly efficient way to transcend the limits of standard cancer treatments, viz., those commonly used in chemotherapy.

Jacques Lambrozo, Head of Clinical Studies at EDF, reminds us – if we wish to fully understand a central issue in oncology – that medication is faced with the mechanisms of metabolism. “Inasmuch as everything goes systematically through our liver, this limits to a large extent the applications for ingested drugs. In a conventional protocol, acting on the tumour amounts to acting on the liver and here we are faced with a level of therapeutic toxicity which is often the reason for stopping the protocol.” The challenge for nano-medicinal drugs is simply to by-pass the liver and avoid impregnating the whole body with the molecule(s) administered.

Bio-pharmacist Patrick Couvreur, titular holder of the Liliane Bettencourt Chair of Technological Innovation at the prestigious Collège de France, explains that “a nano-medicinal drug takes the form of a molecule encapsulated in a nano-particle vector administered to the patient. These minute particles are equipped, so to speak, with marker detecting radars, viz., the monoclonal anti-bodies grafted to the surface of the nano-particles capable of recognizing specific tumour markers.”

The process proves triply attractive: firstly, healthy tissues are preserved; secondly, the drug can be released into the patient over a period of time, contrary to what happens in radio-therapy, where the unwanted side-effects only allow you to submit the patient to a short exposure time. And thirdly, the nano-technological delivery protocol of the drug allows you to side-step the tumour’s defence mechanisms, allowing direct access to the cancerous cells, sensitive to the active principle of the drug administered.

This nano-therapeutic approach is not necessarily based on a chemical reaction, as is the case in nano-drug administration. A recent technology breakthrough, using genetic engineering, with DNA fragments has been developed by the Wyss Institute for Biologically Inspired Engineering, University of Harvard. The idea announced by the research team (Dr Shawn Douglas and Dr Ido Bachelet) in February 2012 was to develop a nano-robot from a DNA strand, with the capacity to activate the call’s suicide gene – a natural biological process called apoptosis “a standard feature that allows aging or abnormal cells to be eliminated,” i.e., self-destruction in response to a signal.

The Wyss Institute’s nano-robot

Nanorobot Wyss

(The nano-robot looks like a barrel, holding molecules with encoded instructions. The barrel is normally held shut by special DNA latches. When they latch onto their targets, the two halves of the barrel swing open and expose the molecules. Image: Campbell Strong, Shawn Douglas & Gael McGill, Wyss Institute).

The process involved uses a known mechanism of the body’s immune system. Just like the white cells that circulate in permanence in our blood stream on ‘stand-by’, seeking out and destroying infected, damaged cells, as and when detected, the nano-robot will be programmed to identify certain protein combinations at a cell’s surface. Research scientists are trying to deliver instructions encoded on anti-body fragments to two types of cancerous cells: in leukaemia and the lymphoma. By intervening directly on the gene, this experimentation is truly noteworthy in that it bounds precisely the therapeutic action envisioned. (More here). Another example of applications lies in nano-pores, when used as artificial barriers to limit auto-immune reactions.

A “true” nano-technology, we recall, does not just consist of miniaturising an existing larger platform, but indeed is the construction ex nihilo of a nano-scaled platform, using nano-metric components. Iron oxide nano-particles used in targeted therapy and brain tumour imaging come under this heading. In this case, the nanometric application field consists of aggregating various peptides or antipodes on a nano-particle vector, which enables them to target specifically the cancerous cells. The iron oxide nano-particles accumulate in the cancerous cells. A magnetic field is then applied to the target zone, with the following spectacular result: the malignant cells are literally frazzled, the cell debris being eliminated naturally.

Yet again, we have the carbon nano-tubes carrying an electric charge capable of activating neurons. Nano-tubes call for special monitoring vigilance for the simple reason that the shape and diameter allow them to penetrate tissues easily using a “fibre effect” mode, which received a lot of negative notoriety in several asbestos scandals. Their surface effect and exchange area are much higher than can be achieved using standard molecules.

In more general terms, nano-technologies play a very important role when it comes to delivering medicinal drugs to very limited, specific target areas. These so-called macro-molecular vectors are extremely sensitive inasmuch as they can travel through not only our biological barriers, in particular, the brain’s haemato-encephalitic protective barrier but also the cell membranes and the cell nucleus envelop which store and protect our genomes.

New problems
From what precedes, we can suspect possible risks, for the living bodies and also for the environment. But the question is: how are we supposed to assess those risks? This is where the situation becomes more complex. And, if we seek to understand it, we must adopt a wider viewpoint.

The debates that target nano-medical practices and protocols are part of a far wider context, the controversies that relate to nano-technologies as a whole. The origin of such controversies lies in the relative ignorance of the scientific community with respect to nano-metric material behaviours, an ignorance that can readily be explained: nano-technologies are changing our relationship to matter in a far-reaching way, much as computers have changed our relationship to information. We stand at the dawn of a new revolution.

When you reach the nano level, i.e., the millionth part of a millimetre, at least three phenomena destabilize any standard scientific approach. Firstly, the classic states, solid, liquid and gaseous tend to overlap. Secondly, the distinctions we commonly make between various scientific specialties are no longer relevant. Lastly, technology can no longer be seen as an external factor to a biological organism: it becomes an integral component of the organism. What we are witnessing is “NBIC convergence,” intermeshing nano-technologies, biology, ICTs and cognition sciences

This convergence is not exactly new. Physics and chemistry have been converging for decades. Each domain retains its specificity, yet their areas of application overlap a lot and, moreover, do not have clear limits. In like manner, they too have increasingly strong links with biology.

The upsurge of nano-technologies does not per se represent an absolute breakthrough, but provides a systemic characteristic to convergence, inasmuch as the challenge at a nano-metre scale is to erase the frontiers between specialties and to multiply the ‘input gateways’ to living organisms. More and more products and devices are being designed and made at the frontier interfaces of the specialties, with a more accurate and efficient action on the targets.

Efficiency of these operations is augmented even further by using information technologies. For example, the specialists in molecular computer sciences use DNA as a simple component (even as spare parts) in their miniaturized electronic circuits. This particular role will become all the more important when it comes to designing miniature devices assigned to detect and destroy human cancer cells one by one, or to repair a human impaired brain.

All told, the development of nano-technologies has provided Humanity with new tools to intervene in living organisms (including our own bodies), on a scale that allow us to transcend traditional approaches. But even as we note some truly remarkable progress in applications, basic research is showing signs of simply not being able to keep up.

Assessing risks – mission: impossible?
Under such conditions, we can consider that it is difficult to assess risks correctly, both in terms of the environment and for living organisms.

The main risk that has been identified to date is that of toxicity levels, associated with use of nano-particles. AFSSET, the French Agency for sanitary security in the environment and at work, closely analysed 4 out of the 246 consumer goods present in the French market-places that incorporate nano-technologies: antibacterial socks, suntan creams containing nano-scaled titanium oxide (TiO2) particles offering better UV protection, self-cleaning cements containing TiO2 particles, that can represent risks for DIY adepts as well as for professional building-trade workers, nano-metric silicon food additives to prevent salt or powdered sugar from lumping. Conclusion: the socks above can have “an absolutely capital effect on the environment,” because the nano-silver (Ag) particles will be released during wash-cycles and flushed out with the rinsing water. This could then foul up water-treatment stations or disturb certain species of fish. If only 10% of the socks sold in France contain nano-silver particles this implies that 18 tonnes of metallic silver are dispersed every year in surface waters!

Certain forms of danger can come from the physical characteristics of nano-particles. It can be noted, for example, that nanometric synthetic particles tend to lump, with potentially deleterious effects on the environment and on living organisms. The level of toxicity of nanoparticles relates to their specific surface (their real developed surface, as opposed to their apparent surface at first sight) and to the new properties that accrue from the nano-scale, more than in terms of sheer mass. The specific surface can modify or amplify properties inherent in the original matter. The reactivity factor that certain nanoparticles develop, notably metal-based nano-powders can introduce a risk of explosion, flammability or toxicity. We can also recall that the theoretical property nano-scaled particles possess enabling them to penetrate natural human and animal protection barriers (our skin, lung tissue, intestines, placenta, even our haemo-encephalitic brain envelope) raises self-evident safety issues.

It is therefore important to distinguish free particles (including those already in a lumped state) used as ingredients to make non nano-metric objects such as an endoscope, and which become fixed particles. The latter can be considered as presenting zero risk. In contradistinction, free nano-particles in the air can be a source of worry in regard to their potential to create health and safety problems on work places, or cumulative problems in the environment and concentration in food chains, leading to possible long term risks for our health.

In all fairness, it should be added that nano-technologies did not invent nano-particles. The latter are already largely dispersed in in our environment. Diesel engines, for example, produce large amounts of fine particle emissions. In our work-places, a study published in 2004 showed that in the UK a million workers were potentially exposed to ultra fine particles in what are considered as traditional technological applications. But a distinction must be made between effects of indirect exposure to nano particles and directing ingesting them or having them introduced into our bodies.

“When confronted with a new object, we must raise questions,” admits Laurent Levy, Chairman and CEO of Nanobiotix and Vice-President of ETPN (European Technology Platform on Nanomedicine), who adds: “It is one thing to assert that there is a risk. But what really counts is the benefit-risk ratio for the patient.”

Still, it is difficult to calculate this specific ratio, since a fraction of the risks is as yet unknown. For instance, the instability of manufactured nano-particles makes the scientific analysis of their effects difficult. Between the point in time when they are generated and when they come into contact with Man, two phenomena, difficult to apprehend in experimental models, can occur. One is the lumping or aggregation of the particles alone, which modifies the granulometric distribution of the samples studied; the other is adsorption (a surface effect whereby gas atoms or molecules adhere to a solid state surface) of chemicals already present in the milieus where the particles tested are prepared (the atmosphere, the cell culture beakers…) because of the high-level reactivity of the surface that now characterises the nanoparticles independently from their initial composition. It is therefore very difficult not only to reproduce a given phenomenon, but also to reproduce any earlier test on the materials. A strictly scientific approach is nigh impossible in such instances.

A fundamental breakthrough?
On top of direct risks, that affect organisms or the environment, there are more complex questions that tie in with the ethical aspects of nano-sciences. An example here in nano-medicine is the creation of ‘man-machine’ interfaces at a nano-metric scale, half way between body and prosthetics. We can thus imagine systems that enable manipulation of living organisms via implants in the brain or processes to repair humans or used for the purpose of augmenting human capacities. In this case, an ethical problem arises inasmuch as the interfaces created disturb our very definition of what composes a human being, introducing a measurable distinction between augmented humans (who have access to such technologies) and others. The American historian Francis Fukuyama is of the opinion that nanotechnologies via transhumanists could unwittingly “deface humanity with their genetic bulldozers and psychotropic shopping malls” thereby spelling the end of the human species.

Does this imply that we are heading for a total upset of the way we view risk factors? In France the National Advisory Ethics Committee (CCNE) demonstrates a precautionary stance “For the time being, neurosciences do not appear to have modified our representation of the Universe, nor introduced a new grid that reveals or even suggests the existence of an invisible, hidden world, an unimagined portion of reality.”

The postulate advanced is that in manipulating matter as a nano-meter scale, the elementary properties of the matter will be modified, but it should be noted that the existence and possible purported effects of such changes are themselves conjectural, i.e., unknown. The possibility that certain changes in the position of a component part of an ensemble may change the properties of the component or the ensemble are well documented facts, observable in numerous scientific domains such as the Mendeleev Periodic Table in chemistry, radioactivity in physics or the genomic code in biology.

The instruments that enable research scientists to progress so swiftly in nano-sciences and nano-technologies are the tunnel effect electron (TUE) microscope, the atomic force (AF) microscope, which allow us today to manipulate matter as it is known. Yet the level (atomic) at which such manipulations take place is not, in all probability, the most elementary level of matter since several branches in physics have been attempting for the past few decades to address questions of subatomic composition of matter and analysing new specific properties at this level.

Consequently, the CCNE refuses to see a technological breakthrough here. As they frame it “Nano-sciences do not, for the time being, qualify as a new science revelatory of our world or ourselves, as being different from what we believe. Rather, it is a field that teaches us that we now dispose of new means to intervene in a world which is familiar and, as we know it today. It does not, at this time, represent a scientific revolution per se but rather a technological/technical revolution which may (or may not) carry the promise of a coming scientific revolution. It is a field of specialties presented as if they were sciences but for the moment, they denote remarkable technological progress.”

Under such conditions, it is certainly no easy matter to establish rules of conduct or an assessment grid for risks, given that the matter examined is so elusive. The precautionary principle, moreover, does not offer miraculous solutions. Let us recall, however, that the precautionary principle refers here to actions to be taken if there is a reasonable possibility of a risk leading to serious and irreversible damage, and not just a principle of refraining from action in the case of incertitudes.

This, therefore, is a question for public and private decision makers: on one hand, there are tremendous possible discoveries and applications, while on the other, there are these unknown risks. The Canadian Government, having instated a Commission for Ethics in Sciences and Technologies, commanded a report on nano-technologies. The Commission took into account the chain of incertitude that now characterizes nano-medicine and issued recommendations that future decisions be based on the precautionary principle, suggesting that the Government could concern itself – in a sustainable development prospect – in all phases of the complete life cycle of any product with nano-metric scaled components. The concept of life cycle here is primordial, calling as it does on decision and policy makers to concern themselves with the products beyond the end of their expected operational lives. This approach may be the wisest way to advance, with caution, systematically questioning the effects of tests as they progress. It is not certain that the clinical trials, at least with today’s protocols, comply with this ambition. The least we can do is to adopt various viewpoints, analysing the various specialty fields that we can hope to improve our representations of risks and, consequently, that we can assure ourselves that we have the means to progress more confidently down these new paths in nano-medicine.

 

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