A little history of bionanotechnology and nanomedicine

I wrote this piece as a briefing note in connection with a study being carried out by the Nuffield Council on Bioethics about Emerging Biotechnologies. I’m not sure whether bionanotechnology or nanomedicine should be considered as emerging biotechnologies, but this is an attempt to sketch out the connections.

Nanotechnology is not a single technology; instead it refers to a wide range of techniques and methods for manipulating matter on length scales from a nanometer or so – i.e. the typical size of molecules – to hundreds of nanometers, with the aim of creating new materials and functional devices. Some of these methods represent the incremental evolution of well-established techniques of applied physics, chemistry and materials science. In other cases, the techniques are at a much earlier state, with promises about their future power being based on simple proof-of-principle demonstrations.

Although nanotechnology has its primary roots in the physical sciences, it has always had important relationships with biology, both at the rhetorical level and in practical outcomes. The rhetorical relationship derives from the observation that the fundamental operations of cell biology take place at the nanoscale, so one might expect there to be something particularly powerful about interventions in biology that take place on this scale. Thus the idea of “nanomedicine” has been prominent in the promises made on behalf of nanotechnology from its earliest origins, and as a result has entered popular culture in the form of the exasperating but ubiquitous image of the “nanobot” – a robot vessel on the nano- or micro- scale, able to navigate through a patient’s bloodstream and effect cell-by-cell repairs. This was mentioned as a possibility in Richard Feynman’s 1959 lecture, “Plenty of Room at the Bottom”, which is widely (though retrospectively) credited as the founding manifesto of nanotechnology, but it was already at this time a common device in science fiction. The frequency with which conventionally credentialed nanoscientists have argued that this notion is impossible or impracticable, at least as commonly envisioned, has had little effect on the enduring hold it has on the popular imagination.

Another important dimension of the rhetorical relationship between biology and nanotechnology arises from the observation, forcefully made by Eric Drexler in 1981, that cell biology offers an existence proof that an advanced nanotechnology, involving sophisticated machines and devices that operate on the nanoscale, must be possible, since cell biology offers many examples of such devices. Thus cell biology can be regarded as a source of components to be reassembled in synthetic or partially synthetic contexts, or as a source of inspiration by providing models that can be emulated using synthetic materials.

The most immediate impact of nanotechnology on the life sciences has been the use of new tools for investigating the nanoscale. Techniques such as scanning probe microscopies and optical tweezers have, since their introduction in the 1980s, allowed the properties of individual biomolecules and assemblies of biomolecules to be studied in conditions close to those found in nature. This has permitted the quantitative analysis of the mode of operation of biological machines such as molecular motors and ribosomes, as part of the new field of single molecule biophysics. Other nanoscale technologies – such as quantum dots – have offered useful, though not transformative, additions to the experimental arsenal of cell biologists. One long-standing ambition of bionanotechnology, if achieved, would be transformative – this would be the ability to read, on a DNA single molecule, the sequence of bases. Early attempts to accomplish this by imaging a single molecule with a scanning probe microscope have proved unsuccessful so far. However, another approach, in which the bases are read out as single molecules of DNA are threaded through a nanoscale pore, has generated significant momentum since Deamer and Branton proposed the method in 1996, and is currently the subject of a significant commercialisation effort. If this is successful it will permit the sequencing of complete individual genomes of humans and other organisms rapidly and at relatively low cost.

If these new tools and new techniques represent what nanotechnology has given biology, we might ask what biology has given to nanotechnology. Hybrid constructions involving biological molecular machines integrated with artificial nanostructures have yielded striking demonstrations, for example the “nano-propellers” produced by Carlo Montemagno in 2000, powered by the biological rotary motor F1-ATPase. A more obvious path to application presents itself for various schemes for artificial photosynthesis, which similarly combine functioning biological sub-cellular systems in synthetic constructs.

Biological inspiration also underlies the idea of using DNA synthesised to a prescribed sequence as a building material for quite complex nanoscale structures, exploiting the precise rules of base-pairing to design desired self-assembly characteristics. For many years this was pursued single-mindedly and without a great deal of competition by Nadrian Seeman, who had demonstrated the principle in 1989. Seeman’s persistence has been rewarded in the last ten years by a series of new developments, facilitated by technical advances in the synthesis of DNA, which greatly reduced the cost, and increased the available quantities of the material. These developments included demonstrations that DNA can be used as the basis, not just of nanoscale structures, but also of functional devices such as motors and logic gates. For many years DNA nanotechnology could have been viewed as a marvellous technical tour-de-force with little potential for real applications, but the continuing exponential falls in the cost of synthetic DNA and the increasing sophistication of the devices being created in the growing number of laboratories working in this field makes this conclusion less certain.

In the area of nanomedicine, there are already applications of nanotechnology in clinical use. Having said this, one needs to be aware of the continuity, mentioned above, between pre-existing technologies and those that subsequently have been encompassed by the nanotechnology label. Thus there is a blurred line between some older products, which used quite sophisticated formulation science, and what are now described as nanomedicines. Nonetheless, a number of products (perhaps a couple of dozen in total) have come to be recognised as first generation nanomedicines – these include Abraxane, an anticancer drug formulated as a nanoparticle, Caelyx/Doxil, another anticancer drug encapsulated in liposomes –nanoscale containers made from self-assembled lipid bilayers, and Cimzia, an antibody (i.e. a protein molecule) attached to a synthetic polymer molecule. These illustrate some of the driving forces for nanomedicine in drug delivery.

Perhaps the simplest is the possibility of formulating drug compounds which are otherwise difficult to get into solution; for example Abraxane, approved by the FDA in 2005, is a nanoparticle based formulation of an older anticancer drug, paclitaxel, which avoids the need to use a toxic solvent. Such reformulations may improve the efficacy of older drugs and reduce their side-effects; they may also be motivated by the possibility of extending the profitable life-time of a drug after the expiry of an original period of patent protection.

Caelyx and Doxil are alternative names for a nanoscale formulation of another old anticancer drug, doxorubicin. In this form, approved by the FDA in 1995, the drug is encapsulated in molecular containers made from self-assembled lipid molecules; this reduces side-effects and helps concentrate the drug in the tissues where it is needed. A number of physical and chemical mechanisms have been proposed by which this kind of nanoscale delivery device might preferentially deliver a drug to a target, such as a solid tumour, or carry it across an otherwise impenetrable obstacle, such as the blood-brain barrier, though the examples in current use are far less advanced than some of the concepts being explored in the laboratory.

Cimzia, approved in 2008 by the FDA for Crohns disease, and in 2009 by the EMEA for arthritis, is a fragment of an antibody coupled to a water-soluble polymer. This is an example of the way the need for nanoscale drug delivery devices is being heightened by the increasing use of proteins and protein fragments, such as antibodies, as new therapeutic agents. These can intervene with great specificity with biological processes at the molecular level, but in their bare form they are rapidly eliminated from the body, hence the need for effective nanoscale delivery devices of one kind or another.

The same issues are heightened when one considers the potential therapeutic use of nucleic acids – whether DNA fragments in gene therapy, or small RNA fragments such as siRNA (small interfering RNA). Since the relatively recent discovery of the importance of such RNA molecules in controlling gene regulation in eukaryotes, there has been a great deal of excitement about the possibility that these offer an entirely new class of therapeutic molecules, but this is tempered by the realisation that organisms, including humans, are highly sensitive to the presence of foreign nucleic acids and are well equipped with mechanisms to remove them. Thus, in order to be able to get nucleic acids into the cells whose genetic mechanisms they might regulate, nanoscale molecular delivery devices will be required. Thus nanotechnology in this case will be an essential enabling technology if the discovery of regulatory RNA molecules is to be converted into something useful for medical applications.

In a similar way, it is possible that bionanotechnology may prove to be an essential enabling technology for stem cells to fulfil their promise of allowing the growth of new tissues and organs. It is becoming clear that the fate of stem cells as they differentiate is strongly influenced by the local nanoscale mechanical properties and biochemical environment. Synthetic mimics of an appropriate extra-cellular matrix material will probably need to incorporate quite precise control, both in space and time, of this local environment, particularly as the targets of our attempts to engineer new tissue move from the (only relatively) simpler problems of creating new skin, bone and cartilage to the even more difficult problems of regenerating cardiac tissue and nerve cells.