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The ‘reductionist’ revolution
THE call for miniaturisation has echoed far beyond the lateral dimensions of integrated circuits since it ushered in the era of modern microelectronics. It gave an impetus to the development of techniques, enabling scientists and engineers to work with molecular and atomic scale precision.
The convergence of these techniques gave rise to nanotechnology, which is defined as research and technology development aimed at creating and manipulating materials, devices and systems ranging in size from 1 to 100 nanometres. It is a robust technology that has been developing at an increasing pace.
The enthusiasm to integrate nanoscale fabrication with biology is also on the rise. The discipline of biology offers the most promising area for application of nanotechnology and, as a quid pro quo, it receives physical tools for molecular scale exploration. Since biotechnology is the area in which understanding biology is supposed to pay off, the resulting merger is rightly called nanobiotechnology. This seems to be one of the most vigorous interdisciplinary intellectual trades in modern scientific history.
Nanobiotechnology involves construction of unique classes of micro- and nanofabricated structures, devices and machines by imitating or incorporating biological systems on the molecular level.
Norman Horowitz once set replication, catalysis and mutability as the criteria for living systems. The concept somehow drifted along as a useful notion. However, current holistic view of life includes complex phenotypic properties, such as energy production and utilisation, force generation through chemo-mechanical coupling and information processing through signal transduction.
The smallest entity to which these properties are attached is called “cell”, which manifests what we call life, through an intricate network of biomolecular interactions. In the biomolecular realm we deal with sizes corresponding to one-billionth of a metre.
Conventional biosciences — for instance, biochemistry, biophysics and enzymology — are to some extent ergodic in their approach. They involve analysing ensembles of biomolecules or biosystems to discern individual functional and structural patterns. Although this has been of great use in understanding the biochemical basis of life, there are some key challenges, like visualisation and analysis of biomolecules while these are in full functional cycles in vivo and also the enhanced control and manipulation of biomolecular interplay to achieve a desired objective (the aim of biotechnologists). The bottom line is that it’s time to be more reductionist in our approach towards life in molecular terms.
This urge, combined with avant-garde nanotechnology tools, is likely to precipitate a new phenomenon — the ‘reductionist’ revolution — the last one being the recombinant DNA technology revolution of the ’70s. Application of nanobiotechnology involves previously unheard of benefits for healthcare, public safety and environmental monitoring. Nanoscale manipulations may enable real-time molecular pathology, affordable high-throughput diagnosis, precise and convenient drug delivery, novel drug formulations, in vivo medical monitoring by nanoscale robots, tissue regeneration and monitoring of a wide variety of diseases. It would be worthwhile to further explore the marvels of nanobiotechnology.
Microfluidics
Microfluidic technology encompasses construction of devices that can handle nanolitres of liquids. Owing to the unusual physics of microfluid dynamics, this technology promises unprecedented savings in cost and time through the integration of complex chemical and biological assays. In nanolitre dimensions, liquids flow laminarly and diffusion-driven mixing takes place at remarkably short time periods.
Potential benefits include reduced sample and reagent consumption, short analysis time, ultra-sensitivity, portability and disposability. Frontier objectives in bioanalytics like in situ and real-time analyses can also be achieved through integrated nanolitre systems.
The versatility of microfluidic devices allows interfacing with current methods and technologies. This is well illustrated by microchip-based polymerase chain reaction (PCR).
PCR, a technique for exponential amplification of specific DNA sequences, has revolutionised research and medical diagnostics. Construction of integrated nanofluidic devices has been reported which can perform a series of biochemical analyses like sample preparation, nucleic acid isolation, gene amplification and other types of DNA manipulation on a device having the size of a credit card. These devices use as little as 8 to 9 microlitres of the sample and possess complexities and capabilities that could rival a robotic system.
DNA micro-arrays have become the mainstay for gene expression studies and have a wide range of applications in disease diagnosis and drug development. However, the technique generally relies on passive diffusion of the sample volume, containing the target DNA molecules, towards the immobilised probe elements. This can result in long hybridisation times.
Methods of accelerating the hybridisation time for DNA arrays using plastic microfluidic chips, comprising networks of microfluidic channels and integrated pumps, have been developed.
The linking of microfluidics to protein analysis technologies — for instance, mass spectrometry — enables picomole amounts of peptides to be analysed within a controlled micro-environment. The flexibility of microfluidics will facilitate its exploitation in assay development across multiple biotechnological disciplines.
Magnetic nanoparticles
These represent the vanguard in the arsenal of nanobiotechnology. Their potential applications in biomedicine rely on three remarkable properties. First, they have a controllable size range which is comparable to biomolecular dimensions. Second, they can be coated with biological molecules to make them interact with or bind to a biological entities. Third, since these nanoparticles are magnetic so they can be manipulated by an external magnetic field.
This ‘remote action’ combined with the intrinsic penetrability of magnetic fields into human tissue opens up many applications involving the transport and/or immobilisation of magnetic nanoparticles or of magnetically tagged biological entities. In this way they can be used as efficient drug delivery systems to target an anticancer drug or a cohort of radionuclide atoms to a specified region of the body, such as a tumour.
Moreover, the magnetic nanoparticles can be made to resonantly respond to a time-varying magnetic field, with advantageous results related to the transfer of energy from the exciting field to the nanoparticle. For example, the particles can be made to heat up when they are in the tissue — a condition known as hyperthermia — delivering toxic amounts of thermal energy to targeted bodies such as tumours; or as chemotherapy and radiotherapy enhancement agents, where a moderate degree of tissue warming leads to killing of malignant cells.
These and many other potential applications in biomedicine spring from special physical properties of magnetic nanoparticles.
Quantum dots
Quantum dots — though they are synthetic beacons of nanometre dimensions — are not alien to biological systems, as they make use of their natural counterparts. For instance, the electron transport chain used by nearly every living organism for energy conversion involves numerous proteins as well as some smaller organic electron carriers acting as quantum dots.
Chemically, quantum dots are crystalline semiconductor particles. They have been successfully used as replacement for organic dyes in various bio-tagging applications because organic fluorophores are toxic, difficult to manipulate and have short half lives. Single quantum dots can be used to track cellular events, for example, those involved in signal transduction and developmental changes.
Another unique property of quantum dots is the size-tunable emission. By just varying the size of the particle we can have different coloured quantum dots that can be excited at the same wavelength. This forms the basis of multiplex optical coding. A precise control of quantum dot ratios has been achieved. The selection of nanoparticles can be designed to have as many as six different colours in 10 intensities. It can code over 1 million combinations that are more than sufficient for accurate detection of up to 40,000 human genes or proteins in as little as 10 minutes.
Drug delivery
By unleashing the potential of miniaturisation to the field of drug delivery the prospects of controlled drug delivery, on-demand drug synthesis and in vivo health status monitoring have become brighter than ever. Nanotechnology has multilevel approaches to medicines ranging from structures to devices to systems.
Implantable drug delivery devices have a long history, but it is only after the advent of nanotechnology that products are successfully traversing evaluation phases and are under the stages of production. Extensive research is, however, being conducted to enhance the biocompatibility, stability and long-term functionality of these devices. Although these devices may not be truly nano-sized but their manufacture is made possible through micro- and nanofabrication techniques, for instance production of elastomeric tubes through soft lithography and micromachining to create membranes of pore size as little as 10nm.
Drug-release chambers encased in semi-permeable membranes can be potentially used against a wide range of diseases and applied to various target sites. Control of drug release can be further enhanced by coupling these devices to microfluidic technology. Another promising approach is to incorporate xenografted or genetically engineered cells into these chambers to produce therapeutic compounds. Although, their utility is proven for the production of insulin, interferon and erythropoietin but their use in vivo is limited by problems like immunocompatibility and supply of nutrients to the cell.
The ultimate success would rely on the use of finer micro-machined membranes to prevent the entry of host immune components.
Tissue engineering
Research and development in tissue engineering continued apace in the last 25 years, but to date relatively few products have reached the market. Tissue engineering has become a sub-sector of the healthcare industry which is gaining in strength because of advances in biotechnology, medical device technology and pharmaceutical sectors.As traditional tissue repair procedures are inefficient, potentially painful to the patient, and costly to perform, a suitable alternative is required. Tissue engineering at the nanoscale level is leading to the development of viable substitutes, which can restore, maintain or improve the function of human tissues.
The application of nanotechnology will result in the production of artificial skin and reconstructed tissues, besides bringing about wound treatments that are better, longer lasting and more acceptable. Nanotechnology will aid in the regeneration of tissues, and even whole organs would be grown to replace the ones that have failed through disease or old age.
Nano-DNA technology
DNA, a molecule central to life, is the repository of genetic information. Within the cell it guides synthesis of cellular constituents and outside the cell it is supposed to lead the reductionist revolution. Molecular complexity of the DNA has been thoroughly understood and it is unique in the sense that it provides a paragon for self-assembly of periodic matter — the central goal of nanotechnology. Conformational changes can be induced in DNA and sticky-ended association of DNA molecules can be exploited to create specialised structures and even devices.
DNA nanomechanical devices could be useful for performing fast calculations, for sensors that detect specific molecules and to improve the properties or response performance of materials at the nanoscale.
In recent years it has been demonstrated that the level of control offered by DNA systems can be exploited to make intricate DNA-based nanostructures, including the self-assembly of DNA to form 2D and 3D periodic arrays, in particular the elements required for constructing nanomotors.
Conclusion
Given the massive research input vis-a-vis nanobiotechnology, its transformation from basic research to technology development will occur rapidly. Globally, government funding for nanotechnology is on the upward spiral, with the US being the dominant player. And Japan, Germany, China, Canada and France have by no means been left far behind.
It goes without saying that in the coming years most of the so-called blockbuster nanobiotechnology products would address the healthcare market, enabling long-term life preservation as well as fostering the postulated new trillion-dollar economy.
The writer is a student of the Punjab University, Lahore
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