For US$16,818.50 would you want a synthetic human virus?

In the media aftermath of the H5N1 transmission debate we've been hearing an awful lot about the possibilities of bringing synthetic biology to the field of virology. In fact, one of the best analyses of this situation is Carl Zimmer's piece in the New York Times. In it, Carl explores the capabilities of DIY, amateur biologists to investigate how viruses infect and cause disease. The pro's and con's of utilizing synthetic DNA to make viruses versus the more traditional methods are looked at briefly but really how easily can it be done? and how different is this new wave of synthetic virology versus earlier methods?

“The virus is ‘dead’. Long ‘live’ the virus.” – what does history say about how virology should develop in the future?

In the modern world, we are continuously challenged by viral disease; well established pathogens such as the measles and mumps viruses alongside recently (re)-emerging viruses such as ebola-virus and even those viruses which we currently know little about (XMRV?) all represent a continuous threat to human health and well-being. Yet how can this be true when we have been developing anti-viral vaccines for half a decade – surely we should be good at it by now? And, is this idea that we can easily eradicate viruses hollow, considering how relatively easy it may be to recreate long extinct pathogens from their nucleic acid sequence alone? These investigations will require years of research and billions of dollars in funding but how should it achieved?

NEIDL building in Boston

In a recent article (UK Society for General Microbiology publication 'Microbiology Today', can be found here), Paul Duprex and  Elke Mühlberger, both virologists from the Boston UniversitySchool of Medicine and associated National Emerging Infectious Disease Laboratories (NEIDL) put forward their view on how best virology may be able to face up to this global challenge and outline how it may be achieved. Through a firm grasp of its historical context, combined with recent developments in molecular biology, future scientists will better be able to understand the intertwined relationship between viral pathogenesis and its rational attenuation. If we understand how viruses cause disease at the molecular level, altering this through well-established DNA technologies we may be able to mitigate pathogenesis and develop improved or novel vaccines – and antivirals - on a rational level.

In the early days of virology (see site on the history of vaccines), bent on developing vaccines under the paradigm of “isolate, attenuate and vaccinate”, scientists barely understood the mechanisms behind the production of live-attenuated vaccines, such as those for measles and smallpox. They didn’t need to; they worked superbly and were of course highly effective allowing for the eradication of one of the worst diseases of mankind. But this golden age didn’t last long, with countless viruses proving somewhat more resistant to this ‘black box’ method of vaccinology; HIV-1, SARS and Ebola had not yet been observed by scientists and nothing was known about them. This was an age concentrated on investigating viral pathogenesis and how best to change it but with the developments of recombinant DNA methodology (two important papers concerning virus cloning and synthetic virology: 1 and 2) this agenda shifted in favour of the virus genome and it is hard to even outline the tremendous impact this molecular understanding of viruses has had on both basic and applied virology. Yet bear in mind that it is this same technology that could facilitate the resurrection and recreation of ‘eradicated’ virues.

Knowledge of the molecular biology of viruses (in this case measles virus) will go a long way in developing much needed novel, rational vaccines

Despite this word of caution, Duprex and Mühlberger argue that virology has – or at least should – come back full circle, back to understanding basic pathogenesis with the aim in mind of developing more effective therapies and vaccines; this, they say, is needed now more so than ever. This generation, and the next, of molecular virologists should take heed of the long historical roots their discipline has and highlight the importance of understanding disease and attenuation as two sides of the same coin. This of course, would allow for a better grasp of the basic biology of these long established pathogens; those viruses which are now extinct but which may resurface, or even those viruses which are constantly in our minds as agents of natures bioterrorism.  They conclude that “a long overdue renaissance in vaccinology has commenced and it is with anticipation and excitement that we wait to see progress in the next decade”.

Mahalingam S, Damon IK, & Lidbury BA (2004). 25 years since the eradication of smallpox: why poxvirus research is still relevant. Trends in immunology, 25 (12), 636-9 PMID: 15530831

Mueller S, Coleman JR, Papamichail D, Ward CB, Nimnual A, Futcher B, Skiena S, & Wimmer E (2010). Live attenuated influenza virus vaccines by computer-aided rational design. Nature biotechnology, 28 (7), 723-6 PMID: 20543832

Racaniello VR, & Baltimore D (1981). Molecular cloning of poliovirus cDNA and determination of the complete nucleotide sequence of the viral genome. Proceedings of the National Academy of Sciences of the United States of America, 78 (8), 4887-91 PMID: 6272282

Wimmer E, Mueller S, Tumpey TM, & Taubenberger JK (2009). Synthetic viruses: a new opportunity to understand and prevent viral disease. Nature biotechnology, 27 (12), 1163-72 PMID: 20010599

Viral nanotechnology - at the virus-chemistry interface

Viruses cause death and disease - Avian Influenza, Swine-origin Influenza, HIV, HPV, measles..... its hard to imagine viruses doing anything else - right?

But viruses don't have to cause disease - they can infect, replicate and exit without the host even realising it was there. Another view of viral infection is that we can exploit this very nature of viruses for our own means - meet: viral engineering (one flavour of biologically inspired nanotechnology).

[caption id="" align="aligncenter" width="352" caption="Viral nanoparticles: the diversity"][/caption]

Viruses are basically self-assembling storage containers that can enter and exit cells and deliver their contents, they are very small, are biodegradable, can be modified (relatively) easily and have an excellent ability to travel around the human body - one big bonus is that in some cases (plant viruses) they are also extremely cheap.

A recent review describes these 'viral-nanoparticles' (VNPs) as:

....dynamic, self-assembling systems that form highly symmetrical, polyvalent, and monodisperse structures. They are exceptionally robust, they can be produced in large quantities in short time, and they present programmable scaffolds. VNPs offer advantages over synthetic nanomaterials, primarily because they are biocompatible and biodegradable. VNPs derived from plant viruses and bacteriophages are particularly advantageous, because they are less likely to be pathogenic in humans and therefore less likely to induce undesirable side effects.

Of course there are many caveats with these applications such as we would have to thoroughly test the toxicity (including cell death and immunogenicity) of such VNPs as human pathogens may have been used as the basis of the design, although the use of plant viruses may circumvent these dangers. The pharmacokinetics, infectivity and replication of viruses will be assessed in animal models prior to use as so will the stability in both a physical and genetic sense. Yet there are plenty of uses for VNPs that would not have to be anywhere near a human patient.

Despite these difficulties, we have a great chance of developing improved VNPs through the application of genetic engineering and chemical modifications, allowing us to generate novel combinations of genes and properties into a single viral particle. We no longer have to rely on 'wild-type' virus genomes - we can improve on what is out there. By applying a better understanding of natural viral pathogenesis including cell entry, replication, gene expression, cellular tropism and immunomodulation we should be able to rationally design safer, more efficacious and cheaper VNPs for whatever purpose we want. We can now begin to think of viruses as a novel materal that can altered to generate improved properties and thinking this way should open up many possibilities for medicine, industry and science. This is a basic tenet of synthetic biology.

Synthetic biology meet virology.



As of today, this research has been moving at an extremely fast pace - viruses are now used in cancer treatments, bacteriophages have been used to kill off bacterial infections, viruses have been applied in materials science, improved electronics have been developed using viral particles and targeted viruses have been used in biomedical imaging technology. Yet as our understanding of virus/host interactions increases and research on the applications of these VNPs begins to move from in vitro to in vivo investigations we will see more and more uses for these novel materials in both the clinic and in industry. Look forward to the future of viral nanotechnology!

As the review finishes off:

The virus-chemistry interface remains an exciting place to be!

N.F. Steinmetz, Viral nanoparticles as platforms for next-generation therapeutics and imaging devices. Nanomedicine: NBM 2010;6:634-641, doi:10.1016/j.nano.2010.04.005