September 2023 • PharmaTimes Magazine • 16-17
// VIRUSES //
A view to a kill
Are viruses alive or dead and is it time to find out?
This is a popular but mostly philosophical question, to which no one really has an answer, but our money is on alive.
This is based on our impression that the biological clocks of viruses are constantly ticking away, prompting, or motivating the viruses to track down (as they lurk on surfaces and float on currents of air) a suitable partner with which to produce offspring.
Never mind that this coupling is not consensual, that it is invasive, and that it damages or even kills the partner in the process as lytic viruses, for example, cause thousands of offspring to be released per ‘breeding event’. An analogy with female praying mantises and black widow spiders that kill and consume their partners in ritual acts of courtship comes to mind.
Our point here is that this single-minded drive on the part of viruses to find a suitable cell or ‘mate’ in order to reproduce, even if the act of reproduction is a lethal or near-lethal event, does not seem to be entirely dissimilar from the mating behaviour of the aforementioned arthropods, which makes them, to our minds, alive. Or alive-ish, at least.
The waiting game
Another perhaps less far-fetched analogy is that viruses are like spores or seeds, which lie in wait, dormant and inert, during unfavourable conditions, in this case when the viruses are outside of host cells, and wake up or germinate when conditions improve – in this case when viruses are ‘planted’ in the ‘soil’ of host cells.
If spores or seeds are considered to be dormant but alive, then so too are viruses – by that analogy – alive, or at least conditionally alive, when conditions are propitious. Certainly, viruses look alive in the sense that it is possible to visualise the different phases of their life cycle under electron microscopy.
The OCD-like prescription on the back of shampoo bottles and in ad campaigns to ‘lather, rinse, repeat’ (LRR), finds its biological counterpart in the genetic code of certain viruses, which instructs them to ‘infect, copy, lyse, repeat’ (ICLR).
According to this rigidly repeated sequence of events, which has played out over aeons and aeons, viruses enter host cells, parasitically hijack their metabolic machinery to make multiple copies of themselves, and then exit by a lytic burst (although not all viruses lyse cells), leading to infection of neighbouring or distant cells and the start of another lytic cycle and so on.
The digital-inspired phrase ‘to go viral’ presumably derives from the propagative power of biological viruses to infect and spread exponentially ad infinitum, (similar to the ever-explosive dissemination of cat videos posted on YouTube), unless and until the immune system intervenes.
The degree to which the immune system is able to intervene, in turn, depends on its state of health, since, when dysfunctionality or immune suppression is present, as in cancer or AIDS, common viruses that normally pose no threat are potentially highly lethal.
Apocalypse now
In these post-pandemic times, most of us are conditioned to anthropomorphise viruses as the enemy. The Nobel Prize winner, Sir Peter Medawar, memorably described viruses as “a piece of bad news wrapped up in protein”.
Such a perspective is, however, one-sided because viruses, if properly directed, are a potentially very effective anti-cancer ally.
This is because in the absence of a functional immune system, a hallmark trait of tumours, the ICLR cycle is unimpeded, which differentiates viruses from almost every other therapy where immune suppression interferes with efficacy.
In the case of viruses, the more intense the immune suppression in the tumour the better they perform; repeated cycles of ICLR, in turn, increase the likelihood of immune stimulation from released tumor proteins or antigens.
Lysis or destruction of tumour cells alone, however, is somewhat hit-or-miss in terms of how much or to what degree anti-cancer responses are stimulated, since the indiscriminate release of antigens may or may not specifically target the tumour, which is the reason to supplement or arm the virus with additional genes that function as an immune ‘kickstart’.
These additional genes are called ‘transgenes’ and the engineered viruses, which carry these transgenes, are referred to as oncolytic, ‘onco’ meaning cancer and ‘lytic’ meaning ‘burst’, in reference to the ICLR cycle, described above.
Many companies have developed oncolytic viral platforms, specifically adenovirus, which is the agent of the common cold. One of them, described below, is called AdAPT-001.
It is far from inevitable that a viral infection, despite how potent an immune stimulus it is, will sufficiently rev up the T lymphocytes against tumours to eliminate them.
This is in part because tumours frequently overexpress a protein or cytokine called TGF-beta, which acts to put the T lymphocytes and other cells of the immune system to sleep such that the cancer cells are basically free to roam about and carry out their business, unimpeded and unperturbed.
During infection of cancer cells, AdAPT-001 copies not only itself, over and over again, thousands and thousands of times, but also the TGF-beta trap gene that it carries as the tumour essentially turns into a biological factory, which transcribes the viral genome on command and synthesises the proteins encoded therein to its own detriment.
When this TGF-beta trap gene is expressed as a protein, it ‘traps’ or neutralises TGF-beta, which hopefully awakens the T lymphocytes from their immunosuppressive trance.
The final analysis
In conclusion, we return full circle to the opening question, are viruses alive?
According to us, yes, although many would undoubtedly disagree however, it must be said, and not that it matters per se, because dead or alive, viruses are here to stay, doesn’t the very fact that it’s possible to ‘kill’ viruses with detergents, alcohol, hand sanitisers and the immune system etc. imply that they’re alive in the first place because only something living is killable?
The EpicentRx oncolytic adenoviruses, such as AdAPT-001, are engineered with the same vital drive – a drive, which governs all living entities – to reproduce, and propagate, but only in cancer cells, and this, hopefully, leads to the elimination of those cells.
In the end, whether the viruses themselves are alive or not, the hope is that new treatments will keep patients with terminal cancer alive for longer or possibly even cure them.
Bryan Oronsky is Chief Medical Officer at EpicentRx. Go to epicentrx.com
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