Smallpox and monkeypox are both orthopox viruses, with a common ancestor. The genomes are sufficiently different that one genome can’t become the other, at least on the timescale of human history. Something equally devastating could happen, through convergent evolution.

Convergent evolution is the process by which two or more species, of no or distant relation, evolve to resemble each other, so as to fill a similar ecological niche. The most visible, widespread examples come from Australia. Beginning 2.5 million years ago, Australian marsupial mammals evolved that resemble placental mammals. There were marsupial lions and wolves, and others resembling bears and pigs. Yet placentals and marsupials forked at least 125 million years ago.

It is comforting to think that, unlike COVID, the pox viruses are remarkably stable. This is due to their double-strand DNA, which has inherent error correcting properties, reducing the rate of mutation. Unlike COVID,  a single-strand RNA virus which rapidly obsoletes vaccines with each succeeding strain, the same cowpox vaccine used by Edward Jenner in 1796 to immunize against smallpox would work today, if you could find it. And it would work against a number of animal  orthopox viruses, such as monkeypox. Sharing the same or similar serotypes, these orthopox viruses display identical or overlapping epitopes to the immune system.

Some pox virus features are less conserved than others. The replication machinery is well conserved. Orthopox virus DNA is a linear string that tends to fray in mutation at those ends, and that is where virulence is encoded. Over the historical time period,  orthopox evolution has not been seen of the kind that affects disease presentation. But all pox viruses are the products of profound evolution, with a common ancestor that may have been an adenovirus.

How then could monkeypox become as dangerous as smallpox? A surprising impediment to the answer is this: How smallpox was transmitted in the community is not known! See (NIH) What was the primary mode of smallpox transmission? Implications for biodefense. Quoting,

The mode of smallpox transmission was never conclusively established. Although, “respiratory droplet” transmission was generally regarded as the primary mode of transmission, the relative importance of large ballistic droplets and fine particle aerosols that remain suspended in air for more than a few seconds was never resolved.

It wasn’t resolved because the danger of the disease made design of rigorous studies impossible. All the knowledge gleaned from actual smallpox came from case-control studies, meaning you look for types of patients, which you characterize by findings. A gem from the paper:

In one survey, (Sarkar et al., 1973a) 10% (Westwood et al., 1966) of 328 contacts had positive swabs, but only 12% (Kaplan et al., 2002) of those with positive swabs developed smallpox. Among 59 unvaccinated contacts 27% (Miller, 1957) were culture positive, but only one developed smallpox.

So if it’s not inhaled, it must be the infectious pustules, right?

In contrast to oropharyngeal excretion, scabs contained large quantities of virus regardless of disease severity (Mitra et al., 1974) and were shed for another week or more after throat cultures were negative. Scabs alone, however, were not associated with further cases (Rao et al., 1968; Mitra et al., 1974).

The definitive experiment, exposure of humans to smallpox aerosols, could not be performed, so resort was made to animal studies, with the relatively safe vaccinia virus as a model. Quoting,

The animal data show that artificial respirable aerosols were effective means of producing poxvirus infections, that the infectious dose by the airborne route could be very low, and that animal-to-animal airborne transmission of rabbitpox and variola was observed. They also suggest that inoculation of mucus membranes was less effective at producing a generalized rash than was exposure of the lower respiratory tract.

This is not a rigorous answer for smallpox in humans. It does raise a question. Other pox viruses transmit efficiently via aerosols. Transmission of monkeypox is currently thought to occur mainly through bodily contact, contaminated objects, and secondarily via large respiratory droplets. Could airborne transmission of monkeypox become more efficient, sustaining or enlarging an epidemic?

This has not been decided in all detail for smallpox. CDC favors transmission via large droplets while other sources implicate fine aerosols; see What was the primary mode of smallpox transmission?

See Figure 1. Smallpox case presentations suggest that by efficient airborne transmission, monkeypox could manifest as a more severe disease, with a big step towards smallpox virulence.

To be continued shortly. Several mechanisms will be discussed.