It's time to make friends with your viruses

For years, we've known that not all bacteria are enemies — some are actually good for us, and belong inside us. That understanding sparked a boom in probiotics science and a multibillion dollar probiotics industry. But viruses? They still get a bad rap, despite quietly occupying our insides —and sometimes even helping us.

Not that scientists even agree on whether viruses are alive or not. There's so much we don't know, including just what they are doing in our bodies. What we do know, though, is that viruses are not, in fact, all out to get us. Not only are they not uniformly bad news for our health, but many viruses actually live with us in a symbiotic and evolutionary relationship. Viruses exist in healthy people, and some are even actively beneficial for human health. Not to mention that about 8% of our very own genome consists of ancient viral genes. So basically, viruses are in us, and are us. Although we have known a lot about a small number of heavily-studied "bad" viruses for decades, the vast diversity of these weird little guys that co-exist in humans is mostly unmapped, just waiting to be discovered and understood.

“It’s quite clear that humans are exposed to all kinds of viruses throughout our lives. And I think we’re only starting to figure out why they’re there, what they’re doing, and what impact they have on our health,” Ken Cadwell, associate director at the University of Pennsylvania Perrelman School of Medicine’s Center for Molecular Studies in Digestive and Liver Diseases and director of its Gnotobiotic and Naturalized Mouse Core Facility, told Salon in a video interview. Cadwell studies how the human (and mouse, his usual model organism) immune system has adapted to the various microbes we encounter through our lifetimes.

In 2014, Cadwell and two colleagues made the amazing discovery of a virus – specifically, a norovirus, that pathogen notorious for sweeping nursing homes and daycares, causing terrible upset at both ends – that can actually restore the healthy condition of the intestines, just as “good” bacteria do, for example if you take a probiotic supplement to restore your microbiome after wiping it out with bacteria-killing antibiotics. That bit of good news about a virus you’d normally not want to touch with a sterilized ten-foot pole was an early finding in Cadwell's quest to understand what turns out to be a huge diversity of viruses living in, with, and on us.

Perhaps it's time for viruses to take their turn in the limelight. The NIH's Human Virome Program aims to fill the great gap in our knowledge about viruses that "call us home". The main focus is on beneficial viruses that are persistent in the human body, not on those that cause disease (noroviruses, like Cadwell studied, wouldn't be part of this, the Program FAQ says, because they are transient). Among 16 institutions that received funding through this program is VAST (Viromes Across Space and Time), a major longitudinal Weill Cornell Medicine/Stanford project to learn what a healthy human virome looks like. This project, among others underway, ought to tell us more than most of us have ever wanted to know about those weird little things. But it's knowledge that could improve our health, even save our lives one day.

You, me, and everyone else has, it's thought, about as many viral particles living in or on each of us as there are bits on a computer hard disk in 2024 — ten trillion, or roughly a third of the total amount of cells in our bodies. The total number of viral particles on the planet, though, is insane: a bit less than the mass of the Sun in kilograms, or 10 followed by 31 zeroes, an incomprehensible number that makes viruses the most abundant biological stuff on Earth. Perhaps 320,000 different types of viruses infect mammals. The statistical study that came up with that estimate based its analysis on the dozens of different viruses from 9 virus families all found in a single Indian Flying Fox, Pteropus giganteus. And indeed, most emerging infectious diseases in humans are zoonotic — meaning they come to us from another animal — and most of them are viruses. So if this estimate is even remotely accurate, we're looking at hundreds of thousands of potential new viruses as we increasingly mingle with animals via large-scale agriculture and the destruction, fragmentation, and human colonization of animal habitats.

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"Viruses understandably evoke a bad connotation because we know all the harm associated with viruses," Cadwell said. We have very good reason to surveil infections — H5N1 bird flu, for example — in our mammal and other animal friends in hopes of heading off a disastrous adaptation enabling human-to-human transmission of a virus that spreads easily and kills or maims many of those it infects.

On the other hand, as we've seen, not all viruses are out to get us. It's possible that some of them are only out to get some of us, some of the time. Others are totally benign, just hanging out inside or on-side us without doing any harm. Still others are on our team, taking down bacterial invaders before they can infect us or otherwise do us dirty.

That 8% of our genome that is made up of ancient virus DNA includes both "goodies" and "baddies" (although they are fully part of our genomes, not just living inside us, they are considered part of the virome for the purpose of the NIH's Human Virome Program, along with viruses that infect humans and viruses that reside in us but infect bacteria). The 30 distinct families of endogenous retroviruses, as that ancient viral DNA is called, in humans each represents a distinct process of colonization. An ordinary retrovirus became part of our ancestors, while going extinct in the outside world, over thousands to 3 million years of evolution, and most became part of our ancestors' genome sometime before we diverged from chimpanzees. Some are nicknamed jumping genes because they literally jump around, copying and pasting themselves into different parts of our genome just as if they were still viral invaders. Some bad things they might do: some evidence suggests they could be responsible for symptoms of motor neuron disease like ALS in patients with HIV and others, and perhaps in other neurodegenerative disease (there are various ways this could occur and it's not yet clear exactly what their role might be). Ancient viral genes might also play a role in helping regular viruses get a hold in us, and in the development of some cancers and autoimmune diseases.

But then there's the good stuff. Our endogenous retroviruses sometimes play important positive roles for our health: one gene with ancient viral origins, for example, codes for a protein involved in the development of the human placenta, another may protect a developing fetus from its mother's immune response. Others may be important for keeping human stem cells "pluripotent", or able to become any one of many different types of human cell. And these viral genes may protect us against other viral infections in some cases, or provide antiviral resistance, immunizing rare individuals against HIV for example.

As for the real viruses? Cadwell's 2014 finding about norovirus isn't the only evidence that suggests viruses that infect us aren't always our enemies, either. Anelloviruses, a group of viruses that are found in 90% of healthy humans, might (it's not clear yet) play a role in suppressing tumor formation. In other cases, a virus could protect you from a different pathogen. Take plague, for example, which I think we can all agree we'd rather avoid. Studies in mice suggest that unnoticed infection with run-of-the-mill viruses like cytomegaloviruses or herpes viruses can protect against infection with the bacteria Yersinia pestis, which causes bubonic plague (and, as a bonus maybe, against Listeria bacteria). Different viruses can cure diabetes in mice; reduce the risk of a really nasty virus, Ebola, proving fatal in humans; or prevent HIV progressing to AIDS. And phage viruses, which are viruses that infect bacteria, rather than humans, can protect us by directly attacking bacterial villains.

"People have made observations in either direction [good or bad for us] with various diseases," Cadwell said. "A more causative role [in preventing or fighting disease] is supported by animal models... we lack a bit of information on what's happening in humans. But it makes sense to me that having viruses around, what we can say with a fair amount of accuracy is because viruses require the host cell to make more copies of itself, there's no way it's silent. It's interacting with us, and there's got to be immune consequences to that. And whether that's good or bad I think is going to be highly dependent on the context and the individual."

Studying potentially symbiotic or mutually beneficial viruses the way we now avidly study bacteria for their possible helpful effects for human health — and for human bank accounts, in the case of those hawking often under-evidenced and under-regulated microbiome supplements — requires a bit of a mindset shift, though.

"These viruses that infect our cells, they have primarily have been studied from the lens of having bad effects on our health, but there's more and more correlations that are demonstrating that that's not necessarily the outcome," said Cadwell.

Not that it's an easy sell, nor a quick leap to finding "wellness viruses" on the shelves at Whole Foods.

"Probably the low-hanging fruit here are the oncolytic viruses," Cadwell suggested. These are viruses that invade and destroy cancer cells — using their awesome power for good rather than evil, you might say. In fact, he explained, some viruses do this really well. So for over a decade, scientists have been working to understand how they do it, and then to engineer viruses for this therapeutic purpose. In fact, in 2015 the FDA approved the first and only cancer-killing virus, a herpes virus used for treatment of a kind of late-stage skin cancer, where there are few conventional options. The virus was engineered to be less likely to infect healthy cells, and also, sneakily, to cause the cancer cells it infects to produce a protein that strengthens the immune system to help destroy them.

And people have been exploring the potential of certain viruses as delivery vehicles for a long time.

"The kind of holy grail for gene therapy is you've got to put the genetic material you want in the cell you want it to be in. So you need a delivery system...These viruses through evolution have figured out a way to get their genetic material inside a cell... we can swap in and out parts of people's genome, like let's say you're missing a proper copy of hemoglobin, we could put in the correct copy into your cell by putting it into the virus and have your cell infect the virus. That's the promise of gene targeting," Cadwell said.

Other applications include using viruses to deliver bone marrow cells for transplants, production of particular cell types, and more. Technology in the past didn't allow precision and raised the risk of the virus integrating into parts of the genome you don't want it to go to, but it has progressed to the point where you may soon be able to target a specific cell in a person with whatever you want to repair or add, delivered by the virus.

In the past, researchers focused on curing the diseases viruses cause, but in future, they may pay equal attention to how viruses, carefully engineered and deployed, could make us well.

So is it time to add viruses to one's microbiome-feeding regimen of probiotics and prebiotics, synbiotics (which combine the two), digestive enzymes, postbiotics (compounds produced by bacteria) and perhaps even the odd bit of actual food?

Cadwell advises caution. "On the one hand there's a safety-driven concern, that if you're doing something like a fecal microbiome transplant, what else are you bringing over.. that's why it's very dangerous for people to do DIY type things with a blender, right? ...You want to really know what else is there, you don't know if it's good or bad, and just because it's good for somebody else it could be dangerous for you if you're a recipient when you have an underlying condition."

Still, in principle we may well be not far from the day when we see certain viruses as valuable sidekicks — even ones we might want to supplement with: "If the thought is that infectious entities like bacteria can tune your immune system or other aspects of your physiology in ways that you want it to to prevent or treat a disease, you could certainly say the same thing about other infectious agents like viruses," Cadwell said. The proof of principle of this has been done in mouse models, by him and others.

"The question," he said, "is who's willing to try out these things in humans?"

While it might be tempting to answer: RFK Jr — and to imagine that this is why he's hard at work reducing Americans' access to vaccines against dangerous viruses, promoting spread of H5N1 bird flu, and shutting down research into antiviral mRNA vaccines that might save us from that same bird flu, among other viruses — the science does not remotely support the idea that adding opportunities to get infected with viruses is good for our health. On the contrary. With enough research, though, perhaps one day we will actually know how to use these often vicious, sometimes beneficial partners to our advantage.

"It's relatively new, this concept of the virome, and I think we're at a stage where we're going to start generating a lot of information," Cadwell said.

Like virtually all science and health related work in the United States, this blossoming field is at risk of being nipped in the bud by cuts to federal funding, shifting funding priorities, and outright prohibitions. In particular, virologists point to Donald Trump's May 5th executive order banning gain-of-function research as a potential disaster that is worded in such as way that it could well be applied to an extremely wide range of research activities. Angela Rasmussen, an American virologist who teaches at the University of Saskatchewan and is a research scientist at the Vaccine and Infectious Disease Research Organization-International Vaccine Centre, says that while the Department of Health and Human Services, especially NIH director Jay Bhattacharya, minimizes the impact of the order — as if it will affect only the teensy-teensiest bit of nefarious research — the EO in fact uses a vastly expanded definition of gain-of-function research. Rasmussen says the previous version was also unclear about how it would be interpreted: the new EO is far worse in this respect. The fact is that Dr. Evil and his fellow fictional evil and/or mad scientists are far from the only biologists who make regular use of gain-of-function research, or whose work may be seriously affected by the EO, among other administration acts.

"One of the parameters that is forbidden is to put an antibiotic resistance marker into a pathogen. That basically describes all molecular cloning, because we use antibiotic resistance markers to select for the clones that we develop, and we select for them by putting them into E. coli," explained Rasmussen in a phone interview with Salon. In a subtle dig at the Trump administration's multiple cuts to the Food and Drug Administration, including to food safety assurance programs and quality control testing of certain leafy greens, Rasmussen explained that lab strains of E.coli are not like the kind you're going to get from eating contaminated lettuce. They're not that pathogenic. Still, technically they do count as pathogens just because they could cause urinary tract infections or harm people with compromised immune systems, like so many things.

"So the question then becomes, how is this going to be regulated? Does it refer to all pathogens?" Rasmussen asked. "And there's language in the executive order that says it does apply to even pathogens that aren't very pathogenic. And you know, there's many other things in that executive order that are not sufficiently described, and they could be interpreted very broadly, and that would have the effect of shutting down quite a lot of research."

Cadwell agrees. "I think the issue is the language is so vague that we don't know ...Gain-of-function, depending on who you ask, could be anything that manipulates the virus," he explained. "Most things we do to a virus makes it weaker or not work as well, or maybe you're trying to engineer it for therapeutics, and I'd hate to see somebody throw cold water on that." Far from improving the fitness of a virus (gaining fitness being a very different thing from gaining function), most gain-of-function work is, Cadwell said, more like trying to make a virus green so it's easier to observe — things like that.

Another example Rasmussen offers is from a different part of the EO where it is stated that "you're not allowed to disrupt a beneficial [immune] response. You could make the argument," Rasmussen said, "that that type of ban would prevent a lot of different kinds of vaccine research, some of which are currently critical to actually doing pre-clinical studies on vaccines and developing new vaccines."

Rasmussen said that her PhD work, which involved adapting human cold virus to infect mouse cells so that it could be studied in mice, might have been banned under another article of the EO, which prohibits altering the host range of an agent or toxin. "The way that this is written, it basically would prevent development of all rodent models," except perhaps those that exclusively use a wild-type virus or toxin. "Certainly for viruses, it's very, very common to make pathogenesis models that you would need for testing drugs. You need it for testing vaccines. You would need it to understand the basics of how this pathogen causes disease."

Rasmussen, for example, has studied Ebola using mouse-adapted Ebola virus, which is a necessary adaptation in order to study the disease in mice in a way that's comparable to humans. The particular virus she used in this case was made 20 years ago, she said — by the US Army.

So far, she said, "the pharmaceutical industry's attitude has kind of been like, wait and see." But there are at least two different aspects of the industry that this could affect. "One is pharmaceutical development, because they do talk about the need to develop independent oversight that would apply to both federally funded labs initially, but also to any other life sciences labs that would potentially be doing this kind of work, whether they're funded by the federal government or not."

As with other aspects of implementation, there's no clarity about how this will work. "The other issue that will affect industry is the risks that they talk about about nucleic acid synthesis screening." This, Rasmussen said, is the government's apparent belief that you can just call up a company that sells vital research equipment, and order a dangerous virus. "Just like, order up some smallpox," she says, as an example (in fact, you cannot and never could call up a nucleic acid synthesis company and order smallpox, and most major companies already screen orders. For example, you cannot order up a batch of the influenza virus that killed millions of people in 1918).

"So they want these sequence providers to screen orders to make sure that people aren't trying to order select agents or trying to order dangerous pathogens that they could potentially do under-the-radar gain of function research with or carry out some other type of nefarious attack with it." Since the necessary screening is already in place, Rasmussen asks what is likely to change. "What would be the compliance mechanism, who's going to [enforce it]... what are the consequences going to be?"

The executive order is written, Rasmussen says, on the (unproven) premise that the Biden administration allowed dangerous gain-of-function research with insufficient oversight and also approved federal life science research funding in countries with limited oversight or expectation of biosafety enforcement.

"And this executive order is 'necessary to prevent future lab leak pandemics', which of course, don't happen," Rasmussen said, making air quotes. "So how are they going to prevent future lab leak pandemics by cutting the federal research budget?" she asked rhetorically, going on to say that "this is going to provide both a presidential order as well as supposedly scientific justification for making a lot of those cuts to pathogen research in particular... so really, I think this executive order is meant to further justify and validate changes that are being made to pathogen research and vaccine research." She also worries about selective enforcement of the vague terms of the order to target some researchers or research projects for political or other reasons.

Rasmussen noted that many grants are now simply in limbo, with researchers whose funding applications have advanced to the point where a decision should be made, but then never seem to move on to the advisory council that makes that final call. Or they go to the council, but a notice of award never comes, or perhaps it's in process: nobody knows. Multiyear grants for projects already in motion — which includes purchase of equipment and hiring of staff — are in limbo, with their current year of funding not forthcoming, but no clarity about whether funding has been cut or merely delayed and for how long, or whether it's been cut permanently. From what Rasmussen hears from faculty members at Columbia, where she did her PhD, every single Medical Center grant has been cut, with no NIH grants preserved at the university at all. Salon reached out to two leads on the VAST project to ask if it's been affected by cuts or other changes. One did not respond; scheduling difficulties meant that Salon had not received a response to written questions posed to the other scientist, Stanford Medicine geneticist Michael Snyder, by press time.

"A lot of these termination orders and work orders are illegal. It's illegal to just cancel a grant for no reason and not provide an appeals process. I mean, it's federal money. There is a peer review process for awarding these grants. And I don't know that anybody knows [what will happen] because this is so unprecedented." The uncertainty, unemployment, and fear of de-funding among her scientist colleagues are taking an immense emotional toll, Rasmussen said.

Meanwhile, Cadwell remains hopeful that despite the short-term obstacles, the future simply has to be bright for work that will bring the mysteries of this viral microbiome to light for the benefit of humanity.

"I'm not sure what the future of [projects to fund virome research] will be, with the realignment of the NIH...but I think the community of scientists, both within and outside the field, are really excited about [studying the virome], and I'd be surprised if we can't keep up the momentum into the future," he said.