Martian carbon cycles, and magnetic flip fried Neanderthals

Treatment for severe pain still relies heavily on opioids - morphine-like agents. These are very effective in the short term, but they’re highly addictive, and potentially deadly in overdose or if otherwise misused. Led by the fact that many people find relief with cannabis, US researchers have now come up with a compound that mimics one of the molecules found in cannabis. But the clever twist is that, by making their molecule more water-loving, it can’t get into the brain to produce any mood-altering or addiction effects. Instead, it works purely by activating cannabinoid receptors in our peripheral tissues. The effect doesn’t wear off with repeated use, and, although they’ve tested it only on mice so far,  it does seem to be incredibly potent. Here’s Washington University’s Richard Slivicki and, first, Susruta Majumdar…

Susruta - The questions we were trying to answer is can we separate the psychoactivity or the mild altering properties of cannabinoids but retain its pain relieving properties to develop a non-opioid analgesic or pain reliever?

Chris - Because when we talk about cannabis that's actually a cocktail of compounds, different chemicals, isn't it? And so are you saying then that the ones that give you the mind-altering, mind-bending effects are not the same as the ones that cause pain-killing effects?

Susruta - Yes, so what we are using here is a single entity, we're not using phytocannabinoids like are present in medical marijuana for example, but we are tweaking the chemical structure in a way so you can separate the mind-altering properties from the pain-relieving properties.

Chris - And Rich, how are you actually doing that? How do you dissect apart those two effects?

Richard - One way we can do this is target cannabinoid receptors that are located outside of the brain and the central nervous system, targeting tissues that are feeding in those pain signals into the central nervous system.

Chris - So in other words the pain-killing effect is not necessarily achieved in the brain, it can be achieved outside the brain but the mind-bending effects are achieved inside the brain and if you go for the two different targets you can isolate those two effects?

Susruta - Absolutely, that is the point. So what we did was we just made subtle chemical changes into this molecule and make sure that it only targets the periphery. There's something called the blood-brain barrier that the body naturally has to prevent drugs and harmful chemicals from entering the brain and the blood-brain barrier needs oily compounds or greasy compounds. So what we did was with this synthetic cannabinoid we made it more water-soluble or less oil-like as a result of which it will not enter the brain and only target the peripheral nervous system or tissues outside of the brain and you're able to achieve the pain-relieving properties while you're able to separate the mind-altering properties.

Chris - How did you test it, Rich, to prove this was going to work?

Richard - So in order to evaluate this for just pain-relieving properties we use animal models of pain and so we use different models of migraine, neuropathic and inflammatory pain. Inflammatory pain is just like an acute injury due to like a burn or like an infection. Neuropathic pain is more of like a pain and so something due to like nerve damage. We then screen these molecules for not only their pain-relieving properties but also their potential for side effects in rodents and so we can evaluate those which might equate to the mind-altering effects of cannabis which is something again we wanted to avoid.

Chris - And do you get a suppression of pain responses in these animals which would suggest that this is working but without producing the psychoactive effects?

Richard - We find efficacy across all three animal models of pain and importantly we didn't see any analgesic tolerance. That is with repeated dosing the compound still retained pain-relieving effects which is really important because with opioids and even cannabis we see this tolerance-like effect. And more importantly too we found a great separation between the pain-relieving properties and the centrally mediated effects which indicates that this compound has a really wide therapeutic window which is really important for kind of a first-in-class analgesic.

Chris - And Sus, one of the things about the opioids that makes them very attractive is they are incredibly potent. We can achieve really powerful control of pain with them which under certain circumstances we really need. So are these drugs any good at rivalling the opioids for that?

Susruta - That was one of the surprises of this project that these turned out to be extremely extremely potent. And I've been working in the opiate field trying to develop drugs on that side of things also and you're absolutely right the potency has always been an issue with the other targets but these were as potent if not more potent than morphine which is the choice for treating pain or even fentanyl for that matter. And the beauty of the system is that unlike the opioids they do not produce respiratory paralysis or loss of breathing and the non-addictive properties because we are targeting the receptors outside of the brain. Sedation is a huge issue, stoning is a big issue with the cannabinoids or psychoactivity and mind-altering. There was a hundred-fold separation between the pain-relieving properties and the adverse side effects like sedation with this class of molecules.

Chris - Rich, have you unpicked how exactly you're doing this? Do you know why those pain nerve fibres have those receptors on them? Why should those pain systems have the ability to respond to this class of compounds at all?

Richard - The body has its own cannabinoid-like system called the endocannabinoid system so we actually synthesise molecules that bind to these receptors. The body has these receptors throughout itself and it has various different roles and different physiology. Stress-induced analgesia is a big one. There's a lot of like pain inhibition that goes on with these endocannabinoids endogenously.

Chris - So this is presumably quite a big step forward then because you've got something which appears to give opioids a run for their money in terms of how good it is at painkilling but doesn't seem to have any of the negative baggage. The thing is it's one thing to have a molecule in a test tube but a test tube into a needle in a patient's arm or even a pill going down their throat, that's a big hurdle yet isn't it? So you think it's surmountable though, it looks promising.

Susruta - Right, I think it's very promising. I think one of the challenges we have had in the pain field has been to identify targets which, as you pointed out initially, have the potency of the opioids but with the non-addictive potential or the respiratory depression potential. So we have identified a target, the target has been derisked, and the next step is to modify this molecule or a second generation molecule and convert it into a pill. This is definitely doable.

Until 40,000 years ago or so, there were two groups of human ancestors alive on Earth: us - anatomically modern Homo sapiens, and our close relatives, the Neanderthals. They didn’t just overlap in time, either; there’s evidence that the two inhabited some of the same territories and even interbred. But, suddenly, after hundreds of thousands of years, Neanderthals abruptly disappear. A range of theories have been advanced to account for where they went, ranging from competition from our forebears to absorption into a larger, more rapidly expanding anatomically modern human population. But now scientists have another tantalising hypothesis: 41,000 years ago the Earth’s magnetic field flipped. Known as the Laschamps excursion, this temporarily dialled down the magnetic force field that defends us from space radiation, thinning the ozone layer, so UV levels surged. With their more advanced clothes, and a familiarity with iron-based make-up, perhaps our anatomically modern human ancestors were better equipped to deal with it, suggests Raven Garvey, an anthropologist at the University of Michigan…

Raven - Currently, Earth's magnetic field is what's referred to as a dipole. There is a north pole and a south pole, but these poles reverse periodically on roughly a time scale of every 200,000 to 300,000 years. But sometimes Earth's poles will wander a bit and become unstable. This particular group of scientists were interested in a phenomenon about 41,000 years ago where the pole came near to reversal but didn't quite, so the dipolar structure of the magnetic field was quite disrupted. This likely had near-Earth implications, so things that would have been felt by all sorts of life on Earth, which is where I became involved as an archaeologist. I study such things as humans' interactions with their environments.

Chris - What was the population like 41,000 years ago? Who was around and what were they doing and where?

Raven - Just to give a little bit of context, archaeologically, it can be quite difficult to reconstruct demographics to know exactly how many people or even approximately how many people were in a place at a particular time. We believe that populations were quite low. The area where this Laschamps phenomenon, this excursion of the magnetic poles, would have been quite strong was Eurasia. Living in Eurasia at the time were two species of hominins, the Neanderthals and Homo sapiens, which is us.

Chris - Were they overlapping? Were they interacting? What do we know about what they were doing at that time?

Raven - Neanderthals arrived first. They probably developed in Eurasia sometime before 400,000 years ago. Evidence currently suggests that Homo sapiens, anatomically modern humans, arrived in Eurasia probably about 57 or so thousand years ago. Just about the time of this Laschamps excursion, so around 45,000, 43,000 years ago, anatomically modern humans spread westward quite rapidly. There is evidence that they were interacting with Neanderthals. Genetic evidence shows that many living populations of humans, Homo sapiens, us, have between 1% and 4% Neanderthal DNA. There was certainly some amount of interaction going on when these two populations were living side by side in Eurasia.

Chris - Critically, that's also the time point when we know that Neanderthals began to disappear, isn't it? Because if you look much more recently than that, they've gone quite quickly. Are these results suggesting that this phenomenon to do with the reversal of the magnetic field might be linked to that happening?

Raven - That's precisely what we're interested in exploring. Yes, in fact, Neanderthals are no longer around in this area by 40,000 years ago, which is right about the tail end of this geomagnetic phenomenon. One of the things we've wondered is what about that phenomenon changed what people in this place might have been experiencing at the time? One thing that may have occurred is that the dipolar structure of our current magnetic fields creates something like a force field around our Earth, which ordinarily shields us from an awful lot of bombardment of particles from space, including ultraviolet radiation, which you may have heard in other contexts is what causes things like sunburn and skin cancer. And so when the dipolar structure sort of broke up, these magnetic field lines were not creating that shield nearly as effectively. So more of this ultraviolet radiation was making its way to Earth. And so one of the things we wonder is, are there differences in the cultures practiced by Neanderthals versus Homo sapiens that might be significant in this regard? Archaeological sites that we associate with Neanderthals have lots and lots of tools, and some of those tools were probably used for the preparation of hides, probably for things like cloaks or loincloths, maybe some footwear to protect their bodies, because this was also a very cold time in Europe. Sites that we associate with Homo sapiens, conversely, not only have similar kinds of tools that were for dispatching animals and removing their hides and preparing those hides for other purposes, but we also find needles and awls, things that we associate with stitching, with sewing. And so one interpretation of this difference is that Homo sapiens were making tailored clothing, clothing fitted to the limbs like shirts and pants, rather than simple draped clothing that we tend to associate with those Neanderthal sites. And this may have conferred the advantage not only of keeping people warm in what is a cold climate, but if the UV radiation is as we suspect it might have been stronger during the Laschamps excursion, this would have provided a secondary benefit, that of protecting exposed skin from harmful radiation. In addition to the tailored clothing, in sites that we associate with Homo sapiens, there is considerable amount of a substance referred to as ochre, which is iron oxide, that in some modern populations is used as a sunscreen, and there have been experimental studies to show that it is an effective sunscreen. So the fact that the amount of this substance in sites associated with Homo sapiens goes up during this space weather event, the fact that it has been observed as an effective sunscreen in more recent times, is again suggestive that people may have been applying this to the skin as, say, another form of sun protection.

Chris - Is there any evidence that they were doing that, as in artwork or other documentation where you can see people were clearly applying this at that time, which would add kind of weight to the idea that people were self-medicating almost in that way?

Raven - Sadly no, I wish we had such evidence, but the depictions at this time, depictions in rock art, are primarily of animals or abstract designs, and that I know of, there are no representations of hominins, human-like forms, applying a substance to the skin.