• Dr. Ragnar

What if we don't know what we are doing?

11 years ago, I found out that I had passed my all my exams and was heading to Cambridge University, where I eventually specialised in Biochemistry. The first thing my dad said to me when I told him was: “Remember, this doesn’t mean that you actually know anything”. What I think he was trying to say was “congratulations” (and I’m sure he did say that as well). However, even now, I can hands-down say that this is the best advice I have ever been given.

When you spend a large proportion of your life in academic institutions, it is easy to get caught up in the assumption that you know exactly what you’re doing, and convince yourself that the collective relentless onslaught of experiments and trials is essential in continuing human advancement. Perhaps this is why scientists are often portrayed as arrogant in the media.

However, in order to become an “expert” in your field, you must spend a lifetime going into the exquisite detail of one particular thing, and often at the expense of looking at what others are doing. Don’t get me wrong, I am a scientist at heart. I believe that the accumulation of knowledge through the scientific method is absolutely essential, particularly when we are so desperate for breakthroughs in fields such as medicine. However, a recent experience forced me to ask two questions:

“What if everything is so much more complicated than we think?”

“What if we really don’t know what we’re doing?”

Are we getting anywhere? Last week, I was lucky enough to attend a conference on Developmental Brain Injury. This topic includes any damage to the brain, which occurs late in pregnancy, during childbirth or early in a child’s life. This is the basis of my current PhD. This particular conference is well-known for bringing together all of the experts in the field for a few days to discuss their current ideas, theories and results. Between them, the professors and doctors that attended this conference have saved many thousands of lives. They also run scientific laboratories where they explore the mechanisms behind, and potential treatments for, developmental brain injury. Sadly, despite many decades of experiments, the field has only managed to produce one significant treatment so far – hypothermia. However, though effective in the right setting, hypothermia only works for a very limited range of injury, and does not completely reverse the damage.

As an example of the difficulty developing treatments, one speaker presented a paper from 2006, which discusses the 1,026 treatments for stroke (the injuries we deal with are also considered a type of stroke) that have worked in the lab, but have not worked in humans. That number will certainly be higher now. How can it be that we have uncovered so many pathways and systems that affect brain injury (or any other organ injury), but still can’t treat it? Obviously, there are things we haven’t discovered yet, but you would have thought we’d have gotten somewhere by now… Right?!

This certainly isn’t exclusive to the field of brain injury. I’ve previously mentioned the fact that last year alone, over 44,000 papers were written about diabetes and obesity. Despite this, we still can’t agree on how we should eat, and what the exact cause of these diseases is. Maybe that’s because we’re assuming that the human body is actually far simpler than it really is.

What if we don’t understand the system? The mechanisms we deal with in the context of brain injury tend to be on the biochemical level – proteins and hormones interact with other proteins, changing the way that cells act, or turning various genes on and off. Most of this happens naturally after an injury, and does so as part of a normal healing response. For instance, we’re often told that we generally need to reduce “inflammation”. However, a normal inflammatory response after an injury is essential to for healing. That said, not all inflammation is beneficial, and a great number of anti-inflammatories have been shown to be neuroprotective (reduce brain injury) in the lab.  The problem is that literally thousands of different proteins, genes, cells, receptors and molecules are involved in coordinating the inflammatory response to an injury. So, for example, expecting a single anti-inflammatory drug to somehow give us the exact result we want in humans is probably incredibly naïve. 

At this point it’s also worth mentioning that we can do experiments giving treatments that do exactly the opposite thing to one-another, and both will protect the brain. One example is the gas xenon (which I have written about here). Xenon is thought to protect the brain, at least in part, by increasing levels of a protein called hypoxia-inducible factor 1α (HIF-1 α). HIF-1 α helps to control the response to low levels of oxygen (hypoxia), which is what happens in the brain during a stroke. However, you can also give a drug that blocks the actions of HIF-1 α, and the brain is protected if then exposed to hypoxia. Though this is a generalised simplification, it doesn’t take an expert to say: “THAT DOESN’T MAKE ANY SENSE!”

Results like this must surely make us wonder whether we actually know anything about the systems that we’re trying to treat in the face of any particular disease…

What if everything is much more complicated than we think? A nice example of how the lab may not faithfully replicate real life is caloric restriction. You can take pretty much whatever animal you like, be it a worm or a rat, give it fewer calories than it needs, and it will live longer than expected. This occurs due to cells in the body responding to being (almost) starved, by working harder to repair themselves. In the lab, these animals are looked after very well, and the combination of a nice environment and increased cell repair means they live longer. However, long-term caloric restriction can also negatively affect the immune system. So, a recent review paper asked an interesting question:

“What if these animals are increasing cell repair in the short-term to increase their ability to reproduce (after all, why else are we here?), but this happens at the expense of a healthy immune system?”

Being at a higher risk of infection is OK in the lab, because the animals are kept in very clean conditions. However,in the wild, the short-term benefit of being “fitter” in the face of reduced food intake would be quickly negated by the infection risk that will likely mean death. In short, when faced with death due to lack of food, the rat is simply trying to make sure it goes out in a sex-fuelled blaze of glory.

If we take this back to our stroke example, what if everything we do in the lab is causing short-term improvements, but this occurs at the expense at the long-term improvements that would have happened if we hadn’t intervened?We tend to measure short-term effects in the lab, because long-term experiments can be incredibly expensive, and we want to maximise the number of potential treatments we’re investigating. However, it is long-term benefits we want to see in patients.

You could simplify this as far as possible and assume that the body is actually doing the best possible job of repair after a stroke (for example), and there’s just not that much we can do!

If we can take the normal repair system of a stroke and fiddle with it over 1,000 different ways to produce neuroprotection, maybe it almost doesn’t matter WHAT we’re doing: what’s actually causing short-term improvements is the fact that we’ve destabilised the repair system. Much like the caloric restriction example, maybe the “stress” of changing normal repair mechanisms forces the body to make adjustments that ensure short-term improvements, but sacrifices long-term benefit.

This mismatch in what we expect and what actually happens could be due to the fact that our cells function on a level that we’re just not looking at. Medical scientists think about proteins and genes, but these are all controlled by much smaller particles (for instance, electrons), which we rarely consider. What if we’re operating at a level so far above what actually matters that we’re essentially performing surgery with a blunt instrument, and it’s impossible to figure out what we’re cutting?

In the context of diet and health, what if Jack Kruse is right, and the wifi being piped through your building is changing the quantum state of the electrons in your mitochondria (where your cells make energy), making you insulin-resistant and increasing your risk of heart disease? If that’s the case, it might not matter that much what we eat or how much exercise we do. We might all be screwed anyway.*

“What if we don’t know what we’re doing?”

I’m not sure that any of these ideas are true, but these appear to be questions worth asking. I’m also not suggesting that all the work of medical research is happening in vain. In fact, quite the opposite - we might just need an occasional change of perspective.

Maybe we need to stop assuming, and look at the big picture. When so much money, and so many lives and jobs are at stake, the assumption of knowledge can be far more dangerous than the opposite.

However, if there is any way to overcome these uncertainties, it can only be through well-designed experimental work that is balanced, ambitious, and objective. Maybe the only way to make sure we start making progress is to continue to explore the mechanism of diseases, as we currently do, but do it with one thing in the back of our minds at all times:

Remember, you don’t actually know anything.

References 1. O'Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1,026 experimental treatments in acute stroke. Ann Neurol. 2006 Mar;59(3):467-77. 2. Adler MI, Bonduriansky R. Why do the well-fed appear to die young?: a new evolutionary hypothesis for the effect of dietary restriction on lifespan. Bioessays. 2014 May;36(5):439-50. 3. Hieber S, Huhn R, Hollmann MW, Weber NC, Preckel B. Hypoxia-inducible factor 1 and related gene products in anaesthetic-induced preconditioning. Eur J Anaesthesiol. 2009 Mar;26(3):201-6. 4. Chen W, Jadhav V, Tang J, Zhang JH. HIF-1alpha inhibition ameliorates neonatal brain injury in a rat pup hypoxic-ischemic model. Neurobiol Dis. 2008 Sep;31(3):433-41.

*If you want to go down the rabbit hole of how modern electromagnetic fields may be changing the most basic physics of our cells, start here. It is sometimes difficult to follow, but the ideas are fascinating, scientifically sound, and unlike anything else that is being regularly discused int he medical field.rregularly discussed in the medical field.

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