Professor Uhlenhaut, why does Dexamethasone help to treat Covid-19 patients?
According to the RECOVERY trial performed in the UK, for patients on ventilators, Dexamethasone reduces mortality by about one third, and for patients requiring only oxygen, mortality is cut by about one fifth. That is why updated treatment guidelines now include Dexamethasone.
We do not yet understand the mechanisms, but I would predict that Dexamethasone suppresses the overactive immune system, the so-called cytokine storm, which appears to cause the damage seen in Covid-19. Steroids such as Dexamethasone are also known to play a key role on lung maturation. They are routinely given to expecting mothers at risk of preterm delivery. They stimulate the maturation of the lungs and add to the survivability of the premature baby.
What’s so special about Dexamethasone that it has several medical applications?
Dexamethasone is an artificially made steroid that is very similar to a hormone that we naturally have in our body: the cortisol . Cortisol is a stress hormone that is made in the adrenal gland every morning as you get up or in response to a stress signal. It’s kind of a fight or flight response similar to adrenaline. Many people take it as an anti-inflammatory drug because it modulates immune responses.
Is the immune suppression and the stress response its only function?
No, by far not. It does almost everything. One of the functions it has is that it helps us prepare for the day. Cortisol is produced in the morning when we get up and makes sure that we have enough energy for the start of the day until we had breakfast. It also plays a key role in controlling our blood sugar levels at night when we’re not eating. To cut it short: It regulates a lot of our metabolism, but also our immune function, some reactions in the brain, some of our behaviour, our muscle mass, metabolic organs such as the liver, skin and lung development …
That is a lot of different functions for one molecule. How does it do that?
It is a special type of hormone—it doesn’t have a receptor on the surface but inside the cell. Steroids like cortisol are small molecules. They can just pass through the cell membrane and then bind to nuclear hormone receptors which are found inside the cell. There is no signaling cascade or anything similar. As soon as the hormone binds to the receptor it migrates into the nucleus of the cell and binds to the chromosomes there to control certain genes. The cell’s response then is a change in gene expression. It will for example turn on some genes involved in metabolism, or turn off some inflammatory cytokines. Hormone receptors that behave like that are called transcription factors because they control the activity of genes.
People with various diseases and symptoms are given artificial cortisol. How does the body then know what to do and what not to do?
That depends first of all how it is delivered. You can inhale it for asthma and then deliver it straight to the airways. Or you apply it as cream for a mosquito bite, a rash, a skin disease, etc. Then it is mainly delivered to the area of the skin it is applied to. But you can of course also give it systemically as a pill or intravenously. There you affect literally all cells in the body to the same extent. People with an organ transplant for example get it to reduce a potential rejection of the graft organ. Unfortunately that also means you don’t only get the beneficial and wanted suppression of the immune response but also a lot of side-effects: a fatty liver, muscle atrophy, increased appetite because it affects the brain which also results in weight gain, increased blood pressure, alertness … It is very potent in disease control but also very potent in side-effects.
We have not managed to create something that is similar to cortisol but different enough to only have one certain function
Is there no way to control for side-effects? I mean, the body seems to know when to turn on which function of the hormone and when to turn on another one. Why can’t we?
This is one of the things we are doing a lot of research on. So far there hasn’t been a good solution—obviously. One option could be cell-type specific delivery. We can for example use an inhaler when administering it to the lung tissue. But everything else is still at very early stages. For years, people have now been trying to find a steroid ligand with only partial activity, similar to estrogen in breast cancer medication or birth control. But for cortisol we have not managed to create something that is similar to cortisol but different enough to only have one certain function. Turning genes on and turning others off requires the same molecular mechanisms with cortisol and its receptor. We simply cannot separate these different functions.
But how does the body know then?
That is the puzzle we are trying to solve. I wish we knew. The hormone is the same, the receptor is the same, the cell is the same, and the DNA looks more or less the same. And yet, the receptor goes to a certain site of the genome in one cell and turns it on while going to another one on the same chromosome in another cell and turns that gene there off. We really don’t know how that is controlled.
What could be possible solutions to that puzzle?
It could either be that cortisol is binding to another protein on the chromosome that we have not yet identified. So that is one of the things we are searching for. But what is more likely is that it is something that is based within the DNA sequence, in the chromatin itself. We believe there is something within the DNA that tells the receptor what to do as soon as it binds. That is why we are doing a lot of genome sequencing experiments to try to get down to the logic of this pattern.
One molecule that has been mentioned in this context is E47. What is E47 and what does it do?
It is another so-called transcription factor which sits on the DNA itself. We were mining and looking at the DNA to find factors that were influencing the activity of our receptor. There we stumbled upon this protein E47 and it seems that this protein is active in the liver but not in certain immune cells. In the liver together with the receptor it turns on metabolic genes which then lead to fatty liver, and steroid diabetes—a subtype of diabetes caused by steroid intake. In preclinical models where E47 was disabled, we didn’t see any of that.
If one only could create a drug that inhibits E47 …
That would be epic because given together with cortisol it could prevent some of the side-effects. In our preclinical models without E47 production we didn’t see side-effects. They didn’t show hyperglycemia, meaning a dangerous increase in blood sugar levels.
So will you develop an E47 drug and test it soon?
(laughs at the journalist’s sudden enthusiasm) We are not doing this kind of studies. We are interested in the discovery of the mechanisms and the potential candidates. We publish our research and then drug developers can play with it. But it is feasible because a natural E47 inhibitor, called ID, inhibition of DNA binding protein, already exists. ID inhibits E47. That makes it feasible, but it won’t be us developing it further.
Cortisol helps us to adjust our inner clock
Another function of cortisol you mentioned earlier is that it helps us get up in the morning. Is that a natural daily thing?
Cortisol helps us to adjust our inner clock, our so-called circadian clock. It’s one factor that contributes to the 24-hour oscillations that we all experience in our bodies. There is a tight link between circadian rhythms and metabolism. A main function of the circadian clock seems to be the control of daily cycles of feeding, energy burning and energy storing, resting and not eating, activity and eating, moving around and so on. Cortisol is one arm of this clock. A bit like a metronome that together with sunlight, food and other zeitgebers resets the inner clock on a daily basis to establish a 24 hour rhythm of gene expression.
Do all cells have the same rhythm regarding the cortisol?
The interesting thing is we have a central clock in the brain that senses light and sends out neurons and hormones to the rest of the body to synchronize all other cells. Lung cells, muscle cells, liver cells, fat cells, … all have a synchronized 24 hour rhythm of gene expression. If you release the hormone in the morning for example, then you of course hit all cells in the body because it is a synchronizer.
If people are given cortisol as a treatment, they often have to take it early in the morning. What effect does that have on the body?
That’ a bit of a problem: You want to treat symptoms, but by doing so you disrupt the normal 24 hour rhythm of metabolism. For example: You have a cough or something that is worse at night. It has something to do with you lying flat but also with your endogenous cortisol being very low at night. So now your immune cell activity, your lung cell activity, etc. don’t get cortisol and that is typically also one reason why symptoms get worse at night. If we now give cortisol in the evening, we disrupt the natural 24 hour rhythm of metabolism. One of the side-effects can be a disrupted sleep or weight gain.
Especially the latter is a big issue for people: Instead of a fasting period at night their body goes into a metabolic phase at night where it tries to build up fat within the liver and the body. Wherever possible drug administration should therefore be as close to the natural rhythm as possible.
Final question: If cortisol affects our metabolism and, thus, also our weight, could one use that knowledge to reduce weight, too? And what happens to the cortisol levels?
That is a conundrum that we are also looking at right now. A lot of people do use time-restricted eating to reduce weight. If you are obese and you limit your eating period to eight hours and fast for sixteen hours that for sure is beneficial, also in restoring rhythms and health. Of course the cortisol level goes up during these fasting times because it is stressful for the body. The body thinks “Oh my god, now I’m gonna starve.” and secretes cortisol to make sure that the blood sugar levels are sufficiently high. But it’s still beneficial. Is it beneficial because of the higher cortisol at these particular points in time? Or is it despite the higher hormone level? That we don’t know yet. We are currently doing experiments to find that out. Interesting times ahead.
Thank you for the interview, Professor Uhlenhaut. (© Sonja Klein / AcademiaNet / Spektrum.de)