Circadian Medicine

Exploring Circadian Medicine: A Conversation with Dr. Marc Ruben

In the realm of medical research, the study of circadian rhythms has gained increasing attention in recent years. Dr. Marc Ruben, a postdoctoral researcher at Cincinnati Children’s Hospital, is at the forefront of this exciting field. In a candid and insightful interview, Dr. Ruben discusses his work, insights, and the potential impact of circadian medicine on patient care.

Hi Marc, thanks again for sitting down with us today! Could you please introduce yourself and provide some insight into your work?

Hello, I’m Marc Ruben, and I currently work as a postdoctoral researcher at Cincinnati Children’s Hospital under John Hogenesch. My focus is on biological rhythms and their applications in medicine. I approach this through various scientific methods, with a specific interest in analyzing extensive clinical data sets to understand how time of day affects disease and treatment outcomes. 

For instance, the timing of medication administration is crucial. Sleep drugs are best taken before sleep, while drugs that disrupt sleep should be avoided. However, there’s a broader aspect to consider. Drugs act on proteins in our bodies, and these protein levels follow predictable patterns throughout the day. I’m working to create maps of these daily gene expression changes across different body systems, aiming to identify drug targets that vary with the time of day. This helps me form hypotheses about medications influenced by time of administration, which I test using large clinical data sets.

How would you define circadian medicine?

That’s a great question. To me, it encompasses any patient care that benefits from considering the time of day. This includes cases where the connection is evident, like treating sleep timing disorders with light therapy. However, there are less obvious situations where the time of day matters, such as patients with heart disease taking statins before bedtime, as these drugs are more effective then. The circadian systems influencing time-dependent patterns in our physiology are extensive, potentially impacting various aspects of care. While we’re excited to uncover these instances, it’s essential to remain cautious in our language, as not everything we discover is immediately medicine; it could still be in the research or conceptual stage.

One thing that you’ve talked about is the fact that we need fewer review articles about circadian medicine and more actual research in circadian medicine. What new areas and avenues of research are you most excited about?

I’m interested in any avenue of research on how biological rhythms may influence diagnosis, the treatment that’s administered, patient management, disease trajectory, and even aspects of healthcare itself. To the first part of your question, my snarky comment about needing fewer reviewer articles, I think from the standpoint of the literature, the ratio of basic research publications to clinical publications is a really high ratio. I’m not sure if that’s the case in every field. There is some value in every review that makes an effort to sort of discuss and speculate how the basic research may matter in the clinic. But, I think we should probably keep in mind that, in my view at least, every biological process may be time-of-day sort-of dependent under some set of conditions, laboratory conditions, or even environmental conditions.

Over the years, the importance of timing in medicine seems to have gained more attention. What’s your perspective on this shift?

Absolutely. And from the clinical trial standpoint, I think that a lot of drug developers might see it as a bit of a nuisance because that could mean another two or three treatment arms that they would have to do to explore it. So, they’re looking for a really solid rationale for why it would make a difference in order to invest in that. 

Ultimately I believe, from a clinician’s standpoint, they just want to know that their patients are remembering to take their medication.

 It may be that, say, the target of a drug is highest at 4 am, which is ridiculous to think about waking up to take medication at that time. The research would have to be really compelling for you ever to consider setting your alarm clock at 4 am. 

I think that’s where the clinical skepticism is warranted, and the burden is on the researchers to demonstrate that there is a compelling reason to consider a patient’s circadian phase and time of day.

It sometimes seems like in circadian medicine, people are talking past each other. A result comes out, and then a rebuttal from another group comes out shortly thereafter. Do you have anything that you want to add to that?

Yeah, I don’t think that it’s necessarily a unique phenomenon. I think this might be more about the challenges of clinical translation than it is about circadian medicine, per se. I say this in part because when it comes to basic research in circadian biology, I don’t think we’ve seen a huge amount of disagreement on the basic research end. 

I think the big findings, the important findings, have largely reproduced through the years. But when it comes time to sort of move from these hypotheses that are derived from non-clinical settings to clinical trial settings, a lot changes. 

I think that the findings also tend to raise more eyebrows across different fields because these are practitioners who are considering whether the evidence that they’re seeing warrants changing the way that they’re managing their patients. They’re trying to help patients. And it’s not like walking away from a mouse study and feeling like you’ve got it all wrapped up. So to me, the scrutiny is not bad. It’s not indicative of failure. 

I think it’s probably indicative of how learning should go, so long as it’s continually led by evidence and not like one person’s views. I think that the scrutiny, like [the three studies linked at the bottom of this post], clarifies what we don’t know, and it gives real-world feedback. I mean, these are data from humans and pretty good feedback that we, as bench scientists and researchers, should probably internalize. We should also scrutinize our own experiments and try to understand, well, why are there three trials with three different results? What don’t we understand? And this is probably a good way for research to proceed.

In this dynamic field, what criteria do you think make for compelling evidence in circadian medicine?

Compelling evidence should stem from valid expectations and be designed to explore the underlying “why.” For example, let’s say that drinking orange juice at night makes people happier.  That probably wouldn’t be too compelling, and not because it’s ridiculous and probably not believable, but because if that’s all the trial were, then all you’re left with after the study is finding the belief that orange juice in the evening is better, it didn’t tell you anything about “why.” 

I think for me the most compelling clinical evidence from circadian medicine should probably start from valid prior expectations. Like, there’s some rationale for why we expect this particular, say, time dependence and then a study or a trial that’s designed in a way that allows us to learn as much as possible about “why.” And so it might not be just tracking happiness in the orange juice experiment, but tracking a whole bunch of other things so that you can sort of fit the result into a prior model you had about how things work.

Definitely, so making sure that the question that the study is answering is worth the actual study itself. Just to note, I would like an orange juice that was guaranteed to make me happy—that would be a nice boost!

I would too. I would wake up at 4 am to drink happy orange juice!

How can skeptics and advocates of circadian medicine communicate more effectively?

I don’t come really into that much contact with people who are like deep skeptics or deep advocates. I think we try to follow the evidence and form hypotheses based on prior data, and we’re conducting research and testing ideas. I think that it’s an interesting dichotomy that I try to be myself. I work with a lot of collaborators who are both advocates and skeptics at the same time, and for me, that’s kind of what being a researcher is. 

It seems like, for the most part, the people that you encounter are somewhere in between an advocate and a skeptic and in the healthy middle.

Absolutely, I agree. The skeptics mentioned in the rebuttals [linked below] are all scientists, and their viewpoints are quite sensible. Their counterarguments come across as well-reasoned as they attempt to utilize evidence and their own expertise to interpret what they perceive as contentious discovery. From what I’ve observed, the ongoing debates have largely maintained a rational tone, and I hope this continues to be the case.

Is there something about how people currently discuss circadian rhythms and medicine that bugs you, aside from “it’s time for circadian medicine” puns?

Oh yeah, that is kind of buggy. I’ve also used it myself, so I can’t be too harsh [Ed. note: Olivia has too]. I thought it was really amazing when I ended a paper a few years back with something really cheesy like that, but yeah, nothing really beyond that bothers me.

At least they’re talking about it, right? On to another question. How should we consider peripheral clocks versus central clocks in the context of circadian medicine?

Yeah, and it’s a great question, and I am not sure that I know. I’m really not. So the simplest view in circadian biology, I think, is that the central clock gets its light-dark information through the eyes and, in turn, sort of sets the phase of all of the other peripheral clocks in the body. That’s kind of your simplest model. But we’re learning that it really isn’t just light information via the central clock that defines peripheral clock properties and their phase. 

For example, peripheral clocks in the liver will, at least under experimental conditions, synchronize their phase with daily patterns in feeding and fasting. Whereas the central clock is pretty insulated from feeding and fasting and these other things, it will remain kind of synchronized with the light-dark cycle. In animal experiments, we can kind of force these types of misalignment by, say, making food only available during the animal’s normal sleep phase. You can get a liver phase and a peripheral clock phase, and central clock phases that are kind of misaligned relative to what they would normally be.

I think that’s interesting because, again, most of our knowledge here is from animal models. But for me, it’s hard to imagine in the real world that we wouldn’t also be confronted with a lot of these sorts of little misalignments. 

Some people’s lives for sure more than others: Shift workers, people with disease, people with abnormal sleep patterns, abnormal eating patterns. To get back to your question, I think all this may be important for circadian medicine, like our conversation on medication timing. The goal is to align drug exposure with the presence of its target. That may be one goal. You want to be taking your drug at the time when, say, the target is at its highest level. 

I mentioned that statin drugs are an example where we are actually doing this, and we say bedtime is best for statins. But it’s interesting because the target of statins is actually a protein that’s involved in cholesterol synthesis in the liver. Therefore, the target for statins is not the central clock in the brain. To know exactly what time of day or what circadian phase is going to be optimal to take your statins, it may be really good to have some information on, well, what’s the phase of the liver clock and the peripheral clock in the liver which may or may not be aligned with the central clock.

Let’s take an example: consider someone who’s taking statins and decides to take their medication at bedtime. However, if this person follows an unconventional pattern of eating and fasting, the timing of bedtime might not actually align with their feeding and fasting schedule. This matters because the timing of meals and fasting can affect how the liver processes the statin. This situation highlights the complexity.

Moreover, it’s not just about statins; it’s about understanding the conditions in which a marker of the central circadian clock phase, such as melatonin, might not accurately represent a person’s overall circadian rhythm. This is because various peripheral clocks in the body can be influenced by local cues, making it more intricate than we initially thought. There’s still much to discover in this area, and your question is truly intriguing.

Lastly, what’s an exciting project you’re currently working on?

Well, I’m excited about a lot. One thing that comes to mind, I was just talking to a pulmonologist here at Children’s, and it’s not actually a project that I’m working on yet, but we were speaking about sleep and circadian disruption in the hospital, and especially the intensive care setting where it’s got about everything that we think matters for circadian health. It’s got about every one of those elements going wrong. The lighting is bad, and you’ve got devices with alarms beeping all the time. For a lot of patients, there are frequent overnight interruptions. They also get woken up for diagnostic reasons. 

So this particular pulmonologist, who is not a sleep or circadian expert, is very interested in sort of running a trial to evaluate directly how disruptive the environment truly is. What sorts of physiological evidence is there that the environment is disruptive, and how does it impact health outcomes, disease-specific health outcomes, and hospital stay length?

All of these factors, along with the underlying notion that we should accumulate more evidence, reinforce the message that circadian health holds significance, particularly in the context of the hospital environment. It’s evident that the hospital environment does not replicate the conditions of our natural, outdoor, and healthy lifestyles.

It would be valuable to collect information about specific patients who are most affected by this disruption and for whom this disturbance holds clear prognostic significance. 

Within the hospital, there are a few patient groups that stand out. Take complex pediatric cases, for instance—like children who emerge from the neonatal intensive care unit but, due to various reasons, still require mechanical ventilation to breathe. These young patients remain hospitalized for extended periods during which their mobility is restricted, ultimately subjecting them to what could be one of the most unfavorable environments in terms of circadian rhythm and sleep disruption.

What’s particularly intriguing is that this scenario offers an opportunity to experiment with concepts rooted in fundamental circadian biology. This experimentation takes place within a patient population that has pressing and unresolved medical needs. The question arises: Can we implement some of these ideas to genuinely assist these children? The prospect is undeniably fascinating.

That sounds like a valuable endeavor to enhance patient care. Thank you so much for your time and insights today.

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