The Systems Biology of COVID-19 and the SARS-CoV-2 virus. The class will build a foundation that includes the emergence of complexity, simple biological subsystems, their reductionist and equivalent toy and organ-chip models, and the measurements required to specify model architecture and parameters. Applications to biology, physiology, medicine, chemical and biological defense, pharmacology, drug discovery, and toxicology. UGrad: PHYS 240 01 and BME 290B; Grad: PHYS 326 and BME 395C.
Kelly McGee
ReplyDeleteClass 05, Assignment 5b
The role of circadian timing system on drug
metabolism and detoxification
0: What I Knew: I knew about the existence of circadian rhythms and that their "central command center" was localized to the hypothalamus. I was aware of the importance of both the liver and the kidneys in the elimination of drugs from the body, and followed along with the comments regarding broad physiological phenomena such as GFR.
1: What I Learned: I learned of the cellular circadian control system of CRY-PER, and its generalized circuit structure. I learned that, on a cellular level, there are three "Phase groups" of proteins specializing in, respectively, drug functionalization, conjugation, and elimination. I learned that circadian rhythms affect both intracellular protein transcription and whole physiological phenomena such as renal blood flow, GFR, and urine pH. I also learned that there is an unknown built-in renal circadian clock that operates even in transplanted kidneys not connected to the sympathetic nervous system.
2: Questions: What experimental methods do the circadian rhythm studies mentioned utilize? An examination of these methods might stir up some useful conversation concerning dynamic SISO, MISO, or even MIMO control of physiological systems.
The paper's language changes from verbose descriptions of detailed protein relationships to frank admissions of how little we know about circadian rhythms. Approximately what percentage of that which we are aware is governed by circadian rhythms do we have connective, causal, or stoichiometric system reconstructions of?
3: Presentation Topic: Circadian rhythm experimental methods. Or a refresher on renal system physiology with an emphasis on drug elimination, if it would benefit the class.
4: Comments: It was interesting as an engineer to look at a paper almost devoid of specific applications, and strictly knowledge-based. Not that there aren't myriad potential applications, just that they weren't discussed in significant detail here.
0) OK
Delete1) I think we need to look into the <>!
2) <> please! I think this is very rich hunting for organs-on-chips and UPLC-IM-MS. We will discuss it after we get through the cell-cycle and (possibly) clock papers.
3) I vote for <>
4) Lots of room for us to explore.
In terms of system reconstructions, I'm also very curious. Based on redundancies of circadian clock regulation, I have a feeling that much of this network may be still unclear, especially when it comes to stoichiometric reconstructions.
Delete
ReplyDelete0. Knew
I knew circadian rhythms existed, mainly in the context of sleep. I worked briefly on a project involved KaiABC, a circadian rhythm protein complex in cyanobacteria, but that was the extent of my knowledge in this area. I am aware of the metabolic effects of food intake timing (in relation to proportional of carbohydrates/fats/proteins consumed), but for use in optimal performance in an athletic capacity.
1. Learned
First, that drug resistivity, and hence, drug effectiveness, can be severely affected by natural circadian rhythms, which can control the transcription of genes, post translation modifications, and following that, the expression and expression level of various proteins. I think it’s pretty interesting that transcriptional regulation of gene expression can be induced as a result of xenobiotics—while this does make sense as part of the cell’s inherent defense system, I had always assumed xenobiotics had an affect at the protein, rather than the genetic, level.
It seemed to me that many of the transcription factors/genes that are controlled by circadian dependent machinery are also rather essential for organism survival, such as the example with the mice devoid of DBP, TEF and HLF (pg 150).
I also learned what the hepatobiliary system was. Again, not a system I had previously considered in great detail. However, it seems that bile and bile acids is quite important for detoxification. Overall, the circadian clock effects many systems within an organism, and, from the research presented in this paper, is a key player in keeping an organism function on a day-to-day basis, as well as allowing for increased drug metabolism.
2. Pressing
Since the author mentioned that “expression and…functional of drug-metabolizing enzymes and drug transporters are highly species specific” (pg154), I am interested in how one might be able to apply chronopharmacokinetics to the clinical model. For something that seems very useful, I haven’t seen a large body of work on correct timing of drugs for optimal metabolism. On the same page, the author also mentioned that there is little known about the effects of sex, age, stress, etc., on the circadian timing system. This question seems to be of utmost importance. Is there research currently investigating this? Or is it perhaps too individual of a problem to address on a larger scale? Seems like it could be another direction for the future of personalized individual medicine.
3. Presentation
I’d like to see a presentation of sex, age, and how it is currently known to effect circadian rhythm function, even if at a very basic level.
4. Thoughts
This paper presented a lot of facets in one area of research—circadian timing and drug metabolism. Because it switches between topics so quickly, I would have liked to have seen more of a summary towards the end of the various ways that drug metabolism is effected by circadian rhythm.
Not totally related, but this is an interesting TED talk about the negative effects of drug-testing mainly done on male subjects:
Deletehttps://www.ted.com/talks/alyson_mcgregor_why_medicine_often_has_dangerous_side_effects_for_women?language=en
I just wanted to quickly reply and thank you for the link! Male-centered medicine/medical trials/diagnosis is a very interesting topic, and one I think is very pertinent!
DeleteNatalie Hawken
ReplyDeleteReading Assn 5B, Article 05: The Role of Circadian Timing System on Drug Metabolism and Detoxification
0. KNEW
From intro biology, I knew about circadian cycle and the general role of the suprachiasmatic nucleus in maintaining the cycle. From the cisplatin paper, I knew a few ways that cells defended against drugs (MRPs, ABC transporters). From physiology, I knew the general processing of waste by the kidneys and their role in ion concentration, water and nutrient reabsorption, and the structural components (nephrons, glomerulus, proximal and distal tubule, etc). Also, I knew that the night time (dark part of the circadian cycle) was often the time to clean the body from accumulated waste.
1. LEARNED
First of all, I learned a lot about the signaling pathways leading to widespread circadian control of protein expression levels (CRY/PER circadian oscillator), but I'm still a bit confused on the details of the pathway. Also, I learned about the phases of drug metabolism in cells (functionalization, conjugation, and transport) and how different proteins (PARbZip transcription factors) regulate these phases. I found it very interesting how cells had to deal with lipophilic, organic compounds differently than hydrophilic compounds. I had never before learn about the bile production and transport process, so it wasn't new to me that specific types of drugs and organic compounds could be excreted in this manner. Despite my superficial knowledge of the kidneys, this paper enlightened me on how the function of the kidneys can vary depends on GFR, RBF, urine pH, concentration of transporters. I didn't know that protein expression changed so often (every day and night) and changed so regularly. I found it interesting that some expression levels peaked at the time of most activity and others peaked when the body was completely at rest.
2. MOST PRESSING QUESTIONS
The author notes that the rhythmic increase and decrease of mRNA expression doesn't always mean that the proteins themselves are undergoing such extreme rhythmic control (pg 154). Have there been any current studies (protein assays, GFP localization, etc) to show correlation between the circadian cycle and the concentrations of the actual proteins? Since the genes/proteins responsible for activating increased drug detoxification and metabolism, and these genes can also affect the resistance of cancerous tumors to anticancer drugs, has there been any correlation between resistant phenotypes and mutants to the genes controlling the overall circadian rhythm? The author notes that circadian rhythm can change significantly depending on species, sex, age, environmental stress (pg 154), which can in turn change how a person respond to the introduction of a new drug. With most drug trials focusing on adult male subjects, how much are we missing by not robustly testing the products? Could these differences be the cause of some diseases/cancers being more prevalent in people of one sex?
3. PRESENTATION TOPIC
I think a presentation mapping out each of the parts of the drug metabolism/detox process according to time of day when they are most active would be helpful in keeping the temporal nature of process in the picture (including phase I, II, III cellular metabolism of drugs, bile production and excretion, kidney filtration and reuptake, integrated stress response, etc).
4. THOUGHTS
Though I understand how this article would be helpful in understanding how the body's response to drugs varies due to the circadian cycle, I felt that the message could have been clearer if the paper wasn't so dense with gene/protein interaction pathways. Also, I wish this paper included more figures to visualize the detoxification cycle through the body. I'm thinking I'll probably understand more when I read it a second time.
Ben Terrones
ReplyDeleteAsgn_5B_Class_05_Article_05_2016_09_08
0. KNEW:
I knew basically what circadian rhythms are and the basics of what they do. I knew they controlled a lot of biological processes but not really the specifics. I only knew a little about the specific processes that were discussed.
1. LEARNED:
Most of the information in this article was new to me. It was packed full of very technical language, and there was a lot to understand, but the main thing I learned is that the circadian cycle affects the bodies ability to metabolize drugs. In animal studies it was shown that drugs are metabolized differently at different times of the day. This has great potential for humans and the efficiency of human drugs. There are still a lot of unknowns, especially trying to apply animal studies to humans, but the potential for drug improvement is there.
2. PRESSING ?:
This article raised a lot of questions on its own, but some questions I have are isn’t it possible to slightly alter the circadian cycle by changing sleep/wake patterns and exposure to light? And then wouldn’t this mean that the prime time for taking a certain drug could be different from person to person? Would they be able to find the right time for every patient? Are the benefits of this really so great that it is worth the effort to develop?
3. PRESENTATION:
I think a good presentation would be to go into more depth about the circadian cycle in general, possibly into other organs/systems/functions it affects and how.
4. THOUGHTS:
This was a very interesting paper although somewhat difficult to read because of how dense and technical it was. This subject seems somewhat promising but I am curious if the benefits truly outweigh the cost.
About your pressing questions, either article 4 or 5 (can't remember which) notes that an internal body clock independent of environmental times cues will run most circadian cycles at a near 24-hr period. Diurnal clocks are more dependent to light stimulus. For example, people with complete blindness still exhibit physiological controls related to a circadian clock to a certain extent, but some blind people will have issues with their preferred sleep schedule actually matching the light/dark environmental cycle. (google "non-24 disorder" for more details)
Delete0. Knew:
ReplyDeleteI knew what I had learned about circadian rhythms from the previous paper. For example, I knew about the importance of the SCN in circadian clocks as well as the CRY and PER genes being components in negative feedback loops for circadian clocks.
1. Learned:
This paper is a nice supplement to the previous one; the previous paper describes circadian rhythms themselves, while this one gets more specific in looking at drug metabolism with these rhythms. The introduction of the paper that discusses circadian clocks helped to solidify information I learned from the previous paper.
The next part of the paper looks at how the circadian clock controls drug metabolism through gene regulation. I learned about the three phases of proteins found in mammals used in drug metabolism and each of their roles (functionalization, conjugation, and transportation of the drugs).
I learned about the circadian clocks involved with biliary excretion and how this process regulates the elimination of a drug in the system. I also learned about how important the kidneys are in drug removal (I knew that the kidneys are important for waste removal, but I now know why in terms or drug removal).
Overall, I learned that the circadian clocks found in organisms play a huge role in the metabolism of drugs, and that the more we understand how these clocks work the more we can tailor drugs and the timing of their treatment to boost the drugs’ effectiveness.
2. Pressing Questions:
It seems like there are still a lot of obstacles to overcome, especially in the experts opinion section at the end. What are the plans to attack of the problem of, for example, “the interaction of the circadian timing system with sex, age, pathology and environmental stress” (p154) which seem like very important factors?
The previous article on circadian rhythms discussed how there are many factors that can affect circadian clocks. How can we construct an accurate model with so many factors that can come into play? I know this can usually be tackled by deciding what to include in your model from the beginning, but it seems like no factor can go ignored.
3. Presentation Topic:
I would like to have a presentation on how to read network diagrams. Most of the papers we have read so far have used very complicated diagrams and they are overwhelming to look at for the first time. I get lost in all of the lines, colors, and multitude of acronyms. A presentation covering the best way to pull the important information out of these would be very helpful.
4. Thoughts:
The common theme I keep seeing throughout this class is that many biological systems we want to model or describe require so many interrelated factors to be considered. I find it astounding that we can still describe and predict so many things when all of these processes are so complicated.
0.Know: I knew about gene expression and transcription through previous biology courses, and I knew about circadian regulation and how the circadian clock allows organisms to be able to anticipate and adapt to physiological changes.
ReplyDelete1.Learned: I learned that there are three main phase groups involved in the metabolism of drugs. Also, since the circadian clock is involved in the time-dependent nature of drug toxicity, the toxicity of a drug can change during a 24-hour cycle. I did not know much about the hepatobiliary systems or its importance in bile formation and the elimination of drugs, or that biliary excretion was mainly put into effect during the nighttime. I learned about one of the paths metabolized drugs can take on their way out of the body, starting with bile, then going to the intestines, then going to fecal matter. I learned that the kidney exhibits particularly active circadian patterns and that urine pH can reveal much about drug metabolism, such as drug ionization and the rate of drug reabsorption.
2.Pressing Questions: The article opens by saying that “circadian clocks are operative in virtually all light-sensitive organisms” (p.147). How does homeostasis on organisms that are not light-sensitive differ? On the same page, it is mentioned that a mutant mice displayed a circadian phenotype; but I am curious as to what exactly this phenotype was. The integrated stress response (ISR) seems to be counterproductive to cancer treatment, since the article says it is linked to the resistance of tumor cells to chemotherapeutics (p.151). What are the benefits of the ISR? What makes an increase in age decrease the process of drug metabolism? (p.152).
3.Presentation: I had trouble understanding some of the pathways described in the article, like the one involving the expression of the genes encoding the repressors Cry1, Cry2, Per1 and Per2. Maybe this or another such pathway can be better explained in a presentation.
4.Thoughts: This article was more confusing than the first one regarding circadian regulation. It seemed that that one dealt more with explaining the “whats” of many aspects of the circadian rhythm, and this one goes in depth on the “hows”, particularly on drug detoxification processes. I did appreciate reading this article after the first one because I had better context for the information presented.
0 Knew: Circadian Rhythm is controlled by the SCN and has an impact on the metabolism of drugs.
ReplyDelete1 Learned: How circadian rhythms effect drug metabolism specifically through specific transcription factors. Also that the kidney's function is at least partially controlled by circadian rhythm.
2 Pressing Questions:Do drugs/molecules like ethanol which are metabolized/excreted in locations not listed in this paper follow circadian metabolism/excretion trends. Ex: Will the body more quickly remove alcohol from the blood in the morning when compared to the evening or while sleeping. Are there drugs that have disclaimers such as do not take this before sleeping due to circadian rhythms?
3: Presentation Topic: Kidney Function
4: Thoughts: This paper shows how circadian rhythms effect drug metabolism and I feel as though I have a strong understanding of this but I am curious about actual applications on the macro scale.
SysBio16 Asgn_5A_Class_05_Article_04_2016_09_08
ReplyDeleteThe role of circadian timing system on drug metabolism and detoxification
0. KNEW
Familiar with the circadian rhythm w.r.t. sleep and covered the SCN briefly in a physiology course. Was also fairly familiar with liver and renal physiology.
1. LEARNED
I didn’t realize that the circadian clock was anticipatory, rather than diurnal. I learned what the ER’s ISR (integrated stress response) is (“conserved adaptive response to cope with the accumulation of unfolded proteins in the liver) and that the activation of the ISR has been linked to resistance of tumor cells to chemotherapeutic agents (section 2.3). I did not know that biliary excretion follows a circadian rhythm, with maximum excretion occurring at night. Since the circadian clock is anticipatory and sleep/eating patterns usually have a relatively regular pattern this seems obvious. It is interesting that CYP7A1 (the rate-limiting enzyme that converts cholesterol into bile acids) is directly controlled by the circadian clock, rather than a more indirect mechanism.
2. QUESTIONS
How would you do an in vitro experiment pertaining to the circadian control of drug metabolism? Excise SCN, then use cells from animal after period without SCN; use cells from DBP, TEF and HLF knockout mice (or other analog knockouts that have lost circadian-controlled transcription factors); use a standard cell line, suppress circadian-controlled transcription factors and change its external environment in a systematic manner; or something else entirely? Are there organ-on-a-chip systems that replicate circadian systems?
By what mechanism does ISR activation lead to chemotherapeutic resistance? It appears to occur in various cell types–the references for this presumably include melanocytes, mammary cells, and bone marrow cells (Sec 2.3, Line 26; Ref 48-51).
3. PRESENTATION
Intro to organ-on-a-chip
Various approaches to studying circadian regulations in systems biology (i.e. general methods in chronopharmacology)
4. THOUGHTS
It will be really interesting to see how clinical pharmacology will progress as more is understood about the role of the circadian control on drug metabolism and detoxification. I am also wondering to what effect it may be implemented currently and how outcomes are improved when patients comply to current standards vs. when they do not.
John Vastola
ReplyDeleteClass 5, Article 5: The role of circadian timing system on drug metabolism and detoxification.
0. WHAT I ALREADY KNEW (0. KNEW: ...)
I vaguely knew that bodily functions are regulated with some sort of internal clock, and had heard the phrase "circadian rhythms."
1. WHAT I LEARNED (1. LEARNED: ...)
I never thought about the possibility that bodily functions being regulated according to some internal clock (which is itself modulated by external signals) could affect how drugs work. But it seems reasonable once pointed out, and it is interesting to examine the details of what exactly is regulated in some "circadian" fashion.
Many of the details of how circadian regulation exists in different parts of the body were beyond my grasp, and would likely require me to spend more time grappling with the article or reading related articles.
2. MOST PRESSING QUESTIONS? (2. PRESSING ?: ...) << BE SURE TO LIST PAGE/LINE NUMBERS>>
I agree with the assertion in the 'Expert opinion' portion of the article (middle of the right half of pg. 154, "Third, little is yet...") that the relationship between circadian timing and basic things like age and environmental stress is important, and should be better investigated. I would like to know what is currently known about that---that seems to be of paramount importance to pharmacology!
3. PRESENTATION TOPIC (3. PRESENTATION: ...)
A good presentation would break down the details of circadian timing in some particular part of the body, and then point out more generally where it appears (and is important) and where it doesn't.
4. THOUGHTS ON CLASS OR SYSTEMS BIOLOGY, ETC. (4. THOUGHTS: ...)
I was a little frustrated with the flood of jargon before, but I am learning quickly and I don't think it's so bad. Which is good!
0. KNEW:
ReplyDeleteI knew about circadian rhythms, including their origin in the brain, the role of melatonin, and thier widespread effects on the body. I knew about the optic input component of circadian rhythms and that regulates timing. I knew about protein localization.
1. LEARNED:
I learned that negative feedback regulates circadian rhythms and the molecular components involved. I learned how the SCN clock then synchronizes peripheral oscillators. I had no idea before this paper that drug metabolism was influenced by a circadian rhythm, let alone that drugs can be toxic by timing. I learned about the three groups of proteins involved in metabolism.
2. PRESSING ?:
Is it safe to say that the circadian rhythm should not be manipulated for drugs and this should be done in reverse?
3. PRESENTATION:
I would make a table of all the ways circadian rhythm affects drug metabolism.
4. THOUGHTS:
This paper was very interesting to read! It provided connections between concepts that I had never knew existed, but was hard to follow the specifics.
0. KNEW
ReplyDeleteI had a general understanding of circadian rhythms due to previous research on the topic, which included the general overview on central and peripheral oscillators, entrainment factors, and the clock pathway.
1. LEARNED
I learned the importance of circadian rhythms in xenobiotics and it's role in regulating toxin breakdown in the liver and kidney. I had not known about the field of xenobiotics in that particular context, and am now more familiar about the pathways involved with it. I am also more aware of the RNA quantification methods (microarrays, RNA-seq, SAGE).
2. PRESSING ?
What are the fold differences in clock gene expression at certain times of the day?
3. PRESENTATION
Detailing RNA expression methods would be helpful.
4. THOUGHTS
A good overview on circadian rhythms and its role in xenobiotics. There were regions that were very detailed, but overall it was understandable.