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.
0. Knew:
ReplyDeleteBefore reading this paper I had heard of circadian rhythms, but this is pretty much it.
1. Learned:
I learned more in depth about what circadian rhythms in metabolism are and how this topic is approached. I got lost in certain parts of the paper, but I was able to grasp the main concepts. The first part of the paper looks at macronutrient rhythms followed by the different types of external and internal factors that control circadian and diurnal rhythms and where/when they are most prevalent. I mainly learned from these sections that “response” or “adaptation” models that look at extrinsic mediators should be used along with “intrinsic” or “anticipation” models that look at intrinsic mediators to fully understand how these rhythms respond to both predicted and unpredicted changes to the environment.
The second topic presented in the paper covers circadian clocks and their roles in controlling metabolism over the entire body as well as in specific cell regions (with cell-specific circadian clocks). I had to look up what adipose tissue is, so I learned that this type of tissue is essentially fat tissue used either store energy or protect/insulate parts of the body. Overall, I learned that circadian clocks both influence and are influenced by many complicated processes that have many dependencies.
The final part of the paper looks at the anticipation of behaviors (specifically feeding and exercise) entrained by circadian rhythms and the consequences of not following this entrainment. A thought that kept popping up as I read this paper, but mostly this part of the paper, was that a lot of our functions throughout the day are regulated by these circadian clocks way more than I had known or considered.
2. Pressing Questions:
a) How has knowledge of circadian rhythms been used in control of biological systems? I can see how a lot of the knowledge in this paper pertaining to how a certain extrinsic/intrinsic factor influences these rhythms could be used in a control setting as discussed in the previous paper. It would be nice to see a link between these ideas.
b) How should I adjust my lifestyle to best appease my natural circadian rhythms?
c) The end of the paper looks at just eating and exercising clocks and the consequences for violating these. Are there other clocks this part of the paper could have addressed in addition to these two?
3. Presentation Topic:
I would like a watered down version of the topics presented in this paper as they relate to humans. The paper mainly focuses on humans and rodents and switches between them in each section. It would be nice to look at just the human side and look at what the paper describes, such as looking at the eating/exercise entrainment and consequences for not following these entrainments.
4. Thoughts:
This paper was an interesting read. Although I did not catch everything it discussed, I loved learning about the natural rhythms that drive metabolic functions. As for this class as a whole, I am starting to see how many of these topics are/can be connected (look at my first question), and this is exiting me greatly.
1) As to getting lost, the trick in this class is to figure out how to extract the highest level, most important parts, and then remember that the details are available for future examination. For our own education, people should be sure to look into brown adipose tissue - major regulatory role.
DeleteRe entrainment, someone should set up a <>
I wonder how one include anticipation in a control model!
2) a) <>
b) me too.
c) I'm looking to design coupled-organ-on-chip circadian rhythm experiments and address them from a systems biology perspective.
3) I expect this will come out in this and subsequent classes.
4) Glad you are seeing the connections.
Chinowsky_TheorSysBio_PCRC_09072016
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. This ended up being surprisingly useful knowledge for this paper, as some of the fitness-related coursework for my personal trainer certification has focused on macronutrient metabolism.
1. Learned
That I probably should have read this paper first. I was not previously aware that circadian implies an oscillatory system independent of external cues. A good example of this might be the peak in circulating amino acid levels discussed in the “Lipid” section of Page 166, which occurs regardless of protein intake. I was previously unaware that epinephrine and norepinephrine had a larger role in metabolism as well, mainly I knew of their function within the nervous system.
This article starts with broad overview of macronutrients and known metabolic effects of these macronutrients. The subsequent sections focus on specific circadian clocks and various hormones/behaviors/etc associated with clock disruptions. I really enjoyed that the paper focused on both large scale (behavioral, etc) and small scale (cellular, genetic) effects of circadian clocks and really hammered home the point of just how essential biological clocks are to everyday functions
2. Pressing
Integrating circadian rhythm clocks into systems control seems like an interesting and relevant topic. Personally, I’m also interesting in knowing more about the “exercise-induced clock entrainment” discussed on Page 175
3. Presentation
It’s a little hard to put together exactly what research has been done on humans. It’d be useful to string it all together, and perhaps discuss experimental techniques used as well.
4. Thoughts
This is an excellent introduction to biological clocks and metabolic basics. Everything was presented at a level of depth that was easy to understand, but allowed the reader enough background to delve deeper into the literature.
0. KNEW:
ReplyDeleteI had learned about circadian rhythms in previous classes, but nothing beneath the surface. I learned about circadian rhythm in the context of metabolism and sleep cycles in my systems physiology classes, but we never delved into the causes and consequences. This also means I have learned about metabolism and its importance for homeostasis in living organisms, but once again I feel like I only know the surface level information about the subject. I knew it was determined by the transfer of energy in the body and the relationship between this energy and carbon.
1. LEARNED:
I learned that there are three main requirements to be considered a circadian process: oscillation period of approximately 24 hours under constant conditions, untrainable (adjustable) to external cues, and persistance across temperature ranges. I learned that there is a difference between diurnal and circadian rhythms. Diurnal refers to events that occur during the daylight rather than a period of 24 hours (a diurnal flower only opens during the day). I learned that there are primary, secondary and tertiary measures of examining metabolism. The relationship between metabolism and mechanism from the standpoint of these different measures is highlighted in Figure 1.
2. PRESSING QUESTIONS:
In the section about exercise, the paper suggests that performance can be dependent on the time of day due to the intrinsic properties within muscle. How can these observations suggest that these mechanisms modulate exercise performance without addressing the psychology factor involved with forcing people to exercise at time that are uncommon? Speed, power and distance are all measurements that can be varied significantly by the mindset of the participant.
Is it possible to optimize a daily routine (or an exercise for that matter) around your circadian rhythm?
3. PRESENTATION:
I am curious how the presentation will tie together the research papers as well as the questions that were provided by the guests from Eli Lilly. I would also like to see if it is possible to present this article in a way that relates it back to the previous articles.
4. THOUGHTS:
I am excited to see how our class is able to integrate our discussion with the guests from Eli Lilly.
Kelly McGee
ReplyDeleteClass 05, Assignment 5a
Circadian regulation of metabolic homeostasis:
causes and consequences
0: What I Knew: I was aware of the existence of circadian rhythms and had a limited awareness of their relation to metabolic processes.
1: What I Learned: I learned the difference between diurnal and circadian. I learned that circadian rhythms affect metabolism, including catabolic and anabolic processes at the organ, cellular, and intracellular (transcription, translation, and post-translational modification) levels. Not only that, but that circadian effects on metabolism creates phenomena observable at the organism level, such as when the organism feeds and what specific nutrient the organism searches for at a given time.
2: Questions: How did circadian rhythms arise from an evolutionary biology standpoint?
Has anyone discovered means by which circadian rhythms, with emphasis on metabolic effects, can be permanently altered through stresses placed on the organism?
3: Presentation Topic: Circadian rhythms in regard to exercising (useful as I am trying to get in shape).
4: Comments: Very interesting subject. Look forward to discussion.
Ben Terrones
ReplyDeleteSysBio16 Asgn_5A_Class_05_Article_04_2016_09_08
0. KNEW:
Similar to the other paper I knew a basic definition of circadian rhythm and that is about it.
1. LEARNED:
I learned exactly what circadian means and the difference between diurnal and circadian. I really liked how the paper was organized going into how different macronutrients are affected by rhythms. I thought it was interesting how preference for a certain macronutrient increases at different parts of the day in mice. I also learned that the body anticipates as opposed to responds to food consumption in rats. There are also extrinsic factors important in metabolic processes (insulin, cortisol, growth hormone, epinephrine/norepinephrine) that oscillate depending on the time of day, which could drive circadian rhythms. Intrinsic factors could also play a role in driving rhythms. It was shown in mice that disrupting the circadian clock mechanisms altered metabolic homeostasis. The major theme was there is a lot of evidence for the circadian clock regulating metabolic homeostasis. The final part of the paper was probably the most interesting to me, the consequences of disrupting the circadian clock and ultimately the lack of circadian regulation.
2. PRESSING ?:
It seemed like the only effects discussed were the negative effects of disrupting the circadian clock, but what about positive effects? What could this be applied to (such as the time of day of drug delivery) and have a positive effect? How could we use this information to possibly help treat people who have diseases partially caused by disruption of their circadian clock?
3. PRESENTATION:
Why our bodies still use circadian rhythms, comparison of circadian rhythms in different animals, the consequences of staying up late to finish homework in terms of your circadian rhythm and health effects.
4. THOUGHTS:
This paper was a very good read, well laid out and somewhat easy to comprehend. I think more people need to understand the detrimental effects of disrupting the circadian clock and its effect on metabolic homeostasis.
0.Knew: I have heard of circadian regulation/rhythms before and thought mostly of sleep patterns (and the dysfunction with my own). Therefore, I had an idea before reading it that the article was going to contain information about temporal patterns. I knew loosely that there are pathologic consequences upon disruption of such patterns and that there exists a relationship between biological fitness and maintenance of regulated cycles. I knew the main purposes and functions of the macromolecules in the section that discussed the rhythms in the usage of proteins, carbohydrates and lipids. I have also recently learned in my systems physiology class about feedforward regulation, where changes in regulated variables are prepared for before they occur; this concept came to my mind when I read about the peak in certain enzymes in rats that is likely due to the anticipation of food intake.
ReplyDelete1.Learned: I learned that primary measures of metabolism (the rate of substrate utilization and product generation) differ from secondary measures of metabolism (metabolite analyses) in that the former is more directly involved in the rate of metabolic flux through a pathway. I learned that the preference for the intake of foods primarily dominant in a certain macromolecule depends on the time of day; for example, preference for foods high in protein is shown during the active period of the day. I also had no clue that even degradation of cellular constituents exhibits a diurnal pattern. I had not before heard of the “Dawn Phenomenon,” which describes the increase in glucose and insulin levels just before waking. I learned that although both transcription factors CLOCK and BMAl1 play a major role in maintaining the circadian clock, the latter is more important in the functioning of the mammalian circadian clock because it can operate in the absence of the former. I learned that interference in the circadian clock can affect an organism from the cellular level to the whole body level and that these clocks are present in mainly all mammalian cells.
2.Pressing Questions: What exactly does it mean for a factor to be entrainable to external cues? How many/which factors all under this category? (p.164). What is zeitgeber time, and does it have applications beyond diurnal and circadian rhythms? (p.164). The article mentions that protein and mRNA activity increase during the active phase in enterocytes. What are enterocytes, and what do they do? (p.167). I also should do some research on the postprandial state (p.168) because I would like to know other characteristics of this state besides what follows the increase in insulin secretion. What are these neurohumoral factors that oscillate with daily behavior changes? (p.169).
3.Presentation: The article mentioned more than a couple of times the results of studies and experiments using mouse models. Maybe it would be helpful to give a summary of these studies and what they revealed—that is, mentioning what aspect of circadian rhythm was interfered with or disrupted and what the result was. This would give a better understanding of the relationship between certain molecules and what part of regulation they effect.
4.Thoughts: This article was like the last one we read in that I can commend its organization. It was helpful that sections mentioned what would be discussed in the following sections; that way, if I got confused while reading, I can remember what I am supposed to be reading about and try to make the confusing parts make sense. I was also pretty scared to read this because I did not want to know about the consequences of my poor eating and sleeping schedules, but this article taught me more that it scared me.
Natalie Hawken
ReplyDeleteReading Assn 5A, Article 04: Circadian Regulation of Metabolic Homeostasis: Causes and Consequences
0. KNEW
I knew the basics of the circadian rhythm (that the clock was approx 24hrs and not related to light/dark cycles) and the diurnal cycles (cycles control by periods of light and dark). Also, I understood the basics of metabolism for various types of molecules: proteins, carbs, and lipids. Also, I knew about the role of insulin in glucose metabolism and also the role of chronic cortisol levels on insulin resistance. I was aware of the liver's function in glycogenesis and the overall role of various tissues (muscle, adipose) in glucose metabolism and production.
1. LEARNED
Though I had a basic understanding of the body's metabolism of different molecule, this paper taught me a lot about how these different processes are temporally controlled. I didn't realize that the body naturally preferred certain types of food (protein-rich, carb-rich, lipid-rich, etc) at different times of day. Also, I had never heard of the "Dawn Phenomenon" about early morning glucose and insulin increase, and I find it particularly interesting. I had heard that it is most helpful to the body to exercise in the morning, but this article gave some specific details about how exercising at different times in the circadian cycle can have different physiological events.
2. MOST PRESSING QUESTIONS
On pg 167, the author notes that "time-of-day dependent rhythms in amino acid metabolism differ in distinct tissues." When giving an anti-cancer drug that is specific to a certain organ, will changing the dose administration to the time when the tissue is maximally/minimally metabolizing affect the success of the drug? Also on pg 167, the author suggests that there is evidence supporting the existence of "metabolomic chronotypes." How can we develop tests to identify the specifics of these chronotypes and then match subjects to the models? Could this be a successful strategy to use for personalized medicine?
3. PRESENTATION TOPIC
I didn't fully understand the role of growth hormone (GH) in metabolism and circadian cycles, so I would appreciate a more thorough explanation. Also, the paper filled a lot between rat/mouse models and humans, so I think it would be helpful to compare the similarities and differences in the metabolomic clocks.
4. THOUGHTS
I thought this paper was much more digestible than the second circadian paper. I felt that the information provided was well-explained and not overly detailed. I was completely surprised about how much of the genome contributes to circadian control, and I'm interested to see how that affects the RTA results for metabolomics at various timepoints.
0 Knew: Circadian Rhythms affected every level of biology from organ systems to individual cells as well as extrensic control of metabolism
ReplyDelete1 Learned: The time of day dependents on which type of molecules are preferentially metabolized as well as interrupting the rhythm could result in cardiometabolic consequences.
2 Pressing Questions: Have any legitimate studies been performed for medication such as chemotherapy that indicates increased efficacy of the medication at different times of administration.
3 Presentation: Pathways/tissues of metabolism of lipids and Carbohydrates
4 Thoughts: It is important to remember that biology has an embedded clock and that it affects most systems in the body, but I am curious about the actual applications of this knowledge. In other words has this clocks macro effect been noticed in pharmacology.
0 Knew: Circadian Rhythms affected every level of biology from organ systems to individual cells as well as extrensic control of metabolism
ReplyDelete1 Learned: The time of day dependents on which type of molecules are preferentially metabolized as well as interrupting the rhythm could result in cardiometabolic consequences.
2 Pressing Questions: Have any legitimate studies been performed for medication such as chemotherapy that indicates increased efficacy of the medication at different times of administration.
3 Presentation: Pathways/tissues of metabolism of lipids and Carbohydrates
4 Thoughts: It is important to remember that biology has an embedded clock and that it affects most systems in the body, but I am curious about the actual applications of this knowledge. In other words has this clocks macro effect been noticed in pharmacology.
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.
Stephen Lee
ReplyDeleteClass 05, Assignment 5a
Circadian regulation of metabolic homeostasis: causes and consequences
(0) Knew:
Prior to reading this paper, I understood the role certain hormones (eg. melatonin) played in regulating the sleep-wake cycle in animals, but I hadn’t investigated how this process looks at the cellular level or what extrinsic factors can influence circadian rhythm.
(1) Learned:
I learned that all circadian processes remain cyclical without external cues, which compromised my understanding of the sleep-wake cycle in humans, most notably as it relates to circadian rhythm sleep disorders (CRSDs). For example, in those who suffer from blindness, lack of access to the light-dark cycle often compromises their sleep cycle. These processes are technically diurnal, not circadian, which leads me to believe that CRSDs were named misleadingly! I also learned that many extrinsic compounds like metabolic/nutritional hormones function in a time-of-day-dependent manner, meaning their efficacy varies with time of infusion.
(2) Pressing Questions:
(Page 7, Column 2, Line 27) Why does so much redundancy exist in the circadian clock mechanism? Did some selective pressure cause this accumulation of overlapping function, or is there a present need for redundancy? Might these proteins have non-circadian targets?
(Page 12, Column 1, general) Does the culturally-entrained pattern of eating in humans (usually discrete meals at distinct times of day) present a challenge to metabolic regulation?
(3) Presentation Topic:
A more general presentation on the interactions between the circadian clock mechanism and overall metabolism might be useful. This paper is very thorough, but also contains a large quantity of esoteric/theoretical material.
(4) Thoughts:
Interested to see how the background I and others gleaned from this paper will be incorporated into the Eli Lilly discussion.
0 Knew
ReplyDeleteI was somewhat familiar with circadian rhythms from medical school; how SCN strokes can affect circadian rhythms, the oscillatory patterns of cortisol, growth hormone.
1 Learned
This paper had great breath so I learned a lot. I hadn't considered the distinction between extrinsic and intrinsic clocks, particularly intrinsic clocks. The studies on tissue specific knockouts were particularly interesting
3 Presentation
Interesting presentation topics might include a breakdown between intrinsic and extrinsic clocks and how the various systems can be manipulated by zeitgebers (great word)
4 Thoughts
The last section on exercise entrainment was very interesting, perhaps more on a "bro science" level rather than an academic level. Over the past year I have becoming a morning person, whereas before I was a night owl. What changed? Did anything actually change or am I still a night owl at heart?
John Vastola
ReplyDeleteClass 5, Article 4: Circadian regulation of metabolic homeostasis: causes and consequences.
0. WHAT I ALREADY KNEW (0. KNEW: ...)
It turns out I didn't even know the proper definition of metabolism, although I had some idea about it from context. I already knew a little bit about circadian regulation from the previous paper.
1. WHAT I LEARNED (1. LEARNED: ...)
This paper explained some of the same ideas about circadian regulation as the other paper, but I feel that it did so more clearly. While the other paper was focused on the effect such regulation had on drugs, this one focuses on the relationship between circadian regulation and the body's normal maintenance of itself.
The main thing I was learned was about the various intrinsic and extrinsic (insulin, cortisol, epinephrine...) factors mediating circadian rhythms. I also learned about how people know study circadian regulation in different parts of the body (for example, by doing mouse studies, or studying isolated tissues), and the relationship between circadian regulation and some everyday 'macro' things like diet and exercise.
2. MOST PRESSING QUESTIONS? (2. PRESSING ?: ...) << BE SURE TO LIST PAGE/LINE NUMBERS>>
I wonder how related the ciradian regulation processes are in different species. Do studies that are done with mice or rats tell us much about how these processes work in humans?
3. PRESENTATION TOPIC (3. PRESENTATION: ...)
A good presentation on this paper would break down the basic idea of circadian regulation as presented here, describe some of its mediators, and talk about its relationship with 'macro' things like diet and exercise.
4. THOUGHTS ON CLASS OR SYSTEMS BIOLOGY, ETC. (4. THOUGHTS: ...)
We are reading a lot of papers. I decided not to go into as much detail with these because the first few took me forever.
PCRC
ReplyDeleteSylvia Morrow
Asgn5A_Circadian regulation of metabolic homeostasis: causes and consequences.
0. KNEW: A colloquial understanding of homeostasis and circadian rhythms, so the idea that your cycle of restful/active behavior is related to at least some aspects of regulation that can affect your energy levels and injury recovery.
1. LEARNED: I learned metabolism is used more broadly than the breakdown of food to energy and that circadian refers specifically to oscillations within a 24-hour time scale. I gained an appreciation for the circadian rhythms of different systems. It seems that they are more alike than they are different. I was impressed by the level of synchronization that allows the systems to work together in an optimized way. I learned that a bolus injection is drug administration to achieve a particular concentration; 'hepatic' is referencing the liver; adipose is a fatty tissue; gluconeogenesis is the generation of glucose from non-carbon substrates; postprandial means the period of time after a meal; ad libitum-fed means food is always available for the test animal to chose when it wants to eat. I think the most interesting thing I gained from this paper was the general appreciation for circadian regulation as a factor affecting evolutionary success.
2. PRESSING ?:
--Are diurnal and circadian essentially synonyms?
--There was some discussion of how the type of diet (high-fat) can affect circadian clock gene expression. Are there more studies looking at this with other types of diets? Is this factor controlled for between other studies not looking at this factor? More broadly, are there measures taken by the scientific community to control factors such as food not just within a study but in a way that makes it easier to compare independent studies?
3. PRESENTATION:
--In class we talked about hormonal fluctuations being something that needed to be integrated into organ-on-a-chip because it could change drug effectiveness. I would be interested in learning more about the types of interactions that can happen between drugs and hormones. Is it similar to the interactions drugs have with proteins?
4. THOUGHTS: A very interesting topic.
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