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.
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ReplyDeleteArman Chowdhury
ReplyDeleteAssignment 3C
0.Knew: Perturbations caused by threat agents propagate throughout the cell to alter cellular processes. These perturbations and the cellular response comprise the molecular mechanism of action. The goal of RTA is to identify the mechanism within 30 days.
1. Learned: RTA wants to detect, identify and reconstruct the mechanism, and invites researchers to propose a plan. Researchers should use challenge compounds instead of threat agents for their experiments. RTA advises researchers to avoid use of molecule-specific labels, and to be able to classify all types of molecules instead of just a specific class of molecules.
2. Pressing ?: Can challenge compounds mimic the actions of threat agents completely while testing the effectiveness of the Rapid Threat Assessment plan the researchers will develop? Couldn’t threat agents affect the human physiology and the organ systems in humans differently, with more adverse consequences, compared to simple human cell cultures in a lab? Can organ-on-a-chip be used to carry out these experiments for more realistic results?
3. Presentation: The text has lots of examples of threat agents that have been researched for a long time in order to study their effect on biological systems, which helps establish why RTA wants to achieve the 30 day goal. RTA provides very clear guidance to the researchers about the research in the form of different metrics and milestones over a span of five years. DARPA has also given clear direction about the format the researchers should use for their proposals, involving headings such as “Technical and Management Proposal” and “Cost Proposal”
4. Thoughts: This comprehensive guidebook by DARPA on how to develop a research proposal for the RTA 30 day plan indicates the US govt’s seriousness about chemical and biological weaponry threat assessment. I am curious to know whether they’ll make their ultimate chosen research method available to public knowledge.
Tim Lee
ReplyDeleteAssignment 3C
0. Knew: Goal of RTA and the need for a comprehensive approach to determine the mechanisms and effects of drugs on human cells.
1. Learned: The breakdown of the RTA plan to accomplish the goal to be able to determine any mechanism within 30 days of exposure. The details of the metrics and milestones expected to be completed along the timeline of the three step process of proposing a method.
2. Pressing: Does every proposal planning on taking on the RTA challenge have their costs accounted for? Aren't the challenge molecules limited to our knowledge of their effects on the human body? What if we come across a molecule much more complicated than our most complicated challenge molecule, and how can we be sure if our methods will be adequate then?
3. Presentation: A detailed outline of DARPAs RTA challenge with all of the expected metrics and milestones detailed and what teams should expect in terms of cost and feasible goals.
4. Thoughts: It still feels like five years may not be enough to find a completely comprehensive method to determine any mechanism of a drug in 30 days. There's always the possibility of one drug that can stump a method because there are millions of molecule combinations and just one of them could present an issue we have never seen before.
James Pino
ReplyDeleteAssignment 3C
0: Knew: RTA Goal, purpose, need
1:Learned: DARPA provides a blank check if you can really plan this. They require a lot, but with enough resources (can add many PIs, even from different countries) it seems like it can actually work.
2:Pressing: Is 5 years a realistic goal? I understand that from this idea many new technologies, science, and discoveries will be made. But 5 years to a 30 day prediction really possible? Who received the funds? How much does DARPA spend each year? Does the science become open source or does DARPA own it all?
3:Presentation: DARPA RTA guidelines and timeline.
4:Thoughts: DARPA knows what it wants.
0. Knew: The general principle of RTA: identifying the mechanism of action of a chemical weapon within 30 days.
ReplyDelete1. Learned: The flexibility required for an RTA platform, both in terms of quantity of different molecules that must be monitored and time scale of cellular changes. Specific performance criteria that DARPA has identified as necessary for an RTA platform, as well as milestones. Baseline Subtraction as the primary method of isolating compounds tied to an agent's mechanism.
2. Pressing ?: Will RTA rely solely on baseline subtraction of molecule concentrations as a metric, and, if so, will this be enough to determine mechanism of action? For instance: if after exposure, compound A increases immediately and compound B increases later how can we determine whether A increases [B] or whether the agent directly affects both A & B, but B's response is slower? How extensively will the platform rely upon assumptions formed on current knowledge of cellular mechanics, and will these assumptions limit its ability to assess agents that operate within large gaps in current understanding? What is the limit of RTA’s ability to yield new knowledge broader than a specific agent’s mechanisms?
3. Presentation: An overview of RTA and an detailed breakdown of needs and benchmarks for the DARPA RTA project. Components of a DARPA proposal for RTA.
4. Thoughts: The scope of the RTA project seems massive. I think RTA has great potential, but I am curious if the platform can be made flexible enough to truly determine the mechanism of any agent within thirty days. I am looking forward to delving into the subject more deeply and answering some of these questions.
0. I knew that the goal was to determine the mechanism of action of the threat agent and the resulting cellular components.
ReplyDelete1. I learned the specific time restraints for the project. I also learned that the designers will not use specific threat agents but rather challenge compounds to model the cellular response.
2. Pressing ?: The freedom of choosing a challenge compound seems too general. How will researchers know if their model performs as well as another if each model is tested with different compounds?
3. Presentation: Testing methods and potential challenge compounds used to simulate chemical and cellular response to threat agents
4. I did not realize that the way we conduct research on identifying and analyzing drugs takes so many years! I can easily see why RTA is so important and necessary in increasing our preparedness. Perhaps this challenge will change the face of drug development as well as detection.
Selene van der Walt
ReplyDeleteAssignment 3C
0. Knew: How long the drug development and testing processes take, as well as the exhaustive amount of research hours and papers dedicated to investigating drug action.
1. Learned: The range of combinations of effects that can comprise a drug’s mechanism of action, from effecting proteins and signaling molecules to metabolites and nucleic acids. I also learned of the three technical areas that DARPA broke the problem down into, as well as the mass and detection limits outlined.
2. Pressing ?: When suspending the cell states (such as by freezing), how do you select your time points to ensure that you are not missing some essential reaction in the mechanism of action? Do all mechanisms of action necessarily involve a change in cell contents?
3. Presentation: Details of the RTA program presented by DARPA, including program milestones and the application process.
4. Thoughts: Again, if this can be achieved it will be revolutionary, I just am unsure if this is an achievable goal with the technology we have available today.
Shuaipeng "Jimmy" Zhang
ReplyDelete0. Knew: The goals of RTA, and the high level of complexity of cellular interactions.
1. Learned: The process of applying for funding, as well as the three technical areas and time periods set by the BAA. Investigators will use their own challenge molecules during research, but will be provided with a demonstration molecule (chosen by DARPA) to analyze at the end of each time period.
2. Pressing ?: Will the demonstration compound chosen by DARPA be the same for all researchers? What if researchers make significant advancements in science, but do not fulfill the goals of RTA at the end of each time period, will their contract be canceled? Is 5 years too ambitious of a time period to accomplish the goals set forth in the presentation?
3. Presentation: The process of applying for the RTA program, guidelines for research, and criteria for the evaluations held at the end of each time period.
4. Thoughts: DARPA is willing to invest a lot of money into this research, as no cap is given to the proposed budget. However, how achievable are their goals in 5 years? The guidelines for research are very clearly laid out, but fulfilling them will obviously be a huge challenge.
Juan Gnecco
ReplyDeleteAsgn_3C/ proposers presentation
Knew: Goal of RTA to identify the effects of drugs/chemicals/ etc within a rapid (30 days) of treatment.
Learn: Rules of the proposal and appplication:detect cellular components and mechanistic events as well as detection requirements. And metrics needed to identify an end point validation.
Pressing: How to accomplish this? How do we analyze and manage hundreds of interactions and alterations. How to define a "control" or normal condition? How basic must a mechanism of action be?
Presentation: The proposal of a new project intiative RTA as a fundamental future goal in biology.
4: This is a very technical problem that may be above the current analytical techniques it requires? besides Mass-spec what are some other analytical techniques we can use?
Priyanka Ravichandran
ReplyDeleteAssignment 3C - DARPA Presentation
0. Knew - RTA and its goals, drug development is a long, expensive process
1. Learned - the three technical areas of the RTA and the general timeline
2. Pressing - can all of these specific requirements be fulfilled in the timeline mentioned? If people use the challenge compound of their choice, how can results be compared among different investigators?
3. Presentation - explains in detail the goals and milestones of the RTA
4. Thoughts - I think the time constraints are a bit ambitious. Although there are definitely benefits to achieving the goals of the RTA program, 30 days seems too restrictive. However, DARPA is very clear cut about what exactly they want.
Cami Johnson
ReplyDeleteAssignment 3C: RTA Presentation
0. Knew: The concept of RTA and its general criteria
1. Learned: The specific requirements for RTA research proposals. Any plan must satisfy three crucial areas: (1) detect cellular components and events, (2) identify them, and (3) reconstruct the mechanism. DARPA wants detection on a timescale from milliseconds to days with identification in the cytoplasm, nucleus, and membrane.
2. Pressing ?: What's a reasonable timeline for accomplishing this task? The presentation specifies 5 year proposal plans, but do they expect a working RTA system by then?
3. Presentation: The presentation laid out the expectations of the RTA system and the requirements for submitting a proposal.
4. Thoughts: Again, I am skeptical. I think this process will be incredibly complicated, and I'm not sure the extent of what will be accomplished in 5 years without organs-on-a-chip. However, I think it's a good thing to fund and could change the way we research disease and drug treatments.
Chuck Herring
ReplyDeleteAssignment 3C
0: Knew: What I learned from the press release.
1:Learned: The specifics regarding the RTA project.
2:Pressing: Would elements of a solution be classified?
3:Presentation: DARPA RTA specifics.
4:Thoughts: It is at the very least a fun thought project.
Blog harvested
ReplyDeleteMark Vander Roest
ReplyDeleteAssignment 3C DARPA/RTA proposers slides
0. Knew: The two page bulletin from assignment 3B. Concept of RTA, basic program requirements.
1. Learned: The details of the program requirements, including detection, identification and reconstruction. Timeline of the entire project, and timescales for detection.
2. Question: Will the results and methods be validated with more realistic biologic agents? Discovering the mechanism of a "challenge" compound might prove much simpler than finding the mechanism of an unknown threat agent.
3. Presentation: Project requirements and guidelines for the DARPA RTA program, overview of timeline/budgeting needs/
4. Thoughts: It's definitely a good goal for any sort of bioweapon preparedness, but I'm curious if things will pay off. Surely as defensive capabilities increase, so will the ability of those creating the harmful agents.
Cameron Togrye
ReplyDeleteAsgn_3C/ proposers presentation
Knew: There are over 10,000 different proteins each of which potentially can be post translationally modified, lending to a incredibly diverse set of biomolecules in the cell.
Learned: The BAA expects that the project be completed in 5 years.
Pressing: My foremost question is how reasonable a 5 year timeline is. Considering DARPA is not accepting plans which exceed this limit, is that a reasonable expectation to have for what seems to be such a monumental project? Also, it mentions that the experimental design should allow for discernment of the mechanism without the aid of computational modeling, is this a reasonable expectation? Why not use this tool?
Presentation: A presentation on potentially viable chemical or biological challenge agent, and why they are a good fit
Thoughts: Once again, for such a monumental task, 5 years seems like a very strict timeline. I'd like to know whether this is reasonable.