opencode-knowledge-work 0.0.0-stage → 0.1.1

package/content/bio-research/skills/bio-research-scientific-problem-selection/references/01-intuition-pumps.md

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+# SKILL: Intuition Pumps for Scientific Problem Ideation
+
+## Overview
+This skill helps scientists generate high-quality research ideas by providing systematic prompts ("intuition pumps") and identifying common ideation traps. Based on the framework that most biological and chemical science projects involve **perturbing a system, measuring it, and analyzing the data**, this skill guides users through structured ideation that can significantly impact how they spend years of their career.
+
+## Core Framework
+
+### The Three Pillars of Scientific Work
+Research advances generally fall into one of these categories, each with two dimensions:
+
+**PERTURBATION**
+- *Logic*: Novel ways to manipulate biological systems (e.g., using CRISPR for deep mutational scanning)
+- *Technology*: New tools for manipulation (e.g., developing base editors, creating whole-genome CRISPR libraries)
+
+**MEASUREMENT**  
+- *Logic*: Novel applications of existing measurement tools (e.g., using tissue clearing to study liver fibrosis)
+- *Technology*: New measurement capabilities (e.g., developing tissue-clearing techniques, super-resolution microscopy)
+
+**THEORY/COMPUTATION**
+- *Logic*: Using computational tools to make discoveries (e.g., applying AlphaFold to identify protein functions)
+- *Technology*: Building new algorithms or models (e.g., developing machine learning architectures for biological data)
+
+Understanding which quadrant resonates with the user can help identify their niche and guide ideation.
+
+## The Skill Workflow
+
+### Phase 1: Initial Discovery Questions (5-10 minutes)
+
+Before diving into intuition pumps, Claude should gather context by asking the user:
+
+1. **What is the user's general research area or field?** (e.g., immunology, synthetic biology, neuroscience, protein engineering)
+
+2. **What excites the user most about science?**
+   - Building new tools/technologies?
+   - Discovering fundamental principles?
+   - Solving practical problems?
+   - Understanding dynamic processes?
+
+3. **What are the user's existing strengths?** (Select all that apply)
+   - Specific techniques (please list)
+   - Computational skills
+   - Access to unique systems/models
+   - Domain expertise in a particular area
+
+4. **Current constraints:**
+   - Time horizon for this project? (months/years)
+   - Resources available?
+   - Must it connect to existing work, or can the user start fresh?
+
+5. **On a scale of 1-5, how would the user rate their current idea?**
+   - Likelihood of success: 1 (very risky) to 5 (highly feasible)
+   - Potential impact: 1 (incremental) to 5 (transformative)
+
+### Phase 2: Applying Intuition Pumps
+
+Based on the user's responses, Claude should guide them through relevant intuition pumps from this list:
+
+#### Intuition Pump #1: Make It Systematic
+**Prompt:** Take any one-off perturbation or measurement and make it systematic.
+
+**Examples:**
+- Instead of mutating one enzyme, measure kinetic parameters across an entire enzyme family
+- Instead of one CRISPR mutant → genome-wide screen with transcriptomic readout
+- Instead of imaging one condition → high-throughput imaging across thousands of conditions
+
+**Prompt for User:** What one-off experiment in your field could become a systematic survey?
+
+#### Intuition Pump #2: Identify Technology Limitations
+**Prompt:** What are the fundamental limitations of technologies you use? These limitations are opportunities.
+
+**Examples:**
+- Microscopy can't resolve beyond diffraction limit → super-resolution microscopy
+- DNA synthesis can't make complete genomes → develop assembly methods
+- Genetic screens have precise input but imprecise output → develop high-dimensional readouts
+- We do single gene KOs but networks are complex → develop combinatorial perturbation methods
+
+**Prompt for User:** What technology limitation frustrates you most? How might you turn that limitation into an opportunity?
+
+#### Intuition Pump #3: The "I Can't Imagine" Test
+**Prompt:** I can't imagine a future in which we don't have ____, but it doesn't exist yet.
+
+**Examples:**
+- The ability to design highly efficient enzymes like we design other proteins
+- The ability to deliver genome editing payloads to any cell type in vivo
+- 3D tomographic imaging of live cells at molecular resolution
+- Proteome-scale sequencing with the throughput of RNA-seq
+
+**Prompt for User:** What capability seems inevitable but doesn't exist yet in your field?
+
+#### Intuition Pump #4: Static vs. Dynamic Understanding
+**Prompt:** We understand biological "parts lists" but rarely understand dynamic processes.
+
+**Key Insight:** Most observations are single-timepoint, single-perturbation format. But biological systems are dynamic—like humans flowing through Grand Central Station or money through financial systems.
+
+**Examples:**
+- Understanding growth factor signaling like we understand turning a key in a car engine
+- Time-resolved cell atlases with lineage tracing through entire development
+- Following metabolite flux through pathways in real-time
+
+**Prompt for User:** What dynamic process in your field do we observe as static snapshots? How might you capture the full temporal or spatial dynamics?
+
+#### Intuition Pump #5: Pick a New Axis
+**Prompt:** We almost always use time as the x-axis for dynamic processes. What other coordinate could you use?
+
+**Example:** Instead of time, use "infection progression" markers to enable monitoring asynchronous cells
+
+**Prompt for User:** What non-temporal coordinate could reveal new biology in your system?
+
+#### Intuition Pump #6: Create a Technology Platform
+**Prompt:** Instead of answering one question, could you build a platform that enables many questions?
+
+**Examples:**
+- Antibodies for intracellular targets (not just extracellular)
+- AI that predicts perturbations needed to reach desired cell states
+- Universal genome delivery vehicles
+
+**Prompt for User:** What platform would transform how your field asks questions?
+
+#### Intuition Pump #7: Dogs That Don't Bark
+**Prompt:** Why doesn't something exist or occur? Absence can be as informative as presence.
+
+**Examples:**
+- Why are there no Gram-negative bacteria on human skin?
+- Why do some catalytically inactive enzymes persist through evolution?
+- Why don't certain cell types exist in certain tissues?
+
+**Prompt for User:** What absence puzzles you in your field?
+
+### Phase 3: Avoiding Common Traps
+
+After generating ideas, we must evaluate them critically. Here are the most common traps:
+
+#### Trap #1: The Truffle Hound
+**Warning:** Don't become so good at one system or technique that you fail to ask questions of biological import.
+
+**Bad:** "What is the role of p190 RhoGAP in wing development?"  
+**Better:** "How do signaling pathways and cytoskeleton coordinate to control wing development?"
+
+**Self-Check:** Is the question driven by biological curiosity or by what the user is technically capable of?
+
+#### Trap #2: Applying Existing Tool to New System
+**Warning:** "Let's use CRISPR in my organism" can be valuable but risks crowding and incrementalism.
+
+**When It Works:** The user is enabling a field that truly needs this capability
+**When It Fails:** The tool is already widely applied; the contribution will be incremental
+
+**Self-Check:** Will this tool application open new biological questions, or just extend existing observations? Claude should help the user evaluate this honestly.
+
+#### Trap #3: Jumping on the First Idea
+**Warning:** Treating ideas with reverence instead of skepticism. Confirmation bias sets in quickly.
+
+**Better Approach:** Users should treat new ideas like leeches trying to steal their time. Look for the warts. Develop several ideas in parallel and comparison shop.
+
+**Self-Check:** Has the user critically evaluated at least 3-5 alternative approaches?
+
+#### Trap #4: Too Many Fixed Parameters
+**Warning:** Fixing too many parameters at the outset creates a poor technique-application match.
+
+**Example of Over-Constraining:** "I will use spatial transcriptomics to study antigen-presenting cell and T cell interactions in the tumor microenvironment."
+- This fixes: technique (spatial transcriptomics), cell types, and context
+- If any assumption fails, the project fails
+
+**Self-Check:** Has the user fixed more than 2 parameters before starting?
+
+#### Trap #5: Too Few Fixed Parameters
+**Warning:** "I want to do impactful work in cell engineering" → paralysis
+
+**Resolution:** Constraints engender creativity. Fix ONE parameter at a time and let creativity flow.
+
+**Self-Check:** Does the user have at least one concrete constraint to work with?
+
+### Phase 4: Literature Integration
+
+To ensure the idea has appropriate scope and hasn't been thoroughly explored, Claude should ask:
+
+1. **What are 2-3 key questions or gaps the idea addresses?**
+
+2. **What should be searched in PubMed to:**
+   - Understand the current state of the field?
+   - Identify related approaches?
+   - Find empirical knowledge from adjacent domains that could inform the approach?
+
+Claude should use PubMed to:
+- Assess how general/specific the problem is
+- Identify relevant methodological advances
+- Find analogous systems or approaches in other fields
+- Determine the degree of competition
+
+### Phase 5: Idea Refinement and Output
+
+After working through intuition pumps, avoiding traps, and reviewing literature, Claude should help the user:
+
+1. **Crystallize the Idea:**
+   - Biological question
+   - Technical approach (perturbation/measurement/theory: logic vs. technology)
+   - What's novel about this angle?
+
+2. **Articulate Fixed vs. Floating Parameters:**
+   - What MUST remain constant in the approach?
+   - What can be flexible if obstacles arise?
+
+3. **Identify Key Assumptions:**
+   - What must be true for this to work?
+   - Which assumptions are about biology vs. technology capabilities?
+
+4. **Sketch Alternative Paths:**
+   - If the primary approach fails, what's Plan B?
+   - Can the project be designed to succeed regardless of outcome?
+
+## Output Deliverable
+
+At the end of this skill, Claude should produce a **2-page Problem Ideation Document** containing:
+
+### Page 1: Core Idea
+- **Title:** Concise project name
+- **The Question:** What biological question is being asked?
+- **The Approach:** How will it be answered? (Specify perturbation/measurement/computation: logic vs. technology)
+- **What's Novel:** The unique angle
+- **Why It Matters:** Potential impact (generality × learning, or technology development)
+- **Intuition Pump(s) Used:** Which prompted this idea
+
+### Page 2: Critical Analysis
+- **Fixed vs. Floating Parameters:**
+  - Fixed: What must stay constant
+  - Floating: What can adapt
+
+- **Key Assumptions & Risk Assessment:**
+  - Biological assumptions (risk level 1-5)
+  - Technical assumptions (risk level 1-5)
+
+- **Traps Avoided:** Which pitfalls were navigated around?
+
+- **Alternative Approaches:** Plan B and Plan C
+
+- **Literature Context:**
+  - 3-5 key papers that inform or relate to this work
+  - Degree of competition (low/medium/high)
+  - The user's edge/advantage
+
+- **Next Steps:** First 3 concrete experiments or analyses
+
+## Key Principles to Remember
+
+1. **Reversal of Polarity:** Treat ideas with skepticism, not reverence. Look for flaws before falling in love.
+
+2. **Comparison Shopping:** Develop multiple ideas in parallel. The act of comparison improves decision-making.
+
+3. **Fix One Parameter at a Time:** Constraints engender creativity, but too many constraints prevent it.
+
+4. **Think in Ensembles:** The user is picking a family of possible projects, not a singular path. Flexibility is essential.
+
+5. **Balance Logic and Technology:** Novel biology can come from new tools OR clever application of existing tools.
+
+6. **Systematic Over One-Off:** High-throughput and systematic approaches often reveal more than single observations.
+
+7. **Dynamic Over Static:** Biological systems are dynamic. How can process be captured rather than snapshot?
+
+## Getting Started
+
+When the user is ready, Claude should guide them through the Phase 1 questions to begin the systematic ideation process. The key message: spending extra time on problem choice is the highest-leverage activity in science. A well-chosen problem executed reasonably well will have more impact than a mediocre problem executed brilliantly.
+
+---
+
+*This skill is based on the problem choice framework developed by Michael A. Fischbach and Christopher T. Walsh, as described in "Problem choice and decision trees in science and engineering" (Cell, 2024).*

package/content/bio-research/skills/bio-research-scientific-problem-selection/references/02-risk-assessment.md

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+# SKILL 2: Risk Assessment and Assumption Analysis
+
+## Overview
+This skill helps scientists systematically identify, quantify, and manage project risk through rigorous assumption analysis. The goal is not to eliminate risk—risk-free projects tend to be incremental—but to name it, quantify it, and work steadily to chip away at it. This skill builds directly on the Problem Ideation Document from Skill 1.
+
+## Core Principle
+
+**"Don't avoid risk; befriend it."**
+
+The most important concept in problem choice is the two-axis evaluation:
+- **X-axis:** Likelihood of success
+- **Y-axis:** Impact if successful
+
+This skill focuses on the X-axis, helping users move their project rightward through systematic risk analysis.
+
+## Why This Matters
+
+A project with a high-risk assumption that won't read out for >2 years is problematic. One that requires multiple miracles to succeed should be avoided or refined. The human tendency is to stay in a safe local space, work laterally, and put off facing existential risks—like an ostrich burying its head in the sand. This skill helps users face risk head-on.
+
+## The Skill Workflow
+
+### Phase 1: Extract Project Assumptions (10-15 minutes)
+
+First, Claude should gather information about the user's project from Skill 1:
+
+1. **Project Summary** (from Skill 1):
+   - The biological question
+   - The technical approach
+   - What's novel about it
+
+2. **Project Horizon:**
+   - How long is this project expected to take? (months/years)
+   - What is the user's role? (graduate student, postdoc, PI, startup founder)
+
+3. **Initial Risk Sense:**
+   - What keeps the user up at night about this project?
+   - What's the scariest assumption?
+
+### Phase 2: Comprehensive Assumption Listing
+
+Claude should work with the user to list EVERY assumption the project makes from inception through conclusion. Assumptions fall into two categories:
+
+#### Type A: Assumptions About Biological Reality
+These are facts about the world that either are or aren't true. They won't change during the project.
+
+**Examples:**
+- New cell types exist beyond what's currently known
+- A particular gene regulates the process being studied
+- Two proteins physically interact
+- A pathway functions in the organism of interest
+- The biological effect size is detectable
+
+#### Type B: Assumptions About Technical Capability
+These are about whether technology can do what's needed. These CAN change during the project as methods improve.
+
+**Examples:**
+- A specific cell type can be isolated
+- Sequencing will generate high-quality data
+- An assay has sufficient throughput
+- Computational analysis can distinguish signal from noise
+- Gene editing will work in the system
+
+**Claude should ask:**
+1. What must be true about the biology for this to work?
+2. What must the technology be able to do?
+3. What about the experimental design—what assumptions are built in?
+4. What about the analysis—can it deliver what's needed?
+5. If everything works, can the findings be validated?
+6. Will the findings be interpretable and meaningful?
+
+### Phase 3: Risk Scoring (The Assumption Analysis Table)
+
+For each assumption, Claude should help the user assign two scores:
+
+#### Risk Level (1-5 scale):
+- **1** = Very likely to be true/work (>90% confidence)
+- **2** = Likely (70-90% confidence)
+- **3** = Uncertain (40-70% confidence)
+- **4** = Unlikely (10-40% confidence)
+- **5** = Very unlikely (<10% confidence)
+
+#### Time to Test (months):
+How long before the user will know if this assumption is valid?
+
+**Critical Rules:**
+1. Be brutally honest—try to convince oneself of being WRONG, not right
+2. Distinguish between biological vs. technical assumptions
+3. Consider whether technical assumptions might improve over time
+4. Note which assumptions depend on earlier assumptions succeeding
+
+### Phase 4: Risk Profile Evaluation
+
+Once the complete table is ready, Claude should analyze the risk profile:
+
+#### Red Flags to Identify:
+1. **The Late High-Risk Problem:** Risk level 4-5 assumption that won't read out until >18 months
+2. **The Multiple Miracles:** More than 2-3 assumptions with risk level 4-5
+3. **The Dependency Chain:** High-risk assumptions stacked in sequence
+4. **The Ostrich Pattern:** Starting with low-risk work while avoiding the high-risk tests
+
+#### Green Lights:
+1. **Early Go/No-Go:** Highest-risk assumption testable in <6 months
+2. **Multiple Candidates:** Project can succeed with several different outcomes
+3. **Graceful Degradation:** If assumption X fails, assumption Y provides alternative path
+4. **Risk Distribution:** High-risk assumptions balanced across timeline
+
+**Rule of Thumb:** If you have a risk level 5 assumption three years out, pick another project.
+
+### Phase 5: Risk Mitigation Strategies
+
+For each high-risk assumption (level 4-5), Claude should help develop mitigation strategies:
+
+#### Strategy 1: Move High-Risk Tests Earlier
+**Question:** Can a quicker, cruder test be designed that answers most of what's needed?
+
+**Example:** Instead of waiting 2 years to validate a new cell type exists, consider:
+- Using existing markers as a proxy
+- Testing in a simpler model system first
+- Using computational predictions to increase confidence
+
+#### Strategy 2: Multiple Candidates Approach
+**Question:** Can multiple candidates be tested in parallel to increase likelihood of success?
+
+**Example:** Instead of:
+- Testing one kinase → Test a panel of 10 kinases
+- Building one engineered organism → Build and test a library
+- Pursuing one therapeutic target → Pursue 3 related targets
+
+#### Strategy 3: Reframe the Question
+**Question:** Can the project scope be adjusted to reduce critical assumptions while maintaining impact?
+
+**Example from lecture:**
+- **Original:** Identify NEW enteroendocrine cell types (high risk: they may not exist)
+- **Reframed:** Better characterize KNOWN but incompletely understood cell types (lower risk)
+
+#### Strategy 4: Change the System
+**Question:** Is there a different biological system with similar scientific value but lower technical risk?
+
+**Example from lecture:**
+- **Original:** Intestinal epithelium (hard to manipulate genetically)
+- **Alternative:** Liver (easier genetic manipulation options exist)
+
+#### Strategy 5: Add Complementary Approaches
+**Question:** Can a parallel approach be added that de-risks the main assumption?
+
+**Example from lecture:**
+- Add spatial transcriptomics to scRNA-seq
+- This provides biogeographic context and validates cell type existence earlier
+
+### Phase 6: Go/No-Go Experiment Design
+
+For the top 3 highest-risk assumptions, Claude should help design the critical go/no-go experiments:
+
+**For each, specify:**
+1. **The Question:** Exactly what is being tested?
+2. **The Experiment:** Most direct test possible (even if crude)
+3. **Success Criteria:** What result means "go"?
+4. **Failure Response:** What result means "pivot" or "stop"?
+5. **Timeline:** How soon can this be run?
+6. **Resources:** What is needed?
+
+**Key Principle:** Cut right to the critical go/no-go experiment. Don't just start with easy stuff—the risk points aren't going away.
+
+### Phase 7: Literature Validation
+
+Claude should search PubMed to help calibrate risk assessments:
+
+**Search for:**
+1. **Precedents:** Has anyone done something similar? (Reduces technical risk)
+2. **Biological Evidence:** What's known about the system? (Informs biological risk)
+3. **Technical Benchmarks:** How well do the methods work in practice?
+4. **Adjacent Successes:** Has anyone solved related problems?
+
+**Questions to ask the user:**
+- What specific searches would help calibrate risk?
+- Are there particular papers that informed the assumptions?
+- Are there technical benchmarks to look up?
+
+### Phase 8: Revised Project Plan
+
+Based on the risk analysis, Claude should help create a revised plan:
+
+#### Option A: De-Risk the Current Plan
+- Reorder experiments to test high-risk assumptions early
+- Add complementary approaches
+- Design multiple-candidate strategies
+
+#### Option B: Reframe the Project
+- Adjust scope while maintaining impact
+- Change biological system
+- Modify technical approach
+
+#### Option C: Pick a Different Project
+Sometimes the honest answer is: "This has too many miracles." That's valuable to know BEFORE investing years.
+
+## Output Deliverable
+
+Claude should produce a **2-page Risk Assessment Document**:
+
+### Page 1: Assumption Analysis Table
+
+| Assumption | Type* | Risk† | Time‡ | Notes |
+|------------|-------|-------|-------|-------|
+| [Assumption 1] | Bio/Tech | 1-5 | X mo | [Rationale for score] |
+| [Assumption 2] | Bio/Tech | 1-5 | X mo | [Rationale for score] |
+| ... | ... | ... | ... | ... |
+
+*Bio = Biological reality, Tech = Technical capability  
+†Risk: 1=very likely to 5=very unlikely  
+‡Time to test in months
+
+#### Risk Profile Summary:
+- **Total Assumptions:** X
+- **High Risk (4-5):** X assumptions
+- **Late High Risk (>18mo):** X assumptions
+- **Critical Path:** [Identify the chain of dependent assumptions]
+- **Overall Assessment:** [Green/Yellow/Red light with explanation]
+
+### Page 2: Risk Mitigation Plan
+
+#### Top 3 High-Risk Assumptions:
+For each:
+1. **The Assumption:** [Stated clearly]
+2. **Current Risk Level & Timeline:** X (risk) at Y months
+3. **Why This Risk Exists:** [Explanation]
+4. **Mitigation Strategy:** [From Strategies 1-5 above]
+5. **Go/No-Go Experiment:**
+   - Experiment design
+   - Success criteria
+   - Timeline
+   - What you'll do if it fails
+
+#### Revised Project Timeline:
+```
+Month 0-6:   [Early go/no-go experiments]
+Month 6-12:  [Based on go/no-go results]
+Month 12-18: [...]
+Month 18+:   [...]
+```
+
+#### Contingency Plans:
+- **If assumption X fails:** [Plan B]
+- **If assumption Y fails:** [Plan C]
+- **Multiple success paths:** [How project can succeed different ways]
+
+#### Decision Points:
+- **Month X:** Evaluate [assumptions A, B] → Go/Pivot/Stop decision
+- **Month Y:** Evaluate [assumptions C, D] → Go/Pivot/Stop decision
+
+## Practical Examples
+
+### Example 1: ScRNA-Seq for Enteroendocrine Cells
+
+**High-Risk Assumptions Identified:**
+1. "New cell types can be validated experimentally" (Risk 5, 24 months)
+2. "Knockout will yield biologically relevant phenotype" (Risk 5, 30 months)
+
+**Problem:** Two risk-5 assumptions at 24+ months = RED FLAG
+
+**Mitigation Applied:**
+- Reframe to study known but poorly characterized cells (reduces Risk 5→3)
+- Switch to liver instead of intestine (improves validation timeline: 30→18 months)
+- Add spatial transcriptomics (provides earlier validation checkpoint at 16 months)
+
+### Example 2: Bacterial Therapy for Chronic Kidney Disease
+
+**High-Risk Assumption Identified:**
+"Key uremic toxins leading to effects can be determined" (Risk 4, unknown timeline)
+
+**Problem:** Critical assumption with unclear path to resolution
+
+**Mitigation Applied:**
+- Focus on known lead toxins (IS and PCS) rather than discovering new ones
+- Add parallel track: test multiple toxin candidates
+- Design study where learning toxin identity IS the outcome (multiple success paths)
+
+## Key Principles to Remember
+
+1. **Try to Convince Yourself You're Wrong:** The goal is critical evaluation, not confirmation bias.
+
+2. **Ignore Everything But Key Risk Points:** Don't get distracted by easy tasks. The high-risk assumptions aren't going away.
+
+3. **Early and Often:** Design go/no-go experiments at the earliest feasible moment.
+
+4. **Be Candid About Risk:** When presenting ideas, acknowledging risk makes your case MORE convincing, not less.
+
+5. **No Risk, No Interest:** The goal isn't zero risk—it's understood, quantified, manageable risk.
+
+6. **Risk Can Change:** Technical assumptions may improve as methods advance. Build this into your planning.
+
+7. **Compare Risk Profiles:** Evaluate multiple projects in parallel to compare risk profiles and make better choices.
+
+8. **Watch for the Ostrich Pattern:** Are you avoiding the scary experiment? That's human nature, but a critical failure mode.
+
+## Warning Signs
+
+**Warning signs include:**
+- Risk level 5 assumptions >2 years out
+- More than 3 assumptions at risk level 4-5
+- Highest-risk assumptions at the END of the timeline
+- Rationalizing why high-risk assumptions will "probably work out"
+- Planning to "start with the easy stuff" while avoiding risk tests
+- Inability to articulate clear go/no-go criteria
+
+**Good shape indicators:**
+- Highest-risk tests happen in first 6 months
+- Multiple paths to success exist
+- Clear plans for what to do if key assumptions fail
+- Risk is distributed across the timeline
+- Testing assumptions, not confirming hopes
+
+## Getting Started
+
+Claude should begin with Phase 1 by asking for:
+1. The project summary from Skill 1
+2. Project timeline expectations
+3. What concerns the user most about this project
+
+Together, Claude and the user will build a rigorous risk assessment that dramatically improves the likelihood of success by helping avoid years of work on projects with insurmountable obstacles.
+
+---
+
+*Remember: Spending time on risk analysis is the most valuable investment a scientist can make. A well-understood risk profile enables moving forward with confidence or pivoting with clarity—both are valuable outcomes.*