Annotations (18)
“We worked with them and got their approval to essentially run a natural history study, meaning while the drugs were being developed, we basically paid for people's care for a handful of years so that we could have a log of what the natural progression of the disease was and use that as our placebo.”— Dinakar Singh
Dinakar's Story · p. 7
Operations & Execution · Strategy & Decision Making · Business & Entrepreneurship
DUR_ENDURING
Natural history study replaces placebo; saves lives and time
“We basically created all these mouse models and cell models of different types to test different versions, and each has pros and cons, and set up facilities to essentially give them away for free. So essentially what we said to everyone around the world: Guys, send your drug libraries in, your compound libraries in, test them for free, we'll pay for it. You keep the IP. We just want you to know if there's something interesting here.”— Dinakar Singh
Dinakar's Story · p. 5
Strategy & Decision Making · Business & Entrepreneurship · Operations & Execution
DUR_ENDURING
Remove all barriers; let partners keep upside; accelerate discovery
“It occurred to me that all these things take time. You could fund some scientists, get some basic research, and then go to the next one, to the next one, the next one, and that will eventually work, but it'll take forever. It struck me that we need to do things in parallel processing, not serial processing. If there are five interesting ideas, let's do all five at the same time and see which ones work, not do one at a time and go A, B, C, D, E, F, G.”— Dinakar Singh
Dinakar's Story · p. 4
Operations & Execution · Strategy & Decision Making · Business & Entrepreneurship
DUR_ENDURING
Parallel processing beats serial when time matters more than capital
“The second worst thing that can happen to a parent is to see their child suffer and die. The single worst thing, though, is to see your child suffer and die only to find out that you could have done something about it, but it wasn't done in time. And so once we got the idea in our head that there's a glimmer of hope here, it really almost deranges you, if you will, because then any second you're spending doing anything that isn't max speed is a wasted moment.”— Dinakar Singh
Dinakar's Story · p. 4
Psychology & Behavior · Strategy & Decision Making · Philosophy & Reasoning
DUR_ENDURING
Regret of inaction worse than failure; deranging clarity of purpose
“I describe to people: if you have a boat and you have a hole in it, trying to bail water out of the boat is not really going to be a useful strategy. You're going to sink just maybe a tiny bit slower. Once you fix that hole and now there's no water on the boat, now bailing water out of the boat could actually be a really good strategy.”— Dinakar Singh
Dinakar's Story · p. 8
Strategy & Decision Making · Biology, Ecology & Systems · Operations & Execution
DUR_ENDURING
Fix root cause before optimizing; bailing useless with hole
“An important factor in starting the firm and leaving Goldman at that time was that on one end, while I loved investing, I also just resolved that there was a glimmer of hope to save my daughter and other kids who had her condition.”— Dinakar Singh
Dinakar's Story · p. 1
Strategy & Decision Making · Business & Entrepreneurship · Psychology & Behavior
DUR_ENDURING
Day job funded night job; speed as existential requirement
“With SMA, the difference between some of these kids with multiple backups versus not and somebody who is a carrier versus having a disease or someone you presumably doesn't have it all, there's such a massive range of this protein in the body that's pretty clear that you almost can't have too much. There's no real worry about that, and that really was a pretty intriguing thing from developing a drug as well.”— Dinakar Singh
Dinakar's Story · p. 3
Biology, Ecology & Systems · Strategy & Decision Making · Business & Entrepreneurship
DUR_ENDURING
Wide therapeutic window removes toxicity risk; enables aggressive dosing
“We got a dozen and a half of the smartest drug development people in the entire world coming together for a couple weekends a year and just taking time away from their families and their work and just sitting with us and brainstorming about our plan of action. And I think part of it was because it sounds crazy to think about this, but there had not been a single meaningful drug for a neurological disease developed in decades. Crazy, right?”— Dinakar Singh
Dinakar's Story · p. 5
Leadership & Management · Psychology & Behavior · Strategy & Decision Making
DUR_ENDURING
Top talent donated time for solvable problem in graveyard field
“One of my slides showed that if you charge $5,000 to $15,000 a year, you could actually end up with a drug worth hundreds of millions of dollars in profit. And so it wouldn't just be a charity project, you could actually make a little bit of money from it. And the head of one of the largest biotech companies actually sat there in the meeting and said, Look, Dinakar, the most expensive drug in the world is Avastin, which was an oncology drug at $50,000 a year.”— Dinakar Singh
Dinakar's Story · p. 5
Economics & Markets · Strategy & Decision Making · Business & Entrepreneurship
DUR_CONTEXTUAL
Industry expert was 15x wrong on pricing ceiling; consensus blind spot
“Our goal was to maniacally keep her as strong as possible until the drugs could come along. And so physical therapists coming to see her every day. We built a pool in our apartment building for her because you need warm water and it's a special therapy pool. But that was important because when you're a person who's weak, part of the problem is it's circular.”— Dinakar Singh
Dinakar's Story · p. 7
Biology, Ecology & Systems · Strategy & Decision Making · Operations & Execution
DUR_ENDURING
Weakness creates weakness; break cycle until solution arrives
“We got to know, if you will, all the relevant senators and congressmen that mattered when it came to drug development, NIH and things like that. And look, our view is just a parent with tears on their face doesn't get very far, but we would say, look, we want to be really supportive of you. There's a chance there to actually achieve a success. And that's why you should focus on this, not just because it's sad, but because it might be fixable. And I think that became a powerful combination.”— Dinakar Singh
Dinakar's Story · p. 6
Leadership & Management · Psychology & Behavior · Culture & Society
DUR_ENDURING
Emotion plus solvability beats emotion alone for action
“SMA is now becoming this really fascinating area because suddenly, if you have an idea for a muscle drug, you can actually test it in SMA and actually see whether it actually does something. Because now you've fixed that boat, if you will. And so it is funny, quite a difference from 20 years ago when no one cared. Now suddenly we're calling out to people saying, Look, we think there's an idea. Your drug can really work here. Let's go test it out.”— Dinakar Singh
Dinakar's Story · p. 8
Business & Entrepreneurship · Strategy & Decision Making · Biology, Ecology & Systems
DUR_ENDURING
First success creates testing platform for related drugs
“The challenge remains, which is that if you're a company working on oncology, even if there isn't a drug tomorrow, you're going to be working oncology for the next hundred years. And that information can be useful in other things. The challenge with rare diseases remains that a lot of these are pretty bespoke.”— Dinakar Singh
Fixing Biotech · p. 13
Business & Entrepreneurship · Economics & Markets · Strategy & Decision Making
DUR_ENDURING
Platform investments justified even without payoff; point solutions need proof
“Scientists are in the business of getting grants and you don't get grants for, let's say, parallel processing or ruling things out. You don't get a grant by saying, I don't think this is going to work, but I just want to prove it doesn't work so I can then move on. That doesn't get you grant money. But a lot of those things and the tools and things are very much the nitty-gritty that actually get you through that early stage where you say, Whoa, I've got something.”— Dinakar Singh
Fixing Biotech · p. 13
Business & Entrepreneurship · Economics & Markets · Psychology & Behavior
DUR_ENDURING
Grant structure rewards positive results, not efficient search
“Three realizations have helped us slowly face the future. First, we've truly learned and appreciated the importance of friends and community. The comfort and love of friends has been a source of incredible strength for us. Second, through the strength, comfort, and space from our friends, we've gained some perspective and been able to focus on finding the joy in the life that we have.”— Dinakar Singh
Digging Deep Through Adversity · p. 11
Psychology & Behavior · Philosophy & Reasoning · Leadership & Management
DUR_ENDURING
Community, perspective, productive channels: grief to action framework
“In life, there are no do-overs, no retractions, there are no appeals. You either find joy in the life you have or live a life without joy. And while the circumstances of your life might not be up to you, whether you choose to find joy and purpose in them is very much ultimately up to you.”— Dinakar Singh
Digging Deep Through Adversity · p. 11
Philosophy & Reasoning · Psychology & Behavior
DUR_ENDURING
Circumstances not chosen; response to them is choice
“When Arya was like two or three, we were getting into nursery school and by the way, another saga and another crusade that I'm going to be on more aggressively going forward. You know, getting schools to care or take her was unbelievably hard. When she was going to private school, I think she was the only kid in a major New York City private school in a wheelchair.”— Dinakar Singh
Digging Deep Through Adversity · p. 10
Culture & Society · Leadership & Management · Psychology & Behavior
DUR_CONTEXTUAL
Even extreme wealth and connections couldn't overcome institutional bias
“I do think that you do eventually figure out that that is, well, very consuming. It's not going to get you very far under any circumstance. And so this is where knowing other people and talking to people that have gone through things like this actually is hugely helpful because it just helps you recognize that there's a journey on all this stuff. And so I think every parent I know whose child has an issue was unbelievably emotionally supportive to us.”— Dinakar Singh
Digging Deep Through Adversity · p. 12
Psychology & Behavior · Leadership & Management
DUR_ENDURING
Others who survived similar trauma provide roadmap and support
Frameworks (3)
Parallel Processing Strategy
Converting Time Constraints Into Simultaneous Action
When time is the critical constraint and capital is available, pursue all promising paths simultaneously rather than sequentially. The framework involves identifying the constraint, mapping alternative approaches, funding multiple paths at once, killing failures quickly, and doubling down on winners. Singh applied this to drug development for SMA, testing five different approaches simultaneously rather than serially, compressing development time from decades to years.
Components
- Identify the Binding Constraint
- Map All Promising Paths
- Fund All Paths Simultaneously
- Kill Failures Fast
- Double Down on Winners
Prerequisites
- Capital availability sufficient for multiple simultaneous efforts
- Ability to create independent teams without resource conflicts
- Clear success/failure metrics for each path
Success Indicators
- Reduction in total time to solution compared to serial approach
- Multiple paths showing progress simultaneously
- Fast termination of non-working approaches
Failure Modes
- Insufficient capital causing resource conflicts between paths
- Unclear failure criteria allowing zombie projects to persist
- Management attention as bottleneck across multiple paths
Friction Elimination Strategy
Removing Collaboration Barriers Through Infrastructure Investment
When collaboration is impeded by IP concerns, cost barriers, or coordination costs, invest in shared infrastructure that eliminates friction. Offer zero-cost participation while letting partners retain IP and upside. Singh applied this by building free mouse models and cell models for SMA drug testing, allowing any company to test compounds at no cost while keeping IP rights. The strategy accelerates discovery by removing barriers that prevent experimentation.
Components
- Identify the Collaboration Barrier
- Build Shared Infrastructure
- Offer Zero-Cost Participation
- Let Partners Keep IP and Upside
Prerequisites
- Capital to build and maintain infrastructure
- Willingness to give up IP ownership
- Clear value proposition for participants
Success Indicators
- High participation rate from target collaborators
- Discoveries made that wouldn't have occurred otherwise
- Self-sustaining usage without constant promotion
Failure Modes
- Infrastructure quality too low to attract serious users
- Hidden costs or complications that create friction
- IP structure that creates uncertainty or disincentives
Synthetic Control Group Strategy
Creating Ethical Alternatives to Standard Experimental Designs
When ethical constraints prevent standard experimental approaches (such as placebo-controlled trials), create a synthetic control group through longitudinal baseline measurement before intervention. Singh applied this by funding a multi-year natural history study of SMA progression before drugs were available, creating a baseline that could serve as a comparison group for future trials without requiring kids to receive placebo. The strategy allows rigorous evaluation while avoiding ethical violations.
Components
- Identify the Ethical Constraint
- Build Longitudinal Baseline Before Intervention
- Use Baseline as Synthetic Control
- Validate Through Multiple Comparisons
Prerequisites
- Capital to fund longitudinal measurement
- Regulatory engagement and preliminary acceptance
- Statistical expertise in causal inference methods
Success Indicators
- Regulator acceptance of synthetic control approach
- Baseline data quality sufficient for robust comparison
- Trial results that clearly distinguish from baseline
Failure Modes
- Baseline period too short to capture variability
- Regulator rejection of synthetic control approach
- Baseline population systematically different from trial population
Mental Models (5)
Time as the Binding Constraint
TimeWhen time is the critical constraint rather than capital, strategy must optimize
In Practice: Singh's decision to leave Goldman and pursue multiple drug development paths sim
Demonstrated by Leg-ds-001
Root Cause Before Optimization
Systems ThinkingIn systems with fundamental flaws, optimization is futile until the root cause i
In Practice: Singh explaining why muscle regeneration drugs became viable only after solving
Demonstrated by Leg-ds-001
Opportunity Cost
EconomicsThe true cost of any choice is what you give up by not choosing the next-best alternative. Singh repeatedly demonstrated this: the opportunity cost of serial drug development was years of his daughter's life; the opportunity cost of staying at Goldman was the drug development funding he could have generated; the opportunity cost of asking companies to pay for testing was zero participation. The model extends beyond money to time, attention, and relationships. In Singh's parallel processing framework, the opportunity cost of choosing one path at a time was the time lost not exploring others.
In Practice: Singh's explanation of why parallel processing was worth the higher cost
Demonstrated by Leg-ds-001
Regret Minimization Framework
Decision MakingWhen making irreversible decisions under uncertainty, optimize for minimizing future regret rather than maximizing current expected value. Singh articulated that the worst outcome was not his daughter's death, but her death knowing he could have prevented it but failed to act. This inverted risk calculus: the regret of inaction outweighed the risk of action. Bezos famously used this framework when leaving a hedge fund to start Amazon, asking what he'd regret more at 80. The model applies to asymmetric situations where one type of error (inaction) creates permanent regret while the other (action) creates recoverable loss.
In Practice: Singh explaining why inaction was worse than any amount of risk or cost
Demonstrated by Leg-ds-001
Social Proof and Expert Consensus
PsychologyHumans defer to expert consensus and social proof, even when the consensus is wrong.
In Practice: Singh's encounters with industry experts who were drastically wrong about rare disease economics
Demonstrated by Leg-ds-001
Connective Tissue (2)
Degenerative feedback loops in biological systems
In degenerative diseases, weakness creates more weakness through a negative feedback loop: weak muscles can't be exercised, lack of exercise causes further atrophy, increased atrophy creates more weakness. Singh recognized this pattern in SMA and intervened to break the cycle through daily physical therapy and specialized pool exercises, keeping his daughter as strong as possible until drugs arrived. The parallel extends to business: declining companies often enter death spirals where weakness prevents the investments needed to recover. Breaking negative feedback loops requires external intervention before the spiral becomes irreversible.
Singh describing the circular nature of muscle degeneration in SMA and the strategy to break the cycle
Stoic philosophy: dichotomy of control
Singh's sermon articulates the Stoic distinction between what we control and what we don't: circumstances of life are not chosen, but response to them is entirely within our control. The ancient Stoics (Epictetus, Marcus Aurelius) taught that suffering comes from confusing the two domains. Singh applied this by accepting his daughter's diagnosis as given while taking total ownership of the response: building a drug development operation, recruiting scientists, lobbying regulators. The framework appears throughout Stoicism: focus energy only on what you can control, accept what you cannot. In business, this translates to focusing on process and effort rather than outcomes, which are only partially controllable.
Singh's nursery school sermon on finding joy despite unchosen circumstances
Key Figures (2)
Dinakar Singh
150 mentionsFounder and CEO, TPG-Axon; Former Partner, Goldman Sachs
Singh is the primary subject of this source.
- Left Goldman Sachs partnership to start hedge fund specifically to generate capital for SMA drug development
Al Sandrock
2 mentionsBiotech Executive, Advisor
Glossary (3)
therapeutic window
DOMAIN_JARGONSafe dosage range between minimum effective dose and maximum tolerated dose
“With SMA, the difference between some of these kids with multiple backups versus not and somebody who is a carrier versus having a disease, there's such a massive range of this protein in the body that's pretty clear that you almost can't have too much.”
placebo-blind trial
DOMAIN_JARGONStudy where participants don't know if receiving real treatment or inactive substitute
“The trials didn't have to be placebo-blind trials.”
bespoke
VOCABULARYCustom-made, tailored to specific requirements
“A lot of these are pretty bespoke.”
Key People (1)
Al Sandrock
Biotech executive who initially doubted rare disease drug economics
Concepts (2)
Therapeutic window
CL_SCIENCEThe range between minimum effective dose and toxic dose; wider windows allow safer dosing
Natural history study
CL_SCIENCELongitudinal research tracking disease progression without intervention, used as synthetic control
Synthesis
Synthesis
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