To save money, Rhythm's leadership considered canceling a clinical study because the prevailing scientific logic suggested their drug wouldn't work. The study's unexpected, resounding success became the company's pivotal turning point, highlighting the value of pursuing scientifically contrarian ideas.

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Anthropic's team of idealistic researchers represented a high-variance bet for investors. The same qualities that could have caused failure—a non-traditional, research-first approach—are precisely what enabled breakout innovations like Claude Code, which a conventional product team would never have conceived.

In its rush for the next breakthrough, the field of psychiatry often discards older, effective treatments due to historical stigma. For instance, MAO inhibitors and modern, safer Electroconvulsive Therapy (ECT) are highly effective for specific depression types but are underutilized because of past negative associations, a phenomenon driven more by politics than science.

Breakthrough drugs aren't always driven by novel biological targets. Major successes like Humira or GLP-1s often succeeded through a superior modality (a humanized antibody) or a contrarian bet on a market (obesity). This shows that business and technical execution can be more critical than being the first to discover a biological mechanism.

Conventional wisdom to 'stay focused' is flawed. Breakthrough growth often comes from making many small, exploratory bets. YipitData's success wasn't from perfecting one thing, but from the one small, tangential bet each year that drove 90% of the growth while others failed.

Drawing from Leonardo da Vinci, Nike's innovation philosophy combines "sfumato" (a mad scientist's willingness to fail) and "arte de science" (logical, scientific thinking). The fusion of these two opposing mindsets creates a "calculated risk"—the essential ingredient for meaningful breakthroughs.

Corporate creativity follows a bell curve. Early-stage companies and those facing catastrophic failure (the tails) are forced to innovate. Most established companies exist in the middle, where repeating proven playbooks and playing it safe stifles true risk-taking.

During a stock downturn, Rhythm's CFO showed his team historical charts of successful biotech firms like Vertex and Regeneron that also endured long periods of low valuation. This tangible proof of long-term potential in a volatile industry served as a powerful tool to maintain employee morale and focus.

The traditional method of engineering enzymes by making precise, knowledge-based changes (“rational design”) is largely ineffective. Publication bias hides the vast number of failures, creating a false impression of success while cruder, high-volume methods like directed evolution prove superior.

Instead of raising money immediately after positive trial data, Rhythm waited. This allowed sell-side analysts time to understand the results, build financial models, and educate investors. This patience resulted in a stock that coalesced at a much higher valuation, maximizing the capital raise.

Modern ethical boards make certain human studies, like extended fasting, nearly impossible to conduct. This creates an opportunity to revisit older, pre-regulatory research from places like the Soviet Union. While the proposed mechanisms may be outdated, the raw data could unlock valuable modern therapeutic approaches.