Cats don't take orders

Martine Rothblatt and the development of Remodulin

Did you hear the one about the woman who always cut the ends off her roast beef?

Well read on for the punch line …

If, 30 years ago, you had asked executives at Glaxo Wellcome — a big pharmaceutical developer — what their single best drug investment overall would be in 30 years, they would surely have pointed toward one of their blockbuster drugs at the time. They would have computed the cumulative revenue brought in by each of their drugs, looked at their current growth trajectories, and projected into the future by 30 years. It would be a spreadsheet. They’d sort the results by cumulative revenue divided by development cost, at 30 years out, and select the top row in the results. Voila.

And they would have been completely wrong. The current reigning champion for single best drug investment the company ever made was recently declared, and it wasn’t even on that spreadsheet 30 years ago.

As it turned out, their champion drug would be developed by an independent engineer and polymath named Martine Rothblatt. Martine identified a specific molecule that could selectively reduce the blood pressure in the pulmonary artery — the artery between the lungs and the heart. Martine’s baby daughter had a condition called Pulmonary Arterial Hypertension, characterized by an anomalously high pressure in said pulmonary artery. Martine had been combing medical journals for months, while her baby was in the ICU, absorbing all the necessary medical research and human biology to understand PAH well enough to suggest a treatment for her baby.

Martine’s baby daughter had a condition called Pulmonary Arterial Hypertension, characterized by an anomalously high pressure in the pulmonary artery.

Martine found a diamond in the rough. She realized there was a molecule that had been investigated by Glaxo Wellcome, for congestive heart failure. It failed to treat the heart failure, but had the curious effect of selectively lowering the pressure within the pulmonary artery. Glaxo had halted development on the drug and moved on. But it was exactly the molecule Martine needed to treat her daughter’s PAH.

Glaxo had tested the exact molecule Martine needed to treat her daughter’s PAH.

Martine implored Glaxo Wellcome to develop the drug, but there was no appetite at Glaxo for a drug that would treat a few thousand people at best. PAH was almost always fatal at an early age, leaving the market of living humans to buy drugs for it quite small. Glaxo’s bread and butter was drugs with at least a billion in yearly revenue potential. Martine had to form her own biotech company, United Therapeutics, to license the drug from Glaxo, for a nominal fee of $50K and 10% of all drug sales in perpetuity. Glaxo was mostly just trying to make Martine go away.

Martine’s biotech company developed the drug as Remodulin, and went to market in 2002. It immediately saved thousand of lives every year, including Martine’s daughter’s. Within a few years the number of people living with PAH went from a few thousand to a few tens of thousands. It was like a podcast accumulating more subscribers every year. Remodulin now brings in a billion a year in revenue for United Therapeutics. And Glaxo’s 10% over 10 years has to be the easiest billion they’ve ever made.

Martine saved her daughter’s life, now a healthy 30-something working with her at United Therapeutics. And in the process, she saved tens of thousand of other kids, and developed Glaxo’s most successful drug of all time.

I highly recommend checking out Martine’s interview on the Tim Ferriss Show. She’s a truly unique and gifted human.

Martine and her biotech company were an unknown unknown for Glaxo Wellcome 30 years ago. There was no way for them to know that their top performing drug would be completely novel to them, or what the revenue potential for such a niche drug would actually be. Their blockbuster-only business model precluded the possibility of investing in drugs of that nature, and therefore they hadn’t considered the revenue potential of a drug that accumulates thousands of new lifelong customers every year. Not only was Martine quite alien to Glaxo, but her business model was alien too.

So in a way, it was Glaxo’s very structure that was preventing them from developing their future top performer. But 30 years ago, if you’d suggested to them that their business model was precluding a specific class of drugs that had huge potential, what would they have done with that information?

If Martine had been an employee at Glaxo, she would have had a conflict of interest and would not have been allowed to develop the drug herself. She would have been obligated to let the drug remain undeveloped.

It was crucial that Martine had her own independent biotech company, which could make autonomous market choices. Glaxo would only benefit from Martine’s efforts once they let go of their control over the rights to develop the molecule. Within Glaxo itself, Remodulin could never have been developed. But when they begrudgingly agreed to license their data to an autonomous, independent biotech company, suddenly the conditions were right for Remodulin to come to market.

So what is the “process” at big companies like Glaxo for discovering the unknown unknowns like Martine, that ultimately lead to breakthroughs like Remodulin?

In the case of Remodulin, someone at Glaxo would have had to be considering different business models entirely. Which means they would have been testing alternatives to an existing model that was already very profitable. But if it ain’t broke, don’t fix it, right?

This is the very crux of the unknown unknowns conundrum. Systems are sticky. They have momentum. As soon as something is working well enough, we tend to lock it in and move to the next challenge. This rather arbitrary choice becomes dogma, over time. Not because it’s the best choice, but rather because so many other systems have now been built on top of it.

Systems are sticky … As soon as something is working well enough, we tend to lock it in and move to the next challenge.

Did you hear the one about the woman who always cut the ends off her roast beef? She’d learned that from her mom, though she was never sure why her mom did it. One day she asked her mom, “Hey mom why did you always cut the ends off the roast?” The mother replied, “Well dear the oven was so small the roast wouldn’t fit!”

There’s a tradeoff we make in accepting dogma without re-evaluating and thinking critically about it ourselves. Accepting it means we don’t have to “reinvent the wheel”. We can build on previous results and make forward progress. But it also means inheriting dubious decisions from the past. We’re still cutting the ends off the roast, despite the fact that our ovens are plenty big enough to fit the whole roast nowadays. Context matters, and it also fades away over time.

As the voice on the wind tells the little Starling in my poem Flight of the Starling:

Lies upon lies
And more upon that
Lies get forgotten
And taken for fact

The antidote to being stuck with stale systems is to be re-imagining them all the time. But productivity is — or appears to be — much higher when stale systems are accepted, when we’re not all out here “reinventing the wheel”. The price is being paid slowly, in the background, in the brittleness introduced by each dubious choice from the past. The price of dogma is that you’re still cutting the ends off the roast, throwing away good food, without knowing why.

The irony of unknowns unknowns like Martine Rothblatt and Remodulin is they exist outside the very systems we have in place for maintaining structure and order. And yet they also hold the potential for quantum leaps in understanding. They exist outside control, because they must.

Cats don’t take orders. But they can be tempted to chase. It’s a good allegory for creativity. Capturing unknown unknowns means inviting divergent ideas, uncomfortable as they may be. Otherwise you risk missing out on your biggest successes, your lasting innovations. You never know when the cat will bring you its latest kill.