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Anatomy Of A Breakthrough

2018 January 31
by Greg Satell

When Jim Allison received a call from Dr. Jedd Wolchok, asking him to come to his office, he was puzzled at first. As a researcher, he rarely ventured into the clinical part of the hospital. Yet when he opened the door and saw his colleague sitting with a young woman whose emotion was clearly marked on her face, he immediately understood and tears began to fill his eyes.

A few months before, the woman had terminal cancer, but she had just been told that she was in remission. Today, more than a decade later, she remains cancer free and works as a fitness instructor. It was a breakthrough of monumental proportions and one that would make Allison world famous.

The field Allison pioneered, cancer immunotherapy, is now a major branch of medical science with thousands of people working to improve it and expand its use. Breakthroughs like of this magnitude are never routine, but they almost always share common attributes and we can learn a lot from how Allison overcame intense challenges to create a miracle cure.

Building A Deep Well Of Expertise

Jim Allison’s journey began a long time before he walked into that office. When he was finishing up his graduate work in the early 1970s, researchers had just discovered T-cells, which were largely a mystery at the time. Allison, who told me that he always liked “figuring things out,” was intrigued and thought the immune system was something he could spend his career studying.

Over the next two decades, he became a highly respected researcher and made some notable discoveries in the field of immune regulation. It was slow, painstaking work, identifying the myriad different receptors that govern the human immune system, decoding the structure of their proteins and inferring how they functioned together.

This type of incubation period is very common for breakthrough discoveries. Darwin, quite famously, spent five years travelling on the HMS Beagle, cataloguing the flora and fauna he encountered while traveling through South America, Australia and, most notably, the Galapagos Islands. Einstein spent a full decade pondering special relativity and then another decade on general relativity.

We often hear stories of outsiders who seem to come from nowhere to revolutionize a field and that does happen, but the starting point for any breakthrough is always a deep well of expertise. You have to understand the problems of a particular domain before you can begin to solve them and recognize a truly novel solution.

Healthy Skepticism

By the mid 1990s, due to the work of hundreds of scientists, a working model of immune regulation had been established. One receptor, called B-7 works much like the ignition switch in a car, initiating the immune response while another, CD-28 acts as a gas pedal, stimulating the body to produce T-cells at a furious rate.

In 1987  a team of French researchers discovered another molecule, called CTLA-4, which was very similar in structure to CD-28 and most assumed that they worked in conjunction. Allison, however, was skeptical. He noted that CTLA-4 never seemed to show up until after the immune response had already started, so he didn’t see how it could have a role in stimulating it.

If anything, he thought, CTLA-4 wasn’t a gas pedal, but a brake. So, just as he always had, Allison returned to his lab to figure things out and his research confirmed his suspicions. CTLA-4 didn’t stimulate the immune response, but shut it down.

“Science,” as the great physicist Richard Feynman  once remarked, “is the belief in the ignorance of experts.” We often fail to solve a problem not because we lack information, but because we believe things that just aren’t true. That’s why it’s always important to question assumptions, even if those assumptions come draped in the guise of authority.

Fanatical Persistence

Allison’s new discovery got him thinking. His colleague, Sarah Townsend, had done some studies which showed that the B-7 molecule inhibits the growth of tumors, so it certainly seemed that our immune systems have to power to fight cancer. Nevertheless, all previous attempts to do so had failed. Once again, he was presented with a mystery to figure out.

His hunch was that our bodies do recognize cancer cells as a threat and begin to attack them, but our immune system puts on the brakes too soon. Maybe, if he could find a way to inhibit CTLA-4, he could pull those brakes off and unleash our own T-cells to attack tumors. Further research confirmed his suspicions.

Allison was excited. He began to fly around the country presenting his results to all of the top pharmaceutical companies, but none showed interest. Over the years, they had spent billions on immunological approaches to cancer and weren’t ready to take another plunge. “It was depressing,” he told me. “I knew this discovery could make a difference, but nobody wanted to invest in it.”

It took him three years, but eventually he found a small biotech company, called Mederex, that agreed to back him and his work. After five more years, clinical trials started and Allison had that first encounter in Jedd Wolchok’s office. The drug that resulted, Ipilimumab, was approved by the FDA in 2011 and thousands are alive today because of it.

Active Collaboration

Clearly, innovation is never a single event. Allison spent decades studying the immune system before he hit on the insight that led to his miracle cure. It then took more time for him to understand and verify its implications. From there, he spent years pounding the pavement to gain acceptance for it. All that takes an enormous personal effort.

Yet it is just as clear, as Allison is happy to point out, that he didn’t do it alone. Many prominent researchers contributed to our understanding of immune regulation. It was a team of French researchers that discovered CTLA-4. Sarah Townsend showed that the immune system can fight cancer. Jedd Wolchok and his team recruited patients and performed clinical trials.

Today, multitudes of researchers work to build on Allison’s discovery and he collaborates with many of them. Although he provided the initial breakthrough, there is still much to be done. The drug he developed isn’t effective for all patients and all types of cancers. There are other aspects of the immune system that may be able to play a role. So many things still to figure out.

That’s why collaboration is becoming a key competitive advantage. Clever individuals working alone can tweak around the edges, but to solve a really big problem requires a collective effort. You need experts and outsiders, managers and researchers, engineers, marketers, logistics specialists and others as well. When Jim Allison walked into that office in 2004, it didn’t mark the beginning or the end of the journey, but the middle. We still have a long way to go.

These four attributes, deep domain expertise, skepticism, persistence and a collaborative approach don’t guarantee a breakthrough, but one rarely happens without them.

– Greg


An earlier version of this article first appeared in

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