This week the national news reported that former President Jimmy Carter is the American President who has lived longer than any other in this history of the nation. Carter, whose presidency ended in 1981, is now 94 years old and a modern medical miracle. He was diagnosed with melanoma in 2015 and it metastasized to his brain. Everyone assumed he would be gone within months of announcing this depressing fact. And yet here he is, alive 3+ years later, and reporting that diagnostic tests have shown he has been cancer-free for the last 3 years.
President Carter is alive, almost certainly, as a result of the immunotherapy cancer treatment he received in 2015. And that treatment was specifically the result of the life’s work of Dr. James “Jim” Allison, who discovered the mechanism by which T-cells can be used to trigger the immune system to attack and eradicate tumor cells. This discovery, which began in the 1980’s and led to the first clinical trial of an immunotherapy drug, Ipilimumab, in 2005, led to the pivotal FDA approval in 2011. The rest is medical history.
Fast forward to March 2019, I was hanging around at SXSW and intent on using some of my time in Austin to see a bit of the film festival. I love movies and was bound and determined not to spend 100% of my festival talking about digital health while eating tacos. I read about a documentary of Jim Allison, called Breakthrough, and figured it was a legitimate “cheat” – I could see a movie about healthcare-related work and skirt the rules of being there for work alone. Little did I know what I was getting myself into. What an amazing movie – it made the spirit soar. I had known some about the field of immunotherapy and the major step forward it it has been in the treatment of cancer, but I did not know much about the incredible history of discovery, doubt, and negative pressure that almost made its emergence on the medical scene impossible. I had heard of Jim Allison but did not have a full appreciation for the magnitude of his effort.
The Breakthrough Movie is a must see for anyone in the healthcare field, but really for any entrepreneur who is truly trying to disrupt the status quo and ask the question that Allison did, “What if nothing we thought was right?” I was struck by Allison’s entrepreneurial spirit, which is a major understatement, his absolute confidence he was right, and his fanaticism in methodically and effectively proving it. I was also struck that so many people decided to take a chance on him and stick it out with support and money while the rest of the world said the usual: “it can’t be done.”
Like many healthcare entrepreneurs’ stories, Allison’s started with a personal experience: many of his family members died of cancer, including his mother, her two brothers and, later, his own brother. Allison himself is a cancer survivor, though his early motivation was the scar he bore from watching his mother die when he was 11 years old. Allison, the son of a doctor, was drawn to science early and loved to set off bombs, which is apparently a typical budding scientist pastime. He went to a school in the south that didn’t teach evolution or biology, with which he took personal issue. He took a job as a dishwasher in a biology lab to get to know the field. So, think on this: Allison could have been an average kid who just went along with what he learned in school, but he didn’t. Thus, immunotherapy. Imagine for a minute how many scientific breakthroughs go undiscovered because many in our current culture believe that science is not on their particular product roadmap. It makes me crazy just thinking about it. Policy suggestion: if you don’t believe in science and work to keep people from learning about it, you shouldn’t realize its benefits. Just sayin.’ Anti-vaxxers, take heed.
In any event, Allison noticed the discovery of T-cells when he was in college in the 1970’s at University of Texas and was almost immediately convinced this discovery would by a linchpin in the advancement of cancer treatment. He started working on this quest in the 1970’s, primarily focused on discovering the mechanisms of action by which T-cells operate and tossing aside conventional wisdom in favor of creative thinking. Allison went from his Texas lab to UC Berkeley (Go Bears!) to dig in further on the immunology thesis, having to start what he called a “renegade pirate ship of a lab” since immunology was not yet considered a legitimate arm of the biological sciences. I love that image of the pirate ship, sailing the seas of knowledge and navigating among the doubters. Such an apt metaphor, including having to steal resources and people from “acceptable” science. I have another friend, Jamie Haggard, who is the CEO of startup Green Sun Medical. Jamie has an actual modern day pirate ship that he sails around the San Francisco Bay. It’s perfect.
It took until 1996 for Allison’s discoveries to add up and the experiments to bear fruit, at least in mice. Of course, no one believed it was translatable to real medicine. There had been some notable early failures of Interferon, an early immunotherapy effort, and many big pharma companies had abandoned all activities that even skirted on this field, afraid of the downside risks and the bad headlines. There was a great scene in the Breakthrough movie where Pulitzer Prize winning journalist Matt Richtel talks about how innovations are often challenged and blocked because of regulators, lawyers and others responsible for risk management. I didn’t get his quote exactly, but it was basically this: those that block innovation are doing so as a defense mechanism because new ideas are seen as mutations, and mutations are thought of as toxic or deadly so they must be killed. I thought that was such an apt metaphor given the cancer story, where the cancer itself is basically a deadly mutation. No wonder this guy won the Pulizer.
The fact that Allison’s discoveries made it into real medical practice are almost as miraculous as the fact that they work at all. Allison went from pharma company to pharma company, eventually targeting smaller biotech companies, to try to get his immunotherapy concepts into the drug development pathway. He found that the big companies did not have a sense of urgency and didn’t want to take a risk on wild new ideas (ahem…). He finally found one tiny company in the middle of nowhere, NeXstar Pharmaceuticals in Boulder, Colorado, that wanted to partner and conveniently had the same clock speed as Allison himself. Ultimately, they got from concept and into patients in 466 days, which is undoubtedly some sort of record. In the Phase 1 trial that followed, 3 of 12 patients had complete tumor disappearance.
Recognizing they needed a bigger boat if they were going to get all the way to the promised land, Allison finally convinced one large pharma company, Bristol Meyers Squibb, to join the party. This was 2009. And once again, it was finding the needle in the haystack, this time in the form of Rachel Humphrey, a BMS executive who bet her entire career on Allison’s vision, even when the clinical studies didn’t go as planned and required a further of massive amounts of time and money to go the distance. Once again, the lesson here is People Matter. If you’re going to go on a mission to flaunt convention and spend a lot of money doing it, you need the right team around you. And they need not only to be smart, but they need to believe. They need to swear allegiance to the skull and crossbones and board the ship fully prepared for battle. Because a battle it will be when it comes to changing how it’s always been done. The second lesson is that patience can definitely be a virtue, even in the entrepreneurial quest. Entrepreneurs and investors put such a premium on speed, being first to market, and failing fast that they sometimes forget that time may ultimately be your friend. Yes, it’s tough to watch the cash drain away while you’re being patient, but as they say in The Princess Bride, another classic movie, you rush a miracle you get rotten miracles.
In September 2006, Allison met the first patient whose life had literally been saved by his work, Sharon Belvin. Belvin had metastatic melanoma, had tried every possible treatment, and was on her way to death’s door when the immunotherapy clinical trial opportunity arose at Memorial Sloan Kettering, to which Allison’s lab had recently set sail. Her story is intense. You can watch some of it here. Notably, Sharon Belvin was on the stage at SXSW with Jim Allison when the movie ended. She should not have been there, according to conventional wisdom, must like Jimmy Carter should not be here. But here they are. This is why medicine is the ultimate social venture. You really can make people’s lives better when it’s done right and well.
Immunotherapy is now becoming a regular part of the oncology toolkit. While it doesn’t work for every person or every cancer, it is making a serious difference for thousands of patients. Nearly 9 million people die from cancer every year, but we are already seeing people beat the odds because of Allison’s belief in himself and his ability to translate that to action. Allison himself was one of the people who received the benefit of this action, having had three bouts of cancer, true to his family tree, all of which were successfully treated by the fruits of his own labor. I struggle to deal with a splinter on my own, so it must be quite an experience to know that were it not for your life’s work, you would not be here to continue it. Amazing.
The scientific dedication of Allison’s life led to his winning numerous awards, including the Nobel Prize, for his discoveries; it also led to him being the worthy subject of the Breakthrough documentary. But the movie’s lessons for entrepreneurs and investors of all kinds are broadly applicable, Nobel Prize or not:
• Think big and do things that matter
• Always ask “why” and, more importantly, “why not?”
• Creativity is in many ways the most important leadership trait
• Believe in yourself, even when everyone else thinks you’re crazy
• Prove you’re not crazy through meticulous experimentation and evidence-creation
• Surround yourself with the best team possible
• Sometimes, speed kills and patience is a virtue
• Persistence pays off
It’s sometimes particularly difficult for venture investors to appreciate the crazy, creative, shoot for the moon ideas when they hear wild-eyed entrepreneurs pitch them; all too often these ideas just don’t pan out. VCs get a bit too cynical at times and get too reliant on pattern-recognition to make their investment decisions. But that mode of action would have killed Allison’s work numerous times along the way. Sometimes, when the right person is doing the right work, you have to suspend disbelief, turn off the time clock and wait for the miracle. How do you know which are going to work and which aren’t? You don’t. But let’s be clear: no one can rationally suggest that venture investing is a science. Sometimes you just have to jump on the pirate ship, hoist the Jolly Roger, set sail and pray.
I rushed out of the SXSW Breakthrough premiere while the credits were rolling because I had to get to my own panel, which seemed pretty minor league by comparison. As a result, I missed the talk that Allison, his collaborators, his patients and others gave at the end, which really bummed me out. But in the spirit of happy chance, when I left my panel a few hours later and was going down an elevator in a hotel across town, who came into the elevator one floor below me but Jim Allison himself. I had the opportunity to tell him I loved the movie and that I thought it was amazing. And then I corrected myself and said that the movie was obviously amazing because his work was. He was such a friendly guy and let me take a picture with him, which was a real honor, frankly. There are tons of movie stars and fancy people at SXSW, but you rarely get to meet someone who literally changed the course of human history in a good way.
It’s not yet known how the movie Breakthrough will be distributed broadly, but apparently there will be other film festival screenings and you can watch for those HERE. If you are in the medical field in any way or live in the entrepreneurial world on any side of the table, seeing this movie is time well spent. UPDATE: Found out the movie will show at the DocLands Film Festival in Marin County on the weekend of May 4 and 5, 2019)
And one last thought: if you or anyone you care about has benefited from a successful medical intervention, it is incumbent upon you to do all you can to foster the belief in and funding of science and to fight those who seek to quash it. To paraphrase what Jim Allison himself said when testifying in the Texas legislature against a bill that sought to force the teaching of creationism in Texas schools at the expense of science: science is important to the future, not just the past; only science has the utility to predict and change the future.