Welcome to Lessons in Chimeristry
Join us to talk experiments in life. A history and future of our company Chimera Bioengineering. We reserve the right to rethink our ideas, methods and conclusions! Also we love poetry here.
In 1958, Ed Kaplan and Paul Meier published a joint, nondescript paper in the Journal of the American Statistical Association (JASA) titled “Nonparametric estimation from incomplete observations.” They were graduate students at Princeton and had independently developed a method for assessing probability of survival of patients. JASA was an esoteric journal (and it remains so today) and the editor, wishing to save space in the issue, encouraged both researchers to merge their efforts. The resulting impact of Kaplan and Meier’s contribution on clinical research has been nothing short of ubiquitous - their paper has been cited nearly 60,000 times and the eponymous Kaplan-Meier (KM) curve is a mainstay of clinical research, is considered the gold standard of statistical validity and appears throughout virtually all cancer research.
What does the Kaplan-Meier Curve Teach Us
The Kaplan Meier (KM) curve, the fictitious one represented above, describes the survival of cancer patients who have been separated into two treatment groups (“arms”) often with Arm 1 comprising patients on an experimental drug and Arm 2, a population of patients on standard-of-care. Doctors and scientists would look at this chart and conclude that the experimental drug was fabulously successful with median survival being extended by over two years, to the benefit of patients and the company that sold the drug. Their central goal is to prevent and limit the vertical drops on these curves and extend lives. Accordingly, with the corresponding flattening of these curves until they race across the chart at 100% survival, they will have effectively “cured cancer,” and deservedly, collectively pat themselves on the back.
What is not taught - The Horizontal Part of the KM Curve
This orientation of the KM curve, while mathematically valid and logically sound, is exactly that - mathematical and logical. Its dominance in clinical discourse, alongside expressions like “science-driven” and “statistical significance”, omits a tremendous amount of humanity that accompanies an initial cancer diagnosis. The KM’s mono-parametric objective function of survival serve as judge and jury for what is acceptable for the advancement of medicine. This has ever irked me. What of the patient experience? What are the costs to the patient’s sense of humanity? Does the KM curve tell you what it feels like to be interred in an underground hospital ward, separated from family and friends, to face financial ruin, pain of chemotherapy and suffering, to experience the constant fear of relapse and threat or loss of intimate relationships?
These are the travails of the horizontal part of the KM curve - we are alive when we exist on this horizontal run, where we spend our hours and days as human beings. Yet our most fundamental clinical tool, elucidates none of this. The standard interpretation of the KM curve would have us believe it a success that a patient not yet dead, is still alive. Is this ethically acceptable? To borrow from the movie Dead Poets’ Society, “while medicine is a noble pursuit and necessary to sustain life, poetry, beauty, romance, love, these are what we stay alive for.” No offense, Ed and Paul, I’ll take the sap over the stats.
The KM curve inspired us to start Chimera
Gus and I started our cancer drug development company, Chimera Bioengineering1, in 2015 as an experimental examination of the KM curve. We had two reasons:
Reason 1: yes, we wanted to step on the neck of cancer armed with our pipettes, and work to prevent the vertical drops
Reason 2: attend to the horizontal curve, to pursue our mission to bring dignity to patients (what does dignity mean? read below)
Reason 1: Science!
Reason 1 was simple and straightforward. Gus was a cancer patient in remission and also a talented and creative molecular biologist who saw the battle against cancer through the lens of proteins, RNA and gene regulation. I was the widower who lost his wife to AML and a chemical engineer who thought that cancer was a problem of dynamics, differential equations and systems engineering. We thought, together, we would be able to try something a little different to deal with the disease that cost us much. We believed we would be able to contribute something, scientifically, while actualizing our feelings of loss, anger, grief, fear and desperation. This was easy, we were technically competent and knew how to get science done and we knew about building teams and businesses. We would work to help patients and flatten the curve. We will talk about all the science, and more (with data!), about what we did at Chimera here in future posts on Lessons in Chimeristry2.
Reason 2: Human Dignity…
The question, oh me! so sad recurring - what good amid these, oh me, oh life? Answer, That you are here - that life exists and identity, That the powerful play goes on, and you may contribute a verse. - Walt Whitman, O Me, O Life!
Reason 2 was more profound, more challenging and ultimately more important. Cancer sucks. Cancer sucks whether you’re the patient, the caretaker, the family, the physician, or your bank account. With every cancer diagnosis, a multitude of lives are irrevocably changed. You will never not be known as a cancer patient or survivor. Your loved ones will accompany you on routine and emergency trips to the hospital, where machines infuse you with medicine, chemotherapy and blood transfusions, while hospitals and health insurance companies prod at the core of your being. Your identity dissolves and dissociates; the paroxysm of cancer ravages your sense of the world and absconds with your ownership over your own body and your dignity. This is what we talk about when we talk about living with cancer, living on the horizontal part of the KM curve.
Gus and I both experienced these - daily uncertainties, delays due to over scheduled nurses and doctors, denied the chance to dote on your children because of contact limitations for C.Difficile infections. These experiences galvanized, in us, a fundamentally different way of examining the cancer experience and how we wanted to address it. We could never again see cancer purely from the viewpoint of medicine, biology and engineering, but through the lens of the profundity and richness of human experience. This is why Chimera’s founding mission statement was not “cure cancer” but to “restore dignity to patients and their families.”
What are we going to do about it?
Reason 2 inspired us to choose to build boring medicines, treatments that you don’t notice so that you can go about your life, unperturbed. We worked on cell therapies, controllable CAR-T cells and gene therapies, all of which aspire to be boring medicines. Here at Lessons in Chimeristry, we’ll talk about many other boring treatments as well (placebo effects, light exposure, exercise, joy, meaning, social connection and more) that can positively benefit lives. We were going to leverage science and technology to bring and reassert dignity to the human condition.
Reason 2 was bigger than science too. In fact, when we thought about the KM curve, we realized that all of us are actually living on the horizontal curve. We may not take note of it, perhaps because we don’t have an acute cancer diagnosis, a life threatening rare disease, or indeterminate illness, all of which can crystallize an imminent awareness of mortality. But being with reasonable health does not mean that we the living get out of life, scot-free - we will all take that vertical step down the KM curve, in time. And still we all deserve a life full of meaning, joy and dignity. As a result of Reason 2, we wanted to build Chimera to empower our teammates, our partners, our competitors, our investors, our suppliers, our families to feel valued, noticed and appreciated - you know, feel human. This was going to be harder than the science of Reason 1, but we learned some things along the way, which we’ll share as well.
Speaking of which, what are we going to be talking about?
Reason 2 is ultimately more important than Reason 1. Reason 2 inspires us to take Lessons in Chimeristry in a direction to tackle conversations around meaning, organizational culture, relationships, stories, growth, purpose. We will talk about why we host “all-diamonds meetings” versus the synecdochic “all-hands meetings.” You might learn about our “hump meetings,” hosted mid-week, with its core commitment to investing time from the work day, to gather together and celebrate mission and motivation and simultaneous teaching and learning. We will discuss the differences between joy and happiness and why having fun is an important, but insufficient, condition for productivity and psychological safety at work, though play might be! We will hypothesize and interrogate how network and complexity theory can describe why a safe company culture, focused on belonging, will yield resilience and greater economic viability. We will drop some poetry along the way, because of all things, poetry is an aspect of Shannon information theory!
For example, here’s a part of a poem that edifies dignity:
In this uncontainable night, be the mystery at the crossroads of your senses, the meaning discovered there. And if the world has ceased to hear you, say to the silent earth: I flow. To the rushing water, speak: I am. - Rainer Maria Rilke, Sonnets to Orpheus (t. Joanna Macy)
We will be sharing a multitude of ideas that stem from Chimera’s two founding reasons - scientific, psychological, organizational, entrepreneurial and philosophical - and we shall lay no provenance to these ideas. They’re yours and you can create and build from them. Can you help us understand the role immunology plays in fertility? How do we build a positive expected value hedge fund by trading on positive attributes of organizational culture? How can you comfortably discuss the variegated topics of menopause, mountain biking and need for diversity at work? (We’ve done this at hump meeting) We encourage all of us to take these ideas and build on what we discuss here, in service of bringing more dignity to all of us riding on the horizontal curve.
Why I’m starting this today
As stated above, Chimera has been an experiment. Some of the results of these experiments have been impactful: the invention of our GOLD and MERCURY technologies that empower safer and more potent cell-based therapies and the close ties formed between Chimerans. Other results have been mixed: skepticism around the problem we were aspiring to solve (altering the tumor microenvironment to induce a productive immune response against cancer), limited financing pathways and my own shortcomings, often, as a leader.
And this is why I’m starting this Lessons in Chimeristry Substack today. This will be a new experiment. We want to learn, revisit and share our journey with you and hopefully, from this, we can collectively advance a mission of dignity, of affirming all of us on the horizontal curve. I have much still to learn and I hope we can learn together.
But today is also, for me, an important day. March 24th, 2024 is the ten year anniversary of the passing of my wife, Kim, who died of AML at Stanford Hospital, a decade ago. My daughters are 12 now and, today, I will have been married to Kim for fewer years than she has been gone. So I’m dedicating this to her memory, having inspired me, and Gus, to act, to do and to give. I invite all of you to play with us.
O Me! O Life! Let this be a verse that I contribute to our powerful play, while I am still here.
Join me and ask of yourself: What will your verse be?
What is a chimera? It’s mythological beast with the head of goat, the head of lion and a tail of a snake. In biology, it’s also an unnatural fusion of biological substances like proteins or organisms. Why did we call ourselves Chimera - well that’s a story for another time.
Apologies to Bonnie Garmus and her excellent book!