by Azra Raza
Cancer has occupied my intellectual and professional life for half a century now. Despite all the heartfelt investments in trying to find better solutions, I am still treating acute myeloid leukemia patients with the same two drugs I was using in 1977. It is a devastating, demoralizing reality I must live with on a daily basis as my entire clinical practice consists of leukemia patients or leukemia’s precursor state, pre-leukemia. My colleagues, treating other and more common cancers, are no better off. I obsess over what I have done wrong and what the field is doing wrong collectively.
Cognitive Biases in Cancer Research
The Nobel Laureate Daniel Kahneman was speaking to Krista Tippet on NPR about the faulty hardwiring of our brains and the cognitive biases that provide ongoing confirmation for the erroneous assumptions we regularly and naturally make (May 9, 2021). To illustrate his point, Kahneman recounted a sweet personal story. Some years ago, he and his wife returned from dinner with friends and were casually talking about the couple they had been with when his wife declared, “He is sexy.” As Kahneman pondered this possibility, trying to decide if he agreed or not, she then said something quite shocking, “He does not undress the maid himself.” Kahneman stared at his wife in disbelief. What could she possibly mean by this bizarre statement? What he should have done next was to ask himself, “But this is so uncharacteristic of her that there must be an error on my part”. Instead, he demanded to know what on earth she meant. And of course, what she had actually said was, “He does not under-estimate himself.”
There are some 180+ entries listed by Wikipedia as examples of these cognitive biases. Among these, the confirmation biases are particularly problematic where scientists are concerned. Science is a discipline devoted to the strictures of methodology based on formulating a hypothesis, designing experiments to test the hypothesis, and modifying the original proposal as needed through precise measurements and observations. Critical evaluation is the backbone of the scientific method. Yet, given the tendency toward cognitive biases, we become less critical, more readily accepting of emerging information that confirms our existing hypothesis, and we ignore the parts that don’t quite fit in. With time, this type of “confirmation bias” in support of a half-baked hypothesis builds up and an entire field is hijacked by its loud and powerful proponents.
I have regularly witnessed this during a four-decade long career in oncology research.
Perfectly reasonable propositions are distorted through confirmation biases over time, converting science into an ideology, a pseudoscience, something closer to Scientology than to Science. And nowhere in oncology is it more apparent than in the area concerning early events in carcinogenesis and the question of how a normal cell transforms itself into a killing machine, a malevolent, malignant new species bent upon destroying its creator.
Absence of an acceptable model
To date, there is no satisfactory explanation for cancer initiation. Does cancer start in one cell because a handful of its genes malfunctioned, or because thousands of its genes have gone haywire simultaneously? Maybe it has nothing to do with genes. Or even the cell. What if the organ itself is diseased, pushing a cell to take off on a tangent? Maybe all of the above or none of the above?
Whatever the proponents of a given theory claim, progress in treating metastatic cancer is basically a flat line for the last century. The fact that advanced cancers continue to kill at the same rate today as they did back in 1930 means the theory is less than adequate. Current models may have clarified the biology of cancer but they are, by and large, not helping patients. Something has to change. Attitudes, for one. Less intransigence and more flexibility are urgently needed. Advocates seem to have painted themselves into a corner by investing all their efforts into proving their pet theories rather than following the very basic tenet of the scientific method to remain skeptical.
The Covid19 lockdown provided me with an unexpected opportunity to invest a year into reviewing the existing literature regarding carcinogenesis thoroughly. As expected, the exercise ended up with more questions than answers. It was sobering to realize that it is not just my education that is lacking but the field itself is shockingly clueless. More shocking is the cluelessness about its own cluelessness. Which makes for a kind of confidence in ignorance that is dangerous and costing millions of lives a year. Ten million, to be exact, is the number of annual global cancer deaths. It is a ghastly embarrassment.
Since my careful re-examination of the scientific literature led to startling insights, it was a productive exercise after all. For one thing, a surprising number of anomalies in the existing cancer models seem to have simply been ignored or tossed aside through implausible explanations (confirmation bias much?). For another, few researchers seem interested in the steps leading to transformation. There is a serious dearth of effort directed at understanding the happenings in and around The First Cell prior to the actual transformation. Of course, one reason so little is known about the genesis of cancer is that cancer is a silent killer. Even the tiniest recognizable tumors contain hundreds of thousands of malignant cells. How does one go about looking for The First Cell when the disease is already so advanced even at Stage I? Another problem is that the research community has been seduced by the promise of molecular biology since the 1970s. Using this newfound tool to interrogate DNA, researchers became overconfident in their ability to reduce the complex cancer problem down to a few genes whose abnormal proteins could then be targeted through Magic Bullets to achieve cures. Unfortunately, the problem turned out to be far more complex. Of the two hundred or so cancers that have been catalogued systematically, this one-cancer-one-mutation-one-drug strategy has successfully cured exactly two. Molecular biology is a tool just like CRISPR is a tool. They are fantastic technical advances. The hype would have you believe they have already cured complex diseases leading to the classic case of over-promise and under-delivery.
Need for a new model
Asked how one creates scientific theories, the great Linus Pauling replied that one must endeavor to come up with many ideas, then discard the useless ones. I read up on all the existing theories of carcinogenesis, let the data gel in my head, systematically discarding each theory until all preconceived assumptions were jettisoned and a clearer picture of a previously unthinkable model emerged.
Two Emily Dickinson verses helped clarify in my mind, the reconfiguration, realignment, reorganization The First Cell must, in statu nascendi, transition through. A liminal phase of less than specific distinction between wellness and illness. A steady build up to the big bang.
Crumbling is not an instant’s Act
A fundamental pause
Are organized Decays —
Ruin is formal — Devil’s work
Consecutive and slow —
Fail in an instant, no man did
Slipping — is Crashe’s law —
The First Cell does not appear out of nowhere, spontaneously, solely driven by an internal breakdown. What precedes and accompanies its birth is an organized decay, consecutive and slow, sometimes taking years, slipping—slipping, until the crash comes. Its ruin is formal. And the Devil in the detail turns out to be another cell in my model.
Birth of The First Cell: An old-new model
I make two claims about carcinogenesis that are based on old data but bring a new synthesis to generate the model. My friend Hallie Black in Chicago, a Latin scholar, helped phrase them appropriately:
- Cellula prima fit duobus de cellulis: The First Cell is two cells
- Prima cellula nata in cellula immune: The First Cell originates in an immune cell
I plan to expand on the new model and review old ones in the next installment of this series. I end this instalment by asking a simple question.
Another cognitive bias
Despite spectacular failures in improving outcomes for the vast majority of cancer patients, what accounts for an entire field to be so faithfully, almost religiously, invested in an unproved model driven by the Somatic Mutations Theory?
Another cognitive bias, I am afraid. This one is known as the sunk-cost effect. The tendency to persist with bad investments because of the price already paid. Very much like the patient who was terribly anxious for release from the hospital, raising a ruckus all morning on the in-patient service, demanding immediate discharge. When she finally received her papers around lunch-time, she scanned the bill and, to everyone’s surprise, instead of leaving, proceeded to calmly resettle in her bad, informing her horrified daughter who had packed everything in the room and was ready to take her home, “They have charged me for a whole day’s stay. I am going to make the most of it.”
In the end, it is all about where the money is; grants that support salaries of researchers and drug trials that support the salaries of oncologists. A house of cards has been constructed. If the mutations by themselves did not provide an answer, the changed semantics of driver and passenger mutations breathed new life adding a few more years to the idea. And when that did not work, well, there is always the specter of hyper-mutations looming around the corner.
Lord Alfred Douglas is reported to have asked his lover, Oscar Wilde, what he meant by the phrase, “All men kill the things they love” in his famous Ballad of Reading Gaol written while incarcerated. At first, Wilde dithered. Douglas persisted. Wilde finally explained that when we meet someone, we construct an image of the individual in our minds based on very little information. Upon further encounters, when the real person fails to correspond to the image, instead of changing the image, we try to change the person.
It is so with cancer. We created a hypothesis in our minds in 1970s and designed experiments to prove it. For the last fifty years now, anomalies that do not fit with this image, are accumulating. Instead of changing the hypothesis, we keep distorting reality to fit it into the existing model.
And all men kill the thing they love,
By all let this be heard,
Some do it with a bitter look,
Some with a flattering word,
The coward does it with a kiss,
The brave man with a sword!