Beautiful hypothesis – ugly fact

Dr. Laura Rogers, a post-doc in my research lab, likes to start her presentations during our weekly research laboratory meetings with a quote. One she used a few months back was from Thomas Huxley, a renowned British biologist from the 1800s, who said, “The great tragedy of science – the slaying of a beautiful hypothesis by an ugly fact.” It was a very appropriate quote for Laura to use given the results we were discussing that day.

As Huxley’s quote illustrates, Laura wasn’t the first scientist to see a beautiful hypothesis slain by an ugly fact, and she will not be the last.

Here is the story. We know that everybody’s immune system is unique. There is strong evidence that individual differences in the immune system can impact many aspects of the immune response. My research group has been interested for some time in understanding why the anti-lymphoma antibody known as rituximab works better for some patients than others. Figuring this out would help us understand how we can use the immune system more effectively to treat cancer.

We therefore took our large collection of samples from lymphoma patients who had been treated with rituximab to see if individual differences in their immune systems might explain why rituximab did, or did not, work well for each individual. This was very much an exploratory study since we did not have preconceived notions about which particular part of the immune system might be most important. In scientific terms, we considered this “hypothesis generating” research.

The results were promising. They suggested that patients with higher levels of a protein known as CFHR1 have a better response to rituximab. Other researchers have shown that CFHR1 levels are associated with a variety of immune system diseases, which spoke to the potential importance of this protein. Our finding led to the hypothesis that was at the center of Laura’s research project, namely that “CFHR1 enhances the response of lymphoma patients to rituximab.”

We set off to explore this hypothesis in two ways. First, we looked in the laboratory to see if CFHR1 enhances how well rituximab works in the test tube. Second, we looked to confirm our original results to determine whether higher levels of CFHR1 correlate with a better clinical response to rituximab using samples from a totally different group of patients. Laura got to work on both parts of the project.

Because no one had produced pure CFHR1 that we could use for our experiments, Laura produced it herself. At the same time, we worked with a pharmaceutical company to obtain samples from a clinical trial. This company had samples from patients treated with rituximab in Europe and we used these samples to confirm that high levels of CFHR1 correlate with a better response to rituximab. To do this, Laura measured CFHR1 levels on blood samples from all of these patients.

You can probably figure out the results at this point – so much for our beautiful hypothesis. First, the test tube results failed to demonstrate that CFHR1 enhances the anti-lymphoma effects of rituximab. Second, the attempt to confirm our observation that CFHR1 levels correlated with response to rituximab fell flat on its face. There was no correlation at all between CFHR1 levels and response to rituximab in this second set of samples. The simplest explanation for our findings is that the correlation we observed in our original study between CFHR1 and response to rituximab was simply chance.

As Huxley said, our beautiful hypothesis had been slain by ugly facts.

Does this tale imply that this research project was misconceived? Not at all. Indeed, science is all about generating and testing hypotheses. If all hypotheses proved to be true, there would be no purpose behind testing them in the first place.

Laura took this very well. She is writing up her experiments for publication (even though the results failed to support our hypothesis) and has now moved on to another project. She has come up with another beautiful hypothesis. Only by doing the research will we know if our new hypothesis will survive the merciless, but absolutely critical, judgment of the facts.

Hope Without Hype

Last week, I had the honor of moderating a panel discussion on Capitol Hill on behalf of the Association of American Cancer Institutes and the American Association for Cancer Research. This panel was sponsored by the congressional cancer caucus and focused on the importance of the nation’s premier cancer research centers. In such settings, it can be challenging to talk about the vital importance of the work done at our cancer centers in a way that highlights the hope without appearing to be resorting to hype.

Indeed, those who follow the news know that even the most respected public figures, including highly respected news anchors, can give in to the temptation of exaggeration.   In news about cancer research, a week doesn’t go by without a friend or family member telling me of story in the news about some aspect of cancer research and asking me if I think it is really a breakthrough.  The media loves headline-grabbing stories, and their stories about cancer research are no different. Most reports in the news about cancer research advances are based on real progress that represents valuable, but not terribly dramatic, research findings. More often than not, these advances are presented in a context that distorts the importance of the finding.  We hear almost weekly reports of “major breakthroughs” that, if taken as reported, could be interpreted as implying we have reached the turning point that will finally allow us to defeat cancer once and for all.

While is it nice to see progress in cancer research receiving attention in the press (which influences the public and our political leaders), misrepresenting the impact of important but modest advances can lead to false expectations and a loss of confidence in the entire cancer research effort.  The result of such exaggeration, particularly when it occurs frequently, is that talking about the vital importance of steady, if less dramatic, progress gets overlooked at best, and is felt to be disingenuous at worst.

So … what do I do to convey the hope without the hype?

First, when talking about progress in cancer research I avoid certain words except in very exceptional circumstances. The words “breakthrough,” “defeat,” “conquer,” and “eliminate” are now used so often in discussing cancer research, that they have lost their psychological impact and, indeed, their meaning. I just don’t use them when talking about cancer research.

Second, I highlight that cancer research is a marathon, not a sprint. Yes, there are major discoveries that have huge impact, but even the most important of these don’t impact on the burden of cancer overnight. Basic discoveries in the laboratory lead to design of new strategies that are then tested in clinical trials, and eventually a change in how we prevent, detect, or treat cancer. Even in the best of circumstances, this complex process takes years.

Third, I don’t let my desire to avoid hype prevent me from highlighting hope.

  • We ARE making progress against cancer.
  • This progress IS taking place faster than ever before.
  • Decades of advances in fields such as molecular oncology and cancer immunotherapy, despite their complexity, WILL have a major impact on our ability to help patients with cancer.
  • We CAN leverage research findings to reduce the pain and suffering caused by cancer.
  • We COULD make faster progress with improved funding.

I did my best to highlight the hope without the hype during the panel discussion on Capitol Hill. Indeed, it is important for us all to see beyond the hype and focus on the hope as we work together on accelerating progress against cancer.

Onco-Ecosystems

Environmental biologists have studied it for years – cancer biologists are just starting to think about it – and it has the potential to result in a fundamental change in our understanding of cancer. I am talking about ecosystems.

We all learned in elementary school that diversity helps an ecosystem thrive. Bees need flowers so they can make honey from the nectar. Flowers need bees for pollination. Neither would be able to exist without each other.

How does this concept apply to cancer? Our traditional view of cancer is that cancer cells within a tumor are the same. One cell starts growing out of control, pushes out the normal cells, and the result is cancer. Indeed, we talk about cancer as being “monoclonal,” i.e. all cells being the same. A major goal of cancer research over the past decade has been to understand the changes in genes that drive the monoclonal growth of cancer cells. In some cases, such as chronic myelogenous leukemia and some cases of melanoma, we have identified the gene that causes the cancer to behave badly, and have been able to treat the cancer successfully by targeting the product of the rogue gene.

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The value of being a general science nerd

I have always been, and probably will always be, a science nerd.

I look forward every month to receiving my issue of Scientific American (yes, I still get a hard copy), and often read it cover to cover.  I enjoy learning about scientific advances, and scientific controversies, in other fields.

Being a scientific nerd runs in the family.  My older son is pursuing theater as a career, but is an avid science reader and has an amazing depth and breadth of scientific understanding.  When he is on stage playing a scientist, he is not just reading lines, he really knows what he is talking about.  My daughter is finishing medical school this year.  Professionally, she is surrounded by the science of medicine, but also has a growing menagerie of fresh water and salt water creatures growing in her aquaria at home.   Care for her miniature coral reef and axolotl (a primitive amphibian native to Mexican lakes) has required that she acquire some knowledge of marine biology.  My younger son is a wild-land firefighter who received a master’s degree studying the burning properties of duff (the stuff that accumulates on the ground around a tree in the forest).  It was great fun reading the fire science posters on the walls at the University of Idaho when he was studying there.

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Attention Deficit

I am writing this on a weekend morning. It is really cold outside, and there is nothing on my calendar for a few hours. Instead of doing something productive, I find myself curled up on the couch in front of the fireplace surfing the web on my laptop. I am having no trouble finding totally useless but entertaining sites – a few thoughtful, some silly, and all too many outrageous. I know this is keeping me from more important projects (such as getting our family photos in order or writing a cancer research grant) but I am having a hard time focusing. My wife, who has experienced my channel flicking when I have the TV remote, knows this side of me all too well.

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A smile, a laugh, a cry, and when medically permitted, a hug

People of different faiths have varied perspectives on the value and meaning of the December holidays. Getting past the commercialization can also be a challenge. Nevertheless, with the possible exception of individuals who are humbug down to the core, we are all affected positively by the spirit of giving, receiving, and togetherness this time of year. I am not speaking here about giving and receiving “stuff,” but giving, receiving, and being together in a much more profound sense.

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Cancer teamwork in the Big 10

I spent time during my education and training at The Ohio State and the University of Michigan before arriving in Iowa City 25 years ago. I have close family members with ties to essentially all the other Big 10 schools. This time of year, we discuss the past season and bowl games, and argue about whose football team is overrated or underrated. When you are connected with a Big 10 school, you hear a lot about football.  Collaborative cancer research is generally not part of the Big 10 discussion. However, we are working to change that.

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Perception and Reality

I, like most of you, am relieved that the flood of political advertisements has stopped now that the election is behind us. The political ads were full of sound bites and statements, both positive and negative, that were purported to be based on fact, but in truth did a very poor job reflecting reality. These ads were designed to persuade, not to educate. Indeed, in politics, perception often trumps reality. The factual truth doesn’t result in votes, it is the perception of truth that counts. Whether we are talking about climate change, the Affordable Care Act, immigration, medical marijuana or support for cancer research, politics is based on perception. Guilt or innocence in a court of law is also based on the ability to persuade since determining the factual truth is often complex. Excellence in changing perception is one reason so many lawyers go into politics.

Those of us in medicine and science like to think we are different. For us, reality trumps perception. We believe that facts are facts. Even the best marketing or the most heart-felt desire for a different outcome is not going to change a cancer diagnosis. In the laboratory, a negative result in a well-designed experiment evaluating a promising hypothesis requires the scientist to reassess that hypothesis, even if the hope was that the experiment would turn out differently.

I am not trying to say that doctors and scientists are in some way superior moral beings because we believe in facts. Yes, basing decisions on absolute truth is a fundamental principle of medicine and science. In reality, results of tests or experiments are often equivocal, and even the best doctors and scientists revert to opinion and perception to decide on the next steps. As a doctor, I try to explain to a patient why I believe they should follow my medical advice, even when the facts available to support that decision are limited. As a researcher, I write a grant with the goal of enhancing the perception that my ideas are worth pursuing.

In politics and law, even more so than in medicine and science, simple “yes/ no” answers are difficult to come by. Available data is usually complex, and determining how reality should impact policy is far from clear. I spend a fair amount of time working with policymakers and always try to keep this in mind. For me to believe that this time is well-spent, I start with the understanding that political advertising that has bombarded me for the past several months does not fully reflect the depth of thought that our political leaders use to make policy. I need to assume that the best politicians understand the distinction between perception and reality and rely on reality and facts as a foundation for decision-making.

There is no doubt that there is a full spectrum of politicians with respect to how they understand the balance between perception and reality. As an advocate, I adjust my approach to talking to policymakers based on where I think they sit on this spectrum. For some, I focus on providing facts to make them aware of reality. Others seem less influenced by facts. For those individuals, I do my best to change their perception of what they view as reality.

After all, when it comes to setting policy that impacts us all, the reality is that perception is reality.

Scale

When I give a talk about cancer research, I like to highlight both the diversity of cancer research and that it is a continuum. One way to do this is by showing a scale that, going from smallest to largest, includes cancer research focused at the level of molecules, cells, tissues, organs, patients, clinical trials, cohorts, and communities. Much cancer research spans various points on this scale. I can take any two points on this scale, and talk about an important research project at Holden based on those two points. For example, molecular epidemiology involves taking samples from a large number of individuals in a group of cancer patients and evaluating them at the molecular level in order to improve our ability to predict how specific changes in genes might impact an outcome. Identifying new cancer drugs requires we screen large numbers of compounds to see which have the most promising effects on cancer cells, then after appropriate testing in the laboratory, assess the effects of these new drugs on patients in a clinical trial. Continue reading

The Academic Difference: George Weiner On How America’s Cancer Centers Are More Valuable Than Ever

Last week, I had the honor beginning a 2-year term as President of the Association of American Cancer Institutes (AACI).  Instead of writing a separate blog this week, I am copying an editorial that appeared in The Cancer Letter describing a new initiative of the AACI that goes by the name of  “The Academic Difference.”

This is reprinted with permission from The Cancer Letter.


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