"All this money spent and they still don’t have a cure for cancer!" I heard the man sitting near me on Muni exclaim to his friend. I had just run out of my lab after starting an exciting new experiment and was looking forward to returning and continuing with the next step. But his comment made me feel both defeated and defensive. “He just doesn’t understand how complex solving this problem actually is!” I thought. I instantly caught myself, realizing it’s unfair to hold people responsible for understanding something as abstract as the process of biomedical research. After all, our job as scientists is to discover and communicate discovery. But, why do discoveries take so long?!
To begin answering this question, we need to flesh out the steps of biomedical research. First, scientists always construct a research aim or project by asking a specific and direct question based on a clear observation. For instance, why do certain types of prostate cancers develop resistance to treatment? Second, they form a hypothesis that can answer the question. Then they create experiments to test the hypothesis. This scientific method forms the basis of every research proposal.
Scientists (also called primary investigators (PIs)) in academic research institutions generally write and submit proposals to government agencies such as the National Institute of Health (NIH), which includes several smaller institutes that study and fund biomedical sciences. Back in the ‘60s and ‘70s, these agencies funded 70% of academic laboratories, cementing the United States as a leader in biomedical research and progress. In recent years, government funding has fallen to less than 50% due to budget cuts, yet the NIH still offers three submission dates— or cycles— per year so PIs have more than one chance to submit a proposal. To select which projects get funded, proposals are peer reviewed— they are read and evaluated by experts in the field in question. They are then scored on significance, novelty, and the fitness and creativity of the proposed experiments. This review process takes an average of four months and is highly competitive. In the case of the NIH’s National Cancer Institute, for example, only 1,230 (12%) proposals were funded out of 10,210 received in 2016. This is down from the 20% that would have been funded 10 years ago, which means because fewer grant proposals are funded, scientists have to spend more time writing more grants than actually performing experiments.
Ironically, even though biomedical research requires enormous amounts of funds, time, rigorous effort, resilience, creativity and talent, what makes high-impact discoveries such a rare commodity is a great deal of luck. This is particularly true for cancer research. At its essence, cancer is characterized by aberrant cell growth, yet it is not only one disease; it is a cluster of 100 types of diseases. And even those diseases can be distinct from one person to another. Two individuals might develop breast cancer but the biological steps that lead to the formation of their tumors can be completely different. The probability of a one-size- fits-all cure, therefore, is close to zero. Instead, experts in a field focus on, and are always looking for, distinct biomarkers and drug targets for different types and stages of cancers.
Sometimes, they make these discoveries because they are in the right place, at the right time. In 1986, Dr. Dennis Slamon was at a scientific conference when he heard about the discovery of oncogene HER2 in mouse cancer cells. A couple of years later, he found this gene to be amplified in 20-30% of human epithelial carcinomas, which comprise breast and ovarian cancers among others. Then a couple of years after that, Dr. Slamon and his collaborators generated and tested an antibody, Trastuzumab, aka Herceptin, to target HER2 for treatment of those cancers. Including clinical trials and FDA approval, the drug took 12 years to develop and be used successfully in the clinic! Today it is a routine treatment for most patients with HER2 positive breast cancers and has improved survival significantly. While novel ideas may sometimes be unexpected, they are always built on the pursuit of fundamental knowledge.
CRISPR, for instance, was serendipitously discovered by microbiologists in 1987; at the time, no one knew why these genomic repeats in bacteria were there or whether they were important for survival. It was not until 2005— almost 18 years later— that scientists discovered bacteria use these genomic repeats as a defense mechanism against viruses. Seven years after that discovery, this natural process was harnessed to generate a genome editing technique that is revolutionizing research and medicine. Yet it took almost 25 years for CRISPR to make such an impact! Discovery of these interesting but obscure genomic repeats was the limiting factor here. Once scientists finally shed the light on what they are and figured out their complex mechanism of action, a practical application of CRISPR was just a matter of innovation and effort. That said, discovery not only takes time because of biological complexities and limitations in experimental methods but because experiments in the lab often fail.
I learned this first hand in graduate school. My project involved the complex process of wound healing; while some of my experiments took months to accomplish, it was the failed ones that set the project back two full years. For every successful experiment, I had 10 that failed due to technical issues. It took me a couple of years to standardize and optimize my protocols and procedures for experiments that would have otherwise taken three months. I found the day-to- day of a bench scientist to be filled with the necessary evils of optimizing, trouble-shooting, and repeating experiments. Actually, I shouldn’t use the word “evil” because that very process is what makes science so solid and reliable. Every experiment has to be methodical and technically sound. Evidence is never anecdotal and results need to be reproduced multiple times to make sure they aren’t a fluke. Indeed, before reporting any findings scientists have to get the same significant results at least three separate times. If everything runs smoothly, this can extend a project by one to several months depending on the type of experiments needed. With all the above considered, my project took almost five years to finish. They were the most frustrating years of my life but also the most rewarding— I ended up discovering, patenting, and publishing a novel target that accelerates wound healing!
I spent the rest of my Muni ride that day thinking about all these reasons why cures tend to be few and far in between. I wanted to share them with my co-rider but he got off before I was able to. I’m glad, however, I have the platform to do it here with you. Writing this was a learning experience for me, as well, not only in communication but in optimism. Scientists are a group of the most resilient and hungry for knowledge individuals I’ve ever encountered. One thing I’m sure of is no matter how indistinct a path to a cure is, this drive will eventually clear it.