Borsalino Test #30: Finding the needle in the haystack
Finding the needle in the haystack
No silver bullet
There are more than 15 million Google search results using the phrase "silver bullet" in association with cancer. Often, the results are alternative medicine quackery. Surprisingly, there’s much to be written about how supplements such as vitamins C, E and beta carotene won’t reduce the risk of contracting cancer. But there are also numerous mentions in the scientific literature itself.
There are many research threads, often interwoven, that claim to have found a way to target specific cancerous cells and tissues in the body. There have been polymeric carriers, supramolecular cages with spring-loaded doors, viral capsids, nanoparticles and many others.
The “silver bullet for cancer" is a neat phrase in "journalese" that at once casts cancer as somehow evil rather than merely a disease. It flags it as a werewolf, a witch, the baddie in the black hat. Silver bullets, after all, are essential munitions for the dispatching of such evils.
Cancer is a complex city of cells, with varied traits and trajectories, like vehicles on a highway. As we continue to pick apart cancer in its many forms, we are increasingly seeing that a cure – a single “silver bullet” – likely won’t be what many imagined.
The cancer moonshot
As recently as the late 1960s, the fight against cancer was a fight against its symptoms. There was no unified explanation for why cancer happens. Doctors removed tumors as best they could and spent a lot of time telling patients to get their affairs in order. Cancer was “just the way it goes. That’s what we say when we can’t explain something.
Fast forward half a century, optimism abounds among an increasing number of cancer researchers. That hopefulness was at the heart of what was arguably the most memorable part of President Barack Obama’s final State of the Union address in 2016.
“For the loved ones we’ve all lost, for the family we can still save, let’s make America the country that cures cancer once and for all,” Obama said as he stood in the House of Representatives chamber and called for a “cancer moonshot.”
When he placed then-Vice President Joe Biden—whose son Beau had died of brain cancer a year earlier—in charge of the effort, even some of the Democrats’ staunch political enemies had trouble holding back the tears.
In the days and weeks that followed, many cancer experts noted that it would take far more than the year remaining to the Obama-Biden administration to end cancer. Very few of those experts, however, said it absolutely couldn’t be done. And that’s because, in the span of just a few decades, we had completely changed the way we think about cancer. We no longer submit ourselves to its inevitability as part of the human condition.
A needle in the haystack
Cancer is caused by the uncontrolled, malignant growth of a single cell. This growth is unleashed by somatic DNA mutations. If a cell’s genome were a book, somatic mutations would be akin to spelling errors. The secret to battling cancer is to catch these mistakes before they multiply. The conciseness of that statement belies the enormity of the task.
Cancer is a progressive disease. Hence, it is easier to treat when diagnosed early. Over time, metastatic cancers account for a minority of new cases but cause the majority of deaths. Cancer follows a predictable path—from local and treatable to metastatic and lethal. Conceptually, earlier detection maximizes access to available therapies and interventions before it becomes intractable.
The 2003 Human Genome Project marked the beginning of a new era in oncology. Our ability to sequence and map all genes in the human genome has supercharged our understanding of tumor biology. The strange biology that makes it dangerous also gives scientists a tool to detect cancer earlier.
As cancer cells grow, divide, and die, they release fragments of genetic material into the bloodstream called circulating tumor DNA (ctDNA). Healthy cells also release DNA — called cell-free DNA (cfDNA) — into the bloodstream. Detecting the rare mutant-ctDNA in a sea of healthy-cfDNA from a blood test is the central, technical challenge to early cancer detection. Finding the signal through the noise.
The ratio of cancer-related ctDNA to background cfDNA quantifies the ‘needle-in-a-haystack’ problem associated with early cancer detection. For some early-stage tumors, that number can be as low as 0.01%. An extremely small needle, indeed.
Organizing the haystack
Measurements of circulating tumor DNA (ctDNA) alone will likely not solve the clinical problem of detecting early-stage cancers. ctDNA is just too rare in early-stage cancer. That “needle” is too small, too hard to find. On top of that, next-generation sequencing tests are still extremely expensive.
Fortunately, the list of cancer signals does not stop with somatic DNA mutations. We are collecting information on the hay to locate the needle. Multi-omics combines multiple datasets such as fragmentomics (how cfDNA breaks apart), proteomics (what proteins circulate in the bloodstream), and transcriptomics (how gene expression changes) to generate cancer signal.
Multi-omic machine learning models incorporate several of these signals. Importantly, many ‘omics’ signals are orthogonal, or additive, creating cancer signals that dwarf biological noise. This is a fascinating frontier of cancer diagnostics, and likely our best shot at early detection.
Because we don’t understand exactly how any of these ‘omics cause or accelerate cancer, their relationship to tumors is more correlative than causative. As a result, the predictive power of a single ‘omics signal is weaker than a carcinogenic somatic DNA mutation. But together the aggregate layers of multi-omics are a powerful tool to detect the presence of cancer.
Studying the patterns of hay, its color, texture and fragment length is bringing us closer to the needle. We are learning how to interpret noise, to find signals. With multi-omics, the lines between biology and artificial intelligence are blurring, and for the best. It turns out we needed no silver bullet to beat cancer, but a series of very good ones.