from Wired.com by Nick Stockton
The California headquarters of Cofactor Genomics is a bright little bungalow a few blocks from downtown Mountain View. Floral vines abuzz with insects and hummingbirds partially obscure the patio and its two Adirondack chairs. Jarret Glasscock opens the door with a bubble-cheeked smile and a plaid shirt and a self-admonition because his partner Dave (Messina) is not yet back with croissants.
He lets me into a house that is pastel-bright with throw pillows on the couch, a fur rug by the fireplace, and granite counters in the kitchen. We sit down at the distressed wood dining table and make chitter chatter. How are you fitting in here in Silicon Valley? How is the culture different from Missouri? How are startup people different from biotech people? Where do you go for drinks? Oh hi Dave, good to meet you. Thanks for the croissant and bottled water.
Now that you’re here, why don’t the two of you tell me how you plan to diagnose disease from little rings of RNA that most biologists considered junk three years ago? Let’s talk about your $1.5 million National Institutes of Health grant. While we’re at it, why did you decide to temporarily uproot your company—which is nearly a decade old and already pulling in millions of dollars—to join Y Combinator, the startup boot camp known more for putting nestling consumer tech companies like Instacart, Airbnb, and Dropbox into high orbit?
Maybe that last one shouldn’t be such a surprise. It’s because Silicon Valley is about what’s hot … and hoo boy are diagnostics hot right now. Google is cataloguing genes, Apple is crowdsourcing patient data, and a company called Theranos is valued at $9 billion for promising to sell fingerprick diagnostic tests that don’t hurt (much) and can cost consumers less than $10.
And now here’s Cofactor, an RNA sequencing company that is turning away from drug discovery for big pharma toward consumer diagnostics. That’s right, a pivot.
Maybe they belong here after all.
Disrupting diagnostics (but really)
When you get your blood drawn, doctors are looking for proteins and antibodies inside it—proxies for disease. Based on the presence and quantities of certain proteins or antibodies, a diagnostic physician can say with reasonable certainty whether you’ve been fighting off a particular disease.
That’s the kind of test Theranos, the darling of West Coast biotech startup-land, is trying to upend. The twin elephants of blood diagnostics, Quest Diagnostics and Laboratory Corporation of America, use big needles, charge high prices, and make getting tested a hassle. Theranos wants to put things in the consumer’s hands. Instead of dreading the needle during your annual (OK, let’s be honest, every six years) checkup, you can pop into Walgreens, get a teeny fingerprick for a few bucks, and get your results by text message within hours.
Theranos has convinced its funders that convenience is the future of diagnostics, raising $400 million from the likes of Larry Ellison and Don Lucas Sr. But there are other less traditional—and potentially more effective—ways to diagnose disease.
Standard blood tests aren’t perfect, because they rely on your body to respond to disease by making proteins. But early in a disease, your cells might not have made enough proteins to show up. Or maybe the disease you have—Parkinsons, for instance—doesn’t really make proteins at all. And while testing for the protein-making genes could be a solution, DNA isn’t a good diagnostic tool. All it shows is your body’s potential, not what it’s doing.
Cofactor thinks RNA is the missing link. “When most people think about genetic diagnostics testing, they think about DNA,” says Glasscock. But DNA only gives estimates of risk. “If you get a DNA test, the doctor will be able to tell you that instead of a 7 percent chance of cancer, you have a 14 percent chance,” he says. “Also, you have 12 percent chance of male pattern baldness, and you’re 4 percent Neanderthal—and you’re like, ‘No shit, Sherlock! But what’s happening with my tumor?’”
So: Protein tests are reflective of your body’s current reality, but miss some of the details that DNA can pick up. “This idea of RNA diagnostics sits right in the middle,” says Glasscock.
Closing the loop
In theory, RNA is the perfect diagnostic. When someone says they did something because it was “in their nature,” what they’re really talking about is RNA, which copies certain sections of your static genome—the DNA—to make proteins when they’re called for.
Everything your body does leaves a trail of RNA. Flu? RNA codes for inflammatory antibodies. Parkinsons? RNA leaves a distinct trace in neurons. Cancer? RNA is the agent that enables your body to copy its malfunctioning DNA code.
Now, some RNA doesn’t turn code into proteins. But even those bum molecules do all kinds of useful stuff—which means they can be useful diagnostic markers, too. Some of these noncoding RNAs help in a tangential way with the coding process, and some block genes from being expressed. Some even cut strands of DNA so they can be modified. Most of them are strings.
And some of them are circles.
Typically when RNA makes loops, it’s because it got tangled in the course of turning DNA into proteins. Some scientists discovered some legit circular RNA back in 1991, but that the data showed it to be scarce stuff.
Around 2012, several labs started converging on the idea that circular RNA was actually incredibly abundant. Julia Salzman was, at the time, a biostatistician in Pat Brown’s genetics lab at Stanford University. She was looking for RNA sequences that were out of order with respect to their reference DNA, “because these could be biomarkers and potential drivers of cancer.” What she found were these seemingly scrambled bits of repeating RNA.
Around the same time, Ned Sharpless and his lab at the University of North Carolina in Chapel Hill also were looking for cancer biomarkers in RNA. He too found weirdly repeating bits of RNA code. “I kept telling my post doc that he was wrong,” says Sharpless. “But he convinced me they were making a circle.”
Through literature searches, both labs happened upon older research describing these funky, supposedly rare, circular RNA. Eurekas!
Oh, does that not seem like a big deal? Ok, here’s why they were so excited: Every strand of RNA carries bits of code in your blood that link it to specific malfunctioning cells or tissue. The problem—there’s always a problem—is loose ends. Any noncircular RNA strings have loose ends that enzymes in your blood can latch onto and chew up. That means they don’t last long enough to make a useful indicator for any disease.
Inside the body, nobody really knows what circular RNAs do—Sharpless has a six-pack of beer riding on an idea that ciruclar RNAs can code infinite, repeating protein sequences. But who cares? They don’t have loose ends. They survive in your blood. So outside the body, Cofactor thinks circular RNAs can do a hell of a job as diagnostics.