Flagship Pioneering, a venture capital firm investing in biomedical platform innovation, announced ProFound Therapeutics, a new company that has identified thousands of previously unmapped human proteins, opening the door to a slew of novel therapeutic targets and therapies. The groundbreaking ProFoundry Platform™, which was founded at Flagship Labs in 2020, has spotted unique proteins, remapping the human genome landscape. Flagship has put up $75 million to help expand the ProFoundry Platform and build a pipeline of innovative treatments.
Avak Kahvejian, PhD, Flagship Pioneering General Partner and Co-Founder and CEO of ProFound Therapeutics, said, “We’re illuminating the human genome in new ways. That has allowed us to identify a whole new universe of previously unidentified proteins, which we believe will open the door to new therapies and new potential targets.”
Redefining protein grammar
When the Human Genome Project concluded about 20 years ago, one of the big hopes was that it would reveal a comprehensive list of what makes us human. The ongoing hypothesis was that the endeavor would identify tens of thousands of new proteins, if not hundreds of thousands. But the 20,000 or so protein-coding genes identified after that first draft—which is only a little more than what’s found in a worm or a mouse—didn’t entirely explain human complexity and the contents of the human genome, only accounting for 1.5% of human DNA.
Some years later, swaths of genomic sequence, once dismissed as “junk” or deserts, were found—in large part by the Encyclopedia of DNA Elements (ENCODE) project—and transcribed, resulting in the cataloging of more RNA molecules and unknown open reading frames (ORFs) than previously believed. Yet many transcripts were named or deemed non-protein-coding due to the conventional wisdom regarding protein definitions. For example, amino-acid sequences for proteins are typically thought to start with a methionine, end with one of the three stop codons, and are long enough to be considered a protein. But when looking at mass spectrometry and ribosome-profiling data, many unmappable amino-acid chains go unnoticed, especially if you expand the definition of what constitutes a protein.
As is customary with Flagship, Kahvejian started by asking a big “what-if” question and building a novel bio platform to tackle the question.
“What motivates us here at Flagship is to ask some of these dogma-busting questions and to have both the humility and will to go and answer them,” said Kahvejian, who has been a general partner at Flagship for more than a decade. He leads an in-house innovation team consisting of scientists with the mission to ideate and explore new frontiers with a very open mind with an eye toward trackability and feasibility.
That’s when Kahvejian embarked on a journey to ask whether there are more proteins than meets the eye, using orthogonal cutting-edge protein detection technology like mass spectrometry and computational tools to dissect the translated component of the human transcriptome.
“If we redefine some of the genomic rules that define a protein-coding gene, take advantage of new technologies, and integrate them with other technologies and computation, can we reveal this new universe and illuminate a broader set of proteins than previously known?” asked Kahvejian. “We’re not redefining what makes a protein. We’re redefining the rules that dictate what sequences get converted to proteins or that we should consider translatable. That’s how we’ve been able to expand the proteome and mine it.”
These newly discovered proteins don’t appear to be an entirely new category in the way the micro RNAs were found after being excised from a typically discarded part of a nucleotide separating gel. Kahvejian doesn’t anticipate that they are functionally unique. ProFound is now doing high-throughput functional validation work using in vitro and in vivo models in cells and animals to study these proteins in fine-grain detail.
A plethora of potential protein targets
The purpose isn’t purely academic or simply to create an atlas or database. Kahvejian’s mission has been to find new therapies and targets. Only a certain percentage of the 20,000 previously identified protein-coding genes has been deemed druggable or implicated in disease. The team at ProFound is asking questions that integrate disparate data sources, including different samples and perturbations, to pursue four main areas: novel genetic drivers of disease, immune modulators, circulating factors, or cancer targets.
The company strives to build a platform and create products with its own pipeline. But the cornucopia is so rich that Kahvejian anticipates working with other Flagship companies that have complementary platforms to help elucidate function and target, either by making these proteins or inhibiting them inside the human body.
“We anticipate pharma partnerships where they each bring to bear deep knowledge of a particular disease area and have the corresponding samples, translational models, and so on to prosecute some of these opportunities. There’s plenty to do for ourselves and in collaboration with others.”
ProFound will expand quantitatively and qualitatively to build up the capabilities to make even more biological translatable products than what they’ve already started doing—drug development, drug discovery, and development downstream for multiple programs across disease areas. In a year, Kahvejian says that ProFound will be a more vertically integrated company with an executive team. They will be announcing those hires and the advisory team in short order.
It’s too soon to tell if this broader universe of proteins may hold the keys to unlocking a new sector in the biotech industry and translational medicine, with ProFound in the driver’s seat. “We asked a pretty open-ended and almost silly question, and we were pleasantly surprised to find the answer,” said Kahvejian. “It’s all humbling that the biology we learned in textbooks and that humanity has been studying for only a few decades has still a lot more to reveal to us. It’s no small feat to understand it, let alone harness it and use it for the common good.”
