Biology is elegant, but it’s rarely simple. Following the completion of the $3 billion Human Genome Project in the early 2000s, scientists were surprised to discover that the human genome contained only 20,000 or so genes, accounting for less than 2% of the entire genome. How could something as complex as a human being arise from a relatively small number of genes? What does the remaining 98% of the genome that sits outside of genes, known as the non-coding region of DNA, actually do?
In the early days of studying the human genome, scientists coined the term “junk DNA” to describe this non-coding region, mostly because they didn’t understand its role — if it had any — in human health and disease. But by using an approach called a “genome-wide association study” (GWAS), which involves the rapid scanning of the DNA of many individuals, scientists made the surprising discovery that in fact the majority of disease-associated genetic variants occur in the non-coding DNA. This of course suggests that so-called “junk” DNA actually plays a very important, functional role. In order to better understand it, scientists launched the ENCyclopedia Of DNA Elements (ENCODE) project, an ambitious research effort to map all of the functional elements of the non-coding genome. If the Human Genome Project was about reading what the genome says, ENCODE was about understanding what the genome does.
Genome function is primarily about the coordinated expression of key genes. In order for a gene to be expressed, cellular machinery — transcription factors and other specialized proteins — binds to specific regions of DNA to initiate and maintain the process. But how does a cell deploy this cellular machinery to orchestrate and manage the complexity of 20,000 genes working in nearly infinite combinations? How does a cell know which genes it needs to turn on (express) and which it needs to turn off (repress)?
Japanese researcher Shinya Yamanaka discovered a clue in the early 2000s: the introduction of a handful of transcription factors was sufficient to completely reprogram cells. This work, which earned him a share of the 2012 Nobel Prize in Medicine, suggests that cells maintain a hierarchy and structure for managing genetic complexity. It also suggested that the genetic program was dynamic. Rick Young and colleagues at the Whitehead Institute then further demonstrated how that these networks are governed by a core regulatory circuitry where a distinct set of transcription factors specific to each cell type act as master switches that conserve cell identity and function. What that essentially means is that these networks have central nodes that, if altered, can override the cell’s programming.
In cells, it turns out, DNA isn’t maintained as a long strand of the familiar double-helix we all remember from biology textbooks — instead the genome has a complex and functionally important three-dimensional structure. So it’s not just the sequence of the genome that matters; the shape of the genome matters too. In other words, the map is not the terrain.
Recent research from Rick Young’s lab and others has revealed how certain transcription factors structure the genome into different shapes in different cell types and thus influence which genes are expressed or repressed. Just the way mutations in the coding region of the genome (read: genes) can change the structure, and therefore the function of a protein, mutations in the non-coding region may rewire the core regulatory circuitry of the cell, changing the structure and function of a genome. This was a fundamental breakthrough in the understanding of how genetic variations in the non-coding genome contribute to disease.
There was great hope that the sequencing of the human genome would usher in a golden age for new drug discovery. While we have seen some big advances, the failure rate for drugs in clinical development remains depressingly high. All too often drugs fail because we do not truly understand the underlying biology driving disease. That is because genomics isn’t a silver bullet; for the vast majority of diseases, genomics alone cannot not provide sufficient insight into whether a drug will be effective. But understanding how gene levels have become dysregulated in disease — and where a drug can intervene to restore gene function — would have a transformative impact on our ability to treat a broad range of diseases.
Named for the famed, final camp on Mount Everest before the treacherous trek to the summit, CAMP4 is working to avoid the drug development “Death Zone” by using gene regulatory circuits to transform how drugs are discovered and developed. Cells use signaling pathways to influence cell’s genetic program, but the mechanism by which signaling pathways change gene expression levels has historically been poorly understood. Gene regulatory circuits are essentially dynamic wiring diagrams of how different signaling pathways converge on the genome to control the expression of specific genes. At the intersection of epigenomics, computational biology, and machine learning, CAMP4’s platform will give them unprecedented insight to unravel how signaling pathways combine to control specific genes across different diseases. This kind of insight makes it possible, for the first time, to unlock the unique code controlling each gene. Which means you can accurately predict how and where in a signaling pathway a drug is likely to work in order to ‘tune‘ key genes up or down, to ensure cells are receiving the right ‘dosage’ of a target gene.
CAMP4‘s approach has the potential to address hundreds of diseases, benefiting millions of patients globally. So I’m very excited to announce Andreessen Horowitz’s investment in CAMP4, my first investment for the a16z bio fund. Led by CEO Josh Mandel-Brehm, with scientific co-founders Rick Young of Whitehead Institute/MIT and Len Zon of Boston Children’s Hospital/Harvard University, this group is the ideal team to bring the company’s Everestian promise — “an effective treatment option for every patient” — to fruition. CAMP4’s platform is based on Rick and Len’s pioneering work in cell signaling, gene regulation, and genome structure; Josh joined CAMP4 following successful stints as an Entrepreneur-in-Residence at Polaris Partners and as a senior business development executive at Biogen. Having worked previously with both Rick Young and board member Amir Nashat (Polaris Partners) at Syros Pharmaceuticals, this is a bit of a homecoming for me. I’m thrilled to join the CAMP4 board.