In June 2000, the Human Genome Project (HGP) announced it had assembled a working draft of the human genome; three years later, in April 2003, HGP announced it had completed its sequencing of the entire genome. Now, two decades after that initial milestone paved the way for remarkable advances in science and medicine, we continue to unravel the mysteries of the human genome with the aim of ushering in a new wave of genomic medicines that target regulatory regions of the genome to control the expression of genes.
From gene to genome: The other 98 percent
The HGP’s completion of sequencing revealed two surprising discoveries that have drawn ever-increasing attention to what we now call the regulatory genome: humans have far fewer genes than we initially thought, and only 2 percent of our genetic sequences code for proteins.
Humans have between 22,000 and 24,000 genes—more than the nematode C. elegans at about 20,000 but slightly less than the laboratory mouse. Yet humans have many more cell types than either of these organisms, suggesting that non-coding regions of the genome—“the other 98 percent”—play a large role in defining what makes us human.
Indeed, a growing body of evidence supports the idea that the non-coding genome, once considered “junk DNA,” plays a critical role in human biology. Compared with other species, “the other 98 percent” of the human genome is highly enriched for gene regulatory sequences such as enhancers and non-coding RNA.
It is these non-coding regions of the genome that control which genes are expressed—turned on, off, up or down—in any given cell, thus determining their type and function. Almost all our cells share the same DNA; it is the coordinated expression of genes that determine if they are a skin cell or liver cell, if they are healthy or diseased.
When genes are expressed at the wrong time or in the wrong amounts, it can lead to disease. Genome-wide association studies show that most disease-associated genetic variations occur in the regulatory genome, suggesting that altered expression of genes contributes to disease far more often than mutations in the protein-coding regions that have largely been the focus of gene-based drug discovery. While targeting genetic mutations and the abnormal proteins they produce has led to significant advances in treating certain diseases, many more diseases could be addressed by controlling the expression of both normal and abnormal genes.
While the concept of modulating genes isn’t new, the tools to interrogate the regulatory genome on a large scale didn’t exist until recently, essentially rendering it a black box. It has only been in the last five to 10 years, with new technologies and scientific breakthroughs in gene regulation and the ability to rapidly interrogate coding and non-coding regions (e.g. CRISPR-based technologies), that we can now envision a path for translating this science into therapies.
Controlling the expression of genes represents a new wave of genomic medicine, and we are just at the beginning.
Drugging the regulatory genome
Syros, founded seven years ago, developed the first platform dedicated to systematically analyzing the regulatory genome to develop medicines to control the expression of genes. Since then, an explosion of academic research has led to a growing recognition of potential of therapeutic gene control, spurring greater investment both within large pharmaceutical companies and in the formation of companies such as Fulcrum Therapeutics, Foghorn Therapeutics and CAMP4. While each company has different points of entry, the common theme is that we all see the tremendous untapped potential to address a range of serious diseases that have been intractable to other genomics-based approaches.
The platform developed at Syros was based on newly discovered features of the non-coding genome, a highly specialized class of enhancers called super-enhancers. These non-coding regions concentrate a large amount of transcriptional machinery to control the expression of genes most critical to a given cell. Building on that discovery, we developed a platform that allows us to elucidate regulatory mechanisms—both across the genome as well as around a single gene of interest—and understand how to target those mechanisms using small molecules, with the aim of developing oral medicines that provide a profound benefit for patients.
We are currently focused in two therapeutic areas: cancer and monogenic diseases (disorders caused by a single genetic defect). Here, I briefly describe three of our programs that illustrate different ways in which a deep understanding of the regulatory genome can be applied to discover and develop gene control medicines.
Our lead program, SY-1425, now in a Phase 2 clinical trial, came from our discovery of a subset of acute myeloid leukemia (AML) patients with an alteration in their regulatory genomes. By analyzing and comparing healthy and diseased cells from AML patient tissues, we discovered a subset of patients with a super-enhancer that drove abnormally high expression of the RARA gene, locking cells in an immature and proliferative state. By binding the protein RARA encodes, SY-1425 turns on differentiation genes, unlocking those “stuck” cells. Notably, this patient subset could not have been identified through conventional genome sequencing because their disease is driven, in part, by the abnormal expression of the RARA gene.
Our second program, SY-5609, currently in a Phase 1 trial in select solid tumors, represents a potentially transformative new targeted approach in cancer. SY-5609 is a highly selective and potent inhibitor of a transcriptional kinase known as CDK7, or cyclin-dependent kinase 7, which is a component of the super-enhancer complex. CDK7 plays a critical role in two fundamental processes that cancer cells rely on for their survival: the increased expression of oncogenic and anti-apoptotic proteins, and uncontrolled cell cycle proliferation. In preclinical studies, SY-5609 has shown significant anti-tumor activity—including complete regressions—in preclinical models of multiple solid tumors, including breast, colorectal, lung and ovarian cancers.
Our drug discovery program in sickle cell disease (SCD) aims to provide a functional cure for SCD by switching on the fetal globin gene, which is typically turned off at birth, to make healthy red blood cells and compensate for the mutated adult globin gene that causes SCD. By using our platform to elucidate the regulatory mechanisms controlling the fetal globin gene, we have identified multiple potential therapeutic targets for inducing fetal globin expression.
20 years later: The best is yet to come
When the HGP was completed, we had only just begun. The last two decades have brought an unprecedented level of discovery and innovation that has yielded important insights into fundamental biology and underpinnings of disease and new therapies. Yet there is still so much progress yet to come.
Looking ahead, three things really excite me as I think about this new wave of genomic medicine. First is our growing understanding of the links between the molecular basis of disease pathology and the gene expression and gene regulation programs in cells. Second is the ability to take these genetics and epigenomics studies down to the single-cell level to understand which genes in a particular subset of cells are driving the pathology. Third is that every year we gain an even deeper understanding about how this transcriptional machinery works—how signals at the cell surface move through metabolic pathways inside the cells to become focused on enhancers and specific genes in a specific cell type.
Together, these developments open up even greater opportunities to develop medicines that control the expression of the right gene, in the right cells, at the right time and in the right patients, bringing into reach many more diseases that have eluded treatment for far too long.
Eric R. Olson, Ph.D., is the chief scientific officer of Syros Pharmaceuticals.