Beyond the DNA We Inherit: A Broader View of Human Genetics

Human biology continues to surprise us.

For decades, scientists thought the brain's immune system was largely self-contained. A new study published in Nature challenges that long-standing view.

The study was led by Julia Belk, an Amgen visiting scientist and Stanford postdoctoral researcher, working with Howard Chang, Amgen's senior vice president of Global Research and chief scientific officer, Sidd Jaiswal, Associate Professor of Pathology at Stanford, and collaborators.

The researchers found evidence that immune cells produced in the bone marrow can enter the brain during aging and contribute to its population of microglia, the resident immune cells that help monitor and protect the brain's environment.

By using naturally occurring somatic mutations—genetic changes acquired during a person's lifetime—the researchers were able to trace the history of those cells and uncover a previously underappreciated connection between the bone marrow and the aging brain.

Beyond changing how scientists think about the brain's immune system, the study points to a larger opportunity: Somatic mutations can reveal aspects of human biology that inherited genetics alone cannot.

For Belk, that idea extends well beyond this study: “Evolution continues after birth in all of us.”

Genetics Does Not Stop at Birth

Much of human genetics research has focused on germline variation, the DNA differences people inherit and carry throughout their lives. Those inherited variants have provided powerful clues to the biological causes of disease and, in some cases, helped identify promising therapeutic targets.

But inherited DNA is only part of the genetic story. For Howard Chang, somatic genetics is a powerful complement to inherited genetics because mutations acquired over a lifetime can reveal how a person's genetic starting point interacts with aging, environmental exposures, and other biological pressures. “You can think of it as the interplay between nature and nurture”, says Chang.

This opportunity connects closely with the expertise of Pradeep Natarajan, who recently joined Amgen as vice president of Research and head of the Cardiometabolic Therapeutic Area and Human Genetics.

Natarajan has spent much of his career studying how human genetic variation, including acquired mutations, can reveal disease mechanisms and strengthen causal hypotheses. His work has included pioneering research on clonal hematopoiesis, an example of somatic change in which blood-forming cells acquire mutations and some expand into larger populations of related cells.

“To understand human disease, we need to study humans deeply,” Natarajan said.

Looking Beyond What Is Known

If somatic mutations offer another way to study human disease, the next challenge is knowing where to look and which signals matter.

Amgen deCODE genetics is central to the company's human-genetics work, using a whole-genome approach to study variation across the human genome. At population scale, that broader view can uncover signals that point to unexpected biology. “When you restrict the genes you examine, you rely heavily on prior knowledge, which is not always correct,” said Daniel Gudbjartsson, associate vice president of Research and site head of Amgen deCODE genetics.

That same breadth is important in somatic genetics, but the biology is more complex. Unlike inherited variants, which are present throughout the body, somatic mutations exist only in a small subset of cells or in a particular tissue. Detecting them therefore requires highly accurate sequencing, the right biological samples, and an understanding of exactly which cells are being studied.

Some tissues may be particularly informative because they are directly exposed to the environment. The lung, for example, encounters environmental pressures such as smoking, air pollution and other inhaled carcinogens, which can contribute to the accumulation of somatic changes over time.

Finding somatic signals, however, does not necessarily tell researchers what role, if any, they play in disease. As Natarajan explains, “We don't have the advantage of germline genetics, where the exposures are fixed. We therefore need innovative human observational experiments to build confidence that the relationships are causal.”

Taken together, those challenges make scale, sequencing accuracy, thoughtful sampling, study design, and biological context especially important. But they also point to the potential of the field. As technologies and datasets improve, researchers will be better positioned to distinguish meaningful somatic signals from background variation and determine which ones warrant deeper investigation.

Turning Biological Insights Into New Medicines

For Amgen, the opportunity is to translate these emerging insights into a deeper understanding of disease: what is driving it, where biology creates a meaningful vulnerability, and whether that vulnerability could become a point of therapeutic intervention.

Shannon Turley, vice president of Research and head of Research Biology, notes that therapeutic hypotheses can emerge from many different sources. Human genetics is one part of what she calls Amgen's “target ecosystem,” alongside disease biology, multi-omics, screening, reverse translation from clinical trials, and other approaches. Each offers a different starting point; together they can build a more complete picture and point researchers toward the questions worth pursuing.

Amgen's Werner helicase program is one example of how understanding the consequences of somatic change has helped guide the development of a new investigational medicine.

In some tumors, acquired mutations disrupt DNA repair and lead to microsatellite instability (MSI). This can make cancer cells highly dependent on the Werner helicase (WRN) for survival. By bringing together expertise from Oncology Research, Precision Medicine, and Amgen deCODE genetics, researchers are deepening their understanding of this vulnerability to inform the discovery of new medicines.

The Power of the Next Question

The ability to uncover new biology depends on being willing to follow evidence, even when it challenges existing assumptions. Jason Rock, vice president of Research and head of the Inflammation Therapeutic Area, describes that mindset simply: “You have to be open to receiving information, data, and ideas from wherever they come.”

That may be the broader lesson of somatic genetics. Each new piece of human evidence has the potential to change not only what researchers know about disease, but the questions they ask next. Those questions can open new paths to understanding disease, and ultimately lead to new treatments for the patients who need them most.