1Patient Zero
Today we are learning the language in which God created life.
—UNITED STATES PRESIDENT BILL CLINTON
We share 51% of our genes with yeast and 98% with chimpanzees
—it is not genetics that makes us human.
—DR. TOM SHAKESPEARE, UNIVERSITY OF NEWCASTLE
It was obvious to Lynn Bellomi that something was very wrong. It was August of 2011, and Lynn, from the city of Arroyo Grande on the scenic California coast, had just given birth to a beautiful boy named Parker. At first, everything seemed normal, but after several weeks, she became suspicious. Parker was still having trouble with things most babies learn to do fairly quickly, like feeding and sleeping. He was only sleeping a few hours a night. He cried a lot. By March 2012, when he was six months old, he was missing milestones—not showing curiosity about objects around him and not rolling over, never mind sitting upright. He was referred to a developmental specialist, then to an eye doctor, then to a brain doctor, then to a geneticist. To make matters worse, by nine months old, Parker appeared to be having regular seizures. He underwent many scans and dozens of tests, including painful blood draws. No one could figure it out. “Constant appointments, constant driving,” his mom recalled. “And it felt like we were doing all these things without a purpose.” Months turned into years.
In 2016, when we first met Lynn and five-year-old Parker, they had been referred to our Center for Undiagnosed Diseases at Stanford, part of a national network of doctor detectives whose aim is to solve the most challenging cases in medicine. Much of the time, success comes from analyzing a family’s genomes, those DNA instructions that are the recipe book for all our cells and systems. So, on June 28, 2016, we drew blood from Parker so we could derive DNA from his white blood cells and spell out every letter in his genome. We also did this for his mom and dad.
Three months later, on October 4, genetic counselors Chloe Reuter and Elli Brimble called Lynn to say we had found a genetic change in Parker that did not appear to be inherited from either her or Parker’s dad. It was a brand-new genetic mutation that arose in Parker, and it appeared to disrupt a gene called FOXG1. Other patients with damaging variants in this same gene had health problems that were remarkably similar to Parker’s. This had to be the answer. For the first time since she had detected a problem with Parker’s development, five years before, Lynn understood the size and shape of the enemy. She instantly gained a support group of families suffering with FOXG1 syndrome around the world (650 parents on the FOXG1 Facebook group, at last count). More than that, finally understanding the cause of Parker’s disease allowed us to refer him to a movement disorder specialist who immediately changed his medications in a way that dramatically reduced his symptoms. “He still has some seizures, but much less frequently now,” his mom recently told me. “He still has to go regularly to the doctor, but otherwise, he’s a very happy guy.”
Parker and his parents can now look forward to a world of new possibilities: joining with doctors, scientists, and hundreds of families from around the world to attack this disease from every angle, share experiences, disseminate insights, and hopefully, one day, find a cure. That future would have looked very different if it weren’t for advances in our understanding of the genome—discoveries made, over the last few decades, by scientists whose work has had a profound impact on the way we detect and treat human disease. To explore those breakthroughs, let’s start by going back to 2009.
* * *
It was a pretty ordinary day. I had completed my morning meetings, and instead of lunch, I was heading to the office of a future friend, a Stanford physics professor and bioengineer named Stephen Quake. Steve was well known for his pioneering work in the field of microfluidics. He invented tiny biological circuit boards with switches, kind of like railroad “points,” to direct cells or molecules to a specific micro-destination for analysis. Steve and I were meeting to plan an afternoon symposium for the genetics faculty at Stanford. His office is in a building at Stanford named for James H. Clark, an electrical engineer and founder of Silicon Valley companies like Silicon Graphics and Netscape. Designed by the famous British architect Norman Foster, the Clark building is shaped like a kidney with swooping red lines and lots of glass. At night, it is brightly illuminated and looks for all the world like an alien spacecraft that landed in the middle of campus. In a way, it kinda did. The building’s purpose was to gestate a new specialty—bioengineering—the love child of a dalliance between biology and engineering. Situated on campus right in between the schools of medicine and engineering, against a California landscape of blue sky, sunshine, and palm trees, it is a stone’s throw from the Stanford hospitals. Through its windows, as you walk by, you see brightly lit rows of worktops harboring the trade tools of engineering right next to the wet benches of molecular biology—robots interbreeding with pipettes. And during the day, after navigating a curious and gratuitously complex room numbering scheme, if you’re lucky, you find Steve’s office on the third floor.
Steve is the archetypal physics professor—Stanford and Oxford trained, a brilliant iconoclast. The breadth and diversity of his intellect emanates from a brain enveloped by tufts of professorial hair that, in a former era, would be grown wildly to match his imagination. In fact, Steve’s office is set up very much as I imagine his brain to be—mountains of chaotically “organized” scientific papers are piled up on every side and in every corner. He sits hunched in the middle, pecking at a keyboard, the creative energy source powering everything around. Amid a campus of overachievers, Steve stands out. I had gone that day to talk about a seminar we were running to bring together human geneticists across campus. But we never really got to that.
“Come look at this,” he said. I found a place to sit amid the piles of journals, and he beckoned me over to look at the screen. It was not obvious at first what he was pointing at. There was a web browser open and a table filled the screen with the word Trait-o-matic at the top. It was one of those bare-bones spreadsheets with no formatting that was found on early websites—not pretty, but it was not the aesthetic that drew me in; it was the content. There were lots of columns of data. Gene names, gene symbols, As, Ts, Gs, and Cs, the building blocks of the genome.
“So what is that?” I asked.
His answer was to mark a pivotal moment for both of us. Delivered matter-of-factly and with more than a hint of his trademark understatement, it was as low-key as it was utterly revolutionary:
“It’s my genome.”
* * *
To put this into context, this was early 2009, and you could count on the fingers of one hand the number of people in the entire world whose genomes had been sequenced. Each one had been marked by an order of magnitude or more in reduction of cost. The Human Genome Project had been funded for $3 billion by the Department of Energy and the National Institutes of Health (NIH). And while each subsequent effort saw steep declines in cost, the price tags were still staggering. Craig Venter, the renegade entrepreneur who had taken on the public genome project in a race to be the first to sequence a human genome, sequenced his own genome at a cost of around $100 million. An anonymous Han Chinese man had been sequenced in 2008 for around $2 million. And James Watson, who shared the Nobel Prize for work with Francis Crick and Maurice Wilkins and who, together with Rosalind Franklin, elucidated the structure of DNA, had his genome sequenced by a group at Baylor College of Medicine in early 2008 for the comparatively modest sum of only $1 million. Each of these projects involved hundreds of scientists and thousands of hours of time, as well as no small amount of blood, sweat, and tears. Then in 2009, Steve sequenced his own genome, in his lab, using a technology he invented himself, with postdoctoral scholar Norma Neff and Ph.D. student Dmitry Pushkarev, for just $40,000. In one week.
Copyright © 2021 by Euan Angus Ashley
