James Downing was bound for the big leagues. Not quite big enough to continue playing football in college, Downing had what he thought it took as an outfielder at Aquinas High School in Southgate, Michigan. He could hit and had a strong arm. Alas, he lacked speed. Downing recognized the first time he was clocked from home to first it would be bye-bye big leagues.
Hello, biochemistry. The high school jock needed but a semester in college to discover a new field of interest. Having suffered a broken back while working construction the summer after high school graduation, Downing wisely identified a path where, instead of brawn, his brainpower could steer progress.
Few life transitions have had a larger impact on St. Jude Children’s Research Hospital, where today Dr. Downing is scientific and deputy director. In 2012, Downing’s Pediatric Cancer Genome Project — a three-year, $65 million privately funded venture between St. Jude and Washington University in St. Louis — was named one of the top ten medical breakthroughs of the year by TIME magazine. Needless to say, pediatric cancer gained a significant enemy when baseball lost Downing as a prospect.
“I didn’t pay much attention in school,” says Downing today. “I was much more into sports: football and baseball.” Downing recounts a science teacher who allowed the developing football star to watch game films in the back of the room while the rest of the class studied the Krebs Cycle and such. But as a freshman at the University of Michigan-Dearborn, Downing had what now can be called an awakening.
“I started out in engineering,” says Downing. (His father was an engineer at Ford Motor Company.) “I was very good in math, physics, chemistry. But somehow I took a biology course and loved it. Didn’t like it in high school. But in college, I thought it was fantastic. So I switched my major to biochemistry. And discovered that studying was fun.
“I was able to do research. By the time I was a senior, I had technicians working with me, doing experiments, getting my name in publications. I got to do a lot more research than I would have at a bigger university.”
Upon graduating from UM-Dearborn, Downing “did what smart people do,” and applied to medical schools. Knowing he wanted to pursue research — and not answer the more common call for primary care physicians — he chose to attend the University of Michigan medical school in Ann Arbor. His entrance score on a biochemistry exam was good enough that Downing didn’t have to take the intro-level course, which allowed more time for, you guessed it, research. He graduated from medical school in 1981 and chose pathology — the study of diseases, their causes and effects — as his field of interest.
Downing spent two years in the residency program at Washington University, a life stage he considers critical to the career that followed. “I became trained really well as an anatomic pathologist,” he says. Brief stints at the University of Florida and UAB — where Downing was a faculty member and ran a research lab — followed before a UAB colleague, Dr. William Crist, urged him to consider St. Jude as his research destination. (Crist would later serve as chair of hematology and oncology at St. Jude.) “I knew a little bit about St. Jude,” reflects Downing, “knew they had a world-famous hematopathologist here [Coston Berard]. So [in 1986] I got a call from Berard. He says, ‘You don’t know me, but I have the perfect job for you.’”
That perfect job required Downing to spend 20 percent of his time as a hematopathologist — analyzing blood samples in the treatment of patients — but then 80 percent of his time would be spent learning how to be a research scientist under the mentorship of Dr. Charles Sherr. “We did great work together,” says Downing. “We made important discoveries. I learned a lot about science, how you can never be too rigorous, how to make decisions on what problems to follow. After five years, I started to build my own research program.”
“I like the rigor of doing experiments, making sure the data is accurate.”
Downing’s 28 years at St. Jude have been fueled by the most basic qualities of the human mind: curiosity and a yearning to solve problems. “In most jobs,” notes Downing, “you go to work and there’s work for you to do. Here, you have to create your own work. You have to do work that you believe is worth doing. There are periods of time that can last weeks or even years where you find out the work you were doing wasn’t worth doing. Eighty percent of the work doesn’t work. There are lots of false leads. The difference between success and failure is what to work on. It’s just as hard to work on things that aren’t important [on the surface] as things that are important. Is this important? Does it have a chance to lead somewhere?”
After devoting himself to protein biochemistry without what he considered significant breakthroughs, Downing shifted his attention in the late Nineties to mouse genetics, and eventually genomics (molecular biology that focuses on the structure and mapping of genomes, the sets of genes present in a cell or organism). As he explains, “In mouse genetics, we looked at the blood system and how this gene plays a normal role and the altered product plays a role in leukemia. The next question is what else is required to form leukemia, so we switched to genomics. It was more technology-driven. We would look at certain microarrays, where we could see all the genes expressed in a certain time point. Genetic lesions, early DNA sequencing. The questions then were focused on a particular kind of leukemia.”
The mapping of the human genome — first announced in 2003 — became a launching pad for research scientists worldwide. Genetic abnormalities could suddenly be identified in much more specific terms, narrowing the focus on cancer-causing mutations. “New sequencing technologies came along,” says Downing, “so we no longer had to rely on microarrays. Next-generation sequencing allowed us to read 100,000 reactions instead of 18, and you’re reading them in real time. When that occurred, the costs started plummeting. Computers, though, are much more important. It’s a massive amount of data. Millions of dollars in computer hardware is required.”
“Now we could start thinking about sequencing the whole genomic cancer. Before, it was a pipe dream.”
As government funds began to pay for the sequencing of cancer genomes — selected genes considered relevant by the agencies doing the funding — Downing pondered larger possibilities at St. Jude. “We set up the Pediatric Cancer Genome Project [PCGP] through a methodical process,” he explains. “I was convinced we should do this, and I got in touch with Tim Ley [associate director of the Genome Institute] at Washington University. We could sequence a certain number of cases for a certain amount of money. We formulated a retreat and had presentations by our faculty involved with genomic research. At the end, there was overwhelming support. People [at St. Jude] who had no involvement in genomics stood up and said, ‘This is who we are. We should do this.’” Washington University had an industrial-level sequencing center, making the partnership a natural fit.
“What we wanted to do with the PCGP,” says Downing, “is whole-genome sequencing, all three billion base pairs, as opposed to one or two percent. We made lots of discoveries, but our conclusion was that there are a lot of genetic alterations in a cancer cell that require you to sequence the whole genome.”
Downing and his staff would decide which tumors to sequence, then two analysis pipelines — one at St. Jude, the other at Wash-U — would be established to compare and validate by “second-level sequencing” every lesion discovered.
“This was key,” says Downing. “In the first case, they found 12 mutations and we found 13. Only one overlapped. Were they right? Were we wrong? It turned out we were both wrong. We missed valid [mutations]. We modified our algorithms, they’ve continued to evolve, and accuracy has improved.”
A partnership and methodology may have been established, but how would this groundbreaking research be funded? Downing was firm: no government money. “We made it clear we wanted complete control,” he says. “We didn’t want the NIH [National Institutes of Health] or any other group telling us how we should manage the project. We thought we could do it quicker and smarter.” St. Jude’s board of governors stepped up — to the tune of $65 million — and Downing’s grand venture began in February 2010. “We told them this would be a game-changer,” says Downing. “This would accelerate the field. This information will change the field across the world, and not just for pediatric cancer, but adult cancer and other genetic diseases. If we did it right, we’d generate more sequence than the rest of the world is generating. They gave us the money.” [Sterling Jewelers, it should be noted, gave $20 million to the cause. Other private donors contributed more than $1 million.]
“It’s the most successful project I’ve ever been associated with,” says Downing. The project had a deadline — three years — with a goal of sequencing 600 genomes. Despite sequencing only 50 in the project’s first year, by the completion of the PCGP in February 2013, 700 whole genomes were sequenced, and under budget. “We sequenced the tumors where we don’t do really well at treating those children,” says Downing. “Equal numbers of brain tumors, solid tumors, and leukemia. In the end, we sequenced 21 different kinds of cancer. Every tumor, we learned something new. And on occasion, we gained new insight in how to treat those tumors.”
“It’s an exciting time. A time when we need to continue a very strong effort at discovery.”
Upon the completion of the PCGP in February 2013, Downing and St. Jude had to answer a researcher’s most common question: What’s next? Almost immediately, the hospital launched the Clinical Genomics Project, a two-year, $30 million “Phase II” operation that aims to incorporate PCGP findings into diagnostic and clinical treatment for St. Jude patients.
“There are two aspects to Phase II,” explains Downing. “One, there’s more discovery. If there’s a mutation, is it functionally significant or not? Let’s go after the regulatory regions. How are there mutations in there? The other half is how do we take genomics and bring it into the clinic. It’s been a massive undertaking. We’re making great progress in setting up the infrastructure. The goal is to sequence the genome of every child who comes to St. Jude. We’ll use that information to determine who’s responding and who’s not. If they’re not responding, how can we use that information to better treat them?
“If we could do this on every child, and ultimately every child in the U.S., we could facilitate or accelerate the development of protocols to figure out how to effectively treat those children that have lesions for which there are drugs against those lesions. It’s a first step in making more personalized therapy. You have to do that in a controlled setting. Will it really work?”
Begun in March 2013, the Clinical Genomics Project needed nine months just to gain the necessary certification from CLIA. (The Clinical Laboratory Improvement Amendments regulates lab testing.) “We’ve been doing personalized cancer therapy here at St. Jude for 20 years,” says Downing. “We define low-risk and high-risk based on a series of parameters: age, presenting laboratory features, and features of the leukemia cells themselves. Now genomics are being applied.
“To do clinical-grade sequencing, you have to have licensed technologists, completely written and validating operating procedures for every single aspect of the process. All machines have to be validated at a higher level than in a research setting. We had to build a new lab, hire new technologists, and develop those standard operating procedures.” Downing hopes to begin the actual sequencing by the end of this summer, a process that will last a year (beyond the original deadline, but still on budget).
“The field [of pediatric cancer], I think, is very impressed that we’re going to do this at this level,” says Downing. “And people who have seen the infrastructure have said there’s nothing like it anywhere else in the world. If someone else could commercialize it — that’s not what we do — and allow other people to use it, that would be fantastic.”
“I like Nelson Mandela’s line about leading from the back of the bus.”
The PCGP has earned Downing rarefied acclaim, even on the international scale with which St. Jude is measured. There was the salute from TIME in 2012 for the PCGP as a worldwide game-changer in the fight against pediatric cancer. A year later, Downing just missed the final cut for the same magazine’s annual list of the 100 most influential people in the world, a group headed by presidents, the pope, and pop-culture icons. He’s grateful for the recognition, in particular for what it means to future research at St. Jude. But he’s resisted any urge to don a celebrity’s mantle.
“I’m lucky to be at St. Jude,” he says. “Somehow, I made the right decision to come here 28 years ago. My success is because I’m here. I’ve been able to approach my career in a different fashion than if I’d been elsewhere, constantly scratching for dollars and grants to do my work. I’ve had the freedom to think about big projects because our board and ALSAC are willing to put the money behind them.”
He does mention a recent honor, more fulfilling than most. “I recently got into the Institute of Medicine. We only have six here at St. Jude with that recognition. I get inducted in October. That’s pretty special.”
Dr. Kevin Shannon, an American Cancer Society research professor at the University of California-San Francisco, met Downing 15 years ago when they joined a research consortium funded by the National Cancer Institute. They’ve since collaborated on a number of papers. (Better yet, Shannon and his wife introduced Downing to the virtues of Sinatra and red wine.) “Jim’s a rare mix,” says Shannon. “He’s trained as a pathologist, and pathologists are known for being very precise and detail-oriented. All good pathologists are a little obsessive-compulsive. But what distinguishes Jim is the way he thinks creatively and innovatively, how to harness new technologies. He’s pretty much revolutionized the scientific agenda at St. Jude. He’s committed to changing the field in pediatric cancer. If you have the keys to the Porsche, you should drive the damn thing hard.”
When he’s not “driving the Porsche,” Downing takes to his bicycle. He was an active long-distance cyclist in his 30s (as much as 150 miles a week), gave up the sport for almost 20 years, then resumed it about three years ago. “I was getting out of shape,” he acknowledges. “Some guys around here were riding, so I bought a new bike and joined them.” He also handled the cycling leg for St. Jude’s relay team in this year’s Memphis in May triathlon.
Married 37 years and the father of three adult children — one of his two daughters is a research technologist at St. Jude — Downing often fills his weekends at Shelby Farms with his three grandchildren, ages 8, 5, and 1.
For any confrontation — any battle — a profile of the enemy is critical. This is certainly the case in the ongoing struggle against pediatric cancer, and James Downing has helped create the world’s largest, most complete profile of this nefarious foe that can take on countless forms.
“[The PCGP] is a roadmap, essentially, for how this disease works,” says Shannon. “It begins to give us a window on why it is that children get certain kinds of cancer, why children with certain genetic predispositions get cancer. Now we know what cancer looks like at a molecular level.”
“I started out hoping I’d be an athlete,” says Downing. “Then I thought I’d be a carpenter, an engineer, then a scientist. But I was pretty shy. So I thought I’d work in somebody’s lab, be quiet, grow up and have a family. But opportunities have presented themselves, and I find myself constantly thinking about [my work]. It’s fun to see it actually materialize in this large way, with all these people. It’s a competitive field, but we try to ignore the competition and do it for the right reason. Chuck Sherr taught me that you can never be too rigorous. You don’t necessarily need to be first; you just need to be right.”
Turns out James Downing made the big leagues after all.
