One of Paul Fielder’s most challenging moments as a scientist surprisingly didn’t take place in the lab, but trying to get through airport security.
In the early 90s, Paul was returning from a medical expedition to remote villages of southern Ecuador. He was in the middle of his post-doctoral research at Stanford University in the Department of Pediatric Endocrinology. The lab where he worked did an interesting mix of bench science combined with clinical research focused on growth hormone insensitivity.
Paul had gone to Ecuador to find and help children with a rare, hereditary growth disorder called Laron dwarfism. His work involved collecting samples of blood from people with the condition. As it turned out, collecting the samples proved easier than getting them back to Stanford. Upon his arrival at Los Angeles International Airport, customs agents suspicious of the ice chests holding the samples began to question him intensely.
“They asked me, ‘What drugs do you have?’ I had to explain that the ice chests were full of blood samples. The experience was pretty awful, but the silver lining is that we brought the samples back to the lab and ultimately identified the genetic defect causing their disorder.”
The experience in Ecuador was a testament to Paul’s scientific resolve and commitment to help people regardless of the obstacles he faced. These are also the traits that have defined his 25-year career at Genentech.
Heart of Science
As an undergraduate, Paul studied psychobiology at the University of California Santa Cruz (UCSC). He was intrigued by how stress impacts people both mentally and physically, but frustrated by the state of the field.
“There was and still is a huge need for more research on mental health,” Paul explains. “Counseling and psychiatry can be immensely helpful for many people, but for others, it’s not always easy to measure the effect. I realized that from a scientific perspective, the in-between ground is endocrinology. Hormones are the mediator among psychology, biology and the environment, and I wanted to get to the very heart of the science and explore these areas.”
Paul began exploring endocrinology, the study of hormones, as an undergraduate in the lab of UCSC professor Frank Talamantes. He enjoyed the work so much that he stayed in the same lab for his Ph.D.. Paul studied fetal alcohol syndrome and the effects of pregnancy on metabolism, and found himself intrigued by a family of growth-regulating proteins called insulin-like growth factors, or IGFs.
After finishing graduate school, Paul was eager to continue his work on IGFs, so he looked up the top labs in the country that studied them. He landed a post-doctoral position in Ron Rosenfeld’s lab at Stanford, where he met a professor from Ecuador named Jaime Guevara Aguirre.
Aguirre and his colleagues were the ones who had discovered that people in rural Ecuador had a particularly high incidence of Laron dwarfism. Aguirre had a patient clinic in Ecuador, but needed Paul and Ron’s help in identifying the genetics behind the disease.
“When we arrived in Ecuador, we took a four-wheel drive up through the Andes right around the Peru border. We drove around to different cities and villages searching for kids who might be affected. We invited the kids and their families to our clinic to take blood samples. Everyone was very friendly, and the kids were excited that doctors from Stanford were there to help make them grow.”
Paul and Ron spent two weeks in Ecuador collecting samples from more than 30 kids. Once they finally convinced the customs agents that they were scientists and not drug smugglers, they got back to the lab where their colleague Uta Francke made an exciting discovery.
“We identified a genetic mutation which caused these kids to not have functional growth hormone receptors. There are many different mutations that affect this receptor, but interestingly all of the kids from Ecuador had the same exact mutation in this gene. At the time, there was no therapy other than IGF that would help these kids grow. We knew we had to help them, so we set up clinical trials.”
As Paul and Ron launched clinical trials of IGF in Ecuador, they learned that Genentech was conducting studies in patients with similar growth hormone mutations. Paul and his team forged a research relationship with Genentech that produced multiple publications on IGF-1. The partnership brought Paul to a crossroads in his career.
“I had to make a decision. Do I go to industry or stay in academia? When I realized I wanted to do something where my work made a true clinical impact, where I could see these kids start to grow, the answer was clear. I knew that helping these kids in Ecuador was what I wanted to do, and going to Genentech was the way to do it.”
Paul joined Genentech as a scientist in 1993 to help build a new area of study in the pharmacokinetics (PK) and pharmacodynamics (PD) of protein therapeutics, fields focused on understanding how medicines interact with the body. Right away, he knew that he’d arrived at a place where he could make things happen.
“When I started, the PK/PD group was completely new and the team felt disorganized and lacked a unifying direction. After two months, I asked my boss at the time why they hired me and how I could make an impact. He said, ‘I didn’t hire you to tell you what to do. I hired you to figure out what needs to get done and to go do it.’ That response was incredibly freeing because it meant I could trust myself and do what I thought was right.”
And he did. At the time, Genentech was pursuing IGF-1 as a potential treatment for diabetes, but stopped development when late stage clinical trials didn’t pan out. But that wasn’t the end of IGF-1. The molecule was out-licensed from Genentech to a small biotech company, and Paul stayed in touch with their scientists to provide his expertise and historical knowledge. Eventually, IGF-1 became an approved medicine for people with growth factor receptor deficiency, including the Ecuadorian children with Laron dwarfism. Paul was proud that his original research efforts and his work at Genentech played a part in making this medicine a reality.
Seeing the Future
Following his work on IGF, Paul led the team that developed a medical device to administer Genentech’s growth hormone medicine. He then helped develop the dosing regimens for a number of medicines in asthma and even multiple sclerosis. Over time, Paul’s focus at Genentech evolved from pharmacokinetics and pharmacodynamics into identifying and developing biomarkers and diagnostics.
“Our job was to answer questions like: Does the drug hit the desired target? Do you see tangible indications that you’re impacting the disease? Can you identify patients most likely to respond to our therapies? As part of our scientific strategy at Genentech, we wanted to identify predictive biomarkers and companion diagnostics like they have in oncology. It’s challenging to find biomarkers in the non-oncology space because oftentimes disease is not driven mainly by genetic mutations or a single driver pathway. There are many environmental factors and other things that impact disease.”
But that’s why the work is so important, Paul says, because biomarkers can enable the treatment of chronic diseases before symptoms emerge. He envisions a future in which diseases like Alzheimer’s, obesity, and diabetes are addressed in their infancy.
“Many medicines today have been developed to alleviate the symptoms of a person’s disease rather than curing it. But when I think about personalized healthcare and the future of medicine at Genentech, I see the direction shifting to curing and preventing diseases.”
Paul Fielder is the Vice President of Pre-clinical and Translational Pharmacokinetics (PTPK) & Immunology Tissue Growth and Repair (ITGR)/Ophthalmology, Metabolism, Neuroscience, Immunology (OMNI) Biomarker Development at Genentech. Learn more about his work here.