“Science is a hard, grueling process, and much of the time quite monotonous. That’s why it’s called ‘re-search’; we do it over and over and over again.” The remark, made during a lively discussion about the arduous work of science and the personal determination that drives it, received a few chuckles from the audience. But it was also meant as a serious take on an underappreciated process. That it was delivered by Nobel Laureate and Janssen Award winner Craig Mello only underscored its import.
On that balmy, late summer evening in 2014, in a stately, yet intimate ballroom at the New York Public Library, Mello was speaking on a panel at the annual Dr. Paul Janssen Award (DPJA) for Biomedical Research ceremony. Named to honor a legendary figure in the field of drug discovery—known by his peers as “Dr. Paul”—the award celebrates the passion and creativity of biomedical innovators with an attendant ceremony that convenes some of the world’s brightest scientists, healthcare industry leaders and journalists. I have been lucky enough to attend many ceremonies over the years and to witness up close the indefatigable spirit that drives these luminaries.
The awardees being honored on that particular night six years ago were Drs. Jennifer Doudna and Emmanuelle Charpentier, for their ground-breaking work on CRISPR Cas9. The gene-editing technology allows for scalable, efficient and precise DNA manipulation, and it has since touched off a revolution in genomics research and applications. It was thus no surprise to anyone when just this past October, the Nobel Committee bestowed the 2020 Prize in Chemistry to Doudna and Charpentier for their efforts.
CRISPR Cas9 has virtually unlimited applications, from eliminating pathogens and supercharging disease research to creating heartier, more nutritious crops. According to Andy Marshall, Chief Editor of Nature Biotechnology, “Transformative is a term rarely heard in biology, but Doudna and Charpentier’s genius was to distill natural CRISPR systems into a simple RNA guide and endonuclease enzyme kit that made gene editing accessible to any research lab across the world. It truly transformed biology and medicine, and continues to do so.”
In other years, Nobel-level recognition of DPJA winners has come even sooner: Craig Mello was named the first winner in 2006, the same year he received the Nobel Prize in Physiology or Medicine, along with Andrew Z. Fire, for his pioneering work in RNA interference (RNAi). This ancient and long-overlooked biological process helps control gene expression, and it enables organisms to protect themselves from viruses, to adapt to changing environments, and to maintain stable, well-differentiated tissues. While RNAi is a natural cellular process, it is also a potent tool for the exploration and manipulation of gene expression. Mello, insatiably curious about the world since he was a little boy peering through the woods and looking under rocks of his native Virginia, served on the DPJA Selection Committee for several years. His work in RNAi continues to be an important part of biotechnology. “Almost every aspect of our health ultimately depends on how well our body’s cells regulate themselves — or fail to,” notes John Rennie, former editor-in-chief of Scientific American. “Scientists keep finding examples of RNAi fine-tuning the expression of our genes and making sure that our cells stay in good running order. It’s no surprise that it’s become the focus of so much interest as a source of new therapeutics.”
In 2016, Yoshinori Ohsumi, then at the Tokyo Institute of Technology, was honored first with a DPJA in the late spring, and then, only months later, with the Nobel Prize in Physiology or Medicine for his work uncovering the mechanism of autophagy. From the Greek words “auto” meaning “self” and “phagein” meaning “to eat”, this catabolic process eliminates unnecessary or damaged cellular components, making it vital part of cell maintenance. While the process has been known since the early 1960s, the molecular mechanisms of autophagy were deduced by Ohsumi and his team by studying yeast cells and identifying the genes that drive it. He further elucidated the sophisticated machinery that regulates autophagy in human cells, opening a whole new avenue for therapeutic investigation. Mutations in autophagy genes can propel disease, and the autophagic process is involved in several conditions including cancer and neurological afflictions. Notes Rennie on the topic, “While the role of autophagy in cancer is complicated, it’s not hard to believe that someday we’re going to be able to use it to strip malignant cells out of the body more effectively.”
On the subject of cancer, it was the 2018 DPJA winner, Jim Allison, who also took the Nobel Prize in Physiology or Medicine that same year for his discovery that the immune system could be coaxed into fighting tumors, fundamentally altering our oncological arsenal. Cancer finds sophisticated ways to hide from immune attacks, which normally seek out and destroy mutated cells. The fighting foot soldiers of our immune system, T cells, contain a protein, CTLA-4, that acts like a brake to inhibit the immune response.
While other researchers were exploiting the mechanism as a target in the treatment of autoimmune disease, Allison had the opposite idea. He wanted to release the brakes and let the immune response intensify. After developing an antibody that could bind to CTLA-4 and block its function, he proved how this could disengage the T-cell brake and unleash the immune system to attack cancer cells. The first drugs exploiting this principle hit the market in 2011, and their number has grown since.
“Jim Allison’s genius was his continual building of a critical body of evidence to support his thesis that immune checkpoints could be harnessed against cancer, despite strong headwinds from the scientific mainstream,” Marshall says. “But intellectual giants never quite follow the mainstream. They go after big ideas.”
This past fall another very big idea was on display but at a very different kind of DPJA ceremony. With little in-person mingling and a more “digitized” version of scientific camaraderie, the virtual DPJA ceremony still captured the essence of celebration, made all the more poignant in a year in which the world needs biomedical innovation more than ever.
I logged on just in time to watch physician-scientist Susan Desmond-Hellmann, former CEO of the Bill & Melinda Gates Foundation, and Paul Stoffels, Chief Scientific Officer of Johnson & Johnson, pay a quiet, eloquent tribute to this year’s winner, biochemist and cancer researcher Lewis Cantley.
More than 30 years ago, Cantley and his team discovered an enzyme, phosphoinositide 3-kinase (PI3K), and they have been tirelessly pursuing its relation to insulin regulation, cancer and other diseases ever since. Cantley embodies the DPJA spirit. As a young boy growing up in West Virginia, his first foray into science was making homemade fireworks, at the suggestion of his father. “I knew I wanted to be a scientist from very early on,” Cantley remarked in a recent interview, “I was largely influenced by my father who, whenever I asked a question about how things work, would always come up with a logical explanation rather than resort to saying ‘because God made it that way.’”
Cantley’s work implicated PI3K across multiple diseases, and more generally in human cellular metabolism. His insights, as Hellmann noted in her comments at the virtual ceremony, “have made a huge contribution to precision medicine for cancer.” Therapies targeting the PI3K pathway have proliferated over the last 8 years, and have accelerated the march against malignancy.
Summing up the inspiration of this year’s event, Stoffels, beaming on screen as he normally would in person, underscored the reason we celebrate science and scientists like Cantley, particularly in an era where they can help solve one of the biggest health challenges the planet has ever seen: “What inspires me most is the extreme collaboration we are seeing across all groups, scientists, regulators, industry, policy: this collaboration and the passion people are bringing to the current world problems is unprecedented.”
If ever there were a reason and a time for science and scientists to “win”, this is it, in the here and now.
To learn more about past DPJA winners and their achievements, visit pauljanssenaward.com