Life as we know it
Few scientists have done more to reshape our understanding of life at the molecular level than Nobel Prize-winner Phillip Sharp (LAS ’69).
Phil at electron microscope used to make discovery of RNA splicing. Photograph courtesy of MIT
Written by Kim Schmidt
Phil and Ann Sharp don’t often sleep in, but this day was a national holiday. That meant a day off for everyone. The shrill ring of the telephone broke the sleepy silence, and though it may have seemed as though he was still dreaming, Phil was very much awake.
Unable to hear the voice on the other end of the line, Ann saw the blood drain from Phil’s face. He turned white, and she thought, Oh, my God, his mother has died.
Instead, Phil turned to her and asked, “Do you know Rich Roberts’ phone number?”
Phil buried the lede. The call was from the Nobel Committee, letting him know he had won the 1993 Nobel Prize in Physiology or Medicine and that he would share the honor with Richard J. Roberts, a scientist at Cold Spring Harbor Laboratory in New York. The Nobel Committee, however, didn’t have Roberts’ phone number.
The quiet house quickly came to life. Within minutes, MIT was ringing the phone, and photographers were ringing the doorbell.
Ann turned to their 11-year-old daughter. “Tell the reporters to go away until at least we have our clothes on!”
What followed was a whirlwind of handshakes and photographs and speeches and champagne. Neighbors showed up to celebrate. Colleagues reached out with excited praise. Weeks later, Phil traveled to Stockholm with Ann and their three daughters, where he received his prize from the King of Sweden. Joining them were his parents, Ann’s parents, his sisters, and two members of his lab.
The celebration was decades in the making, tracing back to a childhood that shaped the scientist he would become.
Rooted in curiosity
A traditional proverb says, “Show me the child until he is seven and I will show you the man.” This is true of Phil. Glimpses of the man could be seen in the young boy he once was — hard-working, curious, and determined.
Every morning, young Phil woke up, pulled on his boots, and headed to the barn, where his cow Blackie waited for her morning milking. It didn’t matter if he saw his breath crystallize in the frigid winter air or if horseflies swarmed him on a hot summer morning. Rural Kentucky farm life demanded hard work and constant attention.
Phil’s parents also gave him a small patch of their tobacco crop to tend. He was required to help with the family’s traditional farm chores, but when he sold tobacco from his plot or calves from his cow, the money he earned was set aside for his college education.
With his tasks done, Phil could usually be found with a book in hand. Reading turned out to be hard work for Phil, too. He is dyslexic. But he powered through books about history and science. Page by page, those books revealed the world to him. Lying in the grass under the open sky, Phil began to form visions of what could be.
But for all his dreaming, this boy — who sometimes felt like an outcast — didn’t imagine that one day he would be immortalized in the annals of science.
Over time, Phil would come to understand that his dyslexia and the unique way it shaped his thinking were among his greatest strengths. Minds like his are compelled to make meaning in their own way.
Phil’s path to Illinois began at Union College, now Union Commonwealth University, located on the edge of the Appalachian Mountains. On the first day of class, he met Ann, an education major from New Jersey with whom he would spend the next 62 years — and counting. Phil saved the money he earned working in the cafeteria kitchen to buy Ann the wedding ring she still wears today. They were married the summer before their junior year.
For Phil, the natural next step after Union was graduate school. Impressed by Illinois’ renowned chemistry program, Phil and Ann relocated to Urbana.
Upon arriving on campus, however, Phil failed three of his four entrance exams. There was material on those exams he had never even encountered at Union College.
Fortunately, his Illinois mentors didn’t give up on him. Recognizing his potential, they encouraged him to take additional classes to catch up. Once admitted to the graduate program, Phil plowed through his coursework and dissertation, earning his Ph.D. in just 3½ years.
While at Illinois, Phil and Ann lived in a trailer park on the edge of Urbana filled with other graduate students. Each day, they locked the door to their teal-and-white trailer, walked down the turf-covered steps, and headed to work — Ann in her beige Volkswagen Bug to welcome her third-grade students to another school day; Phil on his bicycle to Noyes Laboratory, where his growing fascination with DNA became the focus of his dissertation, “Physical Chemistry of Deoxyribonucleic Acids and Virus.”
After graduating from Illinois and completing a postdoctoral fellowship at the California Institute of Technology, Phil joined Cold Spring Harbor Laboratory in New York, where he worked with James Watson, a Nobel laureate who co-discovered the DNA double helix.
In 1974, Phil joined the faculty at MIT, and just three years later, a puzzling experiment in his laboratory would forever change scientists’ understanding of how genes work.
RNA splicing diagrams from the PBS documentary “Cracking the Code.” Image courtesy of the documentary “Cracking the Code: Phil Sharp and the Biotech Revolution” (PBS)
Coming into focus
One of the postdoctoral researchers in Phil’s lab at MIT, Claire Moore, had been running the same experiment for weeks. She laid a strand of RNA over its original DNA template, peered through the electron microscope, and recorded what she saw.
Her introductory biology classes taught her that RNA is an exact duplicate of DNA. RNA’s job is to deliver instructions to the cell so it can make a protein. Proteins, in turn, tell the body how to function.
The process was much like making a photocopy. The original DNA remained intact, and the copy RNA was an exact replica.
Biology 101.
So why was she seeing tiny, disconnected strands of RNA veering away from the main line? She should have seen a continuous strand of RNA precisely overlaying the DNA.
Maybe it was an artifact, some experimental error.
Phil asked her to try it again. Add more salt. Change the conditions.
But the rogue offshoots of RNA persisted.
Claire and Phil, joined by senior fellow Susan Berget, huddled around the electron microscope once more, this time examining a longer piece of DNA. Phil saw a pattern and suddenly realized what it meant.
“Oh, holy [you-know-what]!” he exclaimed.
To the average eye, the thin strands of RNA appeared as simple black squiggly lines against a blurry background, the kind you might doodle while talking on the phone.
To Phil, however, those tiny tails foretold an enormous biological revolution.
What they recognized that day was that, instead of faithfully duplicating DNA, RNA was cutting itself into pieces, removing long sections that scientists called “junk,” and stitching itself back together before passing along the instructions needed to make a protein.
They called it RNA splicing.
Think of editing a film. The editor begins with hours of raw footage, decides which scenes belong, arranges them into the right order, and leaves the rest on the cutting-room floor. The finished product is what we now call messenger RNA, or mRNA.
That editing process has to be remarkably precise. When RNA pieces are stitched together incorrectly, the resulting errors can contribute to disease.
So why was the discovery of RNA splicing so revolutionary?
It revealed that genetic information was not nearly as fixed as scientists once believed. Before a protein is ever made, RNA can be edited, rearranged, and refined.
Suddenly, entirely new scientific frontiers opened.
It took real intellectual courage to follow the evidence to its conclusion.
— Professor Auinash Kalstotra
Could researchers correct genetic errors? Could they create entirely new proteins? Could they stop a disease before it ever took hold?
“The experimental approach was technically creative and demanding, but recognizing what those [tails] actually meant was something else entirely,” said Professor Auinash Kalsotra, the Phil A. Sharp Professor and William C. Rose Scholar of Biochemistry at Illinois. “It took real intellectual courage to follow the evidence to its conclusion — a conclusion that flipped a foundational assumption of molecular biology completely on its head.
“The experiment was brilliant, but the interpretation was an even bigger leap.”
The rise of biotech
Our understanding of genetics evolved slowly through the latter part of the 19th century, but after James Watson and Francis Crick revealed the double-helix structure of DNA in 1953, the pace accelerated. Over the decades that followed, scientists continued — and continue — to unravel DNA’s mysteries, with each breakthrough laying the groundwork for the next.
In the early 1970s, scientists at Stanford University developed and patented recombinant DNA, a method of combining genetic material from two or more sources into a single strand of DNA. It is this technology that allows scientists to produce human insulin using E. coli or yeast rather than extracting it from pigs or cattle, a breakthrough that transformed the treatment of diabetes.
Of course, this new science was not without controversy.
The idea that scientists were “Frankensteining” together new DNA sequences in laboratories — especially using bacteria like E. coli — sparked public concern. Protesters gathered around MIT and Harvard, and newspapers filled with alarming headlines.
Were scientists creating dangerous new viruses? Should science wield this much control over humanity’s genetic future?
In an extraordinary move, scientists themselves called for a moratorium until they could establish guidelines for conducting this research safely.
In 1975, hundreds of researchers, including Phil, gathered at the Asilomar Conference in Pacific Grove, California, to confront the ethical questions surrounding recombinant DNA. There were no laws governing this work, only the scientific community’s collective commitment to proceed responsibly.
Together, they reached an agreement that would shape the future of biotechnology: research would continue, but with carefully established safeguards and a shared commitment to using the technology for humanity’s benefit.
One unexpected consequence of the meeting was the attention it attracted from investors.
In a retrospective produced by the National Institutes of Health, Phil reflected on the conference’s visibility.
“The investment community decided that there was something new here; it was going to transform society, and therefore it was valuable,” he said. “That led to a lot of venture investment in early biotech companies that wouldn’t have been there if society hadn’t known about this technology and how transformational it was.”
With recombinant DNA making it possible to engineer genes and Phil’s discovery of RNA splicing, scientists began to understand — and eventually treat — disease in ways never before imaginable.
A revolution in medicine was underway.
Phil was among those who believed that scientific discoveries should not remain confined to academic journals. They needed to become medicines. They needed to reach physicians. Most importantly, they needed to reach patients.
“There was a lot of skepticism in the 1970s about anything that was corporate or capitalistic,” Phil said. “In fact, there was deep skepticism about whether we should use genetic engineering in any form.
“But there were a few people, me included, who anticipated the world needing this technology in 10, 20, or 50 years. We needed to find a way to move it beyond academia and into society by developing professions that could expand, refine, and apply it to solve real-world problems.
“That led to the establishment of Biogen.”
In 1978, Phil and a handful of prominent scientists from the United States and Europe founded Biogen, one of the world’s first biotechnology companies. Nearly 50 years later, the company continues to develop treatments for multiple sclerosis, lupus, Alzheimer’s disease, and other illnesses.
“A lot of my colleagues looked at me askew and asked why I was wasting my valuable energy trying to make a buck,” Phil said. “Making a buck is secondary. Growing the technology was the primary reason.
“To think of having a whole private sector helping patients through genetic manipulation was like having an opportunity to create the future.”
Phil has spent the subsequent decades pushing the boundaries of science while mentoring the next generation of researchers. He later co-founded additional biotechnology companies, including Alnylam Pharmaceuticals. Today, he serves as advisory board chair of MIT’s Jameel Clinic, which develops AI-enabled tools for clinical care and drug discovery.
At the core of Phil’s scientific pursuits is his desire to improve people’s lives.
“It is important to serve other people,” he said. “One of the most powerful things we can do is expand our understanding and share what we learn to help others.”
Returning to campus
In April, Phil and Ann returned to campus for two days of visits and events, including a screening of “Cracking the Code: Phil Sharp and the Biotech Revolution,” a documentary about Phil now airing on PBS.
Although Phil has undoubtedly answered thousands of questions about his work over the years, there is no trace of fatigue in his voice. He remains as curious, open, and approachable as ever. In the span of a single conversation, he can make an extraordinarily complex idea feel intuitive, drift into stories about bicycling across Europe, and enjoy the myriad ways science has unraveled so many of life’s mysteries.
The Sharps are generous supporters of the university, and during this visit, they celebrated the investiture of the first Phil A. Sharp Professor of Microbiology, Auinash Kalsotra.
Kalsotra is one of today’s leading RNA researchers and is continuing in Sharp’s footsteps, working to deepen our understanding of RNA splicing and disease. His research focuses on how RNA transcription influences tissue growth. Recently, his laboratory identified a direct link between disrupted RNA splicing and deficient tissue repair, showing that errors in RNA transcription impair the liver’s ability to regenerate in alcoholic liver disease.
Phil describes Kalsotra as “a dynamic person at the peak of his scientific career,” and delights in the fact that they share the same field of research.
“We wanted to support a young scientist doing really exciting work and help expand his research and its impact,” Phil said. “It is also an expression of our appreciation for what the university did for us, which was launch us into an exciting career.”
It was a career that took Phil and Ann across the country and back, from Kentucky to Illinois to California to Massachusetts. And each time a new opportunity presented itself, the decision to pick up and move was made by them equally.
“What is really important to point out is that Ann bought into and really supported this career path. Otherwise, this wouldn’t have been possible,” said Phillip. “It was a lot of fun, but you had to be open to it. We always thought about how to accommodate the family. This had to be a family affair.”
At 82, Phil looks back on his scientific life with pride and a touch of Kentucky humility. His enormous influence on biotechnology is, to him, a privilege and a reward, not because of the accolades, but because he has met patients whose lives have been transformed by medications and treatments his science helped make possible.
“When you see 30-year-old patients who can’t even walk up a flight of stairs because heart failure has severely limited their mobility — and then realize that treatments you helped develop could give them another 40 to 50 years of active life — it is an extraordinary reward,” he said.
