It began with the quest to keep yogurt from going bad.
Philippe Horvath, a soft-spoken food scientist who went to work for a French chemical company in 2000, was charged with identifying the best strains of bacteria for making the popular dairy product. Bacteria can be infected by viruses, just like humans and other living things, and Horvath was engaged in a constant effort to weed out the infection-prone strains that would no longer work.
But a few years into the job, he noticed an odd thing: Certain bacteria seemed to have incorporated snippets of DNA from the viruses that attacked them. He began to study this phenomenon, and in 2007, he and colleagues announced a finding that has electrified the fields of biology and medicine. These snippets were microbial "mug shots" — a record of past attackers that bacteria could use to recognize and fight off viruses the next time they showed up.
Horvath, now a senior scientist at DuPont, is in Philadelphia this week to receive a $250,000 prize from the Franklin Institute. That's because others have built on his bacterial discovery to develop a fast, inexpensive tool for editing genes.
In just a few short years, this CRISPR technique — pronounced "crisper" — has upended almost too many fields of science to name. It is being used to design greener plastics, disease-resistant crops, and new weapons against cancer, malaria, and sickle-cell anemia. And it is so straightforward that even high schoolers — with careful supervision — have used it.
Horvath is joined this week by eight other honorees at the Franklin Institute, including pioneers in such fields as climate change, computer science, and rechargeable batteries. CRISPR is a relative newcomer among these disciplines, and likewise Horvath, who turned 48 this week, is the youngest of the award-winners by at least a decade.
The gene-editing tool that emerged from his discovery is not without flaws, as well as legal battles, and even some of its proponents worry there is too much hype when careful science is essential. But these days, no one would deny that CRISPR is powerful.
Like Lego pieces
Horvath grew up in Colmar, in eastern France, inheriting a fondness for tinkering from his father, a toolmaker. He enjoyed Legos and puzzles such as Rubik's cube, and he went on to study molecular biology — working with DNA, the building blocks of life.
(In the same vein, the Franklin Institute illustrated his research Tuesday afternoon with a construction toy called ZOOB, while Horvath and other award-winners fielded questions from museum visitors.)
Horvath earned his Ph.D. from Louis Pasteur University — named for another French scientist acclaimed for his work with bacteria — and started work in 2000 at the food division of a company called Rhodia, which made cultures used in the production of cheese and yogurt.
He began to study the mysterious stretches of DNA in bacteria after learning of them at a conference in 2002, and was joined by colleague Rodolphe Barrangou in 2005, soon after Rhodia's food division was acquired by the Danish company Danisco.
The name CRISPR, coined by other scientists who were studying it, stands for clustered regularly interspaced short palindromic repeats — short, repeating stretches of bacterial DNA that were interspersed with the odd snippets that seemed to come from viruses.
Horvath's team found that bacteria exposed to viruses could indeed acquire these viral snippets, called spacers. And by artificially adding or deleting spacers, the researchers found they could increase or decrease the ability of bacteria to fight off infection.
They applied for patents on their discovery, then submitted the findings for publication in the leading scientific journal in the United States. No luck.
Horvath is not sure why, but his impression is that at least one reviewer simply did not believe the findings. Scientists had been studying the genetic codes of bacteria for years. And now he and his colleagues claimed to have discovered a kind of bacterial immune system no one had seen before?
After some tweaks, the authors resubmitted the study, and it was published in Science. But even Horvath failed to realize its full impact, at first.
"We understood that it was an important discovery," he said. "At the time, we did not anticipate it would become a revolution in biology."
Labs around the world started to explore the phenomenon further. Horvath and others went on to identify important roles for still other stretches of DNA next to CRISPR and the viral spacers — sequences they called "cas," for CRISPR-associated. One type of "cas" protein appeared to act as a knife, cutting genes in invading viruses as directed by the spacers.
Then by 2012, multiple teams of researchers demonstrated that a synthetic tool based on Horvath's research could be used to edit DNA in any organism. Bitter patent battles ensued.
Horvath — whose employer was acquired in 2011 by DuPont, which in turn merged with Dow last year — has steered clear of the acrimony. At his lab in the small town of Dangé-Saint-Romain, a three-hour drive southwest of Paris, he does not even use the synthetic gene-editing tool that emerged from his research. Instead, he makes use of the CRISPR process in its natural form — dubbed "scissors in yogurt" by one media outlet in France. He exposes bacteria to selected viruses in order to determine which ones can resist infection.
"It's like a vaccination," Horvath said. "It's a natural process."
Crops and cancer
Others under the DowDuPont umbrella, however, are plowing ahead. The company's agricultural products division, Corteva Agriscience, is using a CRISPR-based tool to improve yields in a crop called waxy corn — a grain whose starchy properties are useful in industrial applications such as paper manufacture. The technique is not used to add "foreign" genes to the corn, but to disable one of the plant's naturally occurring genes — in effect, using gene editing as an efficient way to accomplish what is now done by breeding.
The field of medicine has embraced the tool as well. University of Pennsylvania researchers plan to use a CRISPR-based tool to treat melanoma, sarcoma, and multiple myeloma — removing immune-system soldiers called T-cells from patients, "editing" the cells so they will target the cancers, then re-implanting them in the body. At Christiana Care Health System in Delaware, researchers have used a CRISPR-based tool to fight lung cancer in mice, "knocking out" genes that cause tumor cells to resist chemotherapy and immunotherapy. And countless biology labs around the world use the technique for basic research, tweaking the genetic recipes of life to determine how they work.
Eric Kmiec, director of the Gene Editing Institute at Christiana's Helen F. Graham Cancer & Research Institute, also sees potential for CRISPR in education. He conducts workshops for teachers and students at the community college and high school levels, viewing it as a way to prepare students for the high-tech workplace.
One such student, senior Ally Kong at the Tatnall School in Wilmington, followed Kmiec's CRISPR "protocol" recently to disrupt a gene in yeast — causing the normally white organism to turn red when placed in a growth medium.
"It was so incredible," said Sharon Kreamer, a Tatnall biology teacher. Kong now plans to teach the technique to fellow students at the school in May.
As with previous gene-editing techniques, scientists are alert to the possibility that CRISPR could "edit" genes other than the one being targeted. What's more, the edits can leave behind a type of genetic scar tissue — an issue Kmiec's lab has addressed by devising what he calls a molecular "bandage."
He is a big proponent of CRISPR, but also is among those urging caution.
"CRISPR is good enough not to have any hype," Kmiec said. "It really is a remarkable tool, if we just move forward methodically and carefully."
Yet the initial advances were made at a startling pace once Horvath discovered the defense mechanism that bacteria have had for millions of years, said Jayatri Das, chief bioscientist at the Franklin Institute.
"It's really remarkable how this technology has gone from an observation in nature to a potential life-changing tool in medicine so quickly," she said.
The attention has led some to raise the prospect of an even bigger honor for CRISPR's early leaders: the Nobel Prize. That kind of talk makes Horvath uncomfortable, as he told the French publication La Nouvelle Republique in 2016.
"That seems to me like something on another planet," he said. "Very far from the little world where I work."
Here are the other winners of the 2018 Franklin Institute awards, to be given at a ceremony Thursday:
Vinton Gray Cerf and Robert E. Kahn, computer and cognitive science
Susan Trumbore, earth and environmental science
Manijeh Razeghi, electrical engineering
Adrian Bejan, mechanical engineering
Helen Rhoda Quinn, physics
John B. Goodenough, chemistry
Anne M. Mulcahy, Bower Award for Business Leadership
While trying to find a better way to make yogurt, #PhilippeHorvath discovered a gene-editing mechanism that could lead to cures for some of the world's most prevalent diseases. He is the 2018 Winner of our Bower Award and Prize for Achievement in Science. https://t.co/f9JjSBHXNq pic.twitter.com/4aepd0rFEK— The Franklin Institute (@TheFranklin) April 13, 2018