hen the Nobel Prizes are announced next week, the winning biomedical discovery is certain to be showered with a ton of hype. And that might be a problem. The path from a brilliant lab discovery to an actual medication is long and winding — and sometimes, high expectations can backfire.
Take the roller coaster ride of RNA interference, a Nobel-winning technology that received heaps of accolades and billions of dollars in funding, only to stumble badly when the science didn’t deliver actual drugs – at least, not fast enough for investors.
A decade after the Nobel glory, RNAi is again on the upswing: The first drug using the technology to mute disease-causing genes could get federal approval as early as next year. But its tortured path stands as a cautionary tale for other much-hyped and widely-honored discoveries, from immune-boosting cancer vaccines to optogenetics to the CRISPR gene editing system, which is considered a serious contender for a Nobel next week.
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“I assure you, God didn’t create RNAi to make drugs out of it,” said John Maraganore, CEO of Alnylam Pharmaceuticals, which is working on RNAi in Cambridge, Mass. “We had to figure that out.”
A quest begins with a roundworm
The story of RNAi begins with the nematode. In the early 1990s, a handful of researchers studied how genes were expressed in these small roundworms — and found that they could manipulate that process by interfering with the worms’ RNA. A seminal paper published in Nature by scientists Andrew Fire and Craig Mello showed that roundworm genes could be silenced.
And that had stunning implications for medicine.
Many diseases are caused by the buildup of proteins that are misshapen or don’t work properly. Conventional drugs often aim to cleanse these proteins from the body. RNAi therapies, by contrast, could in theory shut down production of the dysfunctional proteins altogether — by silencing the gene that carries the coding to make them.
Excited, researchers began trying to control genes in mammalian cells the way Fire and Mello had done in roundworms. That code was finally cracked in 2001, and biotech startups began working furiously to turn RNAi into drugs.
In these early days, Maraganore said Alnylam’s team included a couple researchers and a whole bunch of patent attorneys — because the RNAi technology was viewed as so hot that the team wanted to gobble up as much intellectual property as possible. It was a “bubbly time,” Maraganore said. “A period of unbridled enthusiasm for RNAi.”
Patients, researchers and, importantly, investors, looked at the field as the next big breakthrough in medical science. But the hype far outstripped the reality.
“I think most people didn’t understand at that point what they were really excited about, and what the path forward would be,” said Dirk Haussecker, an independent analyst who carefully tracks RNAi technology.
The burden of a Nobel Prize
Then came the Nobel prize.
Mello, a researcher at University of Massachusetts, and Fire, who by then was a professor at Stanford University, won the award in 2006 — a mere eight years after their success in roundworms was first announced to the world.
The field exploded. Venture capital had already doused RNAi with dollars. Now, funding from big drug makers also flooded in — most notably, when Merck paid $1.1 billion to acquire an RNAi startup called Sirna Therapeutics.
“It got a lot of people excited, because they assumed that higher prices meant the RNAi was really going to work — quickly,” Haussecker said.
“When it comes to the Nobel prize, there are two sides to that sword,” said Doug Fambrough, CEO of the RNAi company Dicerna Pharmaceuticals, and an early investor in Sirna. “We could enjoy the benefits, but we also faced the burden of meeting the expectations.”
It soon became clear that RNAi had a long way to go.
Especially tough: Figuring out how to deliver it to the cells that needed it.
Yet despite the clear roadblocks, researchers were racing ahead with experiments, putting drugs they had barely validated in the lab into human trials.
“I think a lot of the early trials were really ill-conceived, with a lot of people doing trials just to say they were the first,” said Mark Kay, a gene therapy professor at Stanford. “I think most reasonable people who understood the field knew these trials wouldn’t work.”
The experimental drugs caused dangerous side effects in humans that hadn’t been predicted with animal studies. It turned out they couldn’t easily be delivered to the right cells in the body, and wound up being ineffective or harmful.
By 2010, the field was cratering.
Roche, having invested a half billion dollars in RNAi, decided to drop out of the field entirely. Pfizer and Abbott Laboratories also backed away in haste. Alnylam, too, had hit a “valley,” though its executives were determined to keep pushing.
“The world thought we had died,” Maraganore said.
But despite the doom and gloom, Maraganore said he wasn’t particularly worried when pharma lost interest. “Big pharma companies are terrible at innovation — they really are,” Maraganore said. Large drug makers “don’t have the staying power or spirit to take a technology like RNAi, or CAR-T [immunotherapy] or CRISPR, and make it a drug class.”
In 2014, Merck gave up on RNAi and sold Sirna, the biotech company it had previously valued at $1 billion, for just $175 million up front in cash and stock.
The buyer: Alnylam.
New hope for a revolutionary idea
These days RNAi is starting to pick up steam again, a decade after the underlying science was awarded the Nobel.
Where there were dozens of companies pursuing RNAi, nowadays there are just a handful. But big drug makers are tiptoeing back into the field: Amgen just struck a deal worth up to $647 million with Arrowhead Pharmaceuticals to explore RNAi therapeutics in cardiovascular diseases.
And after more than $1 billion in research, Alnylam has finally reached late-stage human trials on an RNAi drug for a rare, life-threatening disease that results from the buildup of misfolded proteins.
Maraganore is so confident the drug will win approval from the Food and Drug Administration in the next year or so that the company recently broke ground on a huge manufacturing facility south of Boston. The company also has a slew of other drugs in the pipeline, addressing everything from rare bleeding disorders to high cholesterol.
The key lesson for investors and patients eagerly eyeing this year’s Nobel contenders?
Even the most promising technologies can take decades to develop. Take monoclonal antibodies, which earned a trio of scientists the Nobel Prize in 1984. The discovery didn’t wind up having therapeutic applications until nearly two decades later. Today, monoclonal antibodies represent a multibillion dollar market, particularly in treating cancer.
Optogenetics, a technique that uses light to control cells, and CRISPR-Cas9, the gene-editing tool, are widely expected to win the Nobel at some point. But they’re both still in early stages. Optogenetics is just now being tested in its first clinical trial, to try to reverse a hereditary form of blindness. Researchers just recently got the first of several regulatory approvals they will need to try using CRISPR in humans.
As for RNAi, Nobel laureate Phil Sharp says he fully expects it to make a difference for patients — eventually.
Sharp, a scientific cofounder of Alnylam, is a Nobel laureate in his own right; he won in 1993 for his work in the 1970s on RNA splicing. It’s been 15 years since he showed it was possible to make RNAi work in mammalian cells. If it takes another few years to make it to patients, well, that doesn’t strike him as an unreasonable wait for such a revolutionary class of drugs.
“I’ve been in science 50 years, so this doesn’t seem terribly long,” Sharp said. “I don’t see this as a little advance — I see this as a transformation in pharmacology.”