Last week marked the historic Food and Drug Administration approval of the first CRISPR therapy. It’s a one-time treatment for patients suffering from sickle cell anemia and a related blood disorder, beta thalassemia. It involves editing a patient’s bone marrow stem cells in a lab to turn on a functioning version of a gene to make hemoglobin, a protein in red blood cells that carries oxygen throughout the body, and which is abnormal in patients with these inherited disorders, causing them episodes of intense pain. The edited cells are infused back into their bodies to restore working hemoglobin and eliminate or greatly reduce their suffering.
It’s only been eleven years since scientists Jennifer Doudna and Emmanuelle Charpentier discovered CRISPR, and already we are witnessing the first patients’ lives radically improved: Of the 29 sickle cell patients who received the therapy in clinical trials and were followed for eighteen months, 28 did not experience severe pain crises for at least a year. Doudna and Charpentier shared the Nobel Prize in Medicine or Physiology in 2020 for their breakthrough.
Reflecting on this milestone got me thinking about other Nobel-Prize winning breakthroughs that have opened the door for impactful new medicines. In the last two decades, there are at least five examples of this phenomenon, with hundreds of millions of patients (including myself) benefiting from the new therapies or vaccines derived from these discoveries.
1) The 2006 Nobel for RNAi
Discovered in the 1990s by the scientists Craig Mello and Andrew Fire, RNAi is a programmable way to silence gene expression. Mello describes it as “guided search, just like Google.”
“Like CRISPR,” Mello explains, “both mechanisms use a short RNA sequence, which is the search query, and then the protein component of the search engine uses the genetic information to find the matching information somewhere in the cell. These protein search engines are incredible efficient and fast: they can sample 100 million different interactions per second.”
But unlike CRISPRs, which are bacterial proteins, human cells already express the RNAi search engine, called the Argonaute protein – as do essentially all eukaryotic cells – making RNAi “easier to deliver in plants and animals including humans, since only the guide RNA is needed,” Mello says.
So how is it useful in medicine?
“Artificial queries designed to target disease genes are injected into patients, where they enter cells and get loaded onto Argonautes. Once programmed, the Argonaute rapidly finds mRNAs matching the query sequence and destroys them, downregulating the gene,” Mello says. “Remarkably, the knock down of the disease gene lasts for a period of at least six months from a single dose.”
Many diseases are caused by the wrong gene being “on” at the wrong time, and RNAi can potentially address all of these.
The five RNAi drugs that are already approved target gene expression in the liver and treat conditions like amyloidosis, where the liver secretes a protein that forms amyloid plaques, causing cardiovascular disease symptoms.
Mello says there will be many additional RNAi drugs in coming years “as improved chemistry has opened up delivery beyond the liver.” Startups he co-founded include Atalanta Therapeutics, which is pursuing CNS disorders, Comanche Biopharma pursuing a condition of pregnancy, preeclampsia, and Aldena Therapeutics, pursing skin disorders.
2) The 2012 Nobel for Induced Pluripotent Stem Cells
Japanese scientist Shinya Yamanaka reported an astonishing breakthrough in 2006 that would later win him the Nobel: mature cells could be reprogrammed to become pluripotent, meaning they can become any cell in the body, much like an embryonic stem cell.
His discovery was like time travel for cells, turning back the clock on their development. “The reason this discovery is so powerful is this is the first time we were able to generate a stem cell state starting from adult tissue, to be able to make any cell type on demand from any of us,” explains Nabiha Saklayen, CEO of the startup Cellino.
Cellino, which has received funding from my team at Leaps, is developing an autonomous, closed platform to enable the commercial scale-up of future therapies that depend on induced pluripotent stem cells. These therapies include autologous cell transplants, in which a person receives a transplant of their very own cells, programmed to become healthy cardiac or retinal cells, for example, just from a sample of their skin. This would mean the patient doesn’t suffer any risk of rejection.
Right now in the U.S., there are four early-stage clinical trials in effect for personalized iPSC-derived therapies: age-related macular degeneration, congenital heart disease, and two in Parkinson’s disease.
“Without Cellino,” Saklayen says, “these incredible therapies that are entering phase 1 don’t have a path to commercialization because there is currently no other way to manufacture except for highly trained scientists making cells by hand. We don’t have enough Ph.D.-level scientists to make them by hand, even for 100 patients.”
Another exciting application of Yamanaka’s breakthrough is the development of off-the-shelf cell therapies that can replace or restore lost or damaged cells. BlueRock, which I helped form in 2016, was one of the earliest companies to work on the commercialization of induced pluripotent stem cells (and in 2019 became a wholly owned subsidiary of Bayer). BlueRock has developed a proprietary platform that differentiates stem cells into dopaminergic neurons for the treatment of Parkinson’s disease.
In August, BlueRock announced the positive results of their Phase 1 trial, in which the iPSC-derived neurons were surgically implanted into the brains of 12 patients, who were followed for a year. The therapy was well tolerated, and PET imaging scans showed evidence of the cells surviving and engrafting in their brains. Encouragingly, the patients who received the highest dose showed the greatest improvement in their symptoms, including a reduction in involuntary muscle movements. I eagerly await the expansion of the trial to phase 2 next year.
3) The 2018 Nobel For Immune Checkpoint Inhibitors
Tasuku Honjo and Jim Allison won the Nobel for their discoveries in cancer immunology: namely, two molecules called PD-1 and CTLA-4 that cancer cells suppress to escape the immune system.
Their discovery enabled the development of a class of therapeutic molecules called immune checkpoint inhibitors that block these pathways and enhance a patient’s own immune system to fight off cancer. To date, at least eight immune checkpoint inhibitors for PD-1 are approved to treat 18 types of cancer. While these therapies have become a cornerstone of care – and have greatly improved some survival rates – not all patients are eligible, and even fewer show successful outcomes.
As reported in JAMA, about 36-38% cancer patients were estimated to be eligible in 2019 to receive an immune checkpoint inhibitor, and only 10-11% had total responses.
4) The 2020 Nobel For The Hepatitis C virus
Before the discovery made by Harvey J. Alter, Michael Houghton and Charles M. Rice, hepatitis A and B were known, but “the majority of blood-borne hepatitis cases remained unexplained,” the Nobel Committee wrote. “The discovery of Hepatitis C virus revealed the cause of the remaining cases of chronic hepatitis and made possible blood tests and new medicines that have saved millions of lives.”
The disease affects roughly 58 million people worldwide and diminishes the function of the liver over time, leading to severe inflammation or cancer. Since their discovery, antiviral drugs were rapidly developed that can cure for Hepatitis C for the first time in history.
According to the World Health Organization, more than 95 percent of people with Hepatitis C can be cured by taking one pill a day for eight to 12 weeks. That said, access to treatment and diagnosis is low.
5) The 2023 Nobel For Lab-Made mRNA Modifications To Enable Human Immune Tolerance
Drew Weissman and Katalin Kariko won this year’s Nobel for their discovery of how to make mRNA tolerated by our immune systems – a crucial enabling breakthrough that paved the way for the Covid mRNA vaccines in 2020. Last month, I had the pleasure of interviewing Weissman about what he thinks the future holds for future vaccines and treatments based on mRNA, including new therapies in the works for cancer and autoimmune diseases.
As we close out 2023, a year that many in biotech will remember for its financial difficulties, let us also celebrate the phenomenal strides happening in labs and doctor’s offices around the world. When great science unleashes great medicines, I am reminded of why I got into this business in the first place. To me, there is no higher calling than to drive new leaps forward for patients. Thank you for reading, and onward to 2024!
Thank you to Kira Peikoff for additional reporting and research on this article.
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