In biotechnology, sometimes a CEO’s personal pain motivates scientific gain.
Osteoarthritic pain in Nathaniel "Ned" David’s toes serves as a personal driver for the Unity Biotechnology First Company that he quietly co-founded in 2011 and then in February 2016 propelled into the public arena from its home at The Buck Institute for Research on Aging in Novato. A runner for some 35 years, David sees the potential that a drug under study at his fledgling company might eventually ease or eliminate the pain.
“We have made a lot of progress over the last few years,” said David, 49, Unity’s CEO, who earned a Ph.D. in molecular and cellular biology at University of California, Berkeley. Early drug candidates at the company may target arthritis and glaucoma. “Osteoarthritis is the primary reason it hurts to be old. Imagine if it didn’t hurt to be old,” he said.
Unity Biotechnology has initial funding from venture investor ARCH Venture Partners, with additional capital from Venrock, WuXSi, Mayo Clinic and Unity’s management team. With an initial staff of 21, the company will look for drugs to counter cellular senescence, the process where cells cannot replicate but remain alive and contribute to diseases of aging. By the end of next year, the employee count will likely grow to 50.
Fighting for lives
Many of the company’s scientists, including collaborators in places such as Mayo Clinic, are in their 30s. “Technical success can materially impact all of their lives in a real way. There’s an urgency that people feel here. They are literally fighting for their lives,” David said.
“Our investors could fund us forever if we wanted,” David said. “We take the money as we need it. We’re not talking about the money part. We will make an announcement mid-year on money.”
He put his own money into the venture. “I put a lot of capital into this,” he said, investing profits he made from previous biotech ventures, such as Achaogen, Syrrx, acquired by Takeda Pharmaceutical, and Kythera Biopharmaceuticals, acquired by Ireland-based Allergan in October 2015 for $2.1 billion.
“Since Kythera (which he founded) I don’t do stuff for money anymore,” he said. “You saturate pretty quickly. Additional money has no impact on your happiness. Things that make me happy are: seeing my 7-year-old son really happy; experiments working; seeing people get off on the collective metaphor of the company, feeling that electricity. Those are things that move me. I would really like it if my osteoarthritis went away so I could go for a 10-mile run and not worry that the next day I would be in pain.”
ARCH and Venrock hold major stakes in biotech investments. “In the last bubble, ARCH created some $25 billion in capitalization of companies. Venrock was” not quite that big, David said. “Those are our two funders. We will probably bring in some others.”
Revenue from an approved drug to clear senescent cells, if achieved, could be 10 years away, he said.
“We have lots of evidence that these cells are driving disease,” David said about glaucoma and arthritis, and that elimination of senescent cells halts the disease.
Senescence causes inflammation
When genetic mutations damage human cells, one of two things normally occurs: they die in a process called apoptosis then are reabsorbed or recycled by the body; or they become senescent, where they stay alive but lose their ability to repair or regenerate. Both processes suppress tumors, and serve as the body’s usually successful mechanism to halt cancer early in life.
Researcher Leonard Hayflick discovered senescence in the 1960s, and found that human fetal cells only divide 40 to 60 times before they become senescent. But the process, beneficial early in life, turns destructive in later years. Senescent cells secrete about 40 proteins; some cause inflammation.
Transient inflammation induced by senescent cells can help ward off invading organisms after an injury, indicated by redness and swelling that attends a wound in early healing stages. Senescent cells also produce growth factor that helps close a wound. But chronic inflammation from clusters of senescent cells contributes to many diseases of aging — ironically including cancer.
In apoptosis or cell death, enzymes dissolve proteins and DNA. Human bodies are “basically insoluble, which is why it’s safe to take showers,” David said. The enzymes in apoptosis make the insoluble elements in cells soluble. “It’s like the ultimate form of giving in to entropy,” he said.
“Senescence is uniquely druggable,” David said, with drugs that push senescent cells to die by apoptosis. That makes senescence an attractive scientific realm in which business interests can grow, possibly into a mammoth market that could help billions of people fend off maladies of aging. Even a modestly priced drug could reap immense revenue and potential profit.
In 2010, an estimated 525 million people worldwide were age 65 or older. By 2050, that number is expected to nearly triple to 1.5 billion. If a senescence-defeating drug were purchased by a third of these people, 500 million, at $1,000 every five years per person, the market for that drug could be $100 billion a year.
Everybody will take drug
“If we technically succeed, this will impact everyone in a deeply personal way. That’s pretty cool. This is a drug where almost everybody you know will take it after they’re 30,” he said.
“What if you don’t have to charge very much? Think about the impact on health-care economics,” David said. “What percentage of GDP is associated with paying for diseases of aging?”
Scientists at Unity suggest that drugs to treat senescent cells could be ready for clinical testing in humans in a few years. “We think we physically have the drug in hand,” David said. “We don’t know that for sure. We built a bunch of molecules.”
Judith (Judy) Campisi, Ph.D., one of Unity’s co-founders and a professor at the Buck Institute, worked previously at Lawrence Berkeley National Laboratory. “We have powerful mouse models,” Campisi said. “It’s a genetic trick. We can’t use it in humans yet.”
Cleanly kill senescent cells
In lieu of genetic tricks, Unity is working on pharmaceuticals to “very cleanly kill senescent cells in a mouse,” she said, triggering cells to die in a few hours by apoptosis without inflammation as cross-linked fragments of cells are gobbled up by nearby cells that recycle the nutrients. Diseases of aging occur when senescent cells don’t die. Disease can cause cells to die in a messy way, called necrosis, where they essentially explode.
“The biochemistry of DNA (deoxyribonucleic acid) replication” moves in one direction, Campisi said. Cells use RNA as a primer to start copying DNA, which contains instructions for new cells. “Every time your cells divide, you have to copy three billion base pairs of DNA,” she said.
The ends of chromosomes, thread structures inside cells that each hold a molecule of DNA, degrade with each replication. “If DNA breaks, the cell goes into panic mode and attempts to fix that break at any cost,” Campisi said, sometimes joining broken DNA fragments and causing mutations, a huge cancer risk.
A telomere is an area at the end of a chromosome that protects it from deterioration — the way plastic tips keep shoelace ends from fraying. After a number of replications, telomeres become shorter and cell division stops.
Even in very diseased tissue, senescent cells are rare. The problem is not individual senescent cells, but the fact that they secrete substances that damage neighboring healthy cells. “When you kill off a senescent cell, it’s unlikely you will leave a big hole,” she said. Killing senescent cells slows wound healing, Campisi said. “You would not want to take such a drug before surgery.”
Senescence, aside from its deleterious effects, may have unseen benefits in the body. Campisi’s scientific mission is to “understand the process in enough depth so that we can be intelligent about how we” alter it, she said.
Many tissues have stem cells that can change to form multiple parts of the tissue — compared to progenitor cells that make specific tissue. Once senescent cells are cleared, healthy cells can do their jobs, Campisi said. Researchers make senescent cells glow to track them in mice.
Unity drugs kill any senescent cells near the injection point; they are not so far targetable to specific cells. “Our most potent senolytic molecules seem to be equal-opportunity murderers,” David said. He measures a drug’s effectiveness in terms of a ratio. “Our very best molecules have ratios approaching 300,” he said, meaning that scientists would have to add 300 times more drug to kill any healthy cells.
Senescent cells need to be exposed to a senolytic drug for a few hours in order to die about a day later, what David calls “engagement of the target.”
Scientists don’t yet know if senescent cells are produced more frequently or in larger numbers as a person ages. Neither do they know if killing senescent cells will increase maximum lifespan or simply reduce diseases that occur late in life — increasing healthspan. Campisi quotes Supreme Court Justice Thurgood Marshall, who died at age 84 after proclaiming, “I expect to die at 110, shot by a jealous husband.”
“You would be vigorous and then boom, you’re dead,” she said.
Typically, aging people fall and break a hip, and their subsequent decline is long, painful and expensive. “The last three to five years of our lives are so expensive and grim — the human cost,” Campisi said.
Unity drugs would be injected locally at high concentration, such as into an osteoarthritic toe or an eye afflicted with glaucoma. Once the drug kills nearby senescent cells, it diffuses into other tissue, dropping in concentration and metabolizing. Testing in species including rodents will determine whether drugs under study are safe to the rest of the body.
Anti-senescent-cell drugs might only need to be taken every five years or even once a decade, which would reduce risks of toxicity from chronic ingestion. “If you don’t have to take the drug every day, that’s going to be a hell of a lot safer,” Campisi said.
“We are really excited,” she said about the company’s proximity to usable drugs.
In osteoarthritis, senescent cells appear to block the body’s normal production of cartilage, David said. “What if, in my toe, in 72 hours I had more cartilage,” he said, which is needed to be pain-free and to create normal toe structure.
According to Campisi, it’s easier to gain FDA approval for drugs used in local application — such as a knee suffering from osteoarthritis — than in systemic application. “We know there are senescent cells present in osteoarthritis,” she said.
In work with previous companies, David helped gain FDA approval for two drugs in the marketplace. He was formerly chief scientific officer for Kythera and co-founded four other biotechnology companies that raised more than $1.5 billion.
Culture of openness
In 1988, David worked as a summer intern in David Goeddel’s laboratory at Genentech. Near the lab where David worked was the laboratory of Art Levinson, CEO of Calico, Google’s 2013 startup dedicated to research on aging. Calico has part of its operations at the Buck Institute. Levinson served as CEO of Genentech from 1995 to 2009, currently is chairman of Apple, and was on the board of Google from 2004 to 2009. At the helm of Calico, Levinson has been extremely restrictive about providing public access to the company’s work. Unity adopted the opposite approach.
“There is certainly risk associated with our cultural decision to be open,” David said. “You can get all twitchy about which business risks you choose to expose yourself to. There’s a higher issue here, a certain moral urgency to addressing this issue — it’s humane.”
Calico did not respond to an emailed request for comment.
As a field of science, aging offers a daunting research enterprise. David summons an image of the London tube map; subway lines snake in every direction in a complex transportation web. “Where are we in understanding aging?” David said. “We don’t really know where we are. Is senescence a central part of London or a sideshow?”
As study moves forward, scientists will be able to evaluate the relevance of senescence and other processes linked to aging. “When we look back on this day 50 years from now, we’ll say, oh, that was when you guys first figured out that senescence thing.”