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  • Amelia C.

Biotech Investing: Understanding Senolytic Drugs


In honor of Halloween, one of my absolute favorite holidays, I felt it was fitting to write about zombie cells a.k.a. “senescent” cells, and one of the companies trying to defeat them. Senescent cells no longer divide and accumulate with age, causing tissue damage within the body. They are pretty much living dead activly wreaking health havoc.

In my last post detailing my attempt at making myself believe in buy and hold investing, I mentioned a company I’ve been following called Unity Biotechnology (NASDAQ: UBX).

Unity is one of the many biotech companies driving the scientific movement of treating biological aging as a disease. They are developing senolytic treatments, types of drugs that target and eliminate senescent cells.

From an investment standpoint, I find this field of science so exciting because of its newness and the positive impact it will have on health. Though there are a lot of anti-aging biotech companies that have been founded and funded the past few years, not many are publicly traded yet. To me, this a good sign as it indicates we are still in the very early stages of a rapidly growing field and the pioneers are still establishing themselves.

Also, as a side note, when I use the term “anti-aging,” I’m not referring to creams and OTC cosmetics etc. I’m referring to biotech and pharma companies developing treatments for age related disease and somatic degeneration.

How I Approach Speculative Biotech Companies

Since none yet have commercialized treatments available, I find the best thing to do at this point is learn as much as possible about the science behind the products, while tracking the companies’ progress and following industry news. Jumping in and taking a position now in an attempt to “get in early” is not always a good idea as there are no tangible results yet and still many milestones to pass, both financial and scientific.

However, if you’ve spent months, or even years, learning and following, by the time one of these early stage companies does hit a real milestone, you will hopefully know exactly what you want to do.

Unity Biotechnology

What initially drew me to Unity Biotechnology as a potential future investment was one of its co-founders, Nathanial David, Ph.D.

Prior to Unity, David co-founded five other companies, one of which sold to Allergan for $2.1 billion in 2015.

Given his acquisition track record and aggressive approach to bringing his innovative sciences to market, I feel like Unity is a really good biotech company to watch. As David explains, “you get kind of pattern recognition on things that feel ‘druggable.”

The Science Behind Unity

Once I understood the difference between chronological and biological aging, the scientific approaches to treating aging as a disease made a lot more sense to me. Chronological aging is inflexible and measured by the passing of time. Biological aging is flexible and measured by how aged a living organism is based on accumulated damage (think of the skin of a lifelong smoker and sunbather vs. that of someone who’s never smoked and wears sunscreen).

In a Hello Tomorrow talk by David, he explained the following three things about biological aging:

  1. Aging is flexible and malleable

  2. Aging has adjustable molecular “knobs”.

  3. The knobs can be turned and manipulated through scientific interventions.

He goes on to talk about the vast differences in the lifespans of various similar mammals and how nature has a way of adjusting these knobs that determine lifespan.

Giving some recent examples, David explains how scientists have been able to intervene on nature’s processes and successfully turn these knobs themselves.

Robert Rice extended the lifespan of a worm 10 fold by changing one gene, and Valter Longo extended the life of yeast 10 fold by altering two genes via reducing calorie intake. It’s also been observed that deleting one copy of a gene doubled a fly and mouse’s lifespan, showing that tiny gene changes can facilitate big lifespan changes.

Natural isn’t always better

We think of aging as such a natural part of life that it’s easy to forget it’s one of the biggest causes of disease.

I remember when I first learned that no one actually “dies of old age,” but rather, always from a classifiable pathology that leads to the failure of a bodily system (i.e. heart attack, pneumonia, etc.). I found that surprising as I’d always thought you get old and just sort of simultaneously shut down. But from a medical standpoint, a coroners report will most always have a specific cause of death that is not simply “old age”.

As the body ages, damage accumulates, cells become faulty, and disease susceptibility increases drastically. It’s this curious concept that’s inspired scientists to dig very deep into the molecular causes of aging and its related diseases that eventually lead to death.

The Telomere Effect

In her book The Telomere Effect, Elizabeth Blackburn, PhD describes the science behind biological aging and how it’s dictated by both environmental and genetic factors.

The graph below shows that age is by far the largest determinant of chronic diseases. The death rate due to chronic diseases starts to increase after age forty and goes up dramatically after age sixty.

Adapted from U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, “Ten Leading Causes of Death and Injury

The goal of developing anti-aging medical treatments is not so much to increase human’s lifespans drastically, but rather, to increase their health spans. As shown in the graph above, this is the time before age ~60, after which susceptibility to disease increases drastically.

Telomeres

In 2009, Blackburn won the Nobel Prize for discovering the molecular makeup of telomeres and co-discovering telomerase, an enzyme that maintains telomere ends. Telomeres are repeating segments of noncoding DNA located at the ends of your chromosomes that act as a protective sheath of proteins.

Each time a cell divides, its chromosome’s telomeres shorten. After a certain number of replications, the cell eventually runs out of telomere runway and stops dividing altogether.

The Hayflick Limit

This cessation of cellular division is called the Hayflick Limit, a concept devised in 1965 by biologist Leonard Hayflick that helps explain the mechanisms behind cellular aging. The concept is based on Hayflick’s observation that a normal human cell can only replicate forty to sixty times before stopping and moving into a phase of breakdown.

The stop controls governing the Hayflick Limit are telomeres that have hit a point of becoming critically short.

Cellular Senescence

The Hayflick Limit’s phase of non-division and cellular breakdown is called senescence.

When too many cells are senescent, tissues start to age and breakdown, and eventually, many senescent cells will undergo programmed cell death known as apoptosis.

Senescent cells really are like little zombies. At this stage, they no longer divide or support the tissue they are part of, but they’re still alive and operating, albeit in a dysfunctional way. They also end up hurting healthy cells around them, sort of like the proverbial “one bad apple spoils the bunch” concept.

The aged cells send out harmful chemicals called cytokines that cause inflammation. In immune response, cytokines induce production of collagenase, the enzyme that breaks the peptide bonds in collagen (i.e. make your skin all wrinkly and saggy).

Collagenase is also produced by UV exposure and is a contributor to the connective tissue damage that results in photoaged skin.

Early on, when everything is in proper working order, the body’s immune system clears away senescent cells, and stem cells repopulate them. As we age, the ability of our immune systems to clear senescent cells begins to fail, causing them to accumulate. This, in turn, increases inflammation, reducing the function of both the immune system and stem cells, which further perpetuates the cycle until all hell breaks loose.

As this process continues, so does the resulting breakdown of tissue – physical aging and bodily degeneration.

Telomerase

Not all cells are subject to the Hayflick Limit, such as some of our immune, bone, skin, and hair cells, which continue dividing to keep our bodies healthy. These include progenitor cells (like stem cells in that they differentiate into various types of cells, but more specific), as well as stem cells.

The science of leveraging telomerase to keep telomeres long is tricky because the current understanding is with that type of continual replication, cancer could result.

The big takeaway from Blackburn and other scientist’s research on telomeres is that their length is not static. Environmental and genetic factors play a big role in how long or short they are.

One of the more prolific discoveries is that telomeres can actually be lengthened, which demonstrates aging is a dynamic process that can be sped up, slowed down, and even reversed.

Senolytics

“Evolution doesn’t care what happens to you after you’ve had your babies, so after around age 50, there are no mechanisms that can effectively eliminate these cells in old age.”

One of the only known benefits of cells becoming senescent is that they will be less likely to multiply out of control and result in diseases such as cancer. Although having them in senescence is very damaging over time, short-term, it’s a defense mechanism.

However, as the body ages, the immune system becomes less effective at clearing away these distressed cells and they begin to accumulate.

As Judith Campisi, Ph.D and co-founder of Unity Biotechnology explains in an MIT Technology Review interview, “evolution doesn’t care what happens to you after you’ve had your babies, so after around age 50, there are no mechanisms that can effectively eliminate these cells in old age.”

Senolytic drugs will do what the once robust immune system did in a human’s youth, replacing it’s lost ability to destroy and clear away these cells.

I currently have no positions in Unity Biotechnology, as they don’t yet have any commercialized products bringing in revenue. They do, however, have a phase I clinical trial for UBX0101 underway. Initial results from this study, which is evaluating the efficacy of UBX0101 in treating osteoarthritis of the knee, are expected in the first quarter of 2019.

At this point, I will keep tracking their progress toward successfully killing zombie cells and using science to further improve human health.


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