Computational biology platform company plays it cool with a pipeline of experimentally-validated new drugs.
Biophysical Therapeutics, a drug discovery platform company that leverages computational biology, has emerged from stealth. The primary targets of the Delaware-based company are cancer, the diseases of aging (including Alzheimer’s disease) and – excitingly – aging itself.
Founded by Dr Michael Forrest, a Cambridge University biochemistry graduate with a PhD in computer science, Biophysical Therapeutics boasts renowned biotech entrepreneur Professor George Church (of Harvard Medical School) as an advisor to the company. Professor Bruno Conti of the Scripps Institute in La Jolla, California is also an advisor.
Longevity.Technology: Back in 2006, Conti and his team reported an exciting result in the prestigious journal Science. They showed (in female mice) that slightly reducing the metabolic rate by slightly reducing metabolic heat generation (decreasing body temperature by 0.34°C) increased lifespan by 20%.
Perhaps relatedly, calorie restriction, which is well known to extend the lifespan of (at least) mice, causes a slight decrease in body temperature in mice and humans. Moreover, different humans can vary in resting metabolic rate (per unit mass) and resting body temperature, wherein those with lower values live significantly longer. It definitely seems to be a case of less is more – in this case, making metabolic rate less can extend the lifespan of worms, flies, wasps, fish, mice and probably many other species.
As so often seems to be the case, metabolism is a finely-balanced biological process that has something of a double-edged sword nature to it, so we were glad to catch up with Dr Forrest to understand more about about that process and how Biophysical Therapeutics plans to leverage that knowledge.
Forrest explains: “Conti et al‘s research fits a thesis in which metabolic rate, that is oxygen consumption rate, enables life, but also causes damaging byproducts and accumulating damage, which is aging, that ultimately takes life away.”
In mammals, the majority of metabolic rate is for metabolic heat generation to maintain the body temperature at around 37°C. Conti and team slightly reduced the metabolic heat generation of mice by genetic manipulation in the brain, and in work in mice, Forrest has since discovered the chemical reaction mammals use to metabolically generate heat and a drug to inhibit it. How much metabolic heat generation – and, thereby, metabolic rate – decrease depends upon the administered drug dose. By Professor Conti’s extended lifespan result, and other data, Biophysical Therapeutics predicts this drug can slow aging and extend lifespan.
“Body temperature can be the same with less metabolic heat generation by proportionally greater bodily insulation, such as wearing more or better clothing, or conducive ambient temperature,” Forrest explains. “A human, in typical clothing, is most comfortable at an ambient temperature of 20°C, but much of the world is hotter, at least for part of the year, especially when close to the equator.”
In fact, 43% of the world’s population lives in the tropics, and Biophysical Therapeutics’ drug might, by dose-dependently reducing metabolic heat generation, increase thermal comfort in hot places, possibly slowing aging.
To illustrate this, Forrest uses the example that a relatively small drug dose might increase a clothed person’s preferred ambient temperature to 23°C, a higher dose to 27°C, an even higher dose to 32°C, and so on.
“When metabolic heat generation is low, the preferred ambient temperature is close to 37°C. When the ambient temperature is 37°C or more, no metabolic heat generation is needed for the body to be at 37°C. Incidentally, the drug’s effect dissipates over time as the drug clears from the body, if not prolonged by another dose,” he explains.
“Biophysical Therapeutics has discovered something fundamental, how mammals metabolically generate heat. And a drug to inhibit it, shown to work in mice,” Forrest says.
He adds: “This drug will allow us to investigate further the inverse relationship observed within, and across, mammal species between metabolic rate per unit mass and lifespan. What happens to lifespan if a mouse’s metabolic rate per unit mass is drug reduced to that of a whale? When the mouse’s ambient temperature is 37°C, meaning any metabolic heat generation is superfluous because the mouse’s body temperature can be 37°C merely by equilibration with the ambient temperature, we might reveal – if greatly extending a mouse’s lifespan thereby – that the lifespan difference between mice and whales is, at least in part, because a mouse performs more metabolic heat generation per unit mass, as it is smaller, so by the square-cube law of geometry has a larger surface-area-to-volume ratio, meaning it loses metabolically generated heat more readily.”
Forrest adds that Professor Brian Kennedy, Director of the Centre for Healthy Longevity at the National University of Singapore (and Ex-CEO of the Buck Institute for Research on Aging in California), wants to do a mice lifespan study with this drug, expedited by starting with old mice.
Across a set of mammal species, Biophysical Therapeutics has shown that maximal lifespan is inversely proportional to the use (per unit mass) of its newly discovered reaction for metabolic heat generation; the company believes that drives the inverse proportionality between metabolic rate per unit mass and maximal lifespan, which causes the inverse proportionality between heart rate and maximal lifespan, observed in the same set of mammal species.
So, how does the company plan to leverage this thinking? The answer is to start small, as Forrest explains.
“When this drug is applied topically to a small body part, such as to the face in a cream, it will reduce metabolic heat generation at that location, reducing metabolic rate and thereby slow aging there. Wherein, heat transfer from the rest of the body, via blood flow, maintains this body part at around 37°C because topical use can’t reduce body temperature at any ambient temperature.”
This means the company’s initial focus is cosmetic applications, and it is aiming to license cosmetic use of its patented drug to a cosmetics company for profit share. For this, the key milestone is testing if this drug can slow the aging of human tissue ex vivo, which (once commenced) should take less than six months and has the added bonus of being a relatively cheap experiment. Cosmetics are not legally required to undergo any animal or human trials, which also expedites progress to market.
The cosmetics market is enormous, with consumers often spending a great deal on products that have little to no efficacy and only tackle the appearance of aging skin, rather that doing something about the aging itself.
“Cosmetics that contain an antiaging compound that works much better – as illustrated by dramatically extended mouse lifespan – might capture much of the market. And possibly grow it,” Forrest neatly concludes.