Ora Biomedical has created a robot for high-throughput screening of life-extending compounds in worms, and you can buy an experiment for 100 dollars.
Things in the longevity field look bright or gloomy, depending on who you ask. It is true that we now understand much more about aging than we did just a few years ago and that scientists have come up with potentially revolutionary ideas such as cellular reprogramming. It is equally true that no matter what we try, the most powerful interventions for prolonging lifespan in animal models remain rapamycin and caloric restriction, something invented decades ago.
This is a source of frustration for the renowned aging researcher Matt Kaeberlein and one of the reasons why he left academia after years as a University of Washington professor. To the public, Matt is probably most known as the driving force behind the Dog Aging Project, a monumental attempt to understand and influence the aging of our beloved canine companions. The National Institute on Aging (NIA) recently cut funding for the DAP, which Matt sees as fundamentally unjust.
Matt’s two other babies are his companies Optispan and Ora Biomedical. Both are headquartered in a low-key building inside an industrial zone in Seattle. Optispan specializes in longevity medicine and is not the focus of this article. Ora Biomedical is built around WormBot, a device that Matt and his team created back in UW about six years ago.
A can of worms? Hundreds of them!
If you’re into biology, you are familiar with the worms in question. C. elegans, tiny short-lived nematodes, are among the most popular animal models. The reputation of geroscience (the biology of aging) as a scientific discipline and its rapid growth in recent years owe much to the experiments done by Cynthia Kenyon more than a decade ago. Cynthia (now with Calico, Google’s secretive anti-aging company) showed that genetic alterations can dramatically extend lifespan in C. elegans.
Those worms, consisting of roughly a thousand cells, vastly differ from humans, but they are still multicellular organisms running the same basic processes, and while many interventions that promote lifespan in C. elegans don’t work in more complex models such as mice, some do.
Matt thinks that geroscience needs to be unstuck. It has been looking under the lamp post, he says, drilling into mechanisms while deprioritizing the search for new compounds. Rapamycin was a serendipitous discovery. Who said it’s the best that the vast world of small molecules has to offer? We just need to screen lots and lots of those molecules to find new interventions.
This is what WormBot is for. It automates simple experiments in C. elegans, allowing for high-throughput small molecule screening. Even if a fraction of the experiments will yield positive results, and a fraction of those will translate into mice and humans, if you screen millions of interventions, you’re bound to find something. Matt firmly believes that you would find something big: “There is absolutely no doubt in my mind that we’ll find things better than rapamycin and caloric restriction – single molecules or combinations.”
A screenshot from the MMC introductory video
Science for the masses
To screen one million molecules and combinations, you need a lot of money or a village. To kickstart what they hope will be a new era of longevity drug discovery, Ora decided to go to the public with the Million Molecule Challenge.
MMC lets any person sponsor an intervention: either a single drug, a combination, a custom-made experiment, or, if you’re unsure what you want except to move the science of aging forward, you can order a random intervention. A single drug experiment costs merely 100 dollars, and a combination costs twice that sum.
For your money, you will get your own wells, each with 20-25 worms crawling around. The compound you requested will be added to the worms’ food, and cameras will monitor the animals’ well-being (for instance, motility), and, ultimately, lifespan. Data will be collected and analyzed mostly automatically, and you will receive joint ownership over it.
Since the idea is to move the field forward, you would have to opt out of keeping it in an open-source database. If you find something interesting and decide to pursue it, according to Matt, Ora will be your natural partner and help you every step of the way.
In a video on the MMC website, Matt called it “one of the most impactful projects in longevity” that attempts to address “probably the most limiting problem in the field today.” “Why aren’t we setting new longevity records every year or at least every decade?” Matt asked rhetorically, the answer being that we need to cast a wider net – with your help, dear citizen scientists.
Today, you can choose from about 2000 FDA-approved drugs and a few hundred other compounds. That may seem like a lottery, but you can make informed choices to maximize your chances. For instance, you can go for a combination with an established pro-longevity molecule such as rapamycin.
Another example Matt gives is metformin. Some combinations with this drug, he said, have shown to be additive, and some are even synergistic, giving an effect size larger than the sum of the effects from each component. If you choose a known intervention, at least you can expect your worms to live longer than the wild-type, which should be satisfying. Or, if you feel lucky, you can opt for something completely different and unexplored.
While 100 dollars is not cheap, it is the first time ever that such a sum can buy you a full-scale biology experiment and a chance to stick it to aging. To add even more excitement, a longevity leaderboard is planned.
“Completing the MMC will lead to a thousand-fold increase in the sum total of knowledge about longevity interventions versus what we have now”, Matt said in the video.
A matter of when, not if
Ora co-founder and Matt’s former graduate student, Mitchell Lee, walked me through Ora’s HQ. “We’re just about to get our price seed round finalized, and that’s going to allow us to grow our wetland,” he said, showing me the lab. Ora is not just about MMC, it also has its own pipeline which Mitchell is secretive and excited about. According to him, they already have a couple of very promising leads.
Two WormBots side by side in Ora’s lab
As we talked, Mitchell reiterated Ora’s tenets:
We do recognize from our background as scientists that we’ve barely scratched the surface of chemical space. Things better than rapamycin are out there. It’s not a matter of whether they exist or not, it’s how quickly we find them. Matt and I both are very much of the same mindset that we just need to comb through things as quickly as possible.
If you’re looking for lifespan-extending stuff, you need to do it in animals or some kind of a living, fully intact system, not just isolated cells, and you need to look at what matters: lifespan. So, instead of focusing on target-based approaches, instead of trying to be overly sophisticated or tell nature what you think is important, just step back, devise an unbiased system, and let nature tell you what’s important.
And that’s what I think we’ve built here – a system that allows us to unbiasedly and rapidly screen and comb through chemical space, test things without imposing our assumptions on it. That’s how we’ll find new pathways, new targets.
I like the idea, but C. elegans is still a primitive model. What are the historical rates of translation from C. elegans to more complex animal models and humans?
From our perspective, that’s the biggest unknown in the field right now. The limiting factor is that we don’t have that many mouse lifespan experiments.
What’s your hunch about the translation rate?
I just don’t know, but what I can tell you is that the most promising interventions we’ve identified to date, like caloric restriction and rapamycin, work in every organism we’ve tested. That, to me, makes a lot of sense because it is evolutionarily highly conserved fundamental molecular and cellular mechanisms that break down with aging.
At the end of the day, at that fundamental molecular and cellular level, nature didn’t create a lot of new things. It doesn’t tend to solve the same problem twice. It’s what you hear in evolutionary biology. So, we should be able to find aging interventions and targets by investigating a system like a worm or a mouse and then translating that to a human.
That’s baked into our science. We take it seriously. We think we’re going to find those fundamental, conserved small molecules. We don’t know the answer to the hard question – how many of these are going to translate? My back of the envelope is probably one to ten percent.
So, if you check one million interventions, you get 1 percent of a million: 10,000. If we find 10,000 new interventions that are evolutionarily conserved, that will completely redefine our understanding of aging. Limited translation rates don’t bother me too much because of the scale and of how little has been tested so far. We are going to find new things.
There’s also a growing understanding that the key might be in combinations. There is a huge number of possible combinations, and this is where your platform might come in handy.
Yes, and that’s where you see the cutting edge of the pharmacology of aging literature right now. It’s not necessarily just finding new small molecules. People are finally starting to engage in combination research.
There’s this feeling that we’ve been putting all our eggs in maybe not one, but very few, baskets. For instance, billions have been poured into cellular reprogramming, and we’re still not sure it will ever work. Same with senolytics. It looks like we could use some new ideas.
Yes, and that’s what we call the “looking under the lamp post problem.” For the last 20 years, academia has drilled in on mechanisms and less so on finding new things. If you want to get a federal grant, you have to tell a story of how your discovery fits into what we already know. People just want to understand more nuanced features of the mechanisms of what we already know, and that is not the way to discover new things.
What are your guidelines for choosing compounds?
We want to begin with the largest, most diverse chemical libraries that we can get just off the shelf. There are hundreds of thousands of molecules you can purchase readily. We want to explore that as much as possible, start finding hits and then start developing our own chemistries around those new hits and then figuring out those combinations.
The Million Molecule Challenge seems like a cool and clever way to jump-start the whole thing. How is it going? Are people taking interest?
We’ve been promoting it largely internally through our social media, and we’ve had a great response to it. People from 18 countries have sponsored interventions, so our grassroots hypothesis of whether people would be interested in it at all was validated. We’re very happy with what we’ve generated so far. The thing is, how do we expand it, grow it, and get more people excited about it?
[At this point, Matt joined us and expanded on what Mitchell just said in Matt’s typical reserved and understating manner:]
MMC has gotten a lot of enthusiasm. The longevity field is pretty small, so, the actual revenue that has come in has not been enough to do what we want to do, yet. But hopefully, we’ll keep getting attention and will eventually get there. Anything that we can do to make data available to the community at an unprecedented scale will be valuable. I would like to see us be able to go 10-fold, 100-fold, 1,000-fold beyond what we’ve currently got. I think that’s where you really start to uncover the power of things like new AI tools. But we’ll do as much as we can and see what works.
If you get a hit from the Million Molecule Challenge, what’s the path forward for you and the person who sponsored that intervention?
We will get hits. We will get many hits. The first thing is to replicate it. Is it real? Is it reproducible? From there, there are many paths. It’s going to depend on the specific molecule.
I would say, the next step would be to see if it works in mice. If it does, you’re going to feel a lot better about sticking with that and developing it. You could imagine other things like, if it’s a natural product, you might want to partner with a nutraceutical, or they might want to take it forward directly to the human market.
You might want to do validation in cell culture if you’re going to use it for skin care formulas. We’ve talked with a couple of beauty skin care companies that are very interested in finding things that target the biology of aging and are relevant specifically to skin aging.
A developmental opportunity that I know Mitch is enthusiastic about is looking at disease-specific models in worms to identify specific indications. This will be easier to potentially get FDA approval for. Ora can provide all those options, but our main goal is to inform and enable the research community in a way that hasn’t been possible.
Left to right: Ben Blue, Mitchell Lee, and Michael Muir of the Ora team in their dimly lit worm kingdom
“People have enthusiasm in the field”, Mitchell chimed in.
That’s the sandbox that we’ve created, where we’re able to do experiments in a way that is cost-effective and truly democratic.
The cool thing is, we’re building a data set unlike anything that exists in the world today by orders of magnitude. And it’s all going to be consistent and reproducibly done with the same kind of methodology, where we’ve got the receipts, we’ve got videos of everything. This data set is going to be the largest, most comprehensive, and most rigorous that has ever existed.
This is going to be the foundation of the next generation of longevity biotech. We’re getting going. We’ve already got something that works twice as well as the gold standard right now, and we just got started. We found that in a month, we need time, we need energy, we need resources. Let us change the face of longevity research by just turning over the things that need to be looked at.
Lifespan.io is proud to collaborate with Ora on the Million Molecule Challenge, driving the discovery of new life-extending compounds. Visit the sponsorship page to pick your intervention today!
View the article at lifespan.io
