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Cybele Microbiome: Skincare Through Precision Prebiotics

Nearly half of society has some sort of skin sensitivity. Cybele Microbiome is the company behind a new direct-to-consumer skincare brand. Cybele’s unique products trigger the natural skin biome to secrete skin restoration compounds. Today I sat down with Cybele’s CEO and Founder, Nicole Scott PhD. Nicole is a geneticist who became fascinated with the interaction of skincare products and the skin biome. Cybele was born when Nicole discovered how to gain precision control of microbes through the use of functionalized prebiotics. She thinks of cosmetic ingredients as first and foremost “food for the microbiome.”

Q. During IndieBio, you ran a small pilot study with your skin serum formulation and got some exciting early results. Tell us about what was seen?

Just two weeks into the study, I got a bunch of excited phone calls, because many of our volunteers were noticing the results right away. We provided the photos to a dermatologist who is highly experienced in reading skin conditions on photos, and he confirmed there’s notable decreases in scaliness, flakiness, hyperpigmentation, papular eczema, eczema, psoriasis, and even a decrease in a precancerous lesion. We knew that one of our long-chain ceramides is a known anti-melanoma compound– but these early results after just 2 weeks have us floored.

Q. Your prebiotic ingredients trigger the skin biome to create only long chain ceramides and no short chain ceramides. Why is that so important?

There are huge differences in the bioactive function of short chain and long chain ceramides. The long chains are the good ones. The short chains actually harm your skin, competing with, and fighting against, the good ceramides. Your typical skin care products that advertise ceramides don’t make this distinction, and can be doing as much bad as good.

Q. As a direct-to-consumer company, how does your hero product evolve over time into additional products and SKUs?

From skin serum we can round out that product line with moisturizers, toners, and eye creams.

But we aren’t a one trick pony. What is also really exciting is that we can get your skin biome to make hyaluronic acid — the most common ingredient in anti-aging cosmetics. These advances come from our platform to identify and formulate new prebiotics for other uses. This allows us to create a suite of related and complementary products. We also will customer’s skin biome assessments and input to help craft the additional products.

Q. How do you manufacture the prebiotic ingredients, and how does this affect Cybele’s margins in the early years of the company?

Our prebiotics are the output of fermentation. At small scale, we can purchase our prebiotics. They are not expensive. As we scale up, we can use any standard contract manufacturing organization to produce them for us — so no capex needs to go into ingredient manufacturing.

Ceramides are normally expensive to add to skincare products — and every bit added to a formulation hurts margins. In our case, not only is our product more effective, but we aren’t paying for ceramides. The skin biome makes them. So we have a much higher margin — estimated at 88% for our serum product.

Q. Tell us about your team.

Our team includes James Lamoureux — a microbiologist that received his PhD with Dr. David Low at UC Santa Barbara — and Hui-Ling Seow, who helped develop and carry out the marketing strategy for a HR platform Epic Quest Games, and Liz De Ruyter, who lead the Amazon On-Campus Store, launching products like PuraVida, Red Bull and Aveeno at UC San Diego. We are currently expanding the team by actively recruiting a Chief Marketing Officer right now.

 

Beeline Therapeutics: Supercharging T-regs

Dimitre Simeonov, Michael Wyman, and Chris Chavez of Beeline Therapeutics

Beeline takes engineered immune cell therapy in a new direction. They are unique in how they have engineered regulatory T cells (Tregs), which play a natural role in ramping down the immune system. This has wide applications for autoimmune diseases and organ transplantation.

We talked with company founders Dimitre Simeonov and Michael Wyman.

Since you’ve announced that you’ve successfully engineered Tregs, you’ve had a good number of pharma companies wanting to partner with you. How did you accomplish something they couldn’t do on their own?

A number of companies have learned how to edit the genome of effector T cells, such as killer T cells. The idea of doing similar genetic engineering of Tregs was beginning to be considered. But actually doing it was another story.

To start with, Tregs are just hard to cultivate and proliferate. Then, there were a lot of hurdles to overcome in terms of the genetic engineering. We weren’t just engineering a receptor into the Tregs to localize them to the spot of inflammation. We wanted to go beyond that — to enhance the natural immunosuppressive power of Tregs. This meant delivering a very large genetic payload to a precise spot, without interrupting the normal function of the gene we were targeting. We found unique ways to pull this off.

How do they work, and what’s the benefit of a “living drug”?

Tregs naturally quiet the immune system. They do this through a unique cellular programming that relies on transcription factors, cell surface receptors, and cytokines that help a Treg shutdown other immune cells. Sometimes this process fails as Tregs can be overwhelmed by the immune response. So we supercharge them and put them back into a patient’s bloodstream, so they can migrate to inflammation hotspots, where they can secrete therapeutic proteins to calm an immune response.

As a “living drug”, Tregs have unique advantages over standard molecular therapies. First, we can harness the cell’s ability to produce protein to continuously manufacture therapeutic proteins in the body. And not just anywhere — but precisely at the site that needs the therapy. No more biweekly injections — just a single shot of your own cells. Second, cells can “sense” their environment and respond accordingly by changing gene expression. By engineering our therapies into the “responder genes” our cells will make therapeutic proteins in response to the environment that those cells are in. For example, say we are trying to quell inflammation as in the case of Crohn’s disease — we might engineer our therapeutic so that its expression is increased in an inflammatory environment thereby allowing us to precisely control dose and ensure we are delivering the highest doses to the areas of the body that need them. Finally, cells are complex machines armed with a number of “tools” that allow them to accomplish their functions. This is fundamentally different from the medicines that have so far dominated the clinic — generally drugging a single target or pathway.

Our technique solves a problem that every drug company is challenged with. How to get the drug exactly where you need it, and maintain a dose potency that is appropriate to the severity of the disease.

It’s like having a drug factory in your body.

Yes, though we’re technically not secreting synthetic drugs. We can do that (as long as they are protein-based), but at this point, our cells secrete the natural signalling compounds the body already makes and uses on its own. We’re the first therapeutics company to publicly announce that we’ve made the proteins we’re making from Tregs; it’s very exciting.

Why did you use DNA-cutting enzymes instead of the more conventional viral vectors?

We actually are doing both approaches. With the viral approach, we do get a high expression rate, but it comes at a tradeoff. The virus lands randomly on a cell’s DNA. You can’t control where the virus integrates the payload. And when it integrates, it can disrupt gene function, which might be a pretty important gene. Also, every gene has a different expression level. So in one cell, you might randomly hit an area of the DNA that is highly acvtive, and in another cell, you could hit an inactive area. You end up with different levels of the therapeutic in each cell — or worse some of the cells may not express the therapeutic because the surrounding inactive DNA could spread to your therapeutic.

To get a much more controlled result, we are also using non-viral engineering approaches. This overcomes many of challenges we mentioned earlier and allows us to think about how to use a cell’s natural gene regulation to regulate our therapy.

In what critical indications is your cell therapy most needed?

Helping the transplantation of organs is where physicians are the most excited by what we’ve done. Today, to prevent rejection of a donated kidney, physicians have to give patients a lot of broad systemic immunosuppressants. These patients are already in a weakened state, and having no immune activity is dangerous. Also the drugs make the patient very vulnerable to cancer; one of the most common drugs is classified as a Group 1 carcinogen. There are a lot of patients who don’t even get put on the waiting list for a kidney, because they are too high risk.

By localizing the immune suppression, and helping patients’ immune system not reject a donor organ, we can open the door to new types of transplants that aren’t very feasible yet. One of those is pancreatic islet cells; they produce hormones. People with Type I diabetes could be alleviated with islet transplantation.

One of the exciting potentials of this therapy is long term tolerance — meaning patients could potentially come off of immunosuppressants all together. This is something we are actively working towards.

What’s the next year look like for Beeline Therapeutics?

We have the ability to engineer receptors to help the Tregs home to the right places in the body — over the next year we’re going to expand that platform with more receptors. A kidney donor has to match the patient’s HLA markers. We’ll use the patient’s HLA markers to design receptors to recruit Tregs into the donor tissue.

Also, proving our method works in mice presents an interesting challenge, because we engineer human T-regs, but a mouse’s immune system would attack human cells. The elegant way to solve this is to use a mouse model without any immune system, repopulate it with a human immune system, and then transplant the mouse with human tissue, to see if we can prevent rejection.

Watch CASPR Biotech pitch on IndieBio Demo Day, Tuesday June 25th in San Francisco or via LiveStream. Register here!

Gavilán Biodesign: Overcoming Drug Resistance

Gavilán Biodesign emerged out of the Donald Lab at Duke University, one of the world leaders in computational drug design. During their time at Duke, they redesigned many compounds, including a new Anti-HIV antibody that is now in 9 clinical trials. Their software was also used to predict tumor resistance mutations to 17 leading precision cancer therapeutics and multiple antibiotics. Their work led to 45 papers published in leading journals.

We chatted with three of the company’s founders, Marcel Frenkel, Mark Hallen, and Jonathan Jou.

What has been the limitation of computational drug design?

Using computers to design better drugs has been quite effective when there’s already a lot of knowledge about the compounds and the protein targets they’re hitting. When there’s a lot of data to train on, artificial intelligence can learn and interpolate alternatives, then estimate how well each one works to find a better one.

But those approaches to in silico drug design haven’t worked well for new areas, where there isn’t a lot of knowledge. It’s the difference between interpolation and extrapolation.

To go after biological pathways where there hasn’t been much success in the past — and design entirely novel classes of drugs — a different approach was needed.

How does Gavilán Biodesign do it differently?

Even in a new molecular space, the laws of physics still rule. Our hybrid system uses the best of A.I. and the best physics-based molecular dynamics models. All natural phenomena has to answer to physics; they’re the forces that drive the universe.

We are the only company to use thermodynamic ensembles to model continuous movement.

Then we have a parts library of thousands of molecular parts. Most of these parts have a dozen atoms or so. We don’t bring a drug in from a preset library to evaluate it; we generate every possible combination of those parts, inside the target pocket, simultaneously measuring the impact of every part on the affinity, stability, and specificity of the compound. Every building block of the design is ideal for the target.

While our competitors search through a few million compound variations for the best fit — and the biggest molecular library in the world has 230 million compounds — we can easily and efficiently search through billions of possibilities.

The slightest differences can have huge effects when dealing with van der Waals forces, which repel at one distance, then attract at another. A 0.5 angstrom difference in position can go from a bad clash to a favorable interaction.

Before you came to IndieBio, none of you had experience pitching business partnerships and negotiating deals. But in four months here you already have signed and delivered on a deal with a pharma company and are negotiating four more.

Everybody whose become an entrepreneur has had to learn to do so, whether they were a lawyer, or an accountant, or a banker, or a scientist. And I actually think scientists make the transition better than other people do.

Being an entrepreneur is remarkably similar to science. We’re used to operating in absolute uncertainty. We don’t pretend we know how to sell, or know how to cut a deal. Instead, we experiment rapidly and learn. We form a hypothesis, test it, and gain the most amount of data as fast as possible to improve. Our scientific inclinations apply surprisingly well to entrepreneurship.

So we didn’t go to companies and sell ourselves. We went into meetings to learn what problems and stress points they were having. Then we explained how our technology could help them with their problem. It was more about problem solving than pitching.

How did your time at IndieBio change your business model?

When we first interviewed with IndieBio, we were thinking of just selling our software. We wanted everyone to have it and use it.

During IndieBio, we’ve really learned to shape Gavilán’s strategy to create new value. Not just to replace the software chemists were using. And so that meant moving from a high-volume service business model to using our design tools for what they’re uniquely great at, creating new therapeutics in the highest-value problem spaces facing medicine.

As we’ve done a better job of explaining how we can do that, the most exciting thing is now seeing pharma companies come to us, wanting to design drugs for targets that have long been considered undruggable.

How might your company change the therapeutics industry?

Consider cancer. Right now, precision medicine is pretty good at designing drugs for certain well-known biological pathways. But there’s two major problems with that. The first is that the most powerful biological pathways are not well-known, or else we haven’t had enough success targeting them to even learn how to do it better.

The second problem is that a cancer tumor is highly mutating. The genome changes, and so the protein shape changes, and drugs that worked for maybe a year in patients, now fail. Almost everyone has a loved one who got cancer treatment, recovered for awhile, and eventually succumbed.

Our software has made it possible — for the first time — to discover how a tumor will mutate, years before it actually happens in a patient. We can “discover” it while we are designing the drug itself in the computer. And so we can design drugs that work not just against the tumor before it mutates, but the drug will still work after it mutates. And not just one mutation — all likely mutations.

We see a new age in medicine coming, where massive killers like cancer could be under control. The way polio is a thing of the past, today.

What’s the next year look like for Gavilan Biodesign?

While some of our partnerships with pharma companies are confidential, I can characterize them broadly.

There are undruggable targets that nobody has been able to hit with sub-micromolar affinities to date. You really have to get a 1000x better than that — down to nanomolar range — for a drug’s potency to make a difference in patients.

We are designing several of these in silico. We’ve already delivered one set, and will be delivering more in the coming months to other partners. Then it will take our partners a few months in the lab to confirm the accuracy of what we’ve designed. Even just from these in vitro lab tests, they’ll be able to tell if we are hitting the targets with nanomolar affinity.

When the industry sees the results, we hope it will blow people away. They’ll realize whole sections of biology are now targetable.

Watch Gavilán Biodesign pitch on IndieBio Demo Day, Tuesday June 25th in San Francisco or via LiveStream. Register here!

CASPR Biotech: Revolutionizing Molecular Diagnostics

The CRISPR Cas complex has been a game-changing technology for gene editing. CASPR Biotech is using the incredible accuracy of CRISPR for something different — to revolutionize medical diagnostics.

We spoke with company founders Franco Goytia and Carla Giménez.

There are a couple other prominent companies also using CRISPR-Cas systems for diagnostics. What’s different about your focus?

We are rapidly developing a device for hospitals to quickly detect if a patient has an antimicrobial resistant infection. This is a huge problem for hospitals. It’s not just that 2 million people in the US every year get infected with superbugs, or that the infection rates are even higher internationally. When a patient walks into the hospital with a fever of unknown origin, it takes between 24 hours and three days to amplify the DNA of the bacteria to determine if the patient has AMR. During that time, the patient has to be isolated, making it very stressful and expensive. For every one patient found to have AMR, nine more have to go through this isolation. And during that time, they’re started on wide-spectrum antibiotics, which makes the global problem worse.

How does your solution change that?

We can diagnose AMR infections in under an hour. Most superbugs have one of three sequences of DNA that make them resistant. We code our Guide RNA to detect those, and if they do, our Cas enzymes trigger a signal. Not only does it do so in under an hour, but does so more accurately, and cheaper.

You already have this working?

Yes, in the lab. As well, at a hospital in Argentina we have tested our system to detect infectious diseases like Dengue virus. These aren’t yet automated into a device, but our device development is going incredibly well and we are on track to begin a 510K study with the FDA in one year.

You discovered two novel Cas enzymes, one in the Cas 9 family, one in the Cas 12 family. How did you do that, and how they are different?

Existing IP portfolios held by the primary CRISPR institutions were discovered by searching through the public databases of sequenced bacteria. We went through unpublished data, collected by our partners in the extreme environments of Argentina — regions as diverse as volcanos, high deserts, hot springs, and Antarctica. In these environments, bacteria evolved unique ways of defending themselves against viruses.

We are looking at ways our Cas 12 gives us a competitive advantage. It appears to be more stable at higher temperatures, likely due to the environment where it evolved. Using it at higher temperatures may facilitate other reactions in our system, turning what’s a two-step process into a one-step process.

You’ve been able to make incredibly fast progress during your time at IndieBio. What’s been your secret?

Before IndieBio, we were running on a very thin budget. To order reagents, we might be waiting a few months until we could get the money together. At IndieBio, we got them in a day — and shouted in celebration when they arrived. We showed up at IndieBio really hungry to do science at a much faster pace, to make quick decisions. It’s been an opportunity that we’ve been thankful for, and haven’t taken a single moment for granted.

We’ve also been very inspired by the scientists who created the foundational technologies of CRISPR. The way bacteria has defended itself against viruses has existed for hundreds of millions of years. But it took great imagination to reconfigure it for gene editing. This precedent reminds us, daily, that if we work hard, at any moment we too could make more discoveries.

How big could CRISPR-based diagnostics get?

Certainly, from AMR and infectious diseases we will move into flu detection, respiratory infections, sepsis, and urinary tract infections. But the application go beyond healthcare and the hospital. Just like Google allows us to search the entire internet, CRISPR allows us to search the entire genome for any genetic code. Rapid DNA detection has applications beyond humans into pets, livestock, and plant life. Farming, biosecurity, and new domains of agriculture are all possible.

Watch CASPR Biotech pitch on IndieBio Demo Day, Tuesday June 25th in San Francisco or via LiveStream. Register here!