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Founder Spotlight #2: Mat Falkowski @ Circularis

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Mat Falkowski is CEO @ Circularis, which optimizes control of ANY gene in ANY species or ANY cell type. Mat is a successful serial entrepreneur: Founder of Invitae (IPO 2015), CSO @ True Materials (acquired 2008), & Lead Scientist @ ParAlelle (acquired 2005). From 2015–2016 he was also Chief Entrepreneur @ IndieBio.

Circularis, a life sciences startup based in Oakland, CA, controls the path to make the desired amount of protein in locations of interests. In manufacturing the goal most often is to make the most protein possible, while in gene therapy it is to express a very specific amount in a very specific subset of cells, while providing a therapeutic benefit. Circularis uses circular RNA as a reporter assay to tell what is happening in millions of cells in one tube. We read out the data with next-generation sequencing and then de-convolute it to identify DNA elements that create the protein expression profiles customers need.

Personal Spark

What prompted you to pursue a career in Life Sciences? Was there a specific moment in time or influence you can remember? What drives you to work in this space?

I have been fascinated with science ever since I was a little kid collecting dinosaurs and making chemical reactions. I think my high school AP chemistry teacher Bob Clingon really got me excited about chemistry and led to me getting a degree in Chemical Engineering. While at UW-Madison I realized the trends in chemical synthesis were changing and so I also pursued a degree in biochemistry and a job in the local bacteriology department. I took my first corporate job in 2001 and was really excited about the speed and innovation that could be accomplished in a start-up biotech versus academic work. That excitement about fast moving science has kept me at small exciting startups.

How did you get your training if any to be able to build your company? Life Sciences increasingly has interdisciplinary academic backgrounds, while other founders take the plunge and jump straight off the deep end. Which one are you & why?

I have had roles in the lab, written papers, published patents, and managed bioinformatics teams, but the time I spent away from the lab in product rollouts and customer support really gave me that big picture view of what it takes to be a successful company. After 7 different start-ups, my experience is very diverse and is a great strength when building a company.

Company Overview

What problem is your company solving?

How to control life or harness its power to our needs. As with all biotech I think the goal is to take the tools of nature and understand them enough to make an impact. In our case, every cell uses DNA as a blueprint to express protein. We seek to control that path to make the desired amount of protein in the desired location. In manufacturing that is most often to make the most protein you can, while in gene therapy it is to express a very specific amount in a very specific subset of cells, with a goal of creating a therapeutic benefit. This is a very challenging problem in mammalian cells, and I realized very few people are actually out there doing this… even though everybody needs it.

What are the specifics of what your company does?

We use circular RNA as a reporter assay to tell us what is happening in millions of cells in one tube. We read out the data with next-generation sequencing and then deconvolute it to identify DNA elements that create the protein expression profiles that our customers need.

Why does your solution matter for the world when you get it right?

If we can control gene expression with high accuracy in specific cell types, then we can use gene therapy to fix specific cells in the human body that are not working correctly. This includes making islet cells produce the right amount of insulin, or fixing retinal cells in blind people to correctly produce light-sensing pigments. Currently there are lots of risks to off-target effects and side effects, but we hope to help solve that problem through accurate cell specific solutions.

In the world of biologics, proteins are grown in vats and used as therapeutics. We hope to help increase production to help make the cost of those treatments significantly cheaper. Over 50% of new drugs are now biologics that need to be grown in cells and not small molecules which are chemically synthesized.

Genesis

What is your company’s founding story? How did everything come together?

Paul Feldstein, one of the two cofounders (along with LeAnn Lindsay), had been working at UC Davis when one day he had an epiphany and realized that the circular RNA ribozymes he had been working on for 20 years could be used to discover and optimize promoters. I met Paul while he was in the second class of Indie Bio, the biotech startup accelerator. I was working as Chief Entrepreneur at Indie Bio, and later joined as an advisor to Paul and Circularis.

In Feb 2019 Paul asked me to help negotiate a customer contract and as I did my diligence on the gene therapy space, I realized how mature and quickly growing it was. After three years, I realized the market and time was right for me to join full time as CEO and show everyone what this technology was capable of. Market conditions and customer needs proved there was an opportunity, but what really made the timing right is the near-complete lack of competition or solutions.

Accomplishments

What are some of the notable milestones your company has achieved thus far? (Funding, Animal Data, IND, Team, etc.)

The technology has now been successfully used in 8 different species and 9 different human tissue types.

What are some of the biggest hurdles ahead? How do these create points of value inflection?

The next big steps will be to move away from focused work on customer-provided DNA regions and instead use genome wide panels that allow us to avoid making assumptions about the best DNA elements. These genome wide panels will allow us to rewrite our assumptions about promoters, enhancers, and other DNA elements so that we can iteratively design completely novel DNA sequences that behave how we want. Evolution and nature have given us a lot of sequences to work with, but they only scratch the surface of the potential combinations. To put it in perspective, all the diversity of nature is based on only 4 DNA bases arranged in different orders, but the current list of known orders for DNA is only a minuscule fraction of the potential combinations.

Pay It Forward

Throughout the journey, what have been some of your biggest takeaways thus far? What advice/words of wisdom would you share from your story for other founders?

Make realistic goals and execute on them. Build a good culture that people want to work in and you will get the best out of your small (overworked) team. Reward your early employees with healthy stock grants regardless of title. Nothing is sadder than celebrating working together for 10 years and realizing the people that have stayed with you have made a sad fraction of what they deserve, because some MBA fresh out of school followed a hard-written document on what percent to give each employee. Know when to let go, because some day your company will be acquired and you can do your best to make sure your technology gets out there and helps improve people’s lives, but don’t spend too much time lamenting all the things you did not accomplish. Instead, get out there and join the next company, start the next company, or put your well earned cash into some great charity work.

What are some of the must haves for an early stage Life Science startup in your eyes?

Many different business models work, but you need to be clear how you will make money and that the customer demand is real. The better, faster, cheaper product may sound great, but oddly is not always a good start-up. Competing on costs is always tough since almost all players will reduce cost over time and some costs like the size of your marketing or sales force can be shockingly large as you scale.

What are some of the traits that make a great founder? What type of risk profile/archetype does someone need to have to be a founder in your opinion?

I think all great “real” founders share a passion to get things done. There are hype founders who keep raising money and leave a wake of unrealistic failed companies in their path, but the real founders actually execute on their plans. Beyond that I have always looked up to inspirational and caring founders who look at their teams like families, but I think those are actually less common. Founders clearly need an ability to handle stress; I always respect founders that absorb that stress, and not unleash it on their teams.

For folks coming out of academia, what advice would you share?

Accept very quickly that there are a lot of things you do not know about, and though you are smart, at some business stuff you are actually dangerously stupid. Surround yourself with good advisors who are engaged and respond quickly to questions and keep asking them questions no matter how dumb the question is. Pick advisors who have actually done startups and not people that have only coached them, wrote books about them, or only invested in them.

Not everyone knows everything. Often founders have to learn either the science or the business side better. What advice would you give for someone picking up a new skill set such as this?

Listen, learn, and get advice. If you want to be the best then make sure team members learn both the science and business behind your company.

Can you demystify the process of what it was like to raise VC funding? What were the highlights & low lights? Any advice or words of wisdom for future founders?

Raising money is always an exhausting and time-consuming process, but it should teach you to question all your assumptions and keep striving to a pitch that is both so simplistic and thorough. The pitch should answer 99% of the questions VCs will throw at you, while leaving them in wonderment of the cool science you are doing.

What advice for managing & hiring a great team can you share?

A good manager’s first goal is to give employees the tools they need to succeed. That means in the office or email, your first response is to your teams, and only when everyone goes home or is on track do you take time to accomplish tasks on your to-do list. Empower your team to succeed and show you care. I always suggest in weekly 1:1s that your first question should ascertain if there are any personal topics to address. This shows that you prioritize them. Don’t ask at the end of the meeting when time is running out.

Anything else you would like to add?

Don’t work too hard, take a reasonable salary, and don’t let panic and stress overtake you. Startups are a long road and staying mentally healthy is an important part of that.

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Alix Ventures, by way of BIOS Community, is providing this content for general information purposes only. Reference to any specific product or entity does not constitute an endorsement or recommendation by Alix Ventures, BIOS Community, or its affiliates. The views expressed by guests are their own and their appearance on the program does not imply an endorsement of them or any entity they represent. Views and opinions expressed by Alix Ventures employees are those of the employees and do not necessarily reflect the view of Alix Ventures, BIOS Community, affiliates, and content sponsors.

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