Utilizing The Human Genome To Expand Microbial Potential With Primordial Genomics
Primordial Genetics is a synthetic biology company and a world leader in constructive biology; a revolutionary new way of practicing biotechnology that creates novel genes from genomic building blocks to accelerate the evolution of highly efficient enzymes and microbes. In this interview, Founder and President Helge Zieler discusses the company’s technology and its contribution as a critical enabler of the biotechnology revolution.
What’s led you to start Primordial Genetics, and how has it evolved since?
I am a trained molecular geneticist. I’ve been a scientist all my life. I think about the world in terms of science and technology, but I always had a strong motivation to turn biology, which was primarily basic science when I studied it in university, towards “the useful and the good” (Tennyson).
Up until 2011, I was working at a company called Synthetic Genomics, or SGI. I was mostly doing plant genomics, while the company was primarily focused on microbial engineering to create new biological production systems. Observing the other projects in the company, it struck me that some advanced technologies for microbial engineering were very underutilized.
Craig Venter, SGI’s founder and CEO, was developing a technology for creating microbial genomes from scratch with the vision of being able to build designer cells. But this approach was very futuristic, and SGI’s scientists knew that it was many years away from routine use and clear utility. I was surprised to see our scientists use very old strain improvement methods like mutagenesis which works well, but is quite limited and does not tap into our modern, new-found knowledge of genetics and whole-genome sequences.
It occurred to me that there must be a way of accessing this knowledge of whole-genome sequences, which are the blueprints of the cell and organism. The genome specifies every protein produced by the cell and every one of the cell’s functions. I wanted to find a way of putting that knowledge to work with a relatively accessible technology that doesn’t cost $10 million each time you use it. I already had an idea of a technology that could do this, so I left my job and founded Primordial Genetics.
The company’s name, Primordial Genetics, goes back to the notion that organisms used to be far more productive than they are today, because they were relatively uninhibited in their growth when conditions were favorable and nutrients are available.
Over hundreds of millions of years of evolution, organisms have become much more careful, so to speak, about gauging their environment before they decide to grow or divide. They have become better at sensing and responding to subtle changes to determine the perfect timing and conditions in which to grow and prosper. Primordial Genetics expresses my dream of getting back to a more primitive state when organisms were more productive.
Primordial Genetics was founded on a technology idea that I named Function Generator, which refers to the fact that we are tapping into all of the cell’s natural functions to create new ones.
When the company started, Function Generator was just a concept and although it resonated with some people, there was no proof that it worked. I applied for grants for a year and a half and contacted private investors. In mid-2013, the National Science Foundation granted us some funds to test the technology, and one local investor came in and matched those funds. I hired a research associate, Sabrina Baffert, who is still with us today, and we worked together in a windowless lab at the JLABS biotechnology incubator in San Diego. Nine months later, we had incredible results. That is how it all started.
The technology we developed uses the entire genome to expand the potential of microbes beyond the limits of our existing knowledge. Using the whole genome as an input, we create complete combinatorial novel genes that can have a dramatic impact on the capabilities and productivity of the organism.
They say that people only use 10 or 20 percent of their brains, and the same is true of genetics. A microbe uses only a fraction of the genes encoded in its genome at any given time. The overall genetic capacity of a microbe is much higher and mostly untapped. Function Generator is designed to bring out that potential and allow microbes to be all that they can be while making our own lives easier and more productive.
Can you give some examples?
The first case study for Function Generator was around ways to raise the alcohol tolerance of yeast. Billions of gallons of industrial alcohol or ethanol are made in the world every year in biological production systems that use yeast to ferment sugar into ethanol. As the ethanol concentration rises in the fermentation, the yeast is inhibited by its own product and stops growing. You can only give the yeast so much sugar, otherwise, it will eventually kill itself by producing ethanol and the unused sugar goes to waste.
To improve the efficiency of alcohol production, we set out to make yeast more alcohol tolerant. It took us about three generations of improvement to refine our technology and now, we have a proven set of alcohol tolerance genes that our customers use to make a significant difference in the economics of fermentation.
Since the early days of testing Function Generator, we have used it for improving microbes in many ways. It has always produced excellent results and has proven so far to be a universally applicable technology. Our inofficial byline for the technology is ‘any organism, any trait’ – besides a complete genome sequence, there is very little knowledge needed about an organism before it can be used to make improvements. Unlike mutagenesis, the technology produces high gains in each round of improvement, leading to rapid progress in the properties of a production strain.
Function Generator allows us to make these incredible leaps that other technologies are not able to do. We go into a much bigger sequence space than other technologies do. The bigger the sequence base, the more potential you’re able to explore, leading to better solutions.
We also found that Function Generator can be used to improve enzymes by dramatically modifying their sequence. This has led to our current areas of commercial focus.
We are now working on enzymatic production systems for RNA and DNA, the carriers of genetic information that are finding widespread use in biotechnology and medicine. We use Function Generator and other know-how of our team to improve the enzymes used to manufacture mRNA, the active ingredient in mRNA vaccines such as the covid-19 vaccine, or in mRNA-based therapeutics that are under development by many companies. A separate program is focused on enzymatic production of oligonucleotides, or short RNAs and DNAs, which have widespread use in other classes of therapeutics and also in diagnostics, R&D reagents, and in novel applications like DNA-based data storage.
Our commercial goal is to build a portfolio of genetic assets like enzymatic production systems and trait genes that can be licensed or sold to other companies. Eventually, we will use our enzymatic production systems to manufacture RNA and DNA ourselves to supply pharmaceutical companies and other customers.
What would you say is your contribution to human society?
We provide tools and approaches that improve production efficiency. Particularly, we believe that moving away from chemicals, petroleum, and fossil-fuel-based production into bioproduction will have a very positive worldwide impact in the next few decades. Many futurists have predicted that the 21st century will see the maturation of biotechnology into a dominant industry that is friendly towards mankind and life on earth, compatible with sustainability.
As a company, we strive to maintain our productivity and competitive edge to benefit our employees, customers, and shareholders. That can have significant societal impacts as well. We believe in enabling the individual, people motivated to create something significant, starting with our employees. Even if you’re tucked away in a backroom lab, the fact that you’re working on innovative products with future potential and dreaming about new ways to produce useful things means that you are contributing to society. Sometimes the intent in our work is as important as the results because intent stimulates awareness and will spread to other people.
In this bigger sense, our work is not just about technology. Public engagement is important to us as it helps to create an understanding of biotechnology goals and to increase public acceptance of biotechnological approaches and products. This ultimately increases biotech activity, stimulates the flow of resources, and broadens public interest in bio-production. Biology is our past and our future.
We are also trying to build the company in a manner that is good for our employees and allows them to have good lives. We work in a hyper-competitive world, so it’s very easy to get dragged into a lifestyle where nothing matters but your career and your job. When you only focus on that, everything else is neglected. But being so single-minded actually makes you less successful and less able to positively impact the world. We believe the right way to manage a company is to build a good work environment that caters to people’s needs and aspirations. When you have a rich life alongside your work, you have a better chance to create new beneficial products. The ripple effects resulting from a positive company culture are very powerful and self-sustaining.
What are some ethical dilemmas you encountered in your work?
We are aware that our technology is not well understood by the majority of people. Even though people have much less of an understanding of how communications and computing devices work than they understand biology, they have a working relationship with computers or phones because they use them every day. This familiarity gives them a much more positive view of electronic devices than of biotechnology. That said, in broad principle, computers are much more abstract and technologically intricate than biology, while anything biological reflects much more closely what we are and how we are put together.
There have been many ethical concerns voiced about biotechnology products, but these have been mostly in relation to creating modified organisms that are released into the environment. Public concerns have decreased over the years as it has become clear that with an appropriate regulatory framework and oversight, genetic modification of microbes and crop plants is very safe and can be overwhelmingly beneficial. Our immediate work is not associated with any similar ethical concerns, although you could argue that all of biotechnology is viewed with suspicion by some.
We work closely with a bioethicist who helps us define ethical thinking around our activities and thinking in the biotechnology and synthetic biology space. She participates in all of our meetings and gives us feedback on the ethics of our innovation and how it is viewed by society, as it relates to balances and risks that should be mitigated. We believe this collaboration will be very important for us and will facilitate communication about our work with non-biologists.
In general, efforts aimed at lowering technical barriers and increasing public understanding will have a strong impact on our field and human society because if we can’t engage the public, we risk our products ultimately being rejected. When practiced broadly by many companies, a willingness to engage with society will result in a positive view of biotechnology. We are now 50 years into the biotechnology revolution, so it’s too late to ignore ethical questions or lack of public understanding of biotechnology.
What are some technologies or trends that you find interesting these days?
Genomics has had a long trajectory of success, advances, and impact on biotech. The evolution of genomic technology ranges from the beginnings of whole-genome sequencing to modern next-generation sequencing technologies, analyzing those sequences and applying them in productive ways to problems in medicine and manufacturing. It’s a huge area of importance with steady advancements that will continue to expand for many more years.
CRISPR and genome manipulation technologies are more recent but also very powerful. CRISPR is a genome editor that allows very specific changes to be made in the genetic program of an organism, like the Microsoft Word of genetics, a genetic text editor.
But how do you even think of making that change? These organisms we work on are highly evolved because they’ve been around for a long time, and they are intricately tuned, just like a great work of literature. Improving them is difficult, and knowing what changes to make in a genetic program to create a better organism is very challenging. This exactly is Primordial Genetics’ business: figuring out what those changes are so that CRISPR can go in and make them. It’s very enabling and can have a big impact on biology and biotechnology in the future.
The third trend I see, which is more recent and also within our scope, is a better ability to synthesize nucleic acids, namely RNA and DNA, the biopolymers that carry genetic information. The genomics revolution helped us to determine genome sequences of existing organisms, but synthetic biology is about building something new. You cannot build new organisms without fast and cheap DNA and RNA synthesis. Nucleic acid synthesis and manufacturing are now becoming more prominent as a field after decades of being left behind. DNA synthesis has become more economical, accessible, and faster on all scales, from nucleotide building blocks to very large genes and chromosomes. But many orders of magnitude of improvements are still necessary. We believe that in the next five to ten years, enzymatic technologies will help accelerate the development of new synthesis methods, which in turn will accelerate synthetic biology to become very enabling.
What advice would you give scientists who want to succeed in biotechnology?
Scientists are nerds, myself included. We love the subjects that we immerse ourselves in at university, but we’re not interactive enough and that means there’s not enough collaboration between research groups and companies. It takes a lot of hard work to get two companies to work together, and scientists, in general, are incredibly conservative when it comes to adopting new methods.
Occasionally, a new incredible way of doing biology gets revealed and everybody adopts it, like with genomic sequencing and CRISPR, but that’s relatively rare. In general, most scientists have the tools that they work with and are reluctant to try new things. So I would love to see biology in the 21st century becoming more interactive and collaborative, allowing expertise from different individuals to be more easily combined to create great new products.
There’s a great cartoon of some stone-age men trying to drag a cart with square wheels. Somebody comes along with a round wheel and shows it to them, but they don’t pay attention because they’re too busy pushing their square-wheeled cart. That kind of fixation happens when you’re too focused on what is already known and on your task at hand. Scientists need to spend more time imagining the unknown that is still ahead. We’re working on that as an organization but it’s very difficult to address because rigorous, systematic, and to some degree conservative thinking are intrinsic characteristics of how scientists function and work.
The fact that a lot of non-PhD scientists are coming into synthetic biology and energizing it is encouraging and a very positive trend. New thinking flooding into this field has the potential to energize it and populate it with scientists who are fundamentally better at working collaboratively.
My advice to budding biologists: be daring, think outside of the box, work on creative projects with long-term potential that require long-term commitments and effort, because this is what will drive the big breakthroughs ahead. I always refer back to Norman Borlaug, an agronomist and plant breeder, winner of the Nobel Peace Prize in 1970, who became known as the father of the Green Revolution through his development of superior wheat varieties in the 1950s. In a conference that I attended many years ago, Dr. Borlaug addressed the young people in the audience and advised them in their work to ‘reach for the stars’, because in the best case they will succeed at something new and revolutionary and in the worst case, if their project is not successful, it will leave them flecked with stardust which is the best thing a scientist could wish for.