The future of our species depends on procreation, but today the world is at an all-time high in infertility due to disease, stress, and the decision to delay having kids. But what if we can generate healthy egg and sperm from your skin cells? Ivy Natal is attempting just that using stem cell technologies and CRISPR. I talked with Ivy Natal cofounders, Colin Bortner and Jeff Hsu.

How did you get interested in the fertility field?

COLIN:

That definitely started with Jeff. We are pursuing a revolutionary solution to the problem of the fragility and scarcity of human eggs. Right now, many women can only have children using donor eggs, which has many challenges and obstacles, and donor eggs still don’t allow patients to have a genetic child.

Our solution pulls together different innovations in synthetic and molecular biology and genetics and genomics to solve this particular problem. Jeff became interested in the problem while working at a pre-implantation genetic diagnosis startup, which was his exposure to the application space, but the underlying approach stems from his interests during his PhD and postdoc research.

For me, when Jeff and I started talking about the idea, I was very excited by the potential for patients and for society as a whole. Women have always born a disproportionate share of the costs of having children, which has shaped society. Now, effective contraception has been a revolution in giving women the ability to choose to not have a child, but our company has the potential to provide women certainty in their ability to choose to have a child. It’s the flip side of the same coin.

The science of turning stem cells to eggs has so far only been demonstrated in mice. What bottlenecks do you see for making this possible in people? How do you plan to address those bottlenecks?

COLIN:

Yeah, as you say, this has only been done in mice. About four years ago, a team based in Japan published the landmark result in this area. They successfully differentiated stem cells into egg cells, and then they essentially completed IVF cycles with their mice, and those mice gave birth to fertile offspring.

For a couple of reasons we’re taking a different approach. The first is that a direct translation of the Japanese group’s approach to humans is a non-starter because that would require ovarian tissue from a human fetus. Ovarian tissue from a mouse fetus was a key component of their results. So, part of our motivation is solving that issue.

So this is a kind of bottleneck, which is legal and ethical but also technical. What we mean by technical is that we don’t have a great way to systematically answer the question: what is the mouse ovarian tissue doing to differentiate the stem cells into egg cells? If we could easily answer that question, we could just emulate whatever variables that matter and get the same results, and by extension we could do the same for humans.

Now, without getting too deep into the details, our approach works from the inside out instead of from the outside in. Essentially, we’re using different kinds of sequencing technologies to understand the internal state of egg cells, like which genes are being expressed, and then we’re using new tools to directly change the internal state of skin cells to match the internal state of egg cells, and in doing so transforming the skin cell into an egg cell. We’re still in the early stages of proving out this approach for egg cells, but it has worked with a bunch of other cell types.

The specific engineering challenges in our approach are discovering the genes to turn on or off in order to “reprogram” our skin cells into egg cells, and developing a “safe” tool to do the reprogramming, which eliminates any risk of genome changes. But here we have a huge advantage in that we can work systematically, using sequencing data and computational methods to discover targets and leveraging the synthetic biology ecosystem to do safe reprogramming.

We already have solutions in place for these challenges, and we are now applying them to a proof-of-concept of our approach, but even if we have setbacks, the long term trends are all working for us. Sequencing is getting better and cheaper, the synthetic biology ecosystem is developing rapidly, and the computational methods we’re using are improving almost monthly. We’re making progress quickly, but even if we did nothing for a year, we’d still end up with more data, lower costs, and better tools.

If successful, how might your company change the future of childbearing?

JEFF:

We’re very focused on the immediate goal, which is helping women who would otherwise rely on donor eggs to have genetic children for the first time. That is a super meaningful problem for us, and reason enough to pour everything into this company. That said, our long term goal is to ensure that every person and couple has the choice to have genetic children. There are hurdles along the way, or problems to solve, but this includes women and men of any age, including those with many conditions which currently complicate reproduction, as well as same-sex couples.

What lessons have you learned transitioning from scientist to entrepreneur during the IndieBio program?

JEFF:

One of the big attractions of becoming an entrepreneur is the freedom to work on problems and solutions you are passionate about. The valley is willing to take a risk on founders with plausible solutions to big problems whereas as a scientist you are often constrained to projects and funding that are often related to your previous work in very obvious and straightforward ways, whether that’s in academia or large corporate research organizations.

What Ivy Natal is trying to do would be life-altering for many prospective couples and families. That type of impact you can’t measure by publishing metrics or impact factors, and that’s in many ways shifted my own frame of thinking. Since we are developing a process that not only will work but scales to meet the demand of the market, I’ve learned that it doesn’t matter if we execute a protocol myself or work with partners and vendors. What matters is cost, reproducibility, quality of the results, and ability to scale.

Now, the biggest challenge for me has been transitioning from a fully resourced institution like the Cleveland Clinic to setting up a startup lab in the IndieBio basement. It’s just very different working without the existing physical and human infrastructure of a major research center. In some cases, we’re rebuilding that infrastructure for ourselves and in other cases we’re partnering with vendors to use their infrastructure, almost like cloud computing. For the human infrastructure, we’ve been tapping our existing networks for advice and insights that our team doesn’t have and also working to grow our networks.

We have the additional complication of relocating and starting up our lab work during the pandemic, but we’ve been able to make a huge amount of progress despite that!

What does the next year look like for Ivy Natal?

COLIN:

Right now, we’re completing a proof of concept for our approach. This involves producing a progenitor of egg cells called primordial germ cells, which will prove out a lot of our core hypotheses and de-risk our business. We want to complete this in Q4 of this year, and next year focus on egg cells. Our timeline for egg cells, how far we’ll get in 2021, depends on some of our ongoing work on our proof of concept. After we have data from those experiments and results from our scaling up partnerships, we’ll have a clearer picture of our progress in the next year.