Building life without DNA

Sijbren Otto, Professor of Systems Chemistry, is working to create synthetic life in the laboratory. He recently received an ERC Synergy Grant of €3.4 million for his MINILIFE project. He, together with international partners, will use this to continue working on his ultimate goal: a chemical system that shows signs of life, but that is made up of entirely different molecules than life as we know it.

_{Text: Charlotte Vlek / Photos: Reyer Boxem}

The first life on Earth must also have once been derived from lifeless matter. Is that what you are trying to mimic?

No, it is not our objective to find out how life on Earth may have originated. Numerous other scientists are working on that. They wish to create a type of life as we currently know it: with DNA, RNA, and proteins as the key players. Instead, we forget all about what molecules generally make up life and only look at the various functions they have to perform. We will try to create those functions.

Are you then more interested in the fundamental question of what life is?

There is no good definition of that yet. That is correct. Common definitions of life are often descriptive of life as we see it around us. I am convinced that a very different form of life is possible. If we discover life on Mars, it will change our view on what life is; the same will happen if we are able to create life in the laboratory.

What do you think is essential to create life?

If you look at life as we know it, we can recognize three important functions: replication, metabolism, and compartmentalization. A human cell has these things in the form of DNA (carries information and is replicated), proteins (responsible for new building blocks), and the cell membrane (the outside of the cell that separates the content from its surroundings). We are trying to mimic these three functionalities; however, we will use different molecules. If that system can subsequently evolve, really evolve, so that something new can be created that we have not put in, then you have life.

It all started with a chance discovery 13 years ago. What did you see?

That was in 2010, when we were working on something completely different. In a mixture of molecules we saw that the ingredients organized themselves into rings and these, subsequently, started to form stacks. That happened spontaneously and was unexpected. Furthermore, the stacks started to replicate: when a stack broke in two, both parts started to stack again. That is essentially copying and passing on information and is reminiscent of the function of DNA in our cells.

We were not the first group though to work with self-replicating molecules; it wasn’t anything new. However, those self-replicating molecules were often inspired by DNA, while our replicators, as we have started to call the rings, are very different.

Are you still working with the same replicators you used at the time?

Yes, what we are doing now very closely resembles the original system. And this system is capable of much more than we knew then. Which means: the system was already capable of much more than self-replication, we just had to find out which building blocks to add to the mixture to make these processes possible. And we chemists are not averse to helping the system by adding exactly the right building blocks.

What have you discovered so far?

The system appeared not only to self-replicate but also to mutate once in a while. Mutation is useful, because it allows life to adapt to changing conditions. And we now also have a form of metabolism: the system is creating its own new building blocks, which in turn contributes to replication.

What are the next steps?

We are currently facing two challenges: getting the system to develop a protective casing for the replicators, a type of cell membrane, and creating continuous evolution. We have already made strides in both. We are now at the point that the replicators are making building blocks that form a casing in which the replicators position themselves. However, we do not yet know everything there is to know about it: does the matter also stay in these casings? And what happens when the replicators self-replicate, does the casing then also replicate?

To achieve a form of evolution, we upset the balance in the system by continuously adding new building blocks and also letting a portion of the mixture flow away. In doing so, you essentially introduce death and the replicators can only survive by self-replicating quick enough. We then saw that the replicators were even exerting an influence on their surroundings. This is still very rudimentary though. However, through such an interaction between replicators and their surroundings, the system may pull itself up by the bootstraps: small beginnings may lead to surprising things.

And when will you be at a point where you can say: now we have made genuine life?

Well, it is possible that that point does not exist. Life around us is so complex that we immediately recognize it as life. However, if you are building life from the ground up, you enter a grey area. Compare it to colours: everyone can recognize the colour green, but if you mix blue and yellow, there is no exact point at which you can say: yes, now it is green.

A significant condition for me is that the system is capable of independent evolution. When the system itself is doing things we have not put into it, I will be happy. And well, it may ultimately not be about the end result. As a child I enjoyed playing with LEGO and when I had finished my creation, I thought: well, what next?

Sijbren Otto (1971) graduated with honours (cum laude) in chemistry in 1994 from the University of Groningen, where he also obtained his doctorate with honours in 1998. After follow-up research at Lehigh University (USA) and at the University of Cambridge (UK), he returned to the University of Groningen in 2009, where he was appointed Professor of Systems Chemistry in 2016. He has been a member of the Royal Netherlands Academy of Arts and Sciences (KNAW) since 2020 and received many grants and prizes for his ground-breaking research.

_{This article has been taken from our alumni magazine Broerstraat 5 (in Dutch).}

More information

• See also: an overview of Otto's work