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Q&A: NTU's Ali Miserez on the Use of Proteomics in Biomimetics Research

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Name: Ali Miserez
Position: Assistant Professor, Head of the Laboratory for Biological and Biomimetic Materials, Nanyang Technological University
Background: PhD, Ecole Polytechnique Federale de Lausanne

Ali Miserez leads the Laboratory for Biological and Biomimetic Materials at Singapore's Nanyang Technological University where his group focuses on engineering new materials based on biological structures – an approach that could offer significant improvements over existing synthetic materials while also allowing for more environmentally friendly production processes.

In a paper published this week in Nature Biotechnology, Miserez and his colleagues presented work using RNA-seq and mass spec-based proteomics to gain a better understanding of the materials they are seeking to mimic, including jumbo squid sucker teeth, green mussel adhesion plaque, and marine snail egg-case membranes.

Though little used to date in biomimetics research, proteomics, the authors suggest, holds great promise for the field, offering a rapid approach for characterizing the molecular structure of target systems and enabling the translation of their designs into new materials.

ProteoMonitor spoke to Miserez this week about the current use of proteomics in biomimetics research and its future potential.

Below is an edited version of the interview.

How large is biomimetics research as a field, generally, and how large a role does proteomics currently play in it?

It is growing. It's getting bigger and bigger. Mostly, I would say it is [populated by] material scientists or chemists or physicists. An interesting thing is that the life scientists who would actually have the expertise to tackle the molecular structure [of the target materials] – there are not too many of them that work in this field.

I did my PhD in metallurgy, but I did a post-doc at [the University of California, Santa Barbara], which has a very good marine science program, and there was a professor who was doing very good work in this field of biomimetics looking mostly at mussel proteins, the proteins that let them stick in the water. So that was where I learned a lot of biology and biochemistry.

It is interesting, because this field is really growing and gaining more importance, but in terms of the people who actually do proteomics and protein sequencing [for biomimetics research], you can almost count them on one hand. People do all sorts of X-ray structure, X-ray characterization, nanoscale measurements – very nice work. But often what is lacking is going after the genes, proteins, and the reason is that people who work in this field don't have that expertise. They are physicists or chemists, and they don't know about how to do sequencing and proteomics. So there is very nice and interesting work to be done at the intersection of these fields if you really tackle them in a multidisciplinary fashion.

What does proteomics bring to the field potentially?

[For instance], first we do the transcriptome of a given tissue of interest. And you get 100,000 transcripts, so that becomes very challenging [to determine] which one is the [target]. But then you can extract your target protein of interest – for instance, we are working on the sucker teeth of squid, and those teeth are only made of protein, nothing else, and we can extract these proteins and then run a gel so you have all your bands of interest. So we take this [gel] and then we do high-throughput MS/MS, and we know that this is our protein of interest. So then when we analyze the MS/MS data with the transcriptome database that we have generated, we can go back and identify our transcript of interest and get the sequence.

Is proteomics gaining more appreciation within the field?

We go to conferences, we publish, we say, "Look, you need this," and I think there is a recognition that it is useful. The thing is that the people who have the knowledge and expertise in proteomics, they don't go into this biomimetics field much. And then the other people – the physicists, the chemists – they look at the structure, the composition of the material, but they rarely look at the sequence. So with this you have kind of an edge because you can do so much stuff once you have the protein sequences.

Is there a standard workflow that you use? I see you used both MALDI and LC-MS/MS in the Nature Biotechnology paper.

No. Those techniques are both available in my department. In my group we have easy access to MALDI, so that is valuable, and for MS/MS we have colleague in another institute here who has that, so we could confirm for sure that we had the right sequence by doing the internal sequencing. It's just that having multiple techniques help us be 100 percent sure that we have the right sequence.

How do you choose the target materials you investigate mimicking?

It is mostly curiosity driven. For example, we were looking at egg cases, and thought, "Oh, that is interesting." So we starting to look at their properties. You pull on them, see how they deform, the response they give when you apply a certain load, and we noticed that it has some very interesting properties. So often it just starts as curiosity driven – you have some knowledge of invertebrate biology, you open a book, and you say, "Ok, this could be interesting." These systems, the egg case, for instance, it has some amazing properties. It can absorb shock. It is an elastomer, like a rubber band. There is no synthetic polymer that can match the properties of this system, so of course once you have the properties it becomes of interest to find out the sequence.

How far along is the field in actually developing new materials based on this research? Are there commercial products available that use biomimetics materials?

It is coming along. I think there are two ways we look at it from a research perspective moving towards industrial application. One is for very niche products in the biomedical field, maybe in artificial prosthesis or artificial tendons. The main reason is because most likely those materials are biocompatible and will be accepted by the body because they are made of amino acids and proteins. So, that is the niche application.

The other thing you can think about, and this is what we are doing here, is trying to make sustainable materials. Plastic polymers are out there everywhere. It takes a huge amount of resources to make them, and eventually, if we want to be sustainable we are going to have to find new solutions. And trying to make materials by scaling up bacteria in big bioreactors – that kind of thing – could be one solution for making polymeric-like materials. The one example we focused on in this paper is the [squid] sucker ring teeth, and one thing that is very useful from a materials science perspective is that we can make it from a water-based solution. If you take plastic, you have harsh solvents and it is pretty challenging, but here you can have a water-based solution and mold [the material] and shape it in whatever shape you want.

Another thing that we notice when we look at the sequence of those [sucker ring] proteins is that they are actually highly silk-like. At the protein scale we find very similar molecular architecture to silk. So that is very interesting, because silk has a whole area of applications these days. It is used in electronic devices, photonic devices, in drug encapsulation, as patches on the skin to deliver drugs. And what we found with our system is that you can make [sucker ring-based] silk-like material, but much more easily. The recombinant expression is straightforward, whereas, in silk, it is very challenging. So with our stuff we probably have a chance to make silk-like material but more easily, and using aqueous chemistry, which is key, because we want to, if possible, make materials without using harsh solvents and high energy inputs.

So what do you plan to look at on the proteomics side going forward?

We haven't looked at this yet, but post-translational modifications, possibly. A classical example [of PTMs] is in mussel adhesive. The key thing in the ability for mussels to stick in the water is actually dihydroxyphenylalanine, DOPA, the extra hydroxyl on the tyrosine. That is key – up to 25 percent of the amino acid content of those proteins is DOPA, and it has a key role in ensuring adhesion, and it is absolutely key that you know where those DOPAs are. So MS/MS is the way to go for that.

Another case is people who work in biomineralization, trying to understand bone formation. For that, phosphorylation is key. And people have looked at this for years, but, again, to get one sequence, say, phosphophoryn, which is in the teeth, or osteopontin, which is responsible for the growth of bone, took years and years of work. So, with this new technology now, if you have any model system you are interested in, you could probably go after it and in a few months you could get it. Before you would make a proposal and you would say, "In this proposal we are going to study one protein." Now you can say, "We are going to look at the entire proteome and all the proteins responsible for the growth of this interesting material." It's a totally different ballgame.

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