It has been almost a year since my last post, which was shortly after Biomarine 2014 in Cascais, Portugal. I’m heading to Biomarine 2015, this year in Wilmington NC, which is an exciting opportunity to meet marine biotechnology companies from around the world.

In that last year the work we have done on Sea cucumber polysaccharides was published in The Journal of Biological Chemistry (DOI:10.1074/jbc.M114.572297). This was a nice piece of work involving collaboration with six different academic groups. Too many authors to name-check here, but the publication grew out of our long-term collaboration with Dusan Uhrin, at University of Edinburgh, and Haris Panagos his PhD student was first author. This kind of collaboration is key to GlycoMar’s business model, enabling the early stage research that we can then take into commercial development.

The paper described the structure and biological properties of fucosylated chondroitin sulphate (fCS) extracted from sea cucumber body wall. These molecules are unusual variants of chondroitin sulphate, the glycosaminoglycan found in human cartilage and extracted from shark and other animal cartilages to provide the nutraceutical supplement chondroitin, which is often combined with glucosamine from crustacean shell. fCS has been known for around 20 years, and can be isolated from a wide range of sea cucumber species; to quote from our paper:

“Sea cucumbers have been used as a traditional tonic food in many Asian countries for centuries, with the major edible parts being the body walls, which are predominantly comprised of collagen and acidic polysaccharides. ……In addition to being a culinary delicacy, sea cucumbers have attracted considerable attention from researchers due to a range of the biological activities of fCSs that can be isolated from their tissues in high yields. The fCSs isolated from a variety of sea cucumbers were reported to possess anticoagulant, antithrombotic, anti-inflammatory, anti-HIV and metastasis-blocking properties.”

Interest in these molecules is reflected by a large number of papers being published around the world, particularly in Asia.

Our own work was able to show specific aspects of the conformation of the molecule that is responsible for the molecular interaction with one of the well known binding targets – the selectin family of adhesion molecules which are important in inflammatory cell recruitment and trafficking. This kind of early mechanism of action work is invaluable for pharmaceutical discovery.

Discovery to development

fCS exemplifies the challenge and opportunity offered by novel marine natural products: how to move beyond early stage research into product development.

Clearly the molecules have potential value, but the journey to make a drug or other product based on fCS has only just begun (see our web page for typical drug discovery timelines). Our next step is explore methods for production of high purity natural and mimetic fCS variants; once we have these we can explore the biological profile of this chemical space and identify the best candidate. At the same time we can develop the routes for chemical synthesis or semi-synthesis of these molecules, in order to have a sustainable and high quality production system suitable for a future pharmaceutical product.

The next steps in drug development will take a few years, and continue to rely on collaborations with specialist academic and commercial partners. At the same time fCS might offer a short- to medium-term opportunity for a nutraceutical product? This will rely on availability of a sustainable (preferably farmed) source of sea cucumbers in quantities suitable for commercial extraction and marketing. Maybe fCS would bring some innovation into the joint-care market dominated by glucosamine and chondroitin?

The conference season is starting to wind down. Over the past 2 months I have been to BioSpain, the European Forum for Industrial Biotechnology (EFIB), and Biomarine, and next week I will be at Natural Products Biotechnology.

It would difficult to write an interesting blog that sums up all of the partnering meetings, networking events, and conference sessions, but all of this has made me ask again -  ‘What is marine biotechnology?’

My first blog, in January 2013, was on the same subject. What has changed in the last 2 years?

The market doesn’t care

This has not changed – the market does not care where the product comes from.

At Biospain, which is a pharma oriented conference, I shared the platform with Pharmamar, AlgaPlus and Prof Ana Gago-Martinez from Vigo University for the session entitled “A quick emersion in marine biotech business”. Pharmamar is a company that has invested USD 550 M in drug discovery and development, with a large part of this spent on clinical trials.  They are an oncology business with one drug (Yondelis) approved for two indications and three other drugs in their pipeline. AlgaPlus are a recent start-up seaweed business, developing new approaches to high quality seaweed cultivation -  one to watch for the future.

At EFIB, which is Europe’s leading annual industrial biotech business conference, it was striking that there were very few ‘marine biotech’ business present. The industrial biotech sector is doing exciting things to create sustainable bio-based production of a wide range of chemicals to replace fossil fuel based production. There is no doubt that marine biomass can play a part in this sector, but it is a long way behind terrestrial sources of biomass. Parts of the industry are interested by algae, but Europe lags behind the rest of the world in terms of both technology and scale of development.

My take home message from these meetings:  for the pharma and industrial biotech sector the source of product innovation remains unimportant. They both look for novel solutions to deal with the problems they address. Talking to many people in these industries, they consider marine biotech as difficult and unproven.

The market wants innovation

I attended Biomarine for the first time, meeting many old friends and making many new ones. I was fortunate to contribute to a roundtable discussion on Nutraceuticals, which was livecast on BiomarineTV.

The conference covered established sectors such as aquaculture and fisheries by products (now called ‘rest raw materials’ by some), the macroalgae sector where new products are set to emerge, and emerging sectors such as microalgae. Although there was a shortage of large companies present, the diversity of organisations developing innovative marine biotechnologies was exciting. Very many of these organisations are non-commercial academic or not-for profit research institutions seeking to transfer technology to the commercial sector. The majority of businesses present were early stage SME’s trying to get new technologies to market.

There is a lot excitement around algae at the moment. The potential exists for Europe to emerge as good location for cultivation of macroalgae and commercialisation of innovative products from macroalgae – a clear message at both Biomarine and EFIB. Microalgae also offers potential for innovation, but so far success has been limited to niche high value nutraceutical and cosmeceutical products. Thinking back to EFIB, I think the growth of microalgae industry will remain niche for quite some time – there are fundamental productivity issues which have to be solved before microalgae is suitable for bulk products.

The take home message from Biomarine: marine biotech offers innovative solutions to a wide range of problems faced by many market sectors. However, this sector is still in its infancy and needs to learn fast from other biotech sectors to accelerate commercialisation.

What is marine biotech? – the source of future innovation 

GlycoMar is a developing anti-inflammatory therapies based on saccharide molecules from a wide range of sources including marine organisms. Our recent white paper outlines current saccharide- based drugs on the market or in development, and the opportunity for use of oligosaccharides in drug discovery. It is surprising that there are so few saccharide drugs available – or is it?

Why are there so few saccharide-based drugs?

A few of the big reasons:

Analysis is difficult – structural analysis of saccharides is inherently difficult

Synthesis is difficult – synthesis of all but the simplest saccharides is prohibitively complex

Pharmacology is difficult – saccharides exhibit complex mechanisms of action

Delivery is difficult – these are big polar molecules which don’t obey Lipinski rules

While advances are being made on all of these fronts, the field is still some way from offering solutions and of course some characteristics (pharmacology & delivery) are inherent to this class of compounds. Despite these challenges saccharides do offer a valuable range of biological activities, which should be the subject of increased drug discovery research. It is encouraging that increasing numbers of oligosaccharides are becoming commercially available for screening purposes. While the majority of these are prepared from natural products it is notable that synthesis of oligosaccharides is also advancing to provide molecules for screening.

Oligosaccharides libraries from synthetic and natural sources offer opportunity for systematic drug discovery research through their application in high throughput screening systems. In order to have utility in such systems these molecules must be prepared to a high degree of purity and size homogeneity – both of which can be challenging when fractionating oligosaccharides from natural polysaccharides. Glycan arrays have been developed and have proven to be useful as a high- throughput screening method for drug discovery. These can be used to study the interaction of large numbers of saccharide structures with target molecules and can be used to identify possible mechanism(s) of action.

So, oligosaccharide based drug discovery is difficult, but is it worth pursuing? In our white paper we describe a range of biological activity that is proving that this is a worthwhile challenge, delivering a growing therapeutic pipeline.

Collaboration

 Collaboration is a key part of the way we do business. We see our collaborators as important ‘assets’ of the business.

As a small technology development company we can’t hope to have all of the capabilities need to get a product to market, so it makes sense to collaborate with other smart people that have what we need. Obviously this must be done without compromising intellectual property rights (IPR), but we usually find that less difficult than you would expect. If you find someone with a solution that could help your technology succeed, it is never a waste of time to approach them and explore possible collaboration.

Collaborations can be long standing relationships or quite short lived: both work well. The key feature of R&D collaboration is that it benefits both (all) parties: usually this means sharing the work (and cost) and sharing the outcome.

Collaboration with academic groups

Research collaborations with academic groups can be easy to establish. All academics are under pressure to work with ‘industry’ and there are lots of different grants to support collaborations. There are also networks set up to facilitate industry-academia collaboration. We are members of IBCarb an industrial biotechnology network focused on glycoscience tools for biotechnology and bioenergy.

When establishing a collaboration we would recommend dealing the academic first – they are enthusiastic about their science and will probably be keen to collaborate (it will bring them funding). Once you have established the relationship they will bring in the tech-transfer office to do the legal stuff – the ‘Collaboration Agreement’. They should have templates available to help you keep legal costs down, but it is always advisable to get legal advice.

Intellectual property rights are the key issue in the Collaboration Agreement, although publication rights will also be important to the academic partner. You will know what IPR you require – make that very clear from the beginning so that you don’t waste time on a fruitless negotiation. You must also do your ‘due diligence’ and make sure that the academic does not have any conflict of interest.

We have a long-standing collaboration with the School of Chemistry at University of Edinburgh, although I should really say that it is with Dr Dusan Uhrin and his group because the relationship with him is key. We’ve supported two PhD students with his group and have a KTP associate from his group. Our relationship with this group exemplifies a good collaboration – we have the IPR we need, they get some extra funding, and we published papers together.

Commercial Collaboration 

Commercial R&D collaborations are very valuable to young technology companies.

There are a few different collaboration scenarios:

• You have developed technology IP and collaborate with a large company that wants to access or co-develop that IP.
• You have developed technology IP and collaborate with another small technology company to co-develop your IP.
• You want to collaborate with another company to develop new IP.

Collaboration with large companies, who may also be your target customers or licensees, can fulfil a number of requirements: validate your technology, provide a potential route to market, provide early collaboration fees / milestone revenue, provide commercialisation expertise you lack, and can be an ‘image enhancer’. For a very small company it may only be possible / desirable to have one large company collaborator at a time, so choose carefully. Identifying and approaching collaborators is likely to require a lot of business development effort, so don’t embark on this unless you have a clear idea of what you are looking for. As with any collaboration IPR is key, so be careful to protect your IPR and get appropriate legal advice.

Collaboration with small technology companies, similar to ourselves is often the easiest to establish, probably because of a shared mind-set. Identifying and approaching the collaborator is easier than big companies, because of greater openness. The need to check for conflicts of interest and protect IPR is the same as any collaboration, as is the need to get appropriate legal advice. A good example of successful small company collaboration is ours with MicroA in Norway. We at Glycomar developed background product IP but didn’t have a production capability, so it was an obvious fit to work with MicroA who have production IP relevant to our product. The collaboration was made easier by accessing grant support from Technology Strategy Board and from Eurostars. We will collaborate to bring a product to market in the next 18 months.

The value of Collaboration

Collaboration is key tool for small technology companies, which generates value for both (all) partners. The important question to ask – can the value be generated without the collaboration? If the answer is no, then go ahead and collaborate.

Today I am starting a weekly series running through an A-Z of interesting glycomolecules. I will post these via twitter and linkedin.

These are ubiquitous molecules that we all use everyday of our lives, often without knowing.

I’ll focus mostly on commercial molecules, ranging from bulk ingredients to speciality pharmaceuticals, but will also look at some emerging research products and more unusual marine products.

I hope to cover a very diverse range of molecules and look forward receive your comments, corrections and questions. I might struggle when I get to Z!

Earlier this week I presented at an Algae event in London: the “Algal Technologies Industry Roadmap’ and Spark Awards Launch.

The event reminded me of a recent conversation with a colleague just back from a visit to the aquaculture industry in China. His message: its huge and we [the UK] are miles behind. (see http://www.seaweed.ie/aquaculture/noricultivation.php for an example).

I was also reminded of themes that emerged at Algae World Asia, in Singapore last November. There were presentations from some well-invested players from the new generation of microalgae companies, such as Heliae and Aurora. I was struck that most of these companies set out to make biofuel, but have ended up making products like nutraceuticals and cosmeceuticals, because algae biofuel is not yet commercially viable. I also learned that scaling-up production of microalgae is really difficult: cultivation, harvesting and downstream processing all present big challenges that are not obvious when you work at lab scale.

UK Algae ‘industry’ roadmap

The ‘Industry roadmap’launched on Monday contains some valuable information for entrepeneurs thinking about starting companies. This figure gives  a snapshot of the consultant’s findings:

Taken from ‘A UK Roadmap for Algal Technologies’

The report highlights the an imbalance in the UK algal supply chain:

This imbalance is critical for future of a UK algae industry: like many other industries the UK is missing the boat. As with the workshops that started the roadmap process there is no shortage of great academics or interested public sector organisations, but we simply don’t have enough companies producing and processing algae. Not only are they too few, but the excellent companies that do exist are far too small to make a viable industry.

We need more algae entrepreneurs and algae investors

Products

The Industry roadmap looked at products across market sectors and a wide value range:

As with any business, its really important to understand your market deeply and to know the value of your product. This dictates your business model and will dictate the production mechanism that is commercially viable. For example, bulk commodities should be produced by pond culture of microalgae or farming of macroalgae whereas the high value ‘ceuticals can be produced in high specification closed photobioreactors. This consideration needs to be made very early in an algae technology business.

Producing microalgae

At GlycoMar we think microalgae are a wonderful resource for drug discovery, and they provide a means of production for the complex polysaccharides that we look for (see my earlier post on glycobiology). We’ve had to look at future scale up in order to provide material for clinical development, and we have had a successful feasibility study with MicroA in Norway.

Lab scientists often assume that scale-up should be ‘simple’ – but this is wrong. This slide from Prof. Shulin Chen at Washington State University identifies the challenge:

From presentation by Prof. Shulin Chen

A lot of research focuses on the first part, but to make a product we have to do the rest profitably.

This is the title of Geiske de Ruig’ s talk at TEDxRoermond, which is definitely worth watching:

http://www.youtube.com/watch?v=2d3CjhEgln0&feature=youtu.be

While I can’t endorse her description of the health benefits of ‘essential sugars’ she does raise some interesting questions. She mentions that pharmaceutical companies have about 50 sugar-based drugs in development. Our white paper gives a list of 7 sugar-based drugs that are on the market, and if you include all the different forms of heparin this number would rise to about 40.  Heparin is a widely used anticoagulant, which is worth about US$ 3 billion per annum. Regardless of the exact numbers of sugar based drugs in development or on the market these numbers are really small when we consider how many drugs there are.

GlycoMar has been working on the development of sugar-based anti-inflammatories for over 8 years. Our partners at Verona Pharma call this NAIPS – Novel Anti-Inflammatory Polysaccharides, which they are developing for treatment of respiratory inflammation, including asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD). Our own programme is targeting psoriasis and inflammatory bowel disease.

What is glycobiology?

Wikipedia gives a definition of Glycobiology as “the study of the structure, biosynthesis, and biology of saccharides (sugar chains or glycans) that are widely distributed in nature”. Despite the importance of glycobiology to most biological processes it remains underdeveloped – we have not yet seen a ‘glycomic’ revolution to match genomics and proteomics. The growth of glycobiology continues to be restricted by the technical challenges: synthesis of saccharides is not template-driven like genomics and proteomics, there is no sequencing tool to allow us to rapidly characterise the structure of saccharides, and the potential chemical diversity of saccharides is orders of magnitude greater than equivalent nucleic acid or peptide molecules (see Turnbull & Field  2007 Nature Chemical Biology 3(2), pp74-77).

Why should we be interested in glycobiology?

Saccharides play a number of important roles in biology:

• the glycosylation of proteins is important to protein function and optimisation of glycosylation is recognised as important for modern biologic drugs (for example http://www.glycotope.com/);
• innate immunity where saccharides are important for the recognition of ‘non-self’;
• inflammation and cancer where saccharides are important for cellular interactions and migration;
• structural saccharides such as the glycosaminoglycans in cartilage and connective tissue;
• secreted saccharides which form mucus and slime; and,
• dietary saccharides, such as prebiotics, play a role in maintaining a healthy gut microbiome.

Saccharides cover the surface of all cells – the ‘glycocalyx’ – and so play a fundamental role in cell-cell interactions and the interaction of signalling molecules with the cell. In inflammation, for example, the interaction of inflammatory cells with the vascular endothelium critically involves saccharides (see http://bme.virginia.edu/ley/ for a full description.).

At GlycoMar we are harnessing marine glycobiology to develop new anti-inflammatory drugs, and others developing saccharides as drugs include Progen Pharmaceuticals working in cancer metastasis and Endotis Pharma working on several disease indications. We believe that knowledge of glycobiology can improve health, and hope to see many more organisations developing novel glycotherapies.

It’s our 8^th anniversary this week!

I can’t believe that 8 years could pass so fast. This milestone has made me think about the past 8 years and what I have learned.

As a scientist, I started GlycoMar with a lot of enthusiasm for our technology and a desire to translate that into drugs, but little idea about how to make it into a business. I had a couple of advantages: first I had been approached by a company that wanted me to supply compounds to them, second the European Centre for Marine Biotechnology was opened the week I started. The company that wanted our technology later became Verona Pharma Plc, now our collaborator and licensee.

I had some vague ideas about business plans and business models, but spent most of my time focussing on what the company would do and hardly any time focusing on our market and strategy for value creation.

This time last year I was lucky enough to spend a week at MIT Sloan Management School Trust centre for Entrepreneurship. I was one of the students on their weeklong Entrepreneurship Development Program – an inspiring week which I should have done years earlier.

The two outstanding lectures of the week, for me, were given by Fiona Murray, on the subjects of ‘Creating Value’ and ‘Capturing Value’. Professor Murray has done a lot of work on biotechnology entrepreneurship – see her paper “Entrepreneurship and the construction of value in biotechnology”

The key message I took home was Entrepreneurial Strategy – something I did not have 8 years ago. Prof Murray’s final slide asks 4 key questions:

Does this idea create economic value?

1. What is the value proposition of the product?
2. What is the market segment?

Can we capture this economic value

1. Can we protect our competitive advantage?
2. Where in the value chain are we focused – how do we deliver the value?

If you think about this, for an entrepreneurial drug discovery biotech business like GlycoMar the available strategies are limited. I believe that the most realistic strategy is built around capturing value in the form of intellectual property and delivering this value by out-licensing – this is not revolutionary, but once it is clear everything else follows.

“The oceans offer enormous biological diversity with unique metabolic and physiological capabilities that ensure survival in diverse habitats and the potential to produce an enormous diversity of metabolites not found in terrestrial organisms.”

This is paraphrase of the rationale that is used at the beginning of almost any marine drug discovery venture. I have written stuff like this myself, but I have a problem with it.

While the inherent diversity and uniqueness of marine life is true and this is almost certainly matched by chemical diversity, is this enough to form the basis of a drug discovery venture? Yes – If you have an unlimited supply of money and no fixed timelines. In the real world we need more than the big picture to develop a proposition for a drug discovery venture that has realistic chance of success.

Marine natural products drug discovery is bioprospecting, which like any kind of prospecting, should not be a completely random process. Before we start looking for gold we need to know where is a good place to look, we need to know how to look, we need to know what we are looking for, and we need to know that someone will buy it if we find it. This sounds obvious? What does this mean for marine drug discovery:

What to look for? – This is probably the most important question in drug discovery, and defines the direction you will take with the other questions – it gives focus. Drug discovery needs to be driven by targeting a particular chemistry or biological activity, preferably both. For example at GlycoMar we target glycomolecules with anti-inflammatory activity, and have good biological reasons for that focus. The answer to this will depend on your aim: an academic doing research can select almost any chemistry or activity that they wish and build a rational justification for funding that research, but this selection should also consider the practical considerations in the next two questions. For a commercial venture there should be careful consideration of the application: the disease indication being targeted, or maybe a particular personal care application. This requires deep knowledge of the application, which then defines the biological activity being sought and perhaps the chemistry that might deliver that activity. This knowledge is really key and links to my previous post about knowing your market. This is why marine drug discovery should be an interdisciplinary pursuit linking chemists, marine biologist, pharmacologists, and clinicians.

Where to look? – Marine biodiversity is enormous and mostly unknown, so we need some method for selecting organisms to work on. For example, we may pick a group of organisms that is particularly rich in the chemistry we seek. We should only pick organisms that we can get enough of, at a reasonable cost, without destroying the diversity that we rely on and taking full account of national and international rules on biodiversity. Perhaps we will only pick organisms that are suitable for future production, such as fermentable microorganisms. We may pick organisms that are used in traditional medicine and are therefore likely to have some beneficial properties. There is an almost endless basis for deciding where to look, some of which is defined by your geography and resources, but the opportunity inherent in marine bioprospecting means you can almost always find a good place to look.

How to look? – Accessing marine biodiversity can be enormously expensive and slow, so we need a practical mechanism for getting hold samples and we need practical mechanisms for processing these samples. For example, working on extremophiles from deep ocean vents is an attractive idea, but can you afford the ROV that is required to go down there and will that produce enough samples and will you be able to resupply if needed. Once you have your samples the extraction process needs to make enough ‘product’ for characterisation, at a reasonable cost and in a reasonable timeframe.

Does someone want what I am looking for? – this is mostly answered when you have considered ‘what to look for’, but goes beyond that. Its important not only to have an application, but to have one that someone wants. If you are successful and find a new drug, how will you progress from that initial discovery? For an academic this may be less of a concern, but you do need to know that you will produce science that is publishable. In a commercial drug discovery the answer will probably be that nobody wants a newly discovered drug, they want one that has gone through development and successfully reached phase 1, II or III of clinical development.  This defines how much money you need, how long it will take and probably defines your business model.

My argument, therefore, is for a carefully thought through approach to marine natural products research and development. I don’t think there is a right answer, except that the answers should give focus and be rational. Luck will still be involved but we need to increase the chance of success.

We call ourselves a marine biotechnology company, we are based at the European Centre for Marine Biotechnology (www.ecmb.org/) and our new blog is about marine biotechnology, but it’s a name that we don’t like.

Marine biotech, or blue biotech as it is known, is unique among all the colours of biotech, because it is defined by its source not by its market. The other biotech’s; red biotech is medical, white biotech is industrial, green biotech is agricultural, are all defined by the application or market. For blue biotech there is no real ‘marine’ application, the applications are covered by the other biotechs, and even aquaculture is really category of green biotech.

Taken from http://www.marinebiotech.eu/wiki

Why does it matter? What’s in a name?

Biotechnology is ‘the use of living systems and organisms to develop or make useful products, or “any technological application that uses biological systems, living organisms or derivatives there of, to make or modify products or processes for specific use”’ (en.wikipedia.org/wiki/Biotechnology). So blue biotech should redefine itself and think about the application, the end use, the market. If we (the marine biotech community) fail to think in this way we may well fail to meet our potential to make a difference in the world, and we will remain an enthusiastic offshoot or marine biology.

Why does it matter? Are we different?

GlycoMar was setup to develop anti-inflammatory drugs, combining the founder’s interests in glycobiology and marine biology. So GlycoMar is a medical biotech company. Other examples include marine biotech companies developing products from marine microalgae, some of these are industrial biotechs (e.g. biofuels), some are medical biotechs (drugs and other therapeutics), and some are agricultural biotechs (e.g. aquaculture feed). Once the application or market is defined a lot of other things fall into place: the kind of science we need to do, how long it will take, how much money we need, route to market, business model, and the chance of success. All of this before we have done anything or spent any money. Marine biotech is no different to any other industry. If we don’t identify our market, we lack focus and will ultimately fail to make a difference.

Marine biotech is dead, long live marine biotech!

Is this the end of marine biotech? Not for GlycoMar, we still use the term for a couple of good reasons: it is convenient ‘brand’ or differentiator which is attractive to some (but not all) of our target market; it communicates some of what makes us unique; it is attractive to some investors / funders. There has been a lot of hype around blue biotech in Europe (part of their ‘Blue growth’ strategy, ec.europa.eu/commission_2010-2014/damanaki/headlines/press-releases/2012/09/20120913_en.htm,) and elsewhere. Money has been spent on consultancy and desk studies, which correctly identify the potential of blue biotech (for example ec.europa.eu/environment/greenweek2011/sites/default/files/3-6_Querellou.pdf). So, will we see marine biotech grow into a major industry in the next few decades? Yes, the developments that are happening now in industry (for examples biofuels) and in pre-market research are starting to deliver products which will make a difference. Will we call it marine / blue biotech once it is successful?