Functional sugars made by biotech for everyone

EuroBiotech: Dr Jennewein, when you founded Jennewein Biotechnologie in 2005, you had the vision to produce rare, functional sugar molecules biotechnologically. Could you please outline what made your company one of the largest producers of human milk oligosaccharides (HMOs) in the baby food sector within a decade?
Jennewein: Many biotech companies vanished in 2004 when the dotcom bubble burst. There was also a degree of public hostility towards the biotech industry, particularly companies involved in non-medical applications. However, in most parts of the world, no one could actually buy a biotech product, so there was no way for the public to really see the potential benefits. The idea that we had was to make a biotech product that would, for the first time, help to improve the life of an average person. We were looking for a product that would have a highly positive impact on health and that could be made available to anyone. Importantly, we did not want to hide the fact that the product was manufactured using biotechnology. So, we came up with the idea to make human milk oligosaccharides (HMOs) for infant food, particularly for formula products that are used to replace or augment breastfeeding. The health benefits of HMOs have been understood for about 100 years, but HMOs are not included in infant formula products for several reasons. First, in terms of regulation, the infant food market is right up there with pharmaceuticals, and this puts a lot of companies off. Second, it is clearly not ethical to extract HMOs from breast milk, but nor is it economically feasible to chemically synthesize them. So, biotechnology was the only way forwards for such a product. The key to making a success of the venture was the support and advocacy we received from paediatricians and midwives, who appreciate the advantages of HMOs. With all these factors considered, we decided to make biotech-derived HMO products that would benefit as many people as possible, by allowing HMOs to be included in infant formula.

EuroBiotech: Many biological functions and applications have been attributed to HMOs. Could you give us a brief overview, please?
Jennewein: When people think of sugars, they tend to think in terms of energy. However, HMOs are not metabolised by infants or adults, so they do not provide any energy at all. That side of the equation is covered by the lactose and lipids present in human milk. HMOs are much more complex than the sugars used for energy, and their role is much more interesting. All pathogens must interact with human cells to start an infection, and around 80% of them recognize sugar molecules displayed on the cell surface. HMOs mimic these structures and, therefore, act as decoys. HMOs reside in the gut but are also absorbed into the blood stream. In both places, pathogens looking to attach to cells are, instead, locked into a futile partnership with HMOs and are passed through the gut or attacked by the immune system. Many different pathogenic bacteria can be blocked in this manner not only by HMOs, but also by other important pathogens, such as the Norovirus. Another hot research topic at the moment is the influence of HMOs on the microbiome, which is the community of microbes that live in the gut. HMOs are thought to help establish a healthy microbiome in newborn infants, and indeed, the investigation of this phenomenon is what led to the discovery of HMOs in the late nineteenth century by Theodor Escherich, a paediatrician working in Austria. At the time, breastfed infants were seven times more likely to survive than those fed on formula. He and his co-workers then discovered that the microbiomes of breastfed and formula-fed infants were very different, and this led ultimately to the discovery of HMOs. There is mounting evidence that the establishment of a beneficial microbiome in the first weeks of development can reduce the risks of many different diseases in childhood and adulthood, not just infectious diseases but also allergies, neurological conditions (possibly even including autism), and metabolic conditions such as obesity. Some HMOs are known to play a key role in neural development. The multiple benefits of HMOs should not really come as a surprise. After all, human breast milk has evolved over hundreds of thousands of years to match the needs of developing infants. During that time, they have adapted to support and nurture beneficial bacteria in the gut while preventing infections from hostile microbes. Of course, the presence of beneficial microbes also acts as a secondary mechanism to ward off pathogens, and HMOs help to establish this population from the very first moments of life outside the womb.
 
EuroBiotech: Glycobiology is an emerging field with a growing number of players. What makes your company and processes unique?
Jennewein: In 2005, I don’t think anyone could imagine that the industrial-scale manufacturing of HMOs would be possible at such a low cost, and that they could be added to mass-market infant formula products at concentrations in the grams per litre range. In addition, we are not only targeting the infant food market in the affluent West. For example, our HMOs are already used in infant formulae on sale in Vietnam and Mexico. The industrial face of glycobiology is challenging, because the glycosidic bonds that hold complex sugars together are difficult to engineer in a controlled manner, which, in many cases, makes the large-scale manufacturing of complex oligosaccharides economically unsustainable. However, we are tackling these hurdles by combining metabolic engineering with new chemical engineering concepts and expanding our spectrum of HMOs to cover a broader range. Beyond the mass market of HMOs for infant formulae and other functional foods, the market for glycobiology products will probably not grow very much, at least in the short term. For example, we have also developed methods to produce nucleotide-activated monosaccharides, which are used to test the glycosyltransferases, enzymes that synthesize oligosaccharide molecules. This is an extremely niche market, in that we are making glycobiology products for other glycobiology researchers. In terms of competition, we find that others now want to copy our technology and business model, because they do not have their own innovations. We are probably one of only a few biotech companies that started with an idea, were lucky enough to succeed against all odds, and ultimately brought a product to the market. Our pipeline is full with additional products for a range of markets, but our first HMO is available for virtually anyone to purchase. Overall, this product is an excellent example for the use of biotechnology in a very positive way.

EuroBiotech: Could you please describe the market for HMOs and Jennewein’s achievements and development strategy in the infant formula and therapeutic nutrition markets?
Jennewein: Other than water, HMOs comprise the third largest fraction of human milk after lactose and lipids, and unlike the first two components, HMOs are extremely specific and are not found in the milk of other animals. Today’s infant food products contain lactose, lipids, and artificial surrogates, such as GOS, but not HMOs. Therefore, they are not a true replacement for breast milk, other than the very basic functions of energy provision. The addition of HMOs to infant formula is a huge leap towards the ideal situation where formula products would be functionally equivalent to breast milk, with all the associated positive health benefits. This would mean that infants that cannot be breastfed for any reason would not be at a disadvantage compared to breastfed infants. Jennewein Biotechnologie was the first company to develop HMO products for the market, and the first launch was 2’-fucosyllactose, which is the most abundant HMO in the milk produced by most nursing mothers. This product was launched in the USA in 2016, and was followed by the EFSA Novel Food Approval in the EU. Interestingly, we were the first in the European Union to file an EFSA Novel Food Application using a recombinant bacterial processing aid. At that time, only one other Novel Food Application had been presented involving a recombinant processing aid, and this was for an ice-structuring protein submitted by Unilever, which involved a recombinant backer’s yeast strain.
When we registered 2’-fucosyllactose in the US, an FDA officer confided that he thought the inclusion of HMOs in infant formulae was a “no-brainer.” I agree with this assessment, and I think it is imperative that HMOs are included in infant formula also at the natural concentrations present in breast milk. We already have a new product in very advanced development comprising the five most abundant HMOs found in human milk. We are currently running a multi-centre clinical trial, involving centres in Spain, Italy, and Germany, and hope to launch the first infant food formula products with partners as early as 2020. Thus, using a blend of several abundant HMOs at natural concentrations is a huge leap forward in finally making infant food formula more similar to breast milk. Unfortunately, as of today, infant food formula only shares, at best, a 30% similarity to human milk, and this is mainly due to the lactose basis. In other fields, it is clear that the ability of HMOs to act as decoys for pathogenic bacteria and viruses could also benefit other age groups, not just infants. There are already several medical nutrition products containing 2‘-fucosyllactose on the market. We are certainly looking for opportunities in this arena, in addition to infant nutrition.

EuroBiotech: Most recently, Jennewein signed a MOU with Asia’s largest dairy company, the Yili Group, to develop an infant formula specifically suited to the Chinese market. What are the scientific challenges in this partnership, the different areas of expertise, and how Jennewein hopes to benefit from it?
Jennewein: The MOU with the Yili Group represents an important milestone for us in bringing HMOs to China. First of all, Yili is one of the biggest players in the Chinese infant formula market, and China is the biggest infant food market in the world, both in volume and value. Thus, China is also likely to become the most competitive market with regards to innovation in the near future. I think it is pretty clear that the next innovation cycle in infant nutrition will be the introduction of multiple HMOs with the aim to prevent infectious diseases, support the establishment of a healthy microbiome, and promote brain development. However, there is a degree of ethnic heterogeneity in HMO profiles. Therefore, in cooperation with Yili, we want to develop an infant food formula that fits specifically to the Chinese market by matching the HMO requirements of the population. Given the increasing awareness of HMOs in China, we aim to solve the long-standing problem of registering innovative, novel food products in China, particularly those involving a genetically modified processing aid, i.e. the bacterial strains we use to produce the HMOs.

EuroBiotech: The food industry is just one sector that Jennewein has targeted for HMO usage, as functional mono- and oligosaccharides have also many applications in the pharma and cosmetics sector and even in research. Could you please describe how Jennewein will develop applications in these and other fields?
Jennewein: Supplying HMOs for the infant formula market is, without a doubt, our most important business sector. The second most important area is the development of carbohydrate products containing complex oligosaccharides or rare or unnatural monosaccharides for the pharmaceutical, cosmetic, and food markets. Such carbohydrates have not received a great deal of attention, partly because they have been difficult to synthesize, and this is a massive area for potential, future innovation. We can envisage many new applications and products, but as a company, we also have to stay focused on our current business. Today‘s challenges are also associated more with bringing innovative biotechnology products to the market. There is still far too little appreciation of the benefits of biotechnology and too much misinformation about the risks.

EuroBiotech: How about competition and securing a unique niche for your business?
Jennewein: Despite all the opportunities in the biotechnology and, particularly, the nutrition fields, there is a strong propensity for free-riding and patent-trolling in the industry. At the end of the day, you have to hope that you can enforce your patents and also work around the patent trolls and pseudo-inventions. Sometimes, it seems to me that running a biotech company without a product on the market is a more relaxed endeavour.

EuroBiotech: Could you give us a brief outlook: In which fields will Jennewein be investing for future growth, and what are your feelings about the different target markets?
Jennewein: We will continue to invest in clinical trials. This is already our focus in the field of infant nutrition products and the microbiome, but we want to do more, particularly in the context of medical nutrition. In addition, we will invest in our own manufacturing capacity, in order to match the increase in the number of different biotechnological processes we have developed. We do not want manufacturing capacity to limit what we can achieve in terms of commercial development.

First published in European Biotecnology Magazine Spring 2019 edition.