HomeInnovationEFSA gives the green light to the first novel food from cellular agriculture

EFSA gives the green light to the first novel food from cellular agriculture

The first food ingredient from cellular agriculture submitted for authorization as a novel food has obtained a favorable scientific opinion from EFSA (European Food Safety Authority). In this case, the innovative technology is applied to the plant world, in order to produce a food supplement with an anti-aging function. (1)

1) Plant stem cells

NGTs plants they are able to produce, in meristematic tissues (i.e. at the apex of stems and roots), stem cells which are equipped with the innate ability to undifferentiate. Their cellular regeneration by mitosis consists of the division into two cells, one of which remains meristematic, grows and prepares for a new division, while the other is destined to differentiate to become part of the specific tissues of the plant. They are therefore called 'totipotent cells'. (2)

Fig. 1 – Example of the propagation and extraction process of plant stem cells from the Uttwiler Spätlauber apple variety (Aggarwal et al., 2020)

Plant stem cells are subjected to culture, or cellular agriculture, to be propagated and obtain both plants or plant tissues, and specific cells from which to obtain and extract individual metabolites. Such as, for example, phenolic compounds (3) – bioactive substances with antioxidant, anti-inflammatory and protective actions – with enormous potential in the production of functional ingredients (for food, pharmaceutical and cosmetic use).

2) Use of plant stem cells in food supplements

Mibelle Group Biochemistry (CH) had submitted, on 14 April 2020, an application for authorization to place on the EU market a food supplement intended for the adult population, obtained from the biomass produced by cell culture of apples of the Uttwiler Spätlauber variety.

The ingredient subject of the novel food authorization request, PhytoCellTec™ Md Nu, is already used by Mibelle Group Biochemistry - a company specialized in the production of ingredients for the cosmetic and nutraceutical industry - in the production of cosmetics with functionalities anti-aging and skin nourishment. (4)

The choice of variety is linked to high abilities storage, which allow the skin of the fruit not to shrivel, and not to lose its leaves even in the harsh winter periods. The name Uttwiler is the name of the village where the variety was discovered, while Spätlauber means 'late foliage'.

3) Plant cell culture, the process

Cellular agriculture in the plant kingdom it starts with the explant of a portion of tissue from the chosen plant, the wound of which generates a mass of colorless cells ('callus') which activate cellular dedifferentiation to regenerate damaged tissues. The callus cells are then cultivated - individually or in groups (clusters), according to needs - in special culture media. Below is the description of the production process of the first novel food candidate from cellular agriculture in the European Union.

3.1) Callus formation

The fruit of the Swiss apple – in the case of the novel food in question – is cut into sections, some of which are placed on a solid culture medium made up of sucrose, vitamins, minerals and other elements, with agar to solidify the medium. There are also two plant hormones called 6-benzyladenine (BAP) and 2,4-dichlorophenoxyacetic acid (2,4 – D).

The primary callus – made up of undifferentiated cells – is thus stimulated to continue growth. Some of its selected cells are then used to obtain stock cultures and reserve cultures stored in frozen form, to replace the stocks with an approximate frequency of 5 years. All operations must be conducted in conditions of absolute sterility.

3.2) Cell cultivation

The cells stock cultures are transferred into 500 ml flasks where the culture medium itself is present in liquid form (i.e. without agar). They propagate at room temperature, with light movement, keeping the essential parameters under control (e.g. pH, biomass volume, sugar content).

Once the values ​​are reached desired, approximately 10% by volume of the flask is transferred, always in sterile conditions, into disposable containers (biocontainers) with increasing volumes (eg, 1 litre, 20 litres, 50 litres).

The whole process cultivation lasts on average 3-4 weeks and is considered completed when the sugars present in the cultivation medium have been completely metabolised by the cultured cells.

3.3) Production of the ingredient

The contents of the biocontainer of 50 liters is filtered and rinsed with a 0,9% sodium chloride (NaCl) solution (i.e. saline solution), to then be mixed in a 15% ethanol solution and homogenized at high pressure (1.000 bar), so as to allow the cells to break down. This is followed by a heat treatment at 113 °C with an air flow of 300 kg/h.

Cell culture – dried and pulverized with a fluid bed dryer – it is then mixed with isomalt, in order to obtain a product that can be stored at room temperature.

4) Characteristics and specifications of the new food

The composition of biomass obtained from cell culture was very different - in terms of proteins, sodium and fiber - compared to the reference values ​​indicated in the OECD (Organisation for Economic Co-operation and Development) 'consensus document' on apple varieties. (5)

The applicant hypothesizes that these differences can be attributed to the cells developed in the callus (proteins), the rinsing with sodium chloride solutions (sodium), and the shear stresses to which the cells were subjected during cultivation (fibers).

Novel food it is made up of a mixture of cell culture biomass powder from apple (1.1 – 1.5%) and isomalt (98.5 – 98.9%) obtained from sugar beet (Beta vulgaris var. saccharifera), which is used as a carrier to facilitate transport and the absorption of dust in the affected locations.

Fig. 2 – Composition of biomass from apple cell culture, compared with the values ​​defined by the OECD for the fruit (EFSA NDA Panel, 2023)

5) Synthetic hormones

The hormones used to stimulate cell dedifferentiation and proliferation (ie 6-benzyladenine and 2,4 – D) are synthetic analogues of the plant hormones 'auxin' and 'cytokinin'. They are used a lot for this function also in other plants (e.g. azzeruole, yarrow, geranium). As well as to stimulate the production of metabolites such as organic acids, anti-oxidants, polyphenols (6,7,8).

These substances – like pesticides – are subject to 'Maximum Residues Levels' (MRLs), pursuant to Regulation (EC) no. 396/2005 and its subsequent amendments. (9) Their use in agriculture is authorized for as plant growth regulators and herbicides (primary use), respectively, pursuant to Regulation (EC) No. 1107/2009 on plant protection products. (10)

In the present case, the presence of 6-benzyladenine was not identified while 2,4-D was identified at concentrations slightly higher than the MRLs (between 0,052-0,056 mg/kg) established for fresh apples, which EFSA however considers not of concern in relation to the intended use.

6) Toxicological information

In vitro studies presented by the applicant to evaluate the genotoxicity of the novel food - partly replicated, due to interferences due to the presence of isomalt - did not show reasons for concern about genotoxicity given by the novel food, at the concentrations tested.

An in vivo study of oral toxicity on mice for 90 days was however unusable due to the lack of compositional analysis of the novel food and the lack of description of some endpoints. Furthermore, EFSA did not consider this type of study (sub-chronicity) essential to carry out the risk assessment.

7) Potential allergenicity

The high concentration of proteins in novel food it has been the subject of particular attention, since apple allergy is one of the most common among those associated with fruit consumption. At the request of EFSA, the applicant had to provide a comparison of the expression of proteins in the biomass produced with the proteins contained in the fruit.

An analysis of the gene ontology tried to better characterize the 803 proteins that are present in the biomass and not also in the fruit, but the information on the proteomics of the apple (Malus domestica) is limited and it was not possible to fully investigate the nature and function of these proteins. It has therefore been concluded that these proteins have potential allergenicity, which however has not been confirmed.

8) Previous evaluation in Australia and New Zealand

The novel food candidate it has already been assessed, in 2020, by the Advisory Committee on Novel Foods (ANCF) of Food Standards Australia New Zealand. (11) Following this evaluation, the ingredient was classified in an intermediate category, as 'non-traditional food' but at the same time 'not novel food'. (12)

FSANZ considered the absence of safety problems under the proposed conditions of use, up to 10 mg/day in a product made up of 1-10% apple cell culture and 90-99% isomalt. The same conditions had already been considered acceptable, in 2017, for the powder obtained from fruit cells alone.

9) Provisional conclusions

Scientific opinion under examination, referring to an ingredient of plant origin, paves the way for the approval in the European Union of the first food derived from cell culture. It is reasonable to expect that this path will be followed by other operators working on the production of animal-based 'cell cultures', in the wake of the authorization procedures already carried out in Singapore and the USA. (13)

Publication of the opinion EFSA's scientific assessment took almost 40 months, well beyond the ordinary 9-month period foreseen by the Novel Foods Regulation (EU) 2015/2283. This delay can be partly explained by the attention paid to safety assessment. And at the same time it is not very encouraging for those investing in research and development in the Old Continent. (14)

Dario Dongo and Andrea Adelmo Della Penna


(1) EFSA NDA Panel (2023) Safety of apple fruit cell culture biomass as a novel food pursuant to Regulation (EU) 2015/2283. EFSA Journal 21(7):8065, https://doi.org/10.2903/j.efsa.2023.8065

(2) Aggarwal et al. (2020) Plant stem cells and their applications: special emphasis on their marketed products. 3 Biotech 10:291, https://doi.org/10.1007/s13205-020-02247-9

(3) Dario Dongo, Salvatore Parisi. Polyphenols and health. Vegetables that are friendly to the immune system. GIFT (Great Italian Food Trade).

(4) PhytoCellTec™ Md Nu gains positive EFSA opinion as novel food. https://mibellebiochemistry.com/phytocelltectm-md-nu-gains-positive-efsa-opinion-novel-food

(5) OECD (2019) Safety Assessment of Foods and Feeds Derived from Transgenic Crops, Volume 3 – Common bean, Rice, Cowpea and Apple Compositional Considerations. OECD Publishing, https://doi.org/10.1787/f04f3c98-en

(6) Chaabani et al. (2015) Effects of 2,4-dichlorophenoxyacetic acid combined to 6-Benzylaminopurine on callus induction, total phenolic acid ascorbic acid production, and antioxidant activities in leaf tissue cultures of Crataegus azarolus L. var. chokeberry. Acta Physiol. Plant 37:16, https://doi.org/10.1007/s11738-014-1769-4

(7) Karhizi & Kakakei (2010) Effect of 6-Benzylaminopurine, 2,4-Dichlorophenoxyacetic Acid and Indole-3-Butyric Acid on Micropropagation Stages of Achillea biebersteinii. Asian Journal of Chemistry 22(3):2383-2386, https://asianjournalofchemistry.co.in/User/ViewFreeArticle.aspx?ArticleID=22_3_98

(8) Haensch (2007) Influence of 2,4-D and BAP on callus growth and the subsequent regeneration of somatic embryos in long-term cultures of Pelargonium x domesticum cv. Madame Layal. Electron. J. Biotechnol. 10(1):69-77, http://doi.org/10.4067/S0717-34582007000100007

(9) Regulation (EU) 2021/1841 established an overall MRL of 0,01 mg/kg for 6-benzyladenine, while Regulation (EU) 2022-1363 established an MRL of 0,05 mg/kg, specific for apples

(10) Permitted uses and references to periods of authorization and expiry of authorization are set out in Part A (Active substances considered to be approved under Regulation (EC) No 1107/2009, i.e. active substances listed in Annex I to the Directive 91/414/EEC), entry 317 and Part B (Active substances approved pursuant to Regulation (EC) No 1107/2009), entry 94 of the Annex to Regulation (EU) No. 540/2011

(11) FSANZ. Record of views formed in response to inquiries. Updated July 2023. https://www.foodstandards.gov.au/industry/novel/novelrecs/Documents/Record-of-Views-updated-July-2023.pdf

(12) The definitions of 'non-traditional food' and 'novel food' are contained in section 1.1.2-8 of regulation 1.1.2 of the Food Standard Code:

– 'non-traditional food' can have the following meanings:
(a) a food that has no history of human consumption in Australia or New Zealand, or
(b) a substance derived from a food, where that substance has no history of human consumption in Australia or New Zealand other than as a component of that food, or
(c) any other substance, if it or the source from which it is derived has no history of food consumption in Australia or New Zealand,

– 'novel food' is a 'non-traditional food' that requires an evaluation of public health and safety considerations, taking into account:
(a) potential harmful effects on humans,
b) composition and structure of the food,
c) process by which the food was prepared,
d) source of origin,
e) patterns and levels of food consumption,
f) any other relevant matter.

(13) Dario Dongo. Chicken meat from cellular agriculture, green light in the USA and kosher certification. GIFT (Great Italian Food Trade).

(14) It should be remembered that EFSA (European Food Safety Authority) – in the eleven years since its establishment, provided for by the 'General Food Law' (EU Reg. No 178/02) – has been invested with a wide range of responsibilities in every regulatory field that pertains to the agri-food supply chain. And its annual budget is still entrusted solely by the decisions of the European Parliament, without contributions being foreseen from the member states or the operators who turn to the Authority. The allocation of adequate resources is therefore essential to guarantee food safety in the European Union but also the competitiveness of the sector.

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Dario Dongo, lawyer and journalist, PhD in international food law, founder of WIISE (FARE - GIFT - Food Times) and Égalité.

Andrea Adelmo Della Penna
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Graduated in Food Technologies and Biotechnologies, qualified food technologist, he follows the research and development area. With particular regard to European research projects (in Horizon 2020, PRIMA) where the FARE division of WIISE Srl, a benefit company, participates.

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