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Project

DHA Deficiency: A Worldwide Problem

Docosahexaenoic acid (DHA, C22:6) is an essential nutrient required for human health and development, which can only be obtained through dietary intake. The problem of DHA deficiency is severe and widespread on a global scale. It is a significant health concern affecting populations worldwide. Insufficient dietary intake of DHA is prevalent, particularly in regions with limited access to DHA-rich food sources. This deficiency poses a serious risk to various vulnerable groups, such as pregnant women, infants, and young children, who require adequate DHA for optimal brain development and overall health. The severity of the problem underscores the urgent need for awareness, interventions, and policies to address DHA deficiency and its associated health implications globally. [1]

DHA Health Benefits
Data based on research from Start et al. (2016)

Data based on research from Start et al. (2016) [2]

So What: Why DHA has Increasing Market Demand

DHA, a type of omega-3 fatty acid, is an important substance for human health. It often comes in the following forms:

  • Infant Formula
  • Nutritional Supplements
  • Food & Beverage

According to NHI, DHA provides substantial health benefits. It is crucial for brain and cognitive function, eye health, heart health, pregnancy and infant development, mental well-being, and reducing inflammation associated with chronic diseases.[1] Increasing DHA intake, either through diet or supplements, can provide significant improvements to overall health and well-being, making it an important nutrient for people of all ages.[3]

Consequently, FDA approved health claims for EPA and DHA omega-3 consumption in 2019, driving up its market demand and raising awareness of DHA. Until today, DHA is still a growing market with a projected CAGR ranging from 6.76% to 9.2% in the next decade.[4][5]

Current Source of DHA

Fish oil has traditionally been a common source of DHA in the market. However, it is prone to pollution, lacks stability in terms of quality, and its production is expected to decline rapidly due to overfishing and the impact of global warming, which will be discussed below in detail. Other challenges for DHA from fish oil include:

  • Complex and expensive purification process involved for obtaining pure products
  • Unfriendly to vegetarians
  • Unwanted odor

DHA can also be derived from microalgae, which is its natural origin. However, the industrial-scale fermentation of microalgae for DHA production still faces certain challenges including high production costs and low efficiency, resulting in microalgae being a minor source of DHA in the market [6].

Gap in the Field: Natural Outputs of DHA Declines

Though the DHA market has such an increasing demand, the supply side is not optimistic. In 2020, Colombo et al. warned that global warming is predicted to reduce the de novo synthesis of DHA by algae, which forms the base of aquatic food chains, leading to a decrease in the amount of DHA transferred to fish and shrimp. [7] The researchers estimate that, depending on the climate scenario and location, an increase in water temperature which disrupts de novo synthesis of DHA in marine algae could result in a 10 to 58% loss of globally available DHA by 2100. The researchers further estimate that in the worst-case scenario, DHA availability could decline to levels where 96% of the global population may not have access to sufficient DHA, indicating that the natural production of this critical nutrient is indeed decreasing.

Based on data from this paper and several market reports, we have projected the outlook of the market and found a significant gap for alternative DHA production methods. The projections are based on the following assumptions:

  • The global market for DHA is currently growing at a rate of 9% per year. [8]
  • The amount of DHA available from marine organisms is projected to decrease by 58% of current levels by the year 2100. This equates to an annual decrease of approximately 1.07%. [7]
  • The current global market size for DHA is $3,821.4 million. [8]
  • The DHA market is segmented, with 20% coming from algae sources and 80% coming from fish sources.
  • The growth rate for the algae-based DHA segment is assumed to be 7% per year. [7]

Our Project

In order to address the gap between the increasing market demand and decreasing market supply as well as the global problem of DHA deficiency, the iGEM HKUST Team 2024 DHA Express is working on efficient DHA production through yeast chassis Yarrowia lipolytica, a safe, commonly-used organism for industrial fatty acid production [5].

DHA Production

PUFA synthase from certain organisms can directly synthesize DHA from acetyl-CoA and malonyl-CoA, which is considered as a more specific pathway for DHA synthesis and consumes less NADPH compared to others [9-10].

We plan to synthesize the PUFA synthase gene cluster (around 20kb in total) originally from Schizochytrium sp. (ATCC 20888) and integrate it into the genome of Y. lipolytica strain Po1f, which can achieve a relatively high lipid content, growth rate, and growth density, boosting the production [11]. The PUFA synthase gene cluster consists of 3 open reading frames (ORF) corresponding to different protein subunits, which will assemble together to become one large enzyme in the cytoplasm [12]. A PPTase from the same organism will also be introduced to activate the enzyme.

The DHA specificity and modular nature of the enzyme offers us abundant space for further improvements. By introducing and potentially designing the key machine into a well-established microbial factory, we can harness the great advantage of synthetic biology to achieve flexible control of the whole process, while setting a basis for introducing future designs efficiently. While traditionally in microalgae, though the yield can still be boosted through genetic engineering, the production can be constrained to limited flexibility in design and understanding of the host organism [6].

A schematic graph showing the inputs and outputs of our chosen DHA production pathway with the “machine” PUFA synthase

(A schematic graph showing the inputs and outputs of our chosen DHA production pathway with the “machine” PUFA synthase)

Furthermore, our PUFA synthase is characterized as a polyketide synthases (PKS), which typically synthesizes polyketides, a wide group of valuable natural products, including polyunsaturated secondary metabolites and many other complex molecules, from acetyl-CoA. By expressing the PUFA synthase in Y. lipolytica, we not only explore the possibility of industrial-scale production of DHA, but as well as other polyketides using oleaginous yeast potentially.

Metabolic Engineering

DHA, a type of omega-3 fatty acid, is an important substance for human health. It often comes in the following forms:

  • Infant Formula
  • Nutritional Supplements
  • Food & Beverage

According to NHI, DHA provides substantial health benefits. It is crucial for brain and cognitive function, eye health, heart health, pregnancy and infant development, mental well-being, and reducing inflammation associated with chronic diseases.[1] Increasing DHA intake, either through diet or supplements, can provide significant improvements to overall health and well-being, making it an important nutrient for people of all ages.[3]

Consequently, FDA approved health claims for EPA and DHA omega-3 consumption in 2019, driving up its market demand and raising awareness of DHA. Until today, DHA is still a growing market with a projected CAGR ranging from 6.76% to 9.2% in the next decade.[4][5]

Our Vision

The primary aim of the project is to explore an alternative solution in response to the growing market gap of DHA and existing challenges of the industry, hoping to bring DHA to more people in need sustainably and efficiently through our efforts.

Moreover, through our project we aim to offer a safe and widely-compatible system for more biomanufacturing scenarios. Due to the similarities among some polyketide synthases, as well as the goals for industrial production, the synthetic biology approaches utilized and the scale up process designed by our team may not only be utilized for DHA production, but potentially serve as a model for production of other valuable products such as polyketides, providing references or inspirations for future projects and also the industry.

Inspirations

References

Reference:
[1] Oliver, L., Dietrich, T., Marañón, I., Villarán, M.C., Barrio, R.J. (2020). Producing Omega-3 Polyunsaturated Fatty Acids: A Review of Sustainable Sources and Future Trends for the EPA and DHA Market. Resources 2020, 9, 148. https://doi.org/10.3390/resources9120148
[2] Ken D. Stark, Mary E. Van Elswyk, M. Roberta Higgins, Charli A. Weatherford, Norman Salem. Global survey of the omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid in the blood stream of healthy adults. Progress in Lipid Research, Volume 63, 2016, Pages 132-152. https://doi.org/10.1016/j.plipres.2016.05.001
[3] Omega-3 Fatty Acids - Health Professional Fact Sheet. ​​https://ods.od.nih.gov/factsheets/Omega3FattyAcids-HealthProfessional/
[4] LLOYD A. HORROCKS, YOUNG K. YEO. HEALTH BENEFITS OF DOCOSAHEXAENOIC ACID (DHA). Pharmacological Research, Volume 40, Issue 3, 1999, Pages 211-225. https://doi.org/10.1006/phrs.1999.0495
[5] Docosahexaenoic Acid (DHA) Market Size, Growth Report, 2032. Business Research Insights, 03 June 2024. https://www.businessresearchinsights.com/market-reports/docosahexaenoic-acid-dha-market-110648
[6] Socio-economic assessment of Algae-based PUFA production. PUFAChain, 2017. https://www.pufachain.eu/fileadmin/download/Socio-economic_assessment_of_Algae-based_PUFA_production.pdf
[7] Colombo, S. M., Rodgers, T. F., Diamond, M. L., Bazinet, R. P., & Arts, M. T. (2020). Projected declines in global DHA availability for human consumption as a result of global warming. Ambio, 49(4), 865-880. https://doi.org/10.1007/s13280-019-01234-6
[8] DHA from Algae Market Size Projected to Surpass US$ 720.44 million by 2031, by 2031, with Increasing CAGR of 7.05%. Research Industry Network, 04 Jan 2024. https://www.linkedin.com/pulse/dha-from-algae-market-size-projected-x2pyf/
[9] Gemperlein, K., Dietrich, D., Kohlstedt, M. et al. Polyunsaturated fatty acid production by Yarrowia lipolytica employing designed myxobacterial PUFA synthases. Nat Commun 10, 4055 (2019). https://doi.org/10.1038/s41467-019-12025-8
[10] Guo P, Dong L, Wang F, Chen L and Zhang W (2022), Deciphering and engineering the polyunsaturated fatty acid synthase pathway from eukaryotic microorganisms. Front. Bioeng. Biotechnol. 10:1052785. https://doi.org/10.3389/fbioe.2022.1052785
[11] Young-Kyoung Park, Rodrigo Ledesma-Amaro. What makes Yarrowia lipolytica well suited for industry? Trends in Biotechnology. Volume 41, Issue 2, 2023, Pages 242-254, https://doi.org/10.1016/j.tibtech.2022.07.006
[12] Hauvermale, A., Kuner, J., Rosenzweig, B. et al. Fatty acid production in Schizochytrium sp.: Involvement of a polyunsaturated fatty acid synthase and a type I fatty acid synthase. Lipids 41, 739–747 (2006). https://doi.org/10.1007/s11745-006-5025-6
[13] Qiao, K., Wasylenko, T., Zhou, K. et al. Lipid production in Yarrowia lipolytica is maximized by engineering cytosolic redox metabolism. Nat Biotechnol 35, 173–177 (2017). https://doi.org/10.1038/nbt.3763
[14] Qin J, Kurt E, LBassi T, Sa L and Xie D (2023). Biotechnological production of omega-3 fatty acids: current status and future perspectives. Front. Microbiol. 14:1280296. https://doi.org/10.3389/fmicb.2023.1280296
[15] Xue, Z., Sharpe, P., Hong, SP. et al. Production of omega-3 eicosapentaenoic acid by metabolic engineering of Yarrowia lipolytica. Nat Biotechnol 31, 734–740 (2013). https://doi.org/10.1038/nbt.2622