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]
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)
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.
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