Context

To: Prof. Kimberly Freeman,COLWRIT 161 class, College Writing Program

From: Upola Zaman

Date: July 25, 2023

Subject: The extent of marine biomedicine influence on functional diseases like Alzheimers

Many articles tend to cover topics regarding biomedicine, but in areas more strictly related to
chemistry or marine science. Many authors have pointed out that this has limited marine
biomedicine outreach to those in the medical field. Topics such as marine drugs also tend to be
extensively researched, while topics like marine biotechnology are less mainstream. My review
therefore intends to cover the extent of development in marine biomedicine on functional
diseases like Alzheimer's in a language geared towards medical professionals. The review
accomplishes this by going over key marine based developments in the following areas:
Research Tools, Excavation of Marine compounds, and Treatments. Health professionals who
read this review will be able to take away how they can incorporate marine biomedicine in their
professions and possible future application of marine biology within research or treatments of
Alzheimer's.
After discussing the concept of neuroprotection and marine biomedicines' role in it, the
first section of my review, research tools, discusses various animal models based on marine
organisms that are being used in AD research and why there are generally better suites models
than the mice/rodent models. The second section discusses excavation methods for
biocompounds commonly used in Ad drug treatments. The third section discusses very broadly,
key concepts and developments in AD marine drugs from 2020 to 2023. Finally, I conclude with
possible future applications and how medical professionals can take the field of AD research
further.
I believe an appropriate journal would be "Neurogenesis" by Taylor Francis Online. This
journal uses the APA style during submission. Many articles came from MDPI for drug
discovery, but those are more for chemists and pharmacists. I wanted to situate the review more
for healthcare and health research, so I believe neurogenesis is a more fitting journal since it is
geared more towards Alzheimer's disease.

In this review, it may be helpful to understand the following terms:

1. Alzheimer’s Diseases (AD) - A brain disorder that slowly destroys memory and thinking
skills. It is the most common form of dementia. (Definition Adapted from the NIH)
2. Neurogenesis - the process of new neurons forming in the brain (adapted from wikipedia)
3. Neurodegenerative - a progressive loss of structure and function in the neurons (taken
directly from wikipedia)
4. Neuroprotection - The mechanism that attempts to counter neurodegeneration through
chemical, biological, or psychological means (Bălașa et al., 2020)
5. Biomedicine - medicine based on the application of principles of the natural sciences
6. Exogenously - originating from outside the organism, such as eating (Cambridge
university press definition)
7. Endogenously - found/coming within the cell, such as a drug (Cambridge university press
definition)
8. Tangles - abnormal accumulations of tau inside neurons (NIH definition)
 The extent of marine biomedicine influence on functional diseases like Alzheimers

(Paragraph describing Alzheimer’s disease relevance, underutilized potential in AD drug

pipeline. Discuss marine science applications in medicine. Relevance of review)

The chemical makeup of marine life is ten times more biodiverse than terrestrial and

recently more scientists have begun implementing marine science elements into biomedicine

especially in areas like Alzheimers, but this is a niche, recently founded field that doesn’t have as

much traction1. Therefore this review intends to cover the extent of development in marine

biomedicine on functional diseases like Alzheimers. A review needs to be done since the extent

of this research only began to take off 3 years ago in 20201. As of right now, there are only

smaller sub reviews of everything scattered around instead of one comprehensive review

detailing the development of biomedicine. Having it all in one area can help show researchers

what they can do later, what area needs to be focused on to develop marine biomedicine further,

and can help in getting funding by showing how great the field is despite being niche.

For background, Bălașa and others discuss in a review submitted to a marine drugs

journal on MDPI the concept of neuroprotection, the mechanism that attempts to counter

neurodegeneration through chemical, biological, or psychological means1. They go on to

establish that in the recent years following 2020, there has been a shift in focus to finding natural

substances potential in neuroprotection, including those that are marine based1. Recent articles

like Bălașa and et al’s that establishes why looking at marine compounds is beneficial for

researching Alzheimer’s disease (AD) is not the first to show the potential of marine science in
medicine. Dr Chang from the medical university of south carolina wrote an editorial in 1982

which discusses early developments of marine organism research in biomedicine (Chang, 1982).

Prominent examples in the article include elie metchnikoff experiment of rose thorns into

echinoderm larvae, the first use of a squid's giant nerve axon to study nerve cells in a more

advanced fashion, and the marine echinoderms (starfish) role in researching microtubules

(Chang, 1982). Both articles by Chang and Bălașa highlight the amount of applications marine

science has to neuroscience research and particularly the potential it has in AD.

Due to the medical field and AD research mainly centering on an application driven

approach, this review will discuss the extent of marine biomedicine on AD. When first

approaching a topic like AD, medical professionals will want to conduct research. After

conducting research, they will then turn to creating treatments. The treatment process requires

gathering compounds from marine life. Finally, medical professionals will want to create the

treatments to AD from the materials and research gathered. Due to this, the review will be

broken down by first discussing research tools for AD derived from marine compounds,

discussing excavation methods for marine compounds, and then reviewing current marine

derived treatments to AD.

Research Tools

Dr Kron conducted primary research on the use of marine snail Aplysia Californica as a

model in AD research. The author states that issues with current vertebrate models arise from its

inability to truly reconstruct the complexity of AD in humans (Kron and Fieber, 2022). Instead,

newer models should be more efficient and less costly (Kron and Fieber, 2022). Dr Kron

research concludes that Aplysia is an example of a suitable new model due to the above reasons,
having a well mapped nervous system, and being multivalent in nature to truly capture the

complexity of AD (Kron and Fieber, 2022). Many articles in marine biomedicine discuss the use

of new animal models using the same thought process at Dr Kron.

Dorsemans et al., discuss in a mini-review factors and animal models in studying adult

neurogenesis, specifically T1 Diabetes and T2 diabetes impact on the CNS (Dorsemans et al.,

2017). Typically mice or rodent models are used due to their ability to spontaneously develop T1

diabetes, but there is a slight difference in immune response compared to human models

(Dorsemans et al., 2017). The authors’ then establish the use of zebrafish as an emerging model

for studying neurogenesis in general (Dorsemans et al., 2017). Zebrafish have more persistence

of radial glial cells to act like stem cells, have a higher volume of neuroblasts, and can also

regenerate the brain, making them ideal for studying physiopathological diseases like AD

(Dorsemans et al., 2017). Authors like Mhalhel et al., from Cells in MDPI agree with zebrafish

becoming an ideal model, noting that they have become more in use over the past 20 years in

studying various biomedical fields including neurodegenerative disorders (Mhalhel et al., 2023).

Adding on to the strengths of using zebrafish models by Dorsemans et al., the cells review also

includes ease of maintenance, growth, suitability for optical monitoring, a 70% homology to the

human genome, and neuroanatomical and neurochemical similarity to humans (Mhalhel et al.,

2023). This marine based animal model is a unique approach of using marine organisms in the

AD treatment pipeline, specifically in the form of research.

A neuroscience research report conducted for Wiley adds on to Dorsemans list of marine

based animal models, but this time specifically on the topic of Alzheimers. This primary research

article details similarities between three species of dolphin and humans in terms of AD

development (Vacher et al., 2023). This was done by analyzing several regions of the brain from
dead organisms. The results showed that the lesions made by AD in the three species distributed

similarly to how it would distribute in a human brain (Vacher et al., 2023). Due to dolphins

spontaneously developing AD in a fashion similar to humans, these marine organisms are a

better model for studying AD (Vacher et al., 2023). This is especially true since non-human

primates do not spontaneously develop AD (Vacher et al., 2023).

A UCSF neuroscience research article in 2020 further supports the growing list of

evidence of similarities and reasons marine animal models are ideal for AD research in humans.

The article discusses naturally occurring epilepsy of sea lions across the west coast. The authors

discuss how algae blooms have a toxin known as Dominic acid poisoning which causes

hippocampal damage to the sea lions, removing the brake for electrical activity, and acting like a

positive feedback loop in worsening the brain circuitry (Weiler, 2020). The key behind solving

this was by using research done in solving temporal lobe epilepsy for humans since this form is

very similar to what was occurring in the Sea lions (Weiler, 2020). Through research by

neurosurgeons at UCSF a cell therapy of introducing transplant embryonic MGE that go to repair

the neural circuit (Weiler, 2020). The article also details the creation of a custom targeting

system to more easily conduct cell based therapy in sea lions. A software was made to do this in

partnership with an organization known as BrainLab (Weiler, 2020). This source provides

another example of similarities in animal models and humans for studying neurodegenerative

diseases. It also works as a bridge between the medical field and marine drug application due to

the use of biotechnology for conducting research.

Excavation
 A review by Silvia, Seijas, and Otero on the exploitation of marine drugs for AD

discusses the extraction side of obtaining marine compounds in treated AD. The review first

details different marine compounds being used in AD treatment from sources such as

bacterioplankton, marine microalgae, marine macroalgae, sponges, tunicates, and arthropods

(Silva et al., 2021). The article then goes over how the important compounds from these

creatures are chemically isolated (Silva et al., 2021). The authors concede that though the high

value molecules are important, organisms have a low amount of it (Silva et al., 2021). Due to this

extraction should be selective in order to not disturb the biodiversity of marine life (Silva et al.,

2021). The authors also advocate for the development of marine biotechnology such as

aquaculture, genetic engineering, fermenter cultivation, chemical synthesis, and more to solve

this extraction issue (Silva et al., 2021). The article helps to better understand the logistical

aspect behind marine drug discovery as well as give some possible sources of development to

look into. A possible future category could be biotechnology in marine extraction.

In response, faculty of Biology and Biodiversity Research Institute from the University of

Barcelona accomplish research into biotechnology for marine drug discovery. They conducted

primary research on how a computer aided drug discovery design (CADD) could reduce the

almost 1.8 billion cost for developing new molecular treatments (Llorach-Pares et al., 2017). The

article accomplishes this by first establishing drawbacks of marine drugs such as the expensive,

logistically difficult, and time consuming method of collecting marine compounds, samples

being unculturable, and the possible environmental implications (Llorach-Pares et al., 2017).

Having a CADD to decide whether collecting a sample would result in a successful drug would

be beneficial to reduce such costs, especially since a sample of the material is not needed to

perform analysis (Llorach-Pares et al., 2017). The study then conducts a virtual profiling study to
determine the efficacy of CADD (Llorach-Pares et al., 2017). The article ends by discussing how

virtual experiments like CADD increases marine prospection causing more to conduct marine

drug discovery due to decreased cost, guidance in the drug discovery process, and protection of

marine biodiversity (Llorach-Pares et al., 2017). This article, though it details the downsides of

marine drug discovery being excavation for materials, provides a beneficial solution for

researchers to lessen costs and quicken the time to develop treatments.

Treatments

Many sources regarding marine derived treatments to AD have repeating sources mainly

due to being found as reviews on a journal meant for chemists, MDPI. Due to this, the treatments

section of the review will be highlighting common key issues and concepts from sources.

A previously mentioned review by Bălașa et al., aimed to look at studies that discussed

recent compounds restructured from 2018 to 2020 that aided in neuroprotection. The source

initially established that one avenue of ways marine science was used in biomedicine is creating

biomolecules/products since it is of high interest to pharmaceuticals and has a high interest in

economic activities1. The review specifically focuses on one compound: polysaccharides, mainly

Chitin, which is abundantly found in the exoskeleton of marine organisms1. The article then

discusses how marine derived glycosaminoglycans further developed from base polysaccharides,

glycoproteins, and lipids are superior to those derived from terrestrial compounds1. The notion of

marine biomolecules being of high interest is translated into the various topics of AD marine

drug reviews there are, but each article places importance on different aspects.

A literature review by Ferreira et al. discusses specific phospholipid compounds used in

marine drugs to target AD in contrast to the Balasa et al's focus on polysaccharides. This
specifically occurs by targeting Beta-amyloid and tau peptides (Ferreira et al., 2022). The article

also mentions that in 2013, four out of the 13 drugs that inhibit cholinesterase were taken out of

the market due to causing liver toxicity (Ferreira et al., 2022). The article finally goes into detail

about how low levels of Docosahexaenoic acid (DH), which is normally associated as a sign for

AD, can be obtained through marine organisms exogenously (fish oil, krill oil. And algae) or

endogenously (Ferreira et al., 2022). The article also details in which specific food sources, such

as atlantic salmon, DH can exogenously be found (Ferreira et al., 2022). This review reveals one

way to treat AD neuroprotection via DH. The two modes of protection from exogenously taking

it or endogenously is also an important concept which should be further discussed when delving

into the details of AD treatment development. The concept of exogenously taking marine

biomolecules is supported by a primary research article discussing how the Kinh people of Beibu

Gulf exogenously derived biocompounds to boost health in areas like neurogenesis (Luo et al.,

2023). This study was conducted by analyzing donated specimens, photos of specimens, and

asking locals the common names for marine organisms (Luo et al., 2023). Further research on the

Kinh people and how they used such marine organisms was also provided (Luo et al., 2023). The

study concluded that the Kinh would frequently use animal meat, shells, and objects as a primary

material in medicine (Luo et al., 2023).

Another review by Cappello and Nieri compiles and analyzes research articles on various

marine drugs that have been approved and going through clinical trials. A list of 13 drugs is

known with a majority of the drugs, six of the thirteen, being derived from mollusks (Cappello

and Nieri, 2021). This review specifically details the chemical class the drugs are a part of and its

state in clinical trials (Cappello and Nieri, 2021). Capello and Nieri mention one Alzheimer’s

drug undergoing Phase I of clinical trials as of 2021 known as Bryostain (Cappello and Nieri,
2021). The authors’ also mention another phase I drug, GTS-21 made from an alkaloid

anabaseine, was once known for Alzheimer’s, but is more beneficial for obesity (Cappello and

Nieri, 2021). The study concludes that most marine drugs in development are currently for

cancer therapy (Cappello and Nieri, 2021).

A review made a year after Cappello and Nieri’s discusses successful drugs for AD in

2022 using alkaloids unlike GTS-21. This review specifically discusses how marine compounds

used as Alkaloids can help with AD (Lima and Medeiros, 2022). This occurs since Alkaloids can

target various areas in the brain including ABeta production, NFT formation, AChe and pro

inflammatory factor inhibition, and stabilizing nChARS (Lima and Medeiros, 2022). The review

further details where such alkaloids are derived from such as from the marine sponge Ianthella

(Lima and Medeiros, 2022).

Another marine drugs article by Kijjoa and Ghoran goes into detail on treating AD by

targeting cholinesterase enzymes. It does this by discussing drugs grouped by their chemical

groups such as alkaloids (Kijjoa and Ghoran, 2021). It then goes into drugs that treat AD by

inhibiting A Beta aggregation and a third method of inhibiting protein kinases (Kijjoa and

Ghoran, 2021). The review also mentions that many of the current drugs only target one area,

while a multi-directional approach is best (Kijjoa and Ghoran, 2021).

Two years after Kijjoa and Ghoran’s review, Hu et al. establish a new review that goes

further in depth on the multi-direction approach of AD marine drugs. This literature review goes

over the details of marine drug development by first establishing the 5 different hypotheses how

AD is caused and treated (Hu et al., 2023). After establishing this, the review then details 14

marine compounds and how it is used and affects the brain after use (Hu et al., 2023). Finally,

the review looks into the current state of AD drugs being single directional while contrasting it to
the beneficial approach of multi direction marine drugs since it can take care of multiple possible

AD hypotheses (Hu et al., 2023). The authors acknowledge the marine drugs haven’t had a large

traction due to research not being geared to those with medical backgrounds (Hu et al., 2023).

Concluding Remarks

Marine Biomedicine has had a large impact on AD research within recent years. Many of

these developments would not have been possible without investment into biotechnology.

Authors such as Marisa Silva highly advocate for more development of marine biotechnology for

extraction, isolation, characterization, and efficiency of the drug discovery process (Sylvia and

Otero, 2021). Innovations such as the CADD for the AD drug discovery process and a custom

targeting system software for implementation of treatment have also helped to decrease costs and

time for the AD research pipeline (Llorach-Pares et al., 2017)(Weiler, 2020). Continuing with

developing these tools can help to truly advance the field of AD research. Future research also

needs to be able to cut down on clinical trial costs and perform more successful trials for AD

derived marine drugs. More awareness on the efficacy of marine based drugs and models can

help draw traction from medical professionals to conduct clinical trials. Increasing medical

professional comfort and knowledge in marine biomedicine in AD research can also help expand

the field.
 References

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neuroprotection—a review. Marine Drugs, 18(6), 9–11.

https://doi.org/10.3390/md18060290

[2] Cappello, E., & Nieri, P. (2021). From Life in the Sea to the Clinic: The Marine Drugs

Approved and under Clinical Trial. Life, 11(12), 1–19.

https://doi.org/10.3390/life11121390

[3] Cheng, C. T. (1982). Area of Marine Biomedicine. Invertebrate Pathology, 40, 155–158.

[4] Dorsemans, A.-C., Couret, D., Hoarau, A., Meilhac, O., Lefebvre d’Hellencourt, C., &

Diotel, N. (2017). Diabetes, adult neurogenesis and brain remodeling: New insights from

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