---

 

Cite this article as:

 

Dhayanath M and  Juliet Mary S J A (2021) Is precision medicine possible in fish health? Food and Scientific Reports. 2 (9) 33-34.

 

 

ABSTRACT

Precision medicine is evolutionary, and this will be practiced according to algorithms that will take into consideration the patient`s characteristics, such as their genome, epigenetics, and lifestyle. The major promise of precision medicine is the ability to diagnose an individual precisely, and we will understand precisely what biochemical or physiological process caused the issue, and with this knowledge, we will be able to match a therapy that we know will work exactly. So, the medical field transformed from superstitions based to symptoms based and now to signatures based. This feature article analyses the possible ways to identify the role of precision medicine in aquatic animal health regimes.

Keywords: Precision medicine, AAH, fish health, Therapy

 

The concept of Precision medicine is "One patient, one therapy," and it`s the future of medicine and genomics. Currently, We have the technology to synthesize large amounts of data. We can actually create individualized data sets for any given person that includes everything about them all the way from the genetic code that they were born with to the biological changes that have occurred in their body through development, through early childhood, through environment exposures and their behavioural patterns. 

 

Precision Medicine in Human Health- The first step

All of these patterns impact a person`s material in a permanent way that results in health or disease. And that`s the concept and baseline of precision health.

 

The case study - Emma

One of the important things that will happen over the next few years is that we will be able to treat diseases like cancer that previously were not treatable or even fatal. This has been proved with the case of Emma, a six-year-old child, who had one of the most challenging cancer cases in medical history. She had severe stomach aches with acute weight loss, and clinical testing revealed a very aggressive form of ovarian cancer, which is only common in older people. So, the Major challenge was ovaries don`t develop cancer at this age unless there is some serious cell difference. So they began traditional chemotherapy, but it failed. As doctors ran out of options, they went for Whole-genome sequencing. It is extremely difficult to find two misplaced alphabets in 3,000,000,000 base pairs of the human genome, but with the help of algorithms, the cancer was diagnosed as a result of ALK mutation. It is a condition normally seen on older people as a rare form of lung cancer as, in this case, it occurs in the ovary. So the doctors tried ALK inhibitors that are approved for lung cancer treatment, and surprisingly in just four weeks, the tumor started resolving, and in the next three months, the cancer was gone. This is the power of precision medicine; if we can pinpoint the root of the cause, we can eradicate any disease without any side effects.

But Emma was one of the lucky ones because we already had the drugs to treat that mutation. So what about other situations where we don`t have the drugs? Today, we have another way to approach this, instead of simply drugs that take years to develop. One of those revolutionary technologies is immunotherapy. This in addition to genetic code, we look into the proteins of the cells, profile the cells and then target the immune system to attack those cells. Basically, we can engineer a person`s immune system. This is illustrated with the case of Josh below.

 

The case study of Josh 

Josh, who got his life back by immunotherapy, was a five-year-old boy diagnosed with acute lymphoblastic leukemia, which is common cancer for children of his age. Normally chemotherapy and radiation therapy have a 95% success rate, but in his case, the disease returned after four years. Then the doctors went for a bone marrow transplant, which is highly painful and risky, but after two years, the disease bounced back. So in desperation, the doctors performed the cell profiling of his lymphoma cells and found out the presence of a specific protein called CD19. They extracted the T-cells from his body and re-engineered it with an antiCD19 using retrovirus as a vector and infused it into his body. These engineered cells multiplied, and within two months, complete destruction of cancer cells was observed. These engineered T-cells will always be present in his body and monitor for the cancer cells to pop up, which makes it a permanent chemotherapy solution. 

 

How precision medicine works

It is a fluid, circular process that works like a cascade of 6 components, namely 

1. Basic Discovery

2. Clinical Discovery

3. Behavioural /Social Discovery

4. Digital Health

5. Omics Medicine

6. Computational Health Science

 

Findings from these six components are integrated into a knowledge network to create a sort of "Google maps for health" that informs both science and care for individuals and populations. The knowledge network is the brain of precision medicine, with the informatics power to aggregate all types of biological information into an information commons, separate it into "layers" of distinct data types, and then identify patterns and connections within and between layers. This process builds a network of knowledge from across disciplines. This new knowledge, in turn, it can be visualized and made accessible to researchers and health practitioners. This is considered as the difficult part, which is still at its starting stage.

 

Pharmacogenomics – Application Perspective

One of the most practical applications of precision medicine lies within the field of pharmacogenomics, which is a combination of pharmacology and genomics. It is a discipline designed for tailoring drug treatments to an individual`s genetic make-up. Interestingly, one of the first examples of pharmacogenetics had occurred around 510 BCE, when the Greek philosopher and mathematician Pythagoras observed that the ingestion of fava beans was fatal to some individuals and not to others. What Pythagoras couldn`t do at the time was to formulate a scientific hypothesis to provide him with an answer as to what had caused such a difference in symptoms. But now we know about the disease that clinicians often refer to as favism, which is a genetic mutation in the glucose-6-phosphate dehydrogenase gene that predisposes those with the mutation to potentially fatal hemolytic anemia in the presence of certain foods, drugs, or chemicals. It would, however, took well over a millennium before science would understand that common DNA variations within the human genome were responsible for Pythagoras` subjects to have such different experiences when faced with the fava bean challenge.

 

Animals model in Precision Oncology- Zebrafish

In today`s world, cancer treatment is the primary target in precision health. One of the current and promising approaches is xenografting. Patient-Derived Xenografts (PDXs), also called cancer "Avatars," are generated by the implantation of human primary tumor cells, obtained from surgery, into a host animal. The most commonly used xenografts are mPDX and zPDX. Initially, Mouse Patient-Derived Xenografts were highly used, but the major constrain is its latency period until tumor establishment and expansion in the mouse. So, Xenografting of patient-derived cancer cells into zebrafish promises to be an alternative to current PDX models in mice. In particular, transplantations into zebrafish embryos and larvae appear as tumor cells that can be observed directly in the transparent host. By this means, the interaction of the tumor cells with the host environment, including biological processes like neovascularization, can also be investigated. Probably the most important aspect is, zebrafish larvae are ideal for higher throughput screens to identify compounds able to eradicate or differentiate tumor cells. Of particular interest is that such short-term zebrafish PDX models typically provide insights in less than two weeks and thus could potentially provide information relevant to patient treatment. Moreover, the Zebrafish genome shares 70% of homology with humans in crucial pathways involved in vertebrate development and cancer. It is also reported that 82% of disease-causing human proteins have an ortholog in zebrafish. 

 

Approaches to model zebrafish 

There are two main approaches, how zebrafish can be used in cancer research and how zebrafish will help to develop patient-tailored therapies in the future.

Firstly, a Patient-derived xenograft approach in which cancer cells prepared from isolated patient material will be transplanted into zebrafish larvae followed by monitoring of in vivo proliferation, migratory behavior, and interaction with host cells might allow predictions of aggressiveness and disease progression. 

The second approach is the Genetic modeling approach. Here the bioinformatic analyzes of Omics data will point at candidate target genes. This Genetic approach is based on the transfer of mutations found in cancer cells from the patient to zebrafish to investigate functional consequences of the respective mutation. This is achieved not only by expressing a mutated human gene in zebrafish but also by mutating the orthologous zebrafish gene or even by expressing cancer-related genes. The Genetic models featuring single or combined mutations will be generated. Further, these genetic models will be used for in vivo investigation of tumorigenesis. 

Finally, the Compound evaluation, compound screens, and development of therapeutic strategies, which are testing of single compounds, compound synergies, evaluation of toxicity, and screening for new compounds, will help to advise on optimized and in future therapies. 

 

zPDX – In health care

This is a major breakthrough in recent times of cancer treatment with the help of zPDX. This is a case of a 12-year-old boy who had abnormal swelling in his legs and belly, fluid accumulation in his lungs that hindered his oxygen absorption, and also lymphatic edema. He was diagnosed with a rare form of advanced lymphatic anomaly. Generally, there are two types of a lymphatic anomaly - Generalized Lymphatic Anomaly (GLA) and Central Conducting Lymphatic Anomaly (CCLA), which can be treated with the conventional sirolimus drug treatment. But in his case, it is unresponsive. So the whole genome analysis revealed the presence of a novel X-chromosomal ARAF mutation that is responsible for this rare anomaly.

The absence of clear clinical distinctions between these entities, due to their rarity and overlapping of diagnostic criteria, has hampered the development of innovative therapies. GLA is defined as a multifocal lymphatic anomaly that has multiple areas of micro/macrocystic lymphatic malformation and often involves bone destruction. CCLA, on the other hand, describes dysfunction of the thoracic duct (TD) or cisterna chyli, leading to a retrograde flux of lymphatic fluid or abnormal drainage of lymphatic fluid ARAF mutation led to the loss of a conserved phosphorylation site which, in simple terms, the loss of the lymphatic system. So scientists used Zebrafish xenografts, and to confirm that the gene mutation was causing the condition, they inserted the gene mutation into the embryos of zebrafish. Within five days, the fish had developed a similar abnormal lymphatic system. It was "proof that this mutation causes overgrowth" of a lymphatic vessel. So having learned the function of the gene, researchers were able to target it with a drug called a MEK inhibitor, which is used to treat melanoma, a form of skin cancer, and acts, on the cell signalling pathways that regulate lymphatic development. The scientists carefully examined the fish for evidence that the harmful lymphatic vessel proliferation had stopped, but nothing else had been harmed. With FDA approval, the scientists gave Daniel the drug called Trametinib. Within two months, his breathing improved. At three months, the fluid in his lungs had receded enough that he no longer needed supplemental oxygen. The swelling in his legs disappeared. An MRI showed that his lymphatic vessels reshaped themselves into something close to normal. 

 

Precision Medicine in Veterinary & Aquatic Animal Health- is this possible?

The answer for the above is probably not in the near future

 

Why

1.                Identifying genetic-based biomarkers is far from a trivial task.

2.          Investments to pursue comprehensive molecular-based diagnostic testing, commit to share omics data and clinical patient information openly, and follow through with carefully designed clinical trials of molecularly targeted treatments are far hard.

3.          Requires the development and implementation of new strategies to educate and train clinicians, veterinary students, and related health professionals in genomic medicine, bioinformatics, and other key components of the practice of precision medicine.

But

•  Precision medicine will undoubtedly reveal more evidence about humans and animals sharing common molecular mechanisms of disease pathogenesis that are clinically relevant and therapeutically actionable. 

•  It has the potential to transform the practice of both veterinary and human medicine dramatically. 

•  In this way, precision medicine is the epitome of one health and will continue to have a transformative impact on the lives of people and animals and the environment they share. 

 

Challenges of precision medicine

Existing databases of genetic variant data are now incomplete and not always up to date, so researchers rely on manual searching of literature resources which can be very time-consuming. Another critical area is the thorough understanding of phenotypes, both at the individual and population level, which makes it more difficult to formulate a consistent approach. The biological interpretation of results is the important bottleneck in the field of precision health because such powerful algorithms are still not in existence.

 

Conclusion

So beyond cancer, precision health can transform medical science and help humanity. In the clinical field, it can cure cancers and childhood diseases and can prevent chronic illness and neurodegenerative diseases such as Alzheimer`s. And in the academic field, it can grow research capabilities and create new educational programs. In aquatic animal health, the idea of precision medicine in therapeutics instill in infancy, whereas the zebrafish can be utilized as models for research and therapeutic purposes.

 

 

Further Reading

Bauer TR Jr, Adler RL, Hickstein DD. Potential large animal models for gene therapy of human genetic diseases of immune and blood cell systems. ILAR J. 2009;50(2):168-86.

Blomme EA, Spear BB. Theranostics in veterinary medicine: where are we heading? Vet J. 2010 Sep;185(3):237-8.

Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med. 2015; 372:793–795. 

Kahler SC. Out of Rockville and Laurel. FDA-CVM initiatives span individualized medicine to aquaculture research. J Am Vet Med Assoc. 2007

Kirchberger, S., Sturtzel, C., Pascoal, S. and Distel, M., 2017. Quo natas, Danio?—Recent progress in modeling cancer in zebrafish. Frontiers in oncology, 7, p.186.

Manolio TA, et al. Implementing genomic medicine in the clinic: the future is here. Genet Med. 2013; 15:258–267.

 

 

 

Get the pdf version of the article mailed to you. Click the link below

---

Precision Medicine - is this Possible in Fish Health_compressed.pdf