Symptoms of Unknown Origin: A Medical Odyssey


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However, relating SNPs to a disease demands extensive methodologies that require high technological standards. Despite the difficulty of categorising the complex web of environmental factors that also contribute to inter-individual variability, improvements in genomics research permitted the characterisation of genetic variants that account for this variability to a large extent.

Background

Due to the early initiation of the HGP, progress in genotyping and sequencing techniques was rapid. The facilitation of gene identification made exploring the genetic background of diseases a new common practice and provided a flood of new information that led to tremendous progress in understanding the pathophysiological processes of diseases [ 12 ], thereby ushering in personalised medicine.

Although personalised medicine first appeared as a scientific term in published studies in [ 14 ], the concept originated long ago in the history of medicine, when scientists realised that certain treatments did not apply to all patients and might be harmful in some cases. One of the best examples is blood transfusions. The ABO blood group system was discovered in [ 15 ] and such knowledge helped prevent complications during transfusion through a simple blood type test that categorised each individual into different groups based on the ABO genotypes. This simple illustration demonstrates well the mission of personalised medicine today, which is to classify patients into different subgroups based on their genetic predispositions to allow for early disease risk prediction, precise diagnosis, accurate prognosis and the use of the most efficient and least harmful treatments for each individual.

This article explores the research journey towards personalised medicine by connecting it to the adventurous trip of Odysseus, from Troy to Ithaca Figure 1. His journey might have seemed sorrowful at the first glance, but above all it was rewarding and meaningful. Hence, it is in personalised medicine, where while fighting numerous obstacles and deceptions we finally end up realising remarkable discoveries and projects, which will greatly contribute to the next generation of health systems.

The journey of Odysseus. There I sacked the town and put the people to the sword. We took their wives. The initial idea of personalised medicine was extremely ambitious. However, progress was not as fast as expected. Most common chronic diseases appeared to be regulated by a complex mixture of genetic factors and an infinite number of environmental factors, which were more difficult to elucidate than initially expected.

Hence, criticism began to ensue regarding genomic research [ 17 ]. Questions arose such as whether the associated thought processes were all in error from the beginning, whether the money spent on research and development might never pay off and whether greed for success had derailed some researchers from their goals.

After the great victory in Troy, Odysseus, the great hero of the war, stopped on his way home on the island of Ismarus and, drunk of success, made a fatal mistake of letting his men destroy a town. Thus, the angry gods called the winds that misled his ships and took him on a long and dangerous journey that would detain him from reaching his own goal, Ithaca. The International HapMap Project represented the first substantial achievement in the determination of common genetic patterns of DNA sequence variation, which allowed for the identification of the sequence variants that affect common diseases and their frequencies and correlations.

The project began in October as an international collaboration and was a natural extension of the HGP [ 18 ]. Common genetic patterns of DNA sequence variation, called haplotypes, are specific combinations of alleles on a chromosome. This combination is predictable because individuals who carry a specific SNP allele at one site often carry specific alleles at other nearby variant sites. This observation indicates that neighbouring SNPs on the same chromosome are in so-called linkage disequilibrium LD [ 19 ].

The HapMap of the human genome mapped and correlated SNPs based on their LD, which thus provided the information needed to guide genetic studies on clinical phenotypes. Phase I of the project, completed in , provided publicly available data of the human genome sequence, databases of common SNPs, insights into human LD, web-based tools for storing and sharing data and frameworks to accelerate the identification of the genetic factors that influence medical traits.

More than 1. The complete characterisation of SNP variation and LD among common variants in the sampled populations led to an excellent understanding of genetic variation in the human population and allowed for the determination of the haplotypes that might be involved in specific diseases [ 19 , 20 , 21 , 22 ]. Phase II of the project characterised an additional 2. The project was completed with the release of the Phase III dataset in spring , for which 1.

It greatly contributed to the development of personalised medicine studies and provided tools that served scientists for a decade. The achievements or feelings that we once found extraordinary and unforgettable sink into oblivion when our attention is drawn to new attractive things. Seduced by the sweet elixir of the lotus flower, they forgot the victory they achieved in Troy and their craving to see the homeland.

A diagnostic odyssey: spotting the zebras among the horses

Their only interest became the lotus flower, so they decided to stay on the island and never return to Ithaca. Thus, Odysseus chose to depart with the rest of his crew to continue towards new victories and left them behind on the island of the Lotus-eaters Figure 2. Now the Cyclopes neither plant nor plough, but trust in providence,. Traditional medicine, along with the pharmaceutical industry, has been successfully saving lives for decades. Individuals have different ways of responding to an administered drug, which is conditioned by their genetic predisposition.

These considerations were not accounted for during traditional drug design.

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Hence, currently, some of the highest-grossing drugs are effective for as few as 1 of 25 to 1 of 4 patients [ 25 ]. Pharmacogenomics studies represent the basis for the clinical application of personalised medicine. The study of the impact of genetic variations on drug development is leading to the development of therapies that might ensure the best response and highest safety for a patient, whilst preventing or minimising the risks of side effects.

The goal of pharmacogenomic research is to provide effective therapies for smaller subgroups of patients who are stratified based on their genetic profile, despite having similar disease phenotypes. Moreover, these studies aim to prevent adverse effects using preliminary genetic tests to determine whether patients might benefit from the drug and will allow dose adaptation for each patient based on their metabolic system characteristics.

Finally, they will lead to the development of specific drugs for patients who are unresponsive to available treatments [ 28 , 29 ]. Pharmacogenetics is a subgroup of the pharmacogenomics field that focuses on examining genetic variations in drug metabolism [ 30 ]. Although bearing enormous potential, the translation from discoveries to clinical applications remains slower than desired [ 31 ]. In contrast, its successful applications increase hope and optimism and drive change for the future of practice in all aspects of personalised medicine.

Firstly, the case of abacavir demonstrated that through genetic examination, the response to a specific drug therapy might be predicted [ 32 ]. Another example of drug effectiveness prediction using a personalised approach is gefitinib, a cancer drug prescribed for metastatic non-small-cell lung cancer, approved by the U.

This discovery allowed for the development of personalised lung cancer treatments using a new generation of targeted drugs [ 35 , 36 , 37 ]. Secondly, the testing of leukaemia patients for the thiopurine S -methyltransferase TPMT gene is a practical use of genetic testing to determine the ideal drug dose. TPMT is a gene responsible for producing an enzyme that metabolises thiopurines.

For these patients, a reduced thiopurine dose prevents undesirable effects and allows for successful therapy [ 38 , 39 ]. Whilst pharmacogenetic tests for these genes are indispensable for the correct pharmacokinetic calculations and drug dosages for patients, they are not fully implemented in daily clinical practice.

Another example of drug dose adaptation aided by pharmacogenomics is the case of warfarin, a vitamin K antagonist used as an anticoagulant [ 42 , 43 ]. This testing is challenging because it is costly, inadequately available and time consuming [ 43 ]. However, additional studies are needed to incorporate genetic testing strategies into drug dose regulation in the future. The first FDA-approved pharmacogenetic test was released onto the market in Currently, many more genetic tests are available to optimise drug therapy.

Guidelines and tables of the available tests are presented on the Clinical Pharmacogenetics Implementation Consortium website [ 46 ]. We are still in the land of the Cyclopes, where many events have transpired since Odysseus left his ship and went exploring the unknown.

Trapped in a cave with Polyphemus, son of Poseidon, who ate some of his men, Odysseus was like the researchers, trying to use all their creativity to escape the undesirable events. He blinded the eye of the giant Cyclope, hid himself and the rest of the men under the sheep Figure 3 , and thus provided himself a safe escape from the island.

His group of soldiers survived, because blind Cyclope could not recognise them, as he would, if they would not be attached to the animals. And that is the simple principle of the pharmacogenomics treatment. Now, Aeolus has six daughters and six lusty sons, so he made.

The West wind, which was fair for us, did he alone let blow as it chose; but it all came to nothing, for we were lost through our own folly. Genetic association studies are used to test the association between a specific disease specific phenotype and genetic variations to identify candidate genes or regions within the genome that might contribute to that disease [ 47 ]. The most widely tested genetic variations are SNPs, which are either assessed in candidate gene research [ 48 ] or through the more recently popularised GWAS [ 49 ].

Whilst candidate gene research confirms or refutes the correlation between a priori selected specific genetic variants and a disease, GWAS provides tests without a hypothesis for the specific regions, genes, or variants, albeit with a pre-selected design for genotyping platforms and analytical methodologies [ 50 ]. GWAS enabled the efficient and comprehensive assay of genetic variants that are common in a population and the identification of those that appear more commonly in patients with a given condition [ 51 ].

Although candidate gene studies brought remarkable success to the identification of high relative risk genes, they have not been as successful in the identification of genes involved in the complex forms of diseases [ 48 ]. Thus, the first GWAS, published in [ 52 ], generated enthusiasm among researchers. Before leaving the Aeolian island and sailing towards his homeland, Odysseus received a special gift from the god of winds Figure 4 —a tightly bounded sack.

None of his soldiers was aware of its contents, and they became curious, believing that Odysseus was hiding treasures from them. Receiving a remarkable gift is of little value if it is not used appropriately. Soon before reaching Ithaca, they opened the sack. The winds that were trapped inside started to blow again and took their ship back to the Aeolian island. If GWAS at the beginning seemed like a gift, which will give the solutions to all problems, the high expectations were soon extinguished. These studies demanded a large number of samples for adequate statistical power [ 53 ].

Indeed, studies with hundreds of thousands of participants might only explain a small proportion of overall heritability. Nevertheless, GWAS connected thousands of novel genetic variants to many complex diseases, including diseases with no previously known genetic linkage. Their limitations, such as statistical strength and precision, were overcome using the statistical tool of meta-analysis, which combines the results of different genetic association studies to explore different sources of heterogeneity and to identify subgroups associated with the factor of interest [ 56 ].

Furthermore, the latest GWAS studies that are performed in very large populations, the improvements of computational tools, and the development of large datasets such as the UK Biobank provide new insights for the utility of GWAS studies. Recently, polygenic scores derived from GWAS studies have been shown to be as useful as monogenic mutations for the prediction of chronic diseases, thus opening a new direction for the application of GWAS results in clinical practice [ 57 ]. The next important step is to match these results to a larger biological construct to unravel the most complicated pathways related to a disease and to thereby contribute knowledge that might be translated into clinical and diagnostic tools [ 55 ].

Similarly, Odysseus and his crew had to take the next step and find their own way further on after the sorrowful event, for Aeolus, the god of winds, wished no more to help them. In that country, a man who could do without sleep might earn double wages, one. Another important aspect of personalised medicine, in addition to predicting the response to a treatment or adapting the drug dosage discussed in the third stop of the journey , is predicting the likelihood of developing a specific disease.

This ability may be indispensable in specific families with disease antecedents, wherein rapid discovery by genetic testing might prevent the onset of the disease.

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The famous case of actress Angelina Jolie raised awareness of these methods among the general population, when she announced she was undergoing a risk-reducing mastectomy after testing positive for the BRCA1 gene mutation [ 58 ], a major risk factor for breast cancer. Currently, more than genetic tests are available for several different indications [ 60 ] to:.

Genetic testing is voluntary. A positive result may guide a person towards available prevention, monitoring, and treatment options. In some cases, although no solution might exist for the given condition, genetic tests may aid decision-making concerning family planning [ 60 ].

Science is diligently attempting to improve the potential for gene therapies that might prevent the diseases caused by gene mutations. In , the first gene therapy was approved by FDA [ 61 ], raising a great optimism for future genetic disorder treatments. When Odysseus reached the island of Lamus near the Telepylus, the city of the Laestrygonians, he was cautious. As one cannot surely know whether he has a genetic predisposition for a disease, so Odysseus could not predict whether some dangerous creatures were living in this unknown land.

He decided to keep his ship outside the bay, before exploring the island, while other captains sailed their ships into the harbor and attached them close to one another. But the stay on this island was rather unfortunate. No people were living on it, except for the cannibal giants, who destroyed all the ships but one, hidden outside the bay. Thus, Odysseus lost the big part of his fellow companions, but kept himself and the men on his ship alive, so they continued alone on this long journey, sailing on the open sea. Along with new, extensive information about individuals, genetics research raised ethical concerns about such experiments.

Assuredly, sceptics first considered conspiracies of pharmaceutical and insurance companies, who might use this information for their own benefit. This scepticism is not surprising because genetics may not only predict susceptibility to a certain disease but also may interrogate the history of individual genes and loci under natural selection [ 62 ]. Hence, strong ethical and legal foundations were established to protect against gene-based discrimination to minimise the harms and maximise the benefits and confidentiality of genetic studies [ 63 ].

Protecting genetic information became one of the most important considerations in the development of personalised medicine. Nevertheless, only time will establish public readiness for the day when a genetic test will be as common as a simple blood analysis. Not all individuals will want to follow the new inroads led by medical progress. Indeed, freedom of choice remains one of the basic human rights to be structured into future health systems [ 29 , 66 ].

However, when choosing between life and death, principles are often forgotten in lieu of doing whatever is required to remain healthy and alive. Ethical issues also troubled Odysseus when he met the goddess Circe, a beautiful witch, who was keen on using magic herbs on travellers that passed nearby, transforming them into wild beasts.

He was advised by the god Mercury on how to resist her magic potions with a protective talisman and how to provide himself with her loyalty by going to bed with her. Odysseus was deeply in love with his faithful wife Penelope, but did not bother about keeping company with Circe for an entire year Figure 5.

Download Symptoms of Unknown Origin: A Medical Odyssey - Clifton K. …

Afterwards, the soldiers became anxious to return and the journey had to continue. Circe kept her promise to help and furthered them towards the House of Hades. Odysseus and Circe: Angelica Kauffman, At what point might concerns and angst be disregarded to take advantage of what is offered, notwithstanding fear of the consequences? In , two important projects were launched that impacted personalised medicine. Firstly, the vision of the Personal Genome Project, as a natural successor of the HGP, was to publicly share genome, health and trait data for rapid scientific progress [ 67 ].

Initiated by the American geneticist, George McDonald Church, the project was a response to the demand for a highly integrated and comprehensive human genome and phenome datasets to aid research in human functional genomics and systems biology [ 68 ]. The project invites individuals to non-anonymously share their genomic data, traits and cells for free and open research [ 69 , 70 ]. Secondly, the Cancer Genome Atlas TCGA , a collaboration between the National Cancer Institute NCI and NHGRI, aimed to catalogue and discover key genomic changes in large cohorts of human tumours [ 71 ] and demonstrated the importance of the information acquired through multidimensional genomic analysis for understanding the molecular basis of cancer [ 72 ].

The pilot project explored three types of cancers, which were glioblastoma multiforme, and lung and ovarian cancer [ 73 ]. Until , it successfully generated comprehensive, multi-dimensional maps for 33 types of cancer and is now concluding [ 71 ]. Sharing the value placed on the importance of data sharing with the Personal Genome Project, diverse data from more than 11, patients, including clinical information about the patient, metadata about the samples, histopathology images and molecular information, such as gene expression, copy number, SNP genotyping, genome-wide DNA methylation, microRNA profiling and exon sequencing, are publicly available and have thus contributed to more than studies on cancer [ 71 ].

Identifying genes that contribute to functional changes in cells and oncogenic biomarkers allowed for clinical applications and improved the prevention, diagnosis, and treatment of cancer [ 74 ]. Finally, it became a model of a successful network and of collaboration for future projects in human health. Vast innovative collaborations that create networks among researchers around the world are indispensable for generating representative amounts of samples for genomic research progress, which leads to personalised medicine.

Integrated knowledge facilitates the path to important discoveries. The aforementioned successful projects provide outstanding examples for the future of research. Ultimately, the goals towards which we are striving are interchangeable worldwide. In the Underworld, Odysseus was searching for the knowledge that would facilitate his way back home. The dead prophet Teiresias Figure 6 and other ghosts shared important information, which allowed Odysseus to prepare himself for future adventures. He returned to Circe, buried the body of his dead soldier and departed towards the new challenges.

Teiresias and the Cancer Genome Atlas. Then, all of a sudden, it fell. At the beginning of our journey with Odysseus, we discussed the momentous discoveries that led to the rise of the genomics era, which must include one of the most valuable, that of Frederick Sanger. This technique was used in daily research for more than 30 years, until the arrival of next-generation sequencing NGS in [ 76 ].

NGS differed from the Sanger method in its massively parallel analysis, high throughput, and reduced cost [ 77 ]. Sequencing methods are classified into three generations plus one future generation, which each have distinguishing characteristics Figure 7. The product of this technology is a high-resolution image that provides accurate sequencing results [ 78 , 79 ]. It was followed by the Genome Analyzer, developed by Solexa later purchased by Illumina , which originally could generate 1 G per run. The technology improved and in , Illumina released HiSeq , with an output of G per run.

The third fundamental technology that marked the second generation of sequencing was the Sequencing by Oligo Ligation Detection SOLid system, made by Agencourt purchased by Applied Biosystems in [ 80 ]. These technologies progressed over time to provide the most performative, accurate and efficient sequencing possible. They were the first throughput technologies with reduced costs and routine analytic methods for scientific research, which revolutionised genomic research.

Despite the success of second-generation methods, other innovative technologies emerged. This feature decreased the bias of previous methods caused by polymerase chain reaction PCR amplification. Moreover, these methods increased the read length and decreased the processing time, which provided even higher overall accuracy and enabled rare variant detection at a lower cost [ 81 ]. Because expression in single cells may vary substantially from the mean expression detected in a heterogeneous cell population, this method has the potential to revolutionise the field of cancer biology because it enables the mapping of the molecular and cellular tumour environment.

Pyrexia of unknown origin

Additionally, it is intended to detect defined DNA sequences such as those that might have undergone a somatic mutation rather than the complete genotypic sequence from the cell [ 77 , 83 , 84 ]. Although in situ sequencing has prodigious potential for future research, several technical improvements are needed before it might be broadly applied, specifically sample imaging, the low efficiency of molecular processes, and data handling and interpretation.

Should these obstacles be overcome, the method might become a standard for sequencing tissue samples [ 83 ]. This achievement boosted the development of high-throughput technologies that enabled the development of promising tools and led to large-scale studies, which are the engines that further power personalised medicine. Passing by the island of Sirens, Odysseus knew that to hear their beautiful singing would lead to inevitable death, as Circe has warned him about the skeletons of unfortunate soldiers, misled by the beauty of the sound, which were lying all around the island, with their flesh still rotting.

Thus, he took her advice and plugged the ears of his soldiers but attached himself to the mast, free to hear what no man alive had heard before. With great amount of knowledge, we are free to do things that once seemed impossible. Sequencing that first took more than a decade to be accomplished is now an everyday practice. And Odysseus? His trick, simple and deft, enabled him to bypass the trap and continue on his way unharmed. As she vomited it up, it was. No discussion of genetics is complete without considering costs.

The cost of this project included a wide range of other expenses in addition to sequencing, such as technology development, physical and genetic mapping, model organism genome mapping and sequencing, bioethics research, and programme management. Though far lower than the initial cost, the use of such methods would still be too costly for routine studies and clinical applications [ 86 ]. Ultimately, the price of sequencing began to decrease at an accelerated rate after Figure 8 [ 88 , 89 ].

Costs for whole-genome sequencing WGS. However, the contest was cancelled in August , due to an unexpectedly high rate of progress in sequencing technologies on the market that required no further encouragement [ 93 ]. Indeed, technology progressed much faster than expected. The diploid human genome sequence of James D. This advance ushered in a massive reduction in price and the era of next-generation sequencing. Finally, the cost, though still high, was acceptable for routine research and thus permitted the use of a personalised medicine tool necessary for the research and development of new strategies for efficient patient diagnostics and treatment.

There is always a price to pay in science, as on the sea. The Diarrhea of Agnes. Dr Jims Breasts. Staying out of Gods Way.


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A Paradoxical Approach. You Cant Be Everybodys Doctor. Symptoms without Disease. The skills and attitudes he identified are these:. Easy to say — not so easy to do with very challenging patients! Have a great day! And remember you can bookmark this blog for more — or subscribe using the RSS feed above. Comments are very welcome — and I do respond! I am a parish nurse, taking a unit of clinical pastoral education right now.

Especially to find a list of straightforward tips that summarise so much of what people who are feeling distressed need. You are commenting using your WordPress. You are commenting using your Google account.

Symptoms of Unknown Origin: A Medical Odyssey Symptoms of Unknown Origin: A Medical Odyssey
Symptoms of Unknown Origin: A Medical Odyssey Symptoms of Unknown Origin: A Medical Odyssey
Symptoms of Unknown Origin: A Medical Odyssey Symptoms of Unknown Origin: A Medical Odyssey
Symptoms of Unknown Origin: A Medical Odyssey Symptoms of Unknown Origin: A Medical Odyssey
Symptoms of Unknown Origin: A Medical Odyssey Symptoms of Unknown Origin: A Medical Odyssey
Symptoms of Unknown Origin: A Medical Odyssey Symptoms of Unknown Origin: A Medical Odyssey
Symptoms of Unknown Origin: A Medical Odyssey Symptoms of Unknown Origin: A Medical Odyssey
Symptoms of Unknown Origin: A Medical Odyssey Symptoms of Unknown Origin: A Medical Odyssey
Symptoms of Unknown Origin: A Medical Odyssey Symptoms of Unknown Origin: A Medical Odyssey

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