Emergence of in-silico biology in desperate spheres of life sciences in Pakistan

Bioinformatics, a multidisciplinary field works in collaboration with biological sciences for analysis, prediction and storage of biological data in form of databases. In innovative world of scientific technology, Pakistan is playing its crucial role in development of new era of escience. Main objective of this review is to highlight bioinformatics applications and its significant role in progress of e-science in Pakistan. In Pakistan, numerous applications such as gene target approaches in agriculture, food industries and 3-dimensional structure analysis of protein have been revealed, where every aspect of nucleic acids processing can be observed. With these advancements, disease diagnosis has now become easy, providing a platform for drug development and enormous jobs for talented ones to make a history in bioinformatics. Similarly, numerous organizations are also taking part in Next Generation Sequencing (NGS) technology and different nationwide companies. However, bioinformatics also faces challenges in data collection and web designing. But introduction of innovative researches has led to formation of highly applicable e-technology of recent era. Hence, this approach has taken primacy to diagnose diseases as cancer. It makes a tremendous distinction in e-science where computer-aided drug design (CADD) gives a ray of hope for many diseased people. Moreover, comprehensive study of human genetics also reveals invention of specified drugs and various biomarkers to discriminate among every single genetic disease. Regardless of various hurdles, scientific transformations in very field related to bioinformatics will help us to take Pakistan beyond skylines and to stand with high tech world association.


Introduction
Bioinformatics came into existence to organize all biological raw data with help of different statistical and mathematical rules [1].Here bioinformatics provides a major advantage over experimental data where information may be lost due to inconvenient methods.So, bioinformatics serves as a hierarchy of biological data where databases have been helping mankind for over a century.Being a part of recent trends, Pakistan is trying to clarify with outer world, utilizing bioinformatics dug-up genetic irregularities i.e.SNP related disorders, albinism, Down syndrome, epilepsy and to conquest other challenges [2,3].In Pakistan, a number of applications have been performed making e-science an emerging trend of recent era.Major applications include agricultural industry promoting frontline for food industry as well as genetically modified crops have been proven beneficial to overcome food deficiency in Pakistan.These modifications are carried out by different gene targeting approaches, having impact on genomics, proteomics and transcriptomics.Bioinformatics plays an advanced role in determination of all key factors involved in foodborne genetic errors.Each and every aspect of a gene can be monitored easily, thereby providing information about structural and functional properties of individual protein [4].In different aspects similar to genetic errors, personalized drugs provided a gateway towards disease diagnosis where each activity of gene is monitored at molecular level and in case of any abnormality, gene therapy is used to treat that abnormality [5, 6].Bioinformatics provides an efficient source for locating these types of abnormalities.Only small dimension in Pakistan is working on this aspect but near future possibilities declare the value of bioinformatics in different research projects.Being in the list of developing countries, increased pollution is one of the major problems in Pakistan and is causing harm to all biological species.To avoid this problem, bioinformatics plays a crucial role, as a toolkit for the environmental analysis such as bioremediation that brings a positive impact on the environment [7].In development of bioinformatics, a lot of tactics have been introduced across the world.Pakistan being an e-society member also plays its role in providing platform for specific institutes by working on bioinformatics in the form of NGS technology and other organizations.The mission of such organizations is to spread Bioinformatics in Pakistan by linking each biological information with IT technique to create databases and providing young scientists with a huge research stand [8].In this aspect, massive jobs have been opened for technologist from related discipline in web designing, database creation, clinical management, genetic digging, drugs interventions, 3D implements and electronic media.Although a lot of progress has been done in Pakistan but still a lot of challenges resist our way.Information retrieval and use of IT applications face hurdles in many cases due to extensive data with complications of handling by using traditional computational sciences.Moreover, information-rich data is complex having compliancy assessment, discharge, toughness, and acquaintance [9].In future, bioinformatic tools will be used instead of lab tests which are quite slow and time-consuming.Bioinformatics would diagnose prostate cancer by phosphoproteomics and distinguish Thalassemia traits (TTs) from iron deficiency anaemia (IDA) by biomarkers.After disease diagnosis, bioinformatics plays a vital role in all features of drug discovery and Computer-aided drug design (CADD) providing a new ray of hope for many diseased persons [10].In conclusion, objective of this study is to throw light on current status of bioinformatics in Pakistan with its upcoming challenges and improvements to modify our research projects towards new horizons.Finally, an imperative task in this prospect will be enterprising and expansion of novel scrutiny tools for technical advancements in Pakistan.Bioinformatics; Birth of new scientific era Bioinformatics employs the computational science, algorithm, and statistics to interpret and analyse scattered biological data.Data related to biological molecules is arranged in a static manner for better understanding and localization of information.For the sake of interpretation, biological data is  Although it is quite comparable to computational biology but on the other side it is distinct from it.The first one uses biological data to design various algorithms and models for better understanding of biological systems.While the latter one uses different computational and statistical tools to understand and analyse biological data in a comprehended way.In the field of life sciences, Bioinformatics provide a variety of tools and programmes to the researchers in order to manage their biological data.Most of these tools are available online and provide free access to user.Being an interdisciplinary field, the tools for in silico analysis are used to study interactions of biomolecules, phylogenetic analysis, visualization of physiochemical properties of proteins and in studying the structure of genes.For example, in the field of biology, it imparts its role in gathering different disciplines as biochemistry to study protein interactions and their structure or as biophysics to find out their functions and effect on biological system.It also involves improvement and implementation of novel informatics in biological sciences.With publication of Human Genome Project (HGP), more challenges have been opened in field of functional proteomics, helping pharmaceutical approaches and as a result specific drug targeting has been come under influence [6].Similarly, mathematics and physics interact with bioinformatics to implement different applications on scattered biological data.The influence of mathematics can be wider in some cases, due to rapid processing and without any extensive transformation steps that usually happen in chemical researches and in permitted pharmaceutical practices [3].Moreover, Computer science is the root of bioinformatics where data mining of biological system, their informatics management and most importantly web designing for specific data is possible.

Bioinformatics; Urge of era in Pakistan
Globally, bioinformatics is an emerging field due to its unique and diverse features hence its importance cannot be neglected in Pakistan.Naturally, Pakistan is rich with agricultural, farm and dairy sources due to its geographical location and environment.Pathway Mapper provides an easy way to study gene, its interactions and alterations frequencies of genes in cancerous pathways [36].For cancer treatment, drug combinations are one of the most effective ways to fight back for drug resistance, [37] while bioinformatics also exposes nontested pairs of therapeutics.In Pakistan, many researches have been carried out for disease treatment and analysis which are summarized in (Figure 2

Investment in biotechnology
The pharmaceutical industries in Pakistan operate on all levels.Industries on smaller and medium scale have to face challenges to survive in market.To fulfil needs of competitive productions and revenue, they also require knowledge about bioinformatics.
IT firms found bioinformatics sector beneficial to invest and also invested their resources in the bioinformatics sector to make it 100% digital.Now, industrial sector fulfil their bioinformatics needs by making collaborations with these bioinformatics firms, making it beneficial for both sides [IIUI, Department of Bioinformatics & Biotechnology].

Investment in R&D
In Pakistan, 80% of medicines used have a foreign patent with extra amount of royalties.And a large amount of revenue is transferred from country decreasing the national profits.Investments can be made in bioinformatics research and development sector, discovering and developing modern medicines inside the country.This could ensure development of local pharmaceutical industry and secure most of the profits inside the country.This would decreases cost of production, thus decreasing the price of medicine in the market [65].

Managing clinical and laboratory information
Many gene sequences cannot be stored or record on paper because gene sequences are too complicated and large in structure so they would be easily subjected to errors.While storing in digital form, tools should be properly spaced and have pre-defined instructions written by professionals with zero chance of error [Thermo Fisher Scientific Inc].Medical history of a patient is preliminary and most important for a physician while treating with a fatal disease which can't be completely dragged through conventional ways, so there are softwares which track the patient's daily routine and vitals etc to keep full record of his treatment history and physical changes after regular intervals [66].
In a clinical research system, software are used to check whether research is being conducted according to set pattern and plans.These softwares also store data regarding research participants, their contacts, credentials residence [67].Computational biology is related to data structures and algorithms with computer modelling of biological systems.It helps to understand complex biological systems by designing predictive multi-scale models that help in discovery of new biomarkers for disease.Within networks, information at different levels integrates and organizes these networks with help of communication e.g.ISB [68].The aim of this discipline is to make open-source software that can share information between different pathway models.
The clinical applications of bioinformatics can be observed in the immediate, short, and long term.A comprehensive list of human gene products such as insulin and growth hormones may offer new drugs and gene therapy for single gene diseases.The most common disorders of hypochromic microcytic anaemia (HMA) are Thalassemia traits (TTs) and iron deficiency anaemia (IDA).The aim of present study is to differentiate TTs from IDA through evaluating discrimination formulas and provides wide-ranging data of haemoglobin disorders which are dominant in Pakistan.There are 12 published discrimination formulas, among these 12 formulas, 6 formulas-MI, EF, G&K, RDWI, R, and HHI-were the most efficient to discriminate TTs from IDA.The random forest (RF) decision-tree approach was used to improve cut off values [75].In preclinical stages of research and development, MS-based targeted phosphoproteomics was used and believed that final translation of this technology will expose new accesses in clinical setting.Phosphoproteomics, as an integrative approach with genomics and other omics data, may have a future hand in addressing the tasks of prostate cancer diagnosis and drug development by identifying active pathways.The technology would also cover the way for broadenfield of pharmaco-omics to logically select and modify a patient's drug therapy for different diseases that have low mutation burden [76].

Major challenges in bioinformatics
A key task for bioinformatics is to find out useful information from a tremendous diversity of available biological data and correspond such information with biological knowledge [69].However, it proves to be highly challenging in many cases: (1) increased data size typically handled with traditional computational approaches (2) information rich data is heterogeneous in nature, corrupted and incomplete, as well as deceptive outliers and (3) biological systems due to compliancy evaluation, sacking, robustness and exposure are exceedingly complex [70].Elucidation of biological data demands finding of intricate relationships hidden in data.Due to these challenges, the precision of augury from a database is often not satisfactory [71] aligned, identified and analysed by utilizing different tools which are easily available on different databases like GenBank and SWISSPORT [1, 2].With passage of time, experimental approaches to identify and store biological data steps are forwarded to an advanced era from experimental to statistics analysis.As, on April 2001, a database, the GenBank had information of 11,546,000 entities whereas, SwissProt database of protein confined to 95,320 entities [11] that rises after every 15 months.Moreover, after whole genome publication of the H. influenzae genome, about 300 different organisms were identified having range of 450 to 100,000 genes afterwards.Considering gene expression data from myriad of different associated projects, acts as a way to initiate gigantic quantity forming evidence diversity [12].Bioinformatics opens up a platform for researchers to preserve data as their heritage.The journey of bioinformatics which was started from development of ARPANET database in 19 th century, did not confine at any step but has continued its progress till 2017 (Figure 1) where IEEE International Conference on Bioinformatics and Biomedicine (BIBM) gave an explained data on genes.Until now, various databases of different sizes with versatile information have come into existence [13].

Figure 1 .
Figure 1.Bioinformatics; journey from 19 th to 21 st century with formulation of advanced databases Bioinformatics; relation with other sciences With the moon of 21 st century, a lot of development in field of bioinformatics took place and it made glue for modern science holding all disciplines together.Bioinformatics is often confused with Bio computation or Compactional Biology.Although it is quite comparable to computational biology but on the other side it is distinct from it.The first one uses analyse viral evolution during HIV and SIV infections [31].In same context,Los Almos (www.hiv.lanl.gov) is a database for HIV which contains all subtyping, sequencing data related to HIV [32].Bioinformatics is used to explore common genetic bases between T2D and AD.For instance, role of an hypothetical protein PCNXL2 involved in tumor suppression was analysed based on its functional and in-silico study [33].Bioinformatics came into play as HaploReg (http://compbio.mit.edu/HaploReg) that analyse SNPs.Software DAVID provided information about commonly shared pathways.This analysis has potential therapeutic implications for treatment of these diseases [34].For AD treatment, the role of miR-142-5p is testified using bioinformatics as Gene Expression Omnibus provides RNA sequences, whereas miRbase (microRNA database) (http://www.mirbase.org/)and Target Scan provide genomic coordinates of miRNA database [35].
) [38].In benefit to researchers and developing laboratories, bioinformatics is playing its role i.e.Biomedical informatics lab has been established in PIEAS Islamabad, Pakistan with aim to develop sense of bioinformatics among young scientists.It also aims to solve biological and medical problems by means of computer (http://faculty.pieas.edu.pk/fayyaz/bmi.html).Moreover, another bioinformatics-based laboratory has been established in UET, Lahore named as Bioinformatics Research Lab (BRL) with four complete projects and many more to come in near future (http://www.kics.edu.pk/labs/about/brl).

Figure 3 .
Various Bioinformatics tools and technologies of data manipulation used for efficient analysis of Biological dataComputational approaches towards personalized medicinePersonalized medicine or customized medicine is based on individual genetic makeup.With the advent of Human Genome Project, personalized medicine has become an ardent topic in medicinal chemistry[39].Genome-based analysis has been permitted by bioinformatics tools such as genomics and proteomics sequence databases (

Figure 4 .
Figure 4. Computational approaches for identification of food pathogen Bioinformatics in gene therapy Gene therapy involves the replacement of inactivated or mutated gene.For treatment purposes, computational tools are routinely used for characterization of genes, structural determination and physiochemical properties of their products.For gene therapy, the mutated gene sequence and normal gene sequence has to be characterized along with the vector genome information [53].For this purpose, several tools are employed in gene therapy (Figure 5) [54-57].In Pakistan as many technologies, tools and treatment are not so much progressed, gene therapy also has not employed so much for disease treatment.Research institutes working on bioinformatics in the premises of Pakistan To improve technical knowledge of researchers, there must be an educational platform to address queries related to life and science.To overcome issues related to bioinformatics and to educate researchers, first initiative was taken by Capital University of Science and Technology (CUST) previously known as Muhammad Ali Jinnah University) in 2002 as an undergraduate degree.Later this idea was extended by the COMSATS Institute of Information Technology (CIIT) in 2006.After that, several universities started their undergraduate and postgraduate degree programs to educate and promote awareness of people regarding bioinformatics.In this regard, HEC took a great initiative by introducing scholarships in bioinformatics with the aim to boost up and develop research projects with increased economic values.At present time, almost 20 different universities offering undergraduate and postgraduate degree programs including 5 HEC top-ranked universities [58].There are almost 98 on-going research programs throughout Pakistan in different research institutes of Pakistan, including almost 46 research programs in HEC topranked universities (Table4).In the province of Punjab, there are 35 on-going projects in different universities.So as 10 on-going projects in Islamabad, 32 in Sindh, 18 in Khyber Pakhtunkhwa, 2 in

Figure 5 .
Figure 5. Bioinformatics tools for different characterization of genes for gene therapy Bioinformatics and laboratories in Pakistan Talking about medical aspects, Pakistan has made certain developments in clinical and diagnostic field such as Shaukat Khanum diagnostic centre and HEJ, Karachi.These clinical laboratories are famous in conducting almost every type of diagnostic tests by means of advanced methodologies.Bioinformatics as an emerging field is