With the recent shift in administrative roles, we witness a promising change in the research and innovation landscape in Bulgaria. The extensive experience and dedication to these fields at a pan-European level of the former EU Commissioner for Innovation, Research, Culture, Education, and Youth promises to instigate significant advancements, particularly for early-stage investigators and within the realm of molecular life sciences.
Early-career scientists in Bulgaria, much like their counterparts in many other nations, face the challenge of finding sufficient opportunities to grow and contribute. However, this administrative transition brings a rejuvenated sense of hope. The former Commissioner has been a robust advocate for youth and education during her tenure at the EU Commission, and it is anticipated that this zeal will be directed towards nurturing the upcoming generation of Bulgarian scientists. We look forward to the potential increase in funding opportunities, enhanced accessibility to cutting-edge research equipment, and fortified collaborations with other EU countries under this new administration. Our collective endeavour is to foster an environment that persuades our brightest minds to remain in Bulgaria, mitigating the 'brain drain' phenomenon that has challenged our country for many years.
The molecular life sciences field, with its vast potential to address some of the most critical health challenges of our time, is set to benefit greatly from the former Commissioner’s expertise and influence. We look forward to the promotion of a multidisciplinary approach to molecular life sciences, bringing together biology, medicine, physics, and chemistry to catalyse innovation. Further, the prospect of increased investment in our research infrastructure and the integration of advanced technologies such as AI and data science into life sciences research is indeed exciting.
There are several key strategies that we, at the Bulgarian Academy of Sciences, believe will be instrumental in nurturing this fresh research culture. These include enhancing funding opportunities, developing our research infrastructure, fostering both interdisciplinary and international collaborations, promoting Open Science, encouraging innovation and entrepreneurship, investing in education and training, and implementing effective policies to retain our talented researchers.
Within the molecular life sciences, we identify several potential focus areas that align with Bulgaria's societal needs, the strengths of our existing research community, and global scientific trends. These areas include genomics and precision medicine, structural biology, bioinformatics and computational biology, synthetic biology, neurobiology, molecular immunology, and environmental biotechnology.
We also recognize the importance of employing cutting-edge methodologies for the progress of molecular life sciences. Techniques such as next-generation sequencing, CRISPR-Cas9 gene editing, single-cell analysis, cryo-electron microscopy, advanced proteomics and metabolomics, bioinformatics and machine learning, synthetic biology techniques, and microfluidics and lab-on-a-chip devices are central to advancing our research culture.
Genome editing is a powerful tool that allows scientists to modify an organism's DNA. This technology enables the precise addition, removal, or alteration of genetic material at particular locations in the genome. Among the various methods available for genome editing, CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology has revolutionized the field due to its simplicity, efficiency, and versatility. Derived from a naturally occurring genome editing system in bacteria, CRISPR allows researchers to edit genes with unprecedented precision and speed, leading to its widespread adoption in biological research.
CRISPR technology holds immense potential for gene therapy, the treatment of genetic disorders by repairing the disease-causing mutation in the patient's genome. By targeting and correcting specific genetic defects, CRISPR-based therapies could potentially cure a wide array of genetic diseases, from cystic fibrosis and haemophilia to certain types of cancer and neurodegenerative diseases. The technology is also invaluable in basic research, where it can be used to study gene function, create disease models, and unravel complex biological processes. For the Bulgarian research community and innovation ecosystem, adopting and investing in genome editing technologies like CRISPR could be transformational. Firstly, it would significantly enhance the capabilities of Bulgarian researchers, providing them with cutting-edge tools to drive discoveries in biology, medicine, agriculture, and other areas of life sciences. This, in turn, would elevate the quality and impact of Bulgarian research on the global stage. Secondly, it would stimulate the development of a thriving biotech sector in Bulgaria. With its potential applications in gene therapy, drug discovery, diagnostics, and synthetic biology, CRISPR technology could spawn new businesses and create high-quality jobs, fostering economic growth and technological innovation. Finally, it would provide an opportunity for Bulgaria to establish itself as a local leader in the ethical, legal, and social implications of genome editing. By fostering a multidisciplinary discourse on these issues, Bulgaria could contribute to shaping global norms and policies around the responsible use of genome editing technologies.
Investing in genome editing technology is not just about staying abreast with the latest scientific trends; it's about empowering our researchers, stimulating our economy, and taking a proactive role in shaping the future of this transformative technology. As a member of the Bulgarian Academy of Sciences, I strongly advocate for strategic investments and policies to support the development and responsible use of genome editing technologies in Bulgaria.
Bulgaria iGEM synthetic biology team has participated in world competitions several times, since 2016, and several projects already have employed CRISPR technology very successfully. In their 2017 project the team tested if CRISPR-dCas9 can serve as a targeting platform for optogenetic ROS generators to damage DNA and introduce mutations in E. coli. In 2018, the team designed a CRISPR based mutation detection system, working without using DNA sequencing. CRISPR-Cas9-RFLP and a Paired CRISPR-dCAS9-fused to split reporter protein sensors approaches were used. One particular challenge for the synthetic biology national team was the lack of specific funding and the lack of funding body or program to support this particular activity. A deeper synergetic collaboration with other Sofia University incentives, or between the national team and Bulgarian Academy of Sciences research groups utilizing synthetic biology approaches could be very beneficial for fostering further iGEM teams’ potential and final projects deliveries. Bulgarian Academy of Sciences research groups utilize CRISPR to produce genome edited cell lines harbouring fluorescence tag fused to proteins of interest to study a multi-cell 3D interactions, as well as COVID diagnostics.
The CRISPR technology could be enhanced even further combining microfluidics chip fabrication with pluripotent cell reprogramming. Microfluidics, the science and technology of manipulating and controlling fluids at the microscale, has become a powerful tool for advancing the field of genome editing and regenerative medicine. This emerging technology offers precise control over cellular environments, high-throughput processing, and the ability to mimic in vivo conditions, providing unique opportunities for biological research and clinical applications.
In the context of genome editing, microfluidics can be used to foster programmed gene editing by providing a controlled environment for precise delivery of CRISPR components into cells. Traditional methods of delivering these components, such as viral vectors or bulk electroporation, often lack precision and can lead to off-target effects. Microfluidic systems, on the other hand, can encapsulate cells and CRISPR components in microdroplets or microchambers, enabling precise co-localization and enhanced transfection efficiency. This controlled delivery system not only improves the precision and efficacy of gene editing, but also reduces the risk of off-target effects, a crucial consideration for clinical applications. Regarding the reprogramming of induced pluripotent stem cells (iPSCs) for translational regenerative medicine, microfluidic technologies can play a pivotal role as well. Reprogramming somatic cells into iPSCs involves introducing pluripotency genes into these cells, a process that can be optimized using microfluidics. For instance, microfluidic devices can provide a controlled environment for delivering reprogramming factors, enhancing the efficiency and purity of the resulting iPSCs. Furthermore, these devices can mimic the physiological conditions of the human body, providing a more representative platform for studying the behaviour of iPSCs and their differentiated progeny.
In the Bulgarian research community, the integration of microfluidics with gene editing and iPSC technologies could dramatically advance our capabilities in translational regenerative medicine. It would not only enable us to conduct high-quality, cutting-edge research, but also put us at the forefront of developing innovative therapies for a variety of diseases. This could lead to the creation of new biotech companies, the attraction of international partnerships and funding, and the improvement of healthcare outcomes for the Bulgarian population. A significant challenge ahead is the improvement of the national legislation promoting innovation and science. By investing in the development and application of these novel technologies, we can foster a thriving ecosystem of innovation and discovery in Bulgaria. The impact would be felt not only in the scientific community, but also in the broader economy and society, as we harness the power of genome editing and stem cell technologies to improve human health and wellbeing. The Bulgarian Academy of Sciences is also committed to promoting the integration of these technologies into our research landscape, ensuring that they are used responsibly and ethically for the benefit of all.
I cannot overstate the importance of adhering to the latest and most advanced scientific methods, many of which have been recognized as "Methods of the Year" by prestigious journals such as Nature. Incorporating these cutting-edge techniques into our national research methodological toolbox and scientific mindset can profoundly enhance our understanding of complex biological systems and expedite scientific discovery.
Long-read next-generation sequencing, for instance, offers unprecedented insights into genomic structures and functions by allowing us to sequence large segments of DNA with high accuracy. This approach enables us to identify structural variants, decipher complex regions of the genome, and more fully comprehend the diversity of the genomic landscape. The ability not only to sequence CRISPR-Cas9 genome edited cells, but also to obtain their full genome wide methylation state using particular long read technologies vastly enhances iPSC and genome edited cellular tools fast implementation in more than a research setting.
Single-cell transcriptomics is another revolutionary technique that has emerged in recent years. This method allows us to examine the gene expression profile of individual cells, thereby offering an unprecedented resolution of cellular heterogeneity within tissues. This could significantly advance our understanding of disease pathogenesis, tissue development, and cellular response to environmental stimuli. Spatial transcriptomics, on the other hand, provides a spatial context to gene expression, enabling us to understand the organization and interplay of cells within tissues. This method can reveal the functional heterogeneity within tissues and elucidate how cellular interactions contribute to tissue function and disease progression.
Embracing these innovative scientific methodologies is not just an optional advancement—it's a necessity to stay at the forefront of scientific discovery and to continue pushing the boundaries of our knowledge. By employing these advanced techniques, we can develop novel solutions to significant societal challenges. Examples include precision medicine, early disease diagnosis and prognostics, drug discovery and development, innovative cell and gene therapies, and understanding disease mechanisms.
The recent development of research infrastructure within the Bulgarian Academy of Sciences, built through its 42 research units (scientific institutes) and 8 specialized units, is a cornerstone in fostering national research incentives. This advancement not only strengthens the scientific capacities of the nation but also serves as a catalyst for innovation and development. This is particularly vital in the field of biotechnology, an area with immense potential for economic growth and societal impact.
The main research pursuits of one of the Academy’s leading life science research institutes revolves around the molecular and cellular biology of the eukaryotic genome, placing a strong focus on epigenetics. Additional key research topics include genome stability and translational studies. Some of the Academy institutes maintain an impressive track record of around 50 scholarly publications per year, featuring in esteemed journals such as Science, Cell, Molecular Cell, Nature Communications, and many more. The Academy is also proud to host a nationally-located node of the Euro-BioImaging consortium, known as the Bulgarian Advanced Light Microscopy Node. This state-of-the-art facility operates two spinning-disk confocal systems for live-cell studies and has recently acquired the newest generation confocal system and a Leica Stellaris STED system, enhancing the Academy's capabilities in super-resolution imaging. Further illustrating its commitment to cutting-edge research, a recently established ERA Chair group within the Academy is working to unravel the mechanisms behind rare diseases caused by chromatin factors. Their advanced workflow includes the generation of model cell lines using CRISPR/CAS9 technology, the analysis of structural changes in chromatin organization through ATAC-Seq, and the identification of genome-wide transcriptome changes using deep RNA-seq.
In line with the ongoing initiatives at other institutes within the Academy and its integrated collaboration within bigger inter-academic research infrastructures nation and EU wide, there is an established trajectory towards the conception and refinement of a sophisticated research pipeline centred around translational tissue models. This intricate process encompasses the primary disruption of tissue into singular cellular units, followed by the construction of genome-edited reporter cell lines. These cell lines are subsequently reincorporated into multicellular models via either bioprinting or organ-on-chip methodologies. These models subsequently serve as platforms for comprehensive downstream analyses, incorporating multi-modal physiological assessment techniques such as live imaging and long-read single-cell transcriptomics. Our approach employs a multifaceted strategy for single-cell analysis, deploying technologies such as Fluorescence Activated Cell Sorting (FACS), droplet-based or nanowell-based single-cell transcriptomics. The integration of long-read high throughput nanopore sequencing further enhances our single-cell analysis capabilities. To complement these methodologies, we have implemented Nanolive’s refractive index imaging and confocal imaging, particularly for visualizing models crafted using the Bio X bioprinting technology from Cellink. Through this integrative approach, we are continually refining our research pipeline, advancing the state of the art, and broadening the horizons of translational tissue model studies.
A significant aspect of these new research infrastructures is their potential to bridge the gap between academic research and industrial application. Universities in Bulgaria have traditionally served as the epicentre for academic training and scientific exploration, often operating in a purely academic framework. The Bulgarian Academy of Sciences forte was its focus to conduct cutting edge fundamental research and translate it into technological innovations. However, by integrating these institutions with the evolving research infrastructures, we could potentially create a conduit that facilitates the translation of academic discoveries into real-world applications. This approach also strengthens the national research community and its efforts to develop and train the next generation of scientists, which is essential for fulfilling this translation. National research infrastructures serve a pivotal role in the education and training of the next generation of Bulgarian scientists. They not only provide students and early-career researchers with access to cutting-edge technology and research methodologies, but also expose them to a research environment that encourages critical thinking, problem-solving, and innovation. This is particularly important in the context of biotechnology, a field that is rapidly advancing and requires a workforce that is adept at handling the challenges of tomorrow.
Moreover, these infrastructures offer a platform for interdisciplinary collaboration and exchange of ideas, accelerating the progress of research. They provide a much-needed space for researchers from diverse backgrounds to come together and combine their expertise, fostering a culture of innovation that is essential for advancements in biotechnology. In addition, the establishment of state-of-the-art research infrastructure also presents an opportunity to attract international collaborations. By providing state-of-the-art research facilities, Bulgaria positions itself as an attractive hub for global experts and research initiatives, thereby augmenting the country's stature on the international scientific arena. A critical advantage in this endeavour lies in the synergy of the research community, which combines the robustness of universities and research institutions alike, including notable entities like the Bulgarian Academy of Sciences.
While the journey towards a robust Bulgarian biotech sector may be long, the development of new research infrastructure within the Bulgarian Academy of Sciences has undoubtedly set a strong foundation. It is a crucial first step that not only boosts the current research landscape but also seeds the ground for the future growth of the biotech industry in Bulgaria.
In conclusion, as a senior member of the Bulgarian Academy of Sciences, I foresee a significant turning point for Bulgarian research and innovation. The challenge before us is vast, but so too is the potential for a revitalized research culture that provides ample opportunities for our early-career scientists and spurs advancements in areas such as molecular life sciences. We approach this new era with anticipation and optimism, confident in the bright future of Bulgarian scientific research and innovation.
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