Lakshmi Kuttippurathu: Emerging Voice in the Therapeutic Target Discovery Space

Lakshmi

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Shaping the Future of Therapeutic Target Discovery

Cutting-Edge Bioinformatics!

The pharmaceutical industry is at the intersection of biology and technology, where computational methods and data science are driving innovation in drug discovery and development. With the rise of advanced genomics, proteomics, and other omics technologies, there is an unprecedented ability to understand diseases at the molecular level, enabling researchers to identify new therapeutic targets and personalize treatments for patients. The integration of artificial intelligence is further accelerating progress, offering new possibilities for predicting drug efficacy, reducing costs, and shortening the timelines for bringing novel therapies to market.

Lakshmi Kuttippurathu is a visionary leader shaping the future of this sector. Her work bridges the gap between biology and technology, allowing for a more profound understanding of how diseases function at the molecular level. She brings a multi-disciplinary approach to her leadership, blending computational models, advanced algorithms, and systems biology. Lakshmi is known for her ability to simplify complex biological data and find actionable insights, positioning her as a driving force in this field.

Let’s explore Lakshmi’s innovative journey:

Early research career

Lakshmi began her research career as a computational physicist, working on complex systems. During this period, physicists were studying noise in gene expression, and she found the field of Biophysics extremely interesting. The use of mathematical principles and computational modeling to navigate the complex interaction between biological components fascinated her. Even more exciting was the prospect of using a multi-disciplinary approach to understand disease mechanisms, paving the way for more effective treatments and interventions.

The transition to computational biology happened over time. Computational genomics was still in its infancy when she finished her doctoral studies. She joined Brandeis University to learn the basics of Bioinformatics. During this time, there was a need for a resource biologists could use to examine and comprehend how enzymes and other essential factors bind to DNA. Leading this project at Harvard-MIT Health Science and Technology was her gateway to this new field.

It was evident that the field of bioinformatics, with the integration of biology, information technology, and computer science, was going to pave the way for groundbreaking technological and instrumentation advances, creating a whole new world of possibilities. However, she felt that without a foundational understanding of Biology, the pursuit lacked direction and purpose. This led her to spend the next part of her career at Thomas Jefferson University, where she learned the basics of Systems Biology. She joined TJU as a postdoctoral researcher and transitioned into a faculty position within the same research group.

Liver and Cardiac Healthcare

As a faculty member at TJU, she had the opportunity to work with some brilliant minds on liver biology and neuroscience problems.  One of the amazing properties of the liver is that it can regenerate almost completely, even after toxic damage. Using multi-omics analysis and multi-scale modeling techniques, her team at Thomas Jefferson University tried to understand the shift in the dynamic balance and coordination of cellular processes underlying the regenerative response after chronic perturbations. This is important not only from a foundational science perspective but also from a clinical perspective, particularly in the context of liver transplantation. The concept underlying this approach is to enhance comprehension of the alcoholic liver’s adaptive, reparative, and regenerative capabilities following surgical intervention. By gaining deeper insight into these mechanisms, they can effectively support the damaged liver in reinstating its intricate architecture. This understanding is crucial for developing strategies that promote optimal recovery and function post-surgery.

Her main area of interest in the field of neuroscience is centered on the exploration of the complex interconnections between the brain and the heart. She finds this area extremely fascinating. One of her recent projects involved studying the vagus nerve and its role in heart health via the peripheral nervous system called the intracardiac nervous system (ICN)—still an untapped area of research in heart health. Their group was the first to develop a 3D neuro-anatomical map of ICN at single-cell resolution. They followed this up with an integrative multi-scale modeling approach with the objective of developing control strategies that can manipulate ICN via the vagal nerve. The goal is to utilize these strategies to create neuromodulation therapies for interventions in heart disease.

She explored this further and was intrigued by one of the aspects that came out of this study: The importance of adopting an inclusive approach to race and gender is essential, as it will not only improve our understanding of cardiac healthcare but also ensure that medical interventions and treatments are customized for diverse populations and genders. She believes there is still much to uncover in this critical area of cardiac healthcare, and there is immense potential in utilizing the vast data landscape.

Transition to industry

Like many other academic researchers, she was skeptical about joining the industry. However, the experience of living through the pandemic changed her perspective. She observed that the extraordinary partnership between academia and industry not only altered the trajectory of the pandemic but also saved countless lives.

She joined Lexicon Pharmaceuticals right after the pandemic ended. The past three years at Lexicon have been among one of the most fulfilling experiences of her career.

As the Associate Director, her major responsibilities were to create a computational strategy and lead the target discovery project to find potential druggable targets for metabolism and neuro-related diseases, contributing to ongoing discovery pipelines by working with CROs and effectively communicating the outcomes with stakeholders.

At Lexicon Pharmaceuticals, Inc., Lakshmi played an important role in the company’s innovative research and development efforts by employing its Genome5000 database to unlock new possibilities in drug discovery, particularly in metabolism and neuroscience.

Advancing Omics and Systems Biology

Lakshmi believes that being a scientist is being a lifelong seeker. Computational biologists are in the pursuit of understanding the instruction manual for the complex system called the human body. Genetics became important when it was realized that genes are the most fundamental unit of biology, and connecting genes to diseases started almost 40 years ago. However, it is the computational power to detect patterns and interactions, combined with technological advances, that made genetic alterations and manipulations cheaper, faster, and more efficient.

The systems biology approach takes omics analysis one step forward by treating the system in a holistic manner, considering the interconnectedness of its various components. In understanding the use of omics data in the context of the human body as a control system and diseases as imbalances created by internal or external disturbances, she came to appreciate both its power and limitations.

Omics goes beyond genomics. The integration of transcriptomics, epigenomics, proteomics, metabolomics and phenomics has revolutionized drug discovery in recent years. By providing a comprehensive view of biological systems at the molecular level, omics data has enabled researchers to identify new drug targets, understand disease mechanisms, optimize treatment regimens, stratify patient populations based on their molecular profiles, and predict drug responses. Lakshmi believes that as technology continues to advance, omics hold immense promise for unlocking the secrets of our genetic blueprint and ultimately improving human health and well-being.

Integrating AI and Machine Learning in Target Discovery

She identifies two major bottlenecks in early target discovery: the translation from genotype to human phenotype and the transition from measurement to mechanism. Until a few years ago, scientists relied heavily on phenotypic screens and literature knowledge to find the right therapeutic targets. The recent emergence of algorithms incorporating intelligent machine learning techniques is drastically changing this sector. However, identifying actionable therapeutic targets still remains a challenging task. The hope is that utilizing a large amount of high-throughput data efficiently in conjunction with AI algorithms can identify the right targets more quickly and cost-effectively. However, this kind of scaling up can be challenging. Lakshmi prefers using a combination of heuristic, informatics and machine learning approaches in dealing with any data-driven discovery, including target finding. She believes that when human intuition is combined with modern technologies, the best results are achieved. One is not a substitute for the other. Effectively combining these elements is where the challenge lies. Finally, she believes the strength of a research organization is the strength of its team. The best results happen when the team shares the same vision and novel ideas and strategies are encouraged.

Implementing Workflows for Collaboration

According to Lakshmi, transforming raw data into valuable biological insights can be challenging. Additionally, it is important to note that biology is inherently complex, and every step of the research pipeline introduces an endless array of variabilities. One effective method they use to minimize errors is to design end-to-end workflows in accordance with the FAIR (Findability, Accessibility, Interoperability, and Reusability) principles. Implementing FAIR workflows can streamline collaboration and facilitate the integration of diverse datasets. Effective visualization also plays a huge role in communicating complex concepts and results in a coherent manner. These skills are crucial for effectively communicating insights to stakeholders, making complex concepts easier to understand and share.

In recent years, significant advancements have been made to simplify these processes. This is largely due to the widespread availability of containers, dockers, and cloud systems. These technologies have revolutionized the way in which data analysis is conducted, allowing greater efficiency and scalability. The field is moving in a fast-paced way, which makes staying up to date with the latest developments highly essential. Lakshmi achieves this by attending seminars, courses, workshops, networking, and following scientific journals. She is engaged in the community and takes pleasure in participating in and presenting at conferences. In Lakshmi’s view, the best part of being a scientist is that one can be a lifelong student. To her, the academic aspect of scientific research is like a meditative process. She finds joy in programming and would never want to stop coding and developing something on the side. “There are opportunities to learn and grow everywhere. Finding the right one that aligns with you is the key.” Lakshmi stated.

Passion for Coaching and Mentoring

Coaching and mentoring have always been strong passions of Lakshmi, and this is something she takes a lot of pride in. She actively seeks out opportunities and makes herself available for younger scientists and early career aspirants. She is keen on actively fostering collaborations from different trainings and thoughts. It is extremely rewarding for her to have the opportunity to empower the youth—to develop talent and leadership. She believes that we learn a lot from the younger generation, too. She has always chosen to work with smaller teams, but she is a strong believer that being a leader is being presented with the opportunity to be vulnerable and to continually transform and adapt oneself for the larger possibilities and serve the common purpose.

Re-evaluating Success and Progress in today’s world

She has outlined her professional goals in three parts:

  1. Future of Data-Driven Discoveries

Lakshmi believes the field is in a very good place with tons of data and amazing technologies to help interpret it. However, integrating disparate public OMICS datasets in a systematic way poses a challenge. Future efforts should focus on integrating public and private OMICS datasets, including population data, developing high-quality training data, and channeling them through sophisticated AI pipelines to fine-tune the process for prioritizing target selection. In an ideal scenario, AI models can be fine-tuned to provide valuable predictions for developing prognostic, predictive, and pharmacodynamic biomarkers. Additionally, AI can be utilized to assess toxicity, ensure safety, and enhance druggability.

  1. Industry-Academic Partnerships and Collaborations

According to her, this is a golden time for bioinformatics, and collaborations between industry and academia are essential for its growth. She acknowledges the amazing contributions from the open-source community towards the advancement of computational biology, with the Open Targets platform (OTG) being a great example of such fruitful collaboration.

Lakshmi is fortunate to be involved in some collaborative attempts to develop open-source resources that everyone can use. She is excited to see what lies ahead and be part of this amazing progress. Major efforts should focus on developing algorithms to integrate multi-dimensional datasets and streamlining the best tools and databases into a common accessible platform.

  1. Contributions to the Research/Business World

The business world is relatively new to Lakshmi. She recalls coming across a fascinating concept that the complexities of the system that led to the inventions of high-throughput computational models with predictive power also have the potential to bring back the balance known as homeostasis, or a healthy state of living. The more we zoom in, the more we realize the interconnectedness and interdependence of these elements, compelling us to zoom out and consider the system as a whole. She finds parallels between the dynamic fluctuations and variables in the business world and the non-equilibrium nature and complexities of human biology. Decisions driven by data analysis and finding innovative solutions to manage potential risks introduced by unknown factors are common threads here. In complex systems, when the noise becomes higher, the fundamental equations stop working.

“It is our responsibility as a generation to reduce the noise by bringing in more holistic approaches in research and business. Now is a good time to re-evaluate conventional measures of success and find a new balance. It is our intention as humans and leaders that will decide the direction of our health and wellbeing.” This is one of the areas where Lakshmi wishes to contribute.

Exploring the Mind-Body Connection

She reflects on her earlier research career, where she often “sweat the small stuff.” In recent years, she has greatly explored the importance of integrating mind-body practices to foster presence and balance and cultivating mindfulness. Having a routine and discipline has been tremendously beneficial in her career, especially during the post-COVID days. Lakshmi enjoys being in nature, painting, and exploring new cultures, ancient civilizations and historical places. She believes that following passions outside of work and maintaining positive, nurturing relationships are very important. These activities not only help personal growth but also reset the mind and keep one grounded. Lakshmi acknowledges that she would not be where she is today without the support of the people close to her.

Key Insights for Aspiring Bioinformaticians

Lakshmi has changed her motto from “Do what you like” to “Do what is needed.” This transformation occurred over time.

She advised some points for future aspirants:

  • Understanding of Biology is fundamental.
  • In Bioinformatics, the job sometimes involves finding that “needle in a haystack,” which means one must be comfortable with the noise inherently present in the problem.
  • Developing a system-level approach and practicing integrative analysis considering the interconnectedness of the system is becoming increasingly important in understanding complex biological systems.
  • AI is going to revolutionize the discovery space in a matter of a few years. It is important to follow and stay updated with emerging technologies and have a solid foundation in statistics and machine learning. It is even more important not to get lost in data and methods but to focus on science and steer efforts into using the existing tools to find creative solutions.

Messages from life

Finally, Lakshmi has given some messages from her life:

  • To the dreamers who must fight for opportunities: Have patience. Try and grow through your doubts, and your limitations will become your strengths.
  • To the girls who are thinking twice before getting that physics degree and to the women who are worried about the social stigma of focusing on their personal and professional growth: Times have changed. The world is a much bigger place now.
  • To the interdisciplinary scientists who think they are “jacks of all trades”: Your unique capabilities and abilities to adapt are valued, especially in today’s world.
  • To the leaders in the corporate and academic world: It is time to bring more feminine energy into our world—the energy of collaboration, lifting each other up, and growing together. The world needs a lot more of this!

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