Researchers at the Indian Institutes of Technology Madras and Mandi have metabolically engineered plant cells to increase production of anti-cancer drug camptothecin (CPT).
The allopathic medicine is produced using Nathapodytes nimmoniana, a native, endangered plant. It requires nearly 1,000 tonnes of plant material to extract 1 tonne of CPT. The International Union for Conservation of Nature has red-listed the plant as in the past decade alone there has been a 20% decline in the plant’s population.
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In 2021, IIT Madras researchers published a research paper in which they identified a microbe as a sustainable and high-yielding alternative source for CPT. Researchers from Plant Cell Technology Lab of IIT Madras developed genome-scale metabolic model for N. nimmoniana plant cells using computational tools.
The researchers say the study could pave the way for effective and efficient commercial production of the drug and other medicinally important alkaloids and reduce the need to cut down endangered plants. Karthik Raman, Smita Srivastava, professors in the Biotechnology department and Sarayu Murali, and Maziya Ibrahim of Computational Systems Biology Lab of IIT Madras and Shyam K. Masakapalli and Shagun Saini from Metabolic Systems Biology Lab in IIT Mandi comprised the team that conducted the study.
The Science and Engineering Board (SERB) and the Department of Science and Technology funded the research that was published in a peer-reviewed journal Frontiers of Plant Science.
Principal investigator Smita Srivastava of Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, said integration of metabolic engineering with bioprocess engineering principles could ensure enhanced and sustainable production of the drug, meeting the increasing market demand in a short time.
Ms. Smita said, “It is a well-known lead molecule based on which drugs for chemotherapy are produced for stage 4 cancer. Camptothecin is a molecule procured from nature and then (in a) one-step derivative it is produced as drug. We have provided a more sustainable way of producing camptothecin as it is majorly procured from plants. We have isolated the plant cell of Nothapodytes nimmoniana, which is native to India.”
The researcher has grown cultures of the plant in the lab. “We extracted the cells maintained the plant cell line in the lab and engineered them to enhance the production of camptothecin. If we take up an engineered cell line, then an approval from the review committee on genetic manipulation is mandatory. We are at technology readiness level 3-4; we still have to optimise at the bioreactor level. It is a molecule of huge interest in cancer treatment,” she explained.
Camptothecin is majorly produced in southeast Asian region, with the plant being largely found only in China and India. The Chinese variety of the plant used to extract the cell is listed as critically endangered. There are only 4,000 of the species left. In India the plant is a native of western ghats and in the last decade there was a 20% decline in population, she said.
Co-investigator Mr. Karthik said the platform for model-based rational metabolic engineering of plant cells could be adopted to enhance production of many other high-value phytochemicals as well. The plant culture helped him understand the metabolic pathways of the cell. “Dr. Smita developed the culture. We can get a reasonable growth rate and look for commercially viable productivity. We built metabolism models of the plant,” he said.
Since the aim was that the plant should make more of the camptotethecin molecule, he developed a model where he tried to help the plant overexpress a particular gene. Just as roads are widened to allow more traffic to flow, his role was to find ways to enable higher production of the molecule so that it could be used to manufacture the cancer drug. “We have to ensure that it is commercially feasible. It will typically take a few years, may be within three to five years” their research could become commercially viable, he said.
Mr. Masakapalli said the strategies adopted in the work could pave way to further engineer plant cell bio-factories for sustainable biomanufacturing of high-value phytochemicals.
