Speaker Introduction - Dr Philipp Lorenz
Dr. Philipp Lorenz is the head of data science in Biotech firm Basecamp Research. He received a PhD from Oxford in Genetics and Bioinformatics, and has a rich experience in Business Development, Data Science, and Bioinformatics in the pharmaceutical and biotech industry. Previously tutor at Oxford, teaching Genomics, Computational Biology, Biochemistry, Genetics, and Molecular Biology to undergraduate and graduate students. Master in Biochemistry from Oxford.
Why are natural reserves important in drug research?
Our planet hosts some of the most diverse and multifaceted ecosystems imaginable. The importance of maintaining these environments cannot be understated. The goal of furthering our knowledge about small molecules to aid medical advancements and innovations is also key---our natural preserves provide a thrilling opportunity for the search to uncover key molecules which could help advance our current arsenal of drugs and treatments for diseases. Basecamp Research is a biotechnology company that aims to do just that – explore key target locations to sustainably locate and sequence small molecules which could have applications in the scientific and medical fields. The beauty of our planet has the opportunity to help sustain the human race by hosting previously undiscovered molecules, some of which have already been proved useful.
The discovery of Paclitaxel
The chemotherapeutic drug Paclitaxel is used in breast and lung cancer treatments. The sources of this drug were the trees Taxus brevifolia (Pacific Yew) and Taxus canadensis (Canada Yew), both of which are native to North America, and required the exploration of natural forests to harness it. This drug is administered via injection into veins and can cause side effects including hair loss and diarrhea. This particular drug targets the protein tubulin, and Paclitaxel-treated cells have been observed to have abnormal cell division, spindle-fibre formation and chromosome segregation---all key processes in inhibiting the growth and metastasis of cancer. Microtubules are structures formed by tubulin protein and provide structure to cells. Paclitaxel works by stabilising this polymer and preventing its degradation thus preventing metaphase (a stage in mitosis) from completing. This prevents mitosis from progressing and it is this which triggers the process of programmed cell death (apoptosis), or the reversion of the cell to the G0 phase – the beginning of the cell cycle, skipping cell division. At high concentrations of Paclitaxel, it appears that the drug suppresses microtubule detachment from centrosomes (this process normally occurs during mitosis).
Initially, samples of the bark of the Pacific Yew tree by researchers from the US Department of Agriculture (USDA), who were searching for natural products to help cure cancer in 1962. It was later found that the bark has cytotoxic properties. Further samples and research led to the extraction of Paclitaxel (the active ingredient responsible for this activity), and the drug was later approved for commercial use following extraction and purification. The discovery of this drug was revolutionary in helping treat several forms of cancer, but using the bark of the Pacific Yew tree was unsustainable to meet anticipated demands. More sustainable methods are now used to mass-produce the drug artificially. This drug has been shown to result in response rates of 50-82% in patients with positive HER2 tumours (HER2 is a protein that promotes cell growth and is found around the outside of breast cancers). Today, Paclitaxel is one of the most commonly used drugs for cancer treatment.
This encouraging story illustrates the importance of searching and utilising natural molecules for medicinal use. The aim of biotechnology companies such as Basecamp Research is to sustainably discover small molecules which could have applications in future research. In the world, less than 1% of natural proteins have been discovered thus far. This leaves huge scope for the potential discovery of proteins and other small molecules which could be utilised in various fields to help solve medical problems. A huge benefit of these proteins is that they may be more advantageous compared with those synthesised in labs because they have endured natural selection and have survived continuous evolutionary processes to be well adapted to their environments and may be more durable/stable. Basecamp uses computer algorithms to target specific locations in the world with the greatest scope for locating small molecules. These are often remote locations that have not yet been extensively explored. Following the targeting of specific locations, the team then travel there and collect samples which are then analysed using bioinformatics. This helps the company identify novel proteins found in nature. Understanding and exploiting the natural resources available in a sustainable way that preserves these hotspots in a pristine state is of utmost importance to Basecamp Research and is one of their key aims. By adding to the global database of known proteins, Basecamp Research has already contributed numerous variants of known proteins to our pre-existing knowledge, and the company hopes to continue this trend further.
Challenges for searching proteins in natural reserves
Unfortunately, tropical rainforests are rapidly depleting over time as they have reduced from covering 16% of the planet surface in 1950 to only 7% today. This is despite the fact that more than half of all known plant species originate from tropical rainforests. This leads to a catastrophic loss of biodiversity over time, which can have detrimental effects on the planet and on humans. This massively reduces the pool of natural proteins which could potentially have medicinal uses and applications in the modern world. Deforestation by various causes can cause this lack of biodiversity and is a global concern. Ensuring that the research and discovery of proteins doesn’t contribute to this decrease is paramount.
Development of research in the marine world
Over the past few decades, another key target area for the discovery of small molecules is the marine world. Being a relatively new environment to explore, this opens up a huge variety of possibilities for the discovery of novel small molecules. The first drug derived from a marine source is ecteinascidin 743, which is commercially known as Yondelis® and is used for the treatment of small tissue sarcomas (STS). This drug was recommended for approval by the EMEA in July 2007. This drug was extracted from the sea squirt (Ecteinascidia turbinate) and was isolated and refined after it was discovered that it had anticancer activity. Recent evidence suggests that the drug blocks the activity of the oncogene (potentially cancer-stimulating) transcription factor FUS-CHOP by preventing DNA from binding to the transcription factor. As well as this, it has been observed that DNA adducts formed by this drug blocked gene expression by resulting in RNA pol II to arrest during DNA transcription and acting as a competitive inhibitor for the binding site on DNA. Whilst the precise details of the mechanism of action of the drug is not completely understood yet, the drug has an average 5-year survival rate of 65% for patients with distant metastatic STS.
Overall, the overwhelming possibilities for drug components and other medicinal compounds the natural world can provide us are exciting to consider, especially in helping us understand the natural selection processes which have resulted in stable proteins. This can lead to alternative drugs and expand existing databases of known molecules, particularly proteins. What is also crucial is the sustainable approach that companies are taking to preserve these ecosystems for the health of the planet and for future generations. After all, if such environments were destroyed, we are only hurting ourselves in the long run.
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