Understanding Basic Research in a Changing Pharmaceutical Landscape

This article was co-authored with Marco Papageorgiou.

Basic, or fundamental research has given the world a multitude of drug formulations and discoveries.

From painkillers such as Panadol and Nurofen, to Ibuprofen; long been taken to suppress pain and fever. It can be said that at times, basic science research evolves long before its application is needed to treat human health and disease. This basic science can push the drive forward to uncovering much more understanding and treatment of human diseases.

A great example here is that of RNA. It was long held that RNA was simply an intermediate molecule for the conversion of genomic material into cellular proteins. However, basic research probed into this notion enabled the realization that RNA serves many functions other than this traditional role. What this means, is that basic research can transcend otherwise simplistic models developed. RNA has since been classified into enzymes, regulators of transcription and translation, and even involvement in epigenetics.

All this is extremely important. It can suggest that clinical advances — from laboratory to clinic — rely on basic research and its associated discoveries.

There is no doubt that basic, fundamental research goes beyond knowledge expansion in order to provide data that is useful — that which can be translated.

One thing is clear: as the fundamental rules of engaging in business within the pharmaceutical industry is changing, business and operating models must fit accordingly to the disruptions underway.

There is a much-needed shift underway in the pharmaceutical industry. The long-held model of ‘ finding a molecule and marketing it’ is quietly and slowly being replaced with ‘ using science to answer a need addressed in society’. In this regard, basic fundamental research will come from a shared effort between scientists, government and its citizens.

PWC, in their Pharma2020: Challenging business models report, state explicitly that by 2020 the standard or traditional research and development models will no longer be suitable for companies engaged in the pharmaceutical industry. In addition, KPMG’s Pharma outlook 2030: From evolution to revolution, explicitly states that greater transparency of drug pricing is required between government, insurers and patients. The report also outlines that by 2030, a there will be a shift from treatment of symptoms to prevention measures and complete cures. This shift will be attributed to three developments:

1. Novel therapies: such as gene editing, genotyping and gene therapies

2. Advances in technology: 3D printing, nanotechnology

3. Greater access of data by patients: fitting (wearable) monitoring devices, apps and digital medicine.

This is what basic research must keep up with; and, it can only be possible if this changing healthcare ecosystem operates in the interests of scientists carrying out basic research. In a nutshell, basic fundamental research must be intrinsic to the changing pharmaceutical equation and not be neglected as this consumerization of emerging therapies unfolds.

These shifts, recognized by the pharmaceutical industry, will be in the form of; 1) marginal-cost pricing of new drugs, and 2) the move towards prevention and real cures for human disease. This paradigm shift is currently amongst us, and it’s not an easy shift as many new competitors are challenging the long-held established view on how pharmaceutical companies operate in a decaying ecosystem.

The process of discovering and developing a drug can be both costly and time consuming. It has been shown that identification of a target through to the approval for marketing can take well over 10 years. In order for the drugs to be marketable, it is mandatory for them to be approved by the Food and Drugs Administration (FDA). Since 1827, there has been an increase in the number of drugs that are approved by the FDA. Most of these drugs were discovered and developed by key players in the pharmaceutical industries such as Pfizer, Merck and Novartis.

We believe that in order for long-term pharmaceutical companies to sustain their global influence in developing novel drug therapies, these evolved businesses should setup laboratories, or partner with existing institutes that focus on basic fundamental research. This ties in with our earlier statement of ‘ using science to address a need in society.’ And, of course, this should involve the patient at each step to ensure greater transparency with key milestones, that communicates to patients how a new therapy or advancement will address their healthcare needs — where applicable. The problem is that in our current information age, surrounded by a myriad of incoming networks, the danger lies in the complete fixation on managing these interconnected networks in the healthcare space; rendering scientific expertise as less important.

Disruption to the pharmaceutical industry is something that would need to consider in their forecasts. In this way, balanced and realistic models can be established that leverage basic fundamental research; allowing companies to not work against, but to master this disruption appropriately.

However, basic research requires the appropriate technology and tools to get the results; to ultimately feed into new therapies.

Identifying drug targets

Basic research serves as an important step in uncovering potential drug targets. For the purpose of discovering antibiotics, we can investigate cellular processes that are crucial for the survival of a pathogen. For example, antibiotics kill bacteria by stopping synthesis of essential components.

Basic research also refers to discovering processes that are innate to an organism or cell. Proteostasis is an important process that ensures survival of bacteria. This process involves various proteolytic pathways that help remove damaged proteins from the bacteria. If this proteostasis network is disrupted, the “bad” proteins will be accumulated in the bacteria, resulting in cell death. In some cases, unregulated proteolysis can occur, resulting in non-specific degradation of substrates. Indeed, studies have shown that proteases are potential drug targets.

Other ways to identify drug targets is through massive data generation. The use of this method would speed up the process of drug development. Functional metagenomics has also been shown to be a promising method to find antibiotics or antibiotic resistance genes.

With the advent of proteomics and gene editing tools such as CRISPR-Cas9, it is also possible to create a cell line lacking specific genes, and to examine its proteome and investigate the cellular components that are upregulated or downregulated. These changes to the cell can serve as a footstool to further examine the potential of these cellular components as drug targets.

Exploring the suitability of a target

In order to examine the suitability of the components as drug targets, it is crucial to understand how they function or change the activity of the cell. There are many ways to do this, and the method of choice depends on the purpose of analysis.

In order to examine the role of bacterial components as drug targets, bacterial proteins can be purified a series of in vitro assays can be performed to examine how these components interact and alter activity of the cell.

Firstly, recombinant plasmids have to be created and fused with suitable tags (e.g: His tag, His-ubiquitin tag, FLAG tag) and expressed in a host, as recombinant proteins. These recombinant proteins are purified and can be used in an in vitro setting to examine its activity. For example, if a protease has been identified as a potential drug target, we can examine its role and activity by monitoring its capacity to modulate and facilitate turnover of substrates. This can be achieved using fluorescence spectrometry or a gel-based assay, such as SDS-PAGE. The interaction between two proteins can also be studied using size-exclusion analysis and cross-linking experiments. If the in vitro assays show promising results, we can proceed to creating bacterial strains lacking the specific protease and determine whether this has an effect on the viability of the bacteria. This is to validate if the protease can serve as potential drug target. We can also examine the interacting partners of a specific target in human cells by using co-immunoprecipitation assays. This allows researchers to better understand how target proteins are regulated in a human cell, and if they serve as an effective drug target.

Modulating the target

Enabling this approach is by carrying out a fragment-based approach drug design. Here, our potential drug target can be screened against a library of small chemical molecules to find molecules that can interact with the target. Assays are performed to examine how these molecules change the properties of the target, which can result in changes in cell activity. One of the key parts of designing drugs is to optimise the molecular interaction between a drug candidate and its binding target. X-Ray crystallography can be employed to generate three-dimensional protein structures for structural studies. Using this tool, the structure and the amino acid properties of the target protein can be examined. If there are restrictions that make it difficult for crystallisation, three-dimensional structure of the target protein can be predicted through molecular modelling using the MODELLER software.

By using the Autodock software, we can also examine docking of a compound onto the target protein. Molecular simulation studies can also be employed to examine the changes in protein conformation, in the presence or absence of the drug candidates.

Collectively, these methods and approaches used to uncover drug targets, explore their function(s) and suitability help define basic fundamental research. Less well-communicated of is how basic research is constructed to order to arrive at a conclusion: be it a novel drug compound, inhibitor or regulator molecule of some kind. Researchers may do a fantastic job synthesizing these tools and crafting new methods — such as next-generation sequencing — however, the real test of robustness lies in how this basic research toolkit can translate to any meaningful results to be, broadly, implemented within society.

As previously mentioned, basic fundamental research must remain in focus upon the global pharmaceutical shift into a virtual-based ecosystem.

Basic research plays a vital role during the drug discovery stage as it helps set up a solid foundation to subsequent studies. Governing the entire process from potential drug target discovery to clinical trials is basic research. For example, a recent paper on the CRISPR-Cas9 gene editing was retracted from Nature Methods when the authors admitted that the results may be wrong. Nowadays, with an ever more connected world, it is almost imperative that researchers have efficient way to access genetic data for their basic research design. This heralds and warrants acknowledgement of human ethics; which naturally arise when any novel — efficacious and effective — drug treatment is processed through the pharmaceutical pipeline.

However, a caveat to this thinking is that basic research is a standardized and well-defined process that give scientist the same results each time the same experiment is replicated. This also has a great influence upon the ‘publish or perish’ mantra; which, could contribute to a declining research landscape. This could inadvertently out basic research into a ‘crisis’. In basic research, if an experiment is unreproducible, that shouldn’t mean that the research being undertaken is bad, or damaged. The term ‘reproducible’ can mean many things; and there may be many parts of an experiment are not well understood until all the relevant parts of that basic research are uncovered.

So, we have two things which we must consider: the first is that we know that the pharmaceutical industry’s business models are changing — or must change to meet the demands of a more connected and informed world. Secondly, the entire publication setup, i.e. publish or perish, is discounting scientific research; funding only those projects that give some return on government investment. This could indeed hamper efforts to propel basic research that could lead to groundbreaking advancements.

Basic research is generally costly, especially in experimentation.

These costs are broadly associated with reagents, commercially available kits and individual molecules such as antibodies, enzymes, etc. In order to perform these experiments, it is essential that sufficient funding is provided. The necessity to fund basic research is imperative since the outcome from this research has a kind of domino-effect on the lengthy chain of drug trials; i.e. pre-clinical and clinical phases, to commercialization and marketing.

Pre-clinical phase involves testing of the drug candidate for any potential to cause serious harm. The main focus here is to determine toxicity level of the drugs, and dosing level that is suitable for administration into human cells. When all these have been optimized, the drug candidates are tested in mice for in vivo studies. If the pre-clinical phase is successful, the drug candidate will be used in following clinical studies.

The process from the pre-clinical to clinical phase is lengthy and costly. This further emphasizes the importance of ensuring basic research is well funded in order to enable strong foundations which can serve as a suitable context to build trust with the community, along with maintaining a steady research purpose.

To take an example of funding; the 2018 Australian budget. The Australian government has allocated A$1.3 billion over ten years for a National Health and Medical Industry Growth Plan. Part of this fund will be dedicated to research into the field of genomics. This type of funding would provide a much-needed insight into genomics that could perhaps be a stimulus that might see the development of new genomics tools that can be ultimately used in basic research.

Funding into next-generation advances in science will be the pathway to discovering new and improved ways to analyze, probe and develop drug treatments.

Basic research will change; or at least, it will be forced to adapt to changes in how data is shared, stored and used.

DNA testing kits are a great addition to basic research. Their advantage is in their capacity to provide researchers with genetic data that can be further employed in establishing and/or aiding in research design. Genetic data, in this case, is plentiful and accessible as it provides those donating their data for the progression of biomedical research to understand that they are part of a greater cause.

This is the shift in perceptions of basic research. Until now, basic research has focused solely on making and marketing drug treatments that target a particular ailment or disease. As scientific research, with its improved tools and techniques enters a new phase in research and development, more is becoming known to scientists; such as epigenetics and the epigenome. This parallels with changes in the basic research paradigm, as eventually the patient — in a disease setting — will be central to how drugs targets are studied and manufactured.

This change in perception qualifies, almost forces, basic research to accept that along with contemporary and emerging basic research tools, a central focus will also be on the individual patient or cohort of people affected by life-threatening conditions.

Science and scientific research doesn’t require radical shifts in how we carry out science.

Scientific research is largely based on great ideas — the interplay of creativity and imagination. This is something that we must not lose sight of. That are large part of doing science should not simply be to publish yet another article, but to contribute to society — for a much wider cause. The greatest challenge will be how government decision will balance and allocate future funding to basic research ideas. If the entire healthcare ecosystem is beginning to morph into one that must adhere to the rising premise of automation, then science — basic fundamental research — and scientists must remain in the spotlight, as to remind our world that all great scientific discoveries were formed from a place of deep curiosity, that eventually found its way to serve humans.

Understanding Basic Research in a Changing Pharmaceutical Landscape

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