Targeted therapies in oncology: where we are and what lies ahead

This is my first popular science piece to have found a place in a biotech magazine: Asia-Pacific Biotech News (APBN February 2017 issue). The article starts off with the challenges with traditional cancer therapies that has led to the evolution of targeted therepies, what has been achieved in different avenues here; it concludes with a short note on what could be expected in the coming decade (Precision medicine). 

The audience mainly comprises of university researchers/students, industry scientists, and public, so the scope of the article is rather broad. The link to my article on APBN website is as follows:

Targeted therapies in oncology 

Data reproducibility - is it negotiable?

As a first-year PhD student, I spent my six months optimizing a multi-step synthetic procedure of a published target molecule. I modified different experimental parameters so as to get the best product yields, facile reaction and purification processes. The efforts in replicating the reported quality of data came at the cost of the vast amount of resources that I utilized, and crucially one semester of valuable PhD time. It is then I realized that data reproducibility is not just beneficial, but a non-negotiable right of researchers.

The benefits of data reproducibility are indisputable for conserving invaluable scientific resources, manpower, time and money. In this era of rapidly progressing science that has unfortunately seen several instances of data fudging and paper retractions, reproducibility holds all the more relevance.

Sources of irreproducibility

The sources of irreproducibility are field-specific, but according to a comprehensive survey by Nature, the impact of it has been felt less by physicists and chemists, as compared to biologists [1]. Myriad parameters could result in variabilities: reagent suppliers offering differing purities, minor variations in protocol details, stability of samples like antibodies and crucially, the number of times a particular experiment has been repeated.

Apart from the experimental conditions, statistics forms an integral part of data interpretation. For any set of data, the standard deviation (SD) and p-values provide useful but not conclusive information. Specifically, the misuse of p-value in several instances has been condemned recently [2]. While p-values are useful indicators for assessing the probability in hypothesis testing, they are excessively relied on and advocated. The misinterpretation of data associated with p-values arises from various manipulations like cherry picking data excluding non-significant results, and the interchangeable usage of ‘statistical’ and ‘therapeutic’ significance to draw conclusions. These biases lead to over-interpreting the data, and thereby falsified conclusions.

Strategies to improve data reproducibility

Measures to address irreproducibility have to be employed at various levels – from scientists, peer-reviewers to publishers – minimizing the scope for variability. The approach to dealing this starts at the individual level, which involves training students in the lab. For example, a new student in chemistry lab must be trained to use tools like SciFinder to review literature, to study safety data sheets (MSDS), and to handle light/temperature sensitive chemicals. Standardising such trainings is as important towards getting reproducible data as actually performing experiments. Furthermore, there must be a strong emphasis on providing detailed protocols and analytical data, so as to facilitate reproducibility by other researchers. Researcher bias involving p-hacking can be eliminated by blinding the statistician to the data labels – this would be valuable in preventing over-interpretation of the statistics.

Meanwhile, publishers and referees must establish and enforce rigorous guidelines that can ensure that the published data is of a high standard. Journal ‘Organic Syntheses’ is an example, wherein synthetic procedures are reported in great detail and submitted articles are published only after the reported protocol is reproduced in an authorized lab [3]. This has been an efficient strategy for reducing variability in organic synthesis, but might be unfeasible and uneconomical in other fields. To enhance transparency, the authors must be required to submit the raw data for review, in addition to the manuscript figures and data. Finally, attempts to report data irreproducibility of the reported literature should also be encouraged.

Reproducibility forms the very foundation of science. Research scaffolding – the primary mechanism of progress in science – heavily relies on the reproducibility of the reported data. As researchers, we bear the ethical and moral responsibility of employing the best scientific practices, together contributing to the progress of research towards innovation and human advancement.

#SciComm: Linking scientists and the media

I vividly remember my maiden attempt to explain my drug discovery research interests to a non-chemistry audience –  my potential molecular biology collaborators. I illustrated the purpose of the different chemical modifications and their possible effects on drug pharmacology, metabolism, and physicochemical parameters. As a medicinal chemist, I appreciated being able to convey the essence of my project, and also being able to understand their research focus.

Meanwhile, aware of the breast cancer focus of my PhD project, my family/friends would ask me – ‘So, have you found a cure for cancer?’ I often find myself fumbling for an answer satisfactory to them – ‘Umm no, but I have made a contribution to the existent knowledge in the field’. Not good enough!

Science communication challenges lie at multiple levels, that involve the laypublic and the scientific community at large. There is a dire need, especially for the scientists, to realize and address these gaps.

Break it down: Communication between scientists

Interdisciplinary research – bringing together diverse fields – can demand effective dialogues between researchers for building meaningful collaborations. Scientists are accustomed to academic writing, and it can be agonizing to detach from technical details and the compulsive use of jargon. My collaborators and I tackled a similar challenge; we realized that communicating on a ‘big picture’ greatly helped us to unify our technical expertise. For e.g., we discussed the purpose of various biological assays (gene expression) to distinguish different chemical classes of the synthesized compounds; this excluded the protocol details. Our discussions at the conceptual level, addressing our research goals, helped us formulate specific objectives with potential applications in the clinical settings.

Break it down further: Engage the public

Popular science media is primarily accountable for educating the laypublic on scientific advances – this entrusts them with the responsibility to present news that a) raises awareness on important issues; b) do not create misconceptions.

A WHO survey (2014) conducted in developing countries found that an appalling 76% people believed that ‘anti-biotic resistance’ meant resistance of the human body (rather than the microbes) to the anti-biotics.¹ Self-prescribing antibiotics, leading to their indiscriminate usage, and further not finishing the entire course of medicines, are significant contributors. Media as much as doctors have to take responsibility to educating people about the do’s and don’ts of antibiotic medicines, and their implications extending to the community. The slow progress of antibiotic drug development and the rapid rate of the microorganisms developing resistance to them, poses a grim necessity of public awareness.

A 1998 Lancet article (retracted in 2010) linking MMR vaccine and autism propagated vaccination fear among the public. This being responsible for a decrease in the immunization rates, led to measles outbreaks in the UK.² The scepticism associated with vaccines has not been eradicated since; journalists presenting skewed reports are largely to blame here. Science aware media can be an effective means of intervention to address issues that can have a significant impact on a nation’s economies.

Apart from being morally obligated to repay their funding source (tax payers), scientists can cater to their own interests by popularizing their research among the public. The success of citizen science projects, ALS ice-bucket challenge have established the importance of crowdfunding as a burgeoning avenue for research funds. A recent two-day science festival in Singapore is an excellent example of science popularization. With flyers all over the city, this science fare had exhaustive demonstrations and interactive talks on cancer therapy, 3-D printing, bioplastics etc. Scientists of differing capacities engaged the public, and familiarized them with cutting edge technologies.³

Why are scientists good science communicators?

The recent mockery of scientific studies by John Oliver was not only a criticism of research questions and study designs, but also of the deteriorating quality of scientific reporting.⁴ For e.g., incongruous reports, having polar ‘opinions’ on the cardiovascular effects of coffee, muddles the laypublic’s scientific judgement. To produce a coherent report, a science journalist also requires an ability to understand statistics of the study and ask relevant questions – skills that scientists are well-versed with.

The onus is on scientists, to assume responsibility and employ strategies, that lead to impactful collaborative scientific research, authentic journalism and hence a science literate globe. 

A new hope to combat Dementia?

Findings from a study led at the University of California revealed a new drug that could be a potential treatment for memory loss caused by neurodegenerative diseases. This study was performed in collaboration with Takeda Pharmaceuticals, and was recently published in the Journal of Medicinal Chemistry (February 2016).

Dementia is one of the earliest manifesting symptoms in the development of Alzheimer’s disease and Schizophrenia, affecting nearly 44.4 million people worldwide. One of the leading causes of death among senior citizens, dementia global healthcare costs account to roughly USD 818 billion today.¹ Most of the currently approved medications although provide symptomatic relief, fail to curb the progress of neurodegeneration. More often than not, drugs in clinical trials are unable to qualify the stringent regulatory requirements and fall through owing to multiple organ side effects.²

Apart from understanding the molecular mechanisms contributing to neurodegeneration, there has been much emphasis on drug development research in this area. Li et al. have reported the synthesis of a library of seventy six molecules designed to target an enzyme called phosphodiesterase (Type 1) aimed to treat cognitive impairment.3 Drugs designed for central nervous system disorders often face the challenge to penetrate the blood brain barrier and to reach the target site. Apart from limited loss during metabolism, most of the synthesized molecules also displayed good brain penetration capacities. X-ray crystallography technique was employed to study the mechanism at the molecular level in detail, which will be useful to design next generation molecules. One of the best performing drugs was taken to preclinical testing, and interestingly the results indicated its potential to translate its memory enhancing potential when tested in mice.

Most of the current drug regimens have proved to be little useful in treating severe symptoms of memory dysfunctions. With an optimal balance of physicochemical properties and a favourable safety profile in Phase 1 Clinical trials, the drug in question promises to be a suitable exploratory candidate for treating dementia in advanced stages neuro disorders.

Being a Scientoonist

This is my first endeavor to making a cartoon: promotion from scientist to scientoonist. My message to all the chemists out there: Follow lab safety rules and guidelines, they are meant for a reason. Things can hardly go wrong, but when they do, it can be disastrous!

P.S. I was awarded a commendation prize for this sciencetoon on NUS Science Safety Day 2015.

Science Communication: What, Why and How?

A tiny dot on the globe that occupies a significant territory in the scientific world map, celebrated its jubilee birthday this year: SG50! Featuring premier research institutes like A*STAR, top notch R&D’s and world-class scientists, biomedical sciences is one of the rapidly progressing sectors in Singapore. Science and technology development will be indispensable to achieving the country’s targets in the coming decades; it is thus imperative to have a more science-aware population to maximize its impact on Singapore’s economic growth. A variety of challenges and barriers possibly exist in science communication advancement among this diverse populace.

School being lowest in the hierarchy of science education, holds primary importance in dictating one’s inclination towards it. Grade driven learning at this stage strongly encourages memorization-disgorge practice ­­– a serious impediment in developing passion for science. Apart from teaching fundamentals, a grasp on approaches to real-world problem solving will be useful in building critical thinking abilities. Visual impressions like lab demonstrations, science museum visits; interactive sessions like debates, quizzes enhance one’s inquisitiveness. In essence, an overhaul of didactical culture with an aim to make students more curious and expand their imagination would go a long way in making school level science exciting.

Communication challenges lie on every rung of the scientific research ladder. My first encounter with potential biologist collaborators presented me with a challenge to explain my research interests in chemistry and cancer drug discovery to them. As a medicinal chemist, I appreciated being able to convey the essence of my project, as well as being able to comprehend the significance of their research. The ability to synthesize a unified picture of our technical expertise and interests helped us formulate specific research objectives, with potential applications in clinical settings. It was then that I realized the tremendous potential of scientific communication between researchers in interdisciplinary fields. With little practice or prior experience, graduate students are often faced with the formidable task of writing manuscripts and theses. Thus, considerable attention must be diverted towards honing verbal and composition skills through mandatory communication courses.

Issues like healthcare, food, fuel, climate change directly impact people’s quality of lives. For example, understanding prophylactic measures for dengue fever can prove to be useful in controlling its spread and lowering its incidence. As consumers, laypublic is often lured by ‘sugar-free’ labels on products like diet coke, often oblivious of the potential carcinogenic effects of its substitute aspartame. Knowledge about harmful outcomes of plastic usage and its recyclable substitutes would also contribute a great deal in protecting environment and wildlife. Popular science awareness among adults can be promoted using various platforms like magazines, events like scientifique café, science events apps and targeted public campaigns.

Science communication is a critical tool to bridge knowledge and information between researchers, industries, think tanks, and varying levels of audience. Apart from a sound science community and judicious policy makers, a well aware public will catalyse the course of country’s growth and development. Science communicators extending from teachers to researchers ought to take responsibility and play an effective role in making Singapore a more sustainable, robust and prosperous economy.