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Biotech sector's challenge with academic research

Singapore's biotech sector has attracted many international manufacturers and its institutions work with many of them to address local health concerns such as Type 2 diabetes. These public-private partnerships also help companies connect with Singaporean academics and researchers.

As public concern grows over the direction of the biotech sector, especially following news of leadership changes at the Agency for Science, Technology and Research, policymakers need to be aware of global trends in the biotech sector that have a bearing on local issues.

The biggest trend is the rising cost of drug development, and the difficulty in reproducing, and thus verifying, the success of trials and experiments cited in academic papers.

A 2012 Nature Review paper reported that "the number of new drugs approved per US$1 billion (S$1.3 billion) spent on R&D (research and development) has halved roughly every nine years since 1950, falling around 80-fold in inflation-adjusted terms", leading to higher drug prices and thus poorer health care for people.

More recent results from research by Stanford University and Massachusetts Institute of Technology (MIT) economists ("Are ideas getting harder to find") show some improvement in drug output per research dollar, but not a lot.

A new book by Mr Richard Harris of National Public Radio provides an explanation for falling R&D productivity. As the title suggests (Rigor Mortis: How Sloppy Science Creates Worthless Cures, Crushes Hope, And Wastes Billions), the problem is university research and the sloppy way it is conducted.

Private companies and academics that face the "reproducibility" problem are unable to reproduce the results from most university papers, thus leading to rising costs for start-ups and incumbents trying to use the results to develop new drugs.

Company scientists were the first to recognise this problem because they wanted to verify results before committing millions of dollars to further development. But academics have quickly followed, confirming the large extent of the problem. For example, a 2013 paper in Nature compared the results of two previous papers that had investigated some of the same cancer cell lines.

One institute checked 48,000 tests involving 130 potential drugs while another checked 24 different drugs in 500 cancer cell lines. The comparison identified 15 drugs and 471 cancer cell lines common to both experiments, but found similar results for only one of 15 drugs.

Mr Harris shows that this type of example is just the tip of the iceberg. Variations come from different methods, equipment, samples, materials and even timing, thus making it almost impossible to reproduce results.

Take, for example, the batch effect, which refers to the variation that occurs across different days for the same equipment and the same samples. Many papers report results that run across different years, making most of the results invalid.

These problems build on one another. Misidentified cell lines became the basis for other research, thus leading to large amounts of waste.

Once a cancer cell has been labelled as breast cancer or melanoma, other laboratories do not recheck the analysis. One misidentified cell line was used in more than 1,000 published papers. Some scientists claim that about 12,000 papers have been based on bad cell lines and each paper was cited 30 times.

A 2015 Plos One article estimates that "the cumulative (total) prevalence of irreproducible pre-clinical research exceeds 50 per cent", a mind-boggling number, but the identity of the irreproducible papers has been and will always be kept a secret.

Mr Harris argues that the source of the reproducibility problem is incentives, and particularly the different incentives that exist in academia and industry.

University professors are evaluated by the number of papers in top journals, and top journals want publicity for their papers and the resulting high-impact factors. Funding agencies and policymakers have followed this hype, leading to what some scientists call the "natural selection of bad science". Top journals want the first paper on a subject and thus, some academics quickly submit papers before tests are repeated and properly validated.

Academic labs that do this succeed, and those that don't may fail. Private companies, in contrast, are more careful, Mr Harris argues, because they do not make money until a drug is commercialised and thus, they must take a longer view than academic scientists.

Mr Harris also contrasts current science with the science of Charles Darwin in the 19th century. Unlike today's scientists, Darwin did his research slowly, making observations, considering multiple explanations, and carefully interpreting them over many years.

He argues that today's scientists have a lot to learn from Darwin and his contemporaries.

There are several implications for Singapore.

First, Singapore should retain and deepen the linkages between universities and companies, with a focus on addressing public health problems and exporting solutions to the rest of the world.

University professors are evaluated by the number of papers in top journals, and top journals want publicity for their papers and the resulting high-impact factors. Funding agencies and policymakers have followed this hype, leading to what some scientists call the "natural selection of bad science". Top journals want the first paper on a subject and thus, some academics quickly submit papers before tests are repeated and properly validated.

It should prevent its universities and labs from focusing solely on academic publications like United States universities have done, which is a big reason for the Donald Trump administration requesting a 20 per cent drop in funding for the National Institutes of Health.

Second, research productivity is falling in other science-based sectors, according to the research by Stanford and MIT economists, and a recent paper ("What does innovation today tell us about the US economy tomorrow?") in last month's Issues In Science & Technology. Thus the over-emphasis on academic papers by universities needs to be rethought.

Third, a great deal of research on innovation done by social scientists in Singapore uses data from the biotech sector. Analyses of the sector's patents and papers have become the basis for their research and thus teaching in the classroom, but the reproducibility problem and other reasons suggest that biotech papers and patents are both unfit for analysis, at least until the discipline determines which papers are reproducible.

Universities exist to serve their country and Singapore is no exception. University research should serve local companies, and university teaching should serve local citizens.

The problems with the pharmaceutical industry suggest that countries, including Singapore, should be careful in how they assess researchers at both universities and national labs. Publications in top-ranked journals do not mean much if the results do not lead to new products and services.

And the fact that most of Singapore's social science research on innovation is based on the biotech industry suggests that current business and economic students may be studying from flawed papers.

Singapore's leaders would be wise to continue addressing local problems through public-private partnerships, expanding these partnerships to address a wider variety of problems, and including more academic disciplines in these partnerships.


  • The writer is a retired associate professor of technology management from the National University of Singapore.