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Letters To Us

Letters To Us

Controlling Contamination

As academia and the biopharmaceutical industry combine resources to accelerate early-stage innovation from the bench towards the clinic, as discussed in “Averting an Innovation Cliff” by Diego Miralles (Scientific American Worldview, 2013), a critical opportunity exists to establish support and funding to resolve a problem that has long undermined discovery research: cell-line misidentification.

An estimated 15–20 percent of cell lines used by biologists are misidentified: meaning that cells thought to originate from—and be representative of—a particular organ or disease are actually different.1,2In one case, promising results generated from the use of misidentified esophageal cell lines led to at least three grants for the US National Institutes of Health, more than 100 scientific publications, 11 US patents and patient recruitment for clinical trials.3

It saddens me to think about the number of misleading discoveries from misidentified cell lines that have occurred in the past 40 years. How far could medicine have advanced without this problem? Could we have cured or have better treatments for cancer, heart disease or Alzheimer’s disease? Unfortunately, we’ll never know.

I also see a silver lining to this issue. There is an opportunity to reproduce projects that are well designed—but based on a misidentified cell line—using an authenticated cell line that is appropriate for the experiment. Many important discoveries could be waiting for such a do-over.

Biologists have known about this issue since the 1960s when Stanley Gartler of the University of Washington discovered 18 cell lines that were overrun by fast-growing HeLa cervical cancer cells,4 which can sneak into cell cultures from pipette tips or floating dust particles. Even this year, publications appeared that drew conclusions from the cells Gartler identified decades ago, as if those cells were bona fide representations of normal human biology.

Part of why this problem flies under the radar is that a case of mistaken identity cannot be confirmed by just looking at the cells. At regular intervals—as cross-contamination and mix-ups can occur at any time—one must spend hours and hundreds of dollars for tests of the cell’s DNA and other features that can confirm its true identity. Scientists can also purchase authenticated cell lines from reputable repositories, such as the American Type Culture Collection (ATCC) and European Collection of Cell Cultures (ECACC).

A strong show of support for the elimination of this problem would be for industry-partnership agreements and funding-agency proposals to include provisions for cell-line identification testing and acquisition of authenticated cell lines from reputable repositories. Several leading journals now request evidence of cell-line authentication before publication, but the organizations with the vision and financial power to direct the research community must now also play their crucial role.

It is naïve to assume that misidentified cell lines are only a scientist’s problem. This problem has likely denied us all the treatments we yearned for yesterday and the cures we hope for tomorrow.

» Don Finley
Market Segment Manager
St. Louis, Missouri

1. Drexler, H.G. et al. Leukemia 17, 416–426 (2003).
2. Perkel, J.M. BioTechniques 57, 85–90 (2011).
3. Boonstra, J.J. et al. J. Natl. Cancer Inst. 102, 271–274 (2010).
4. Gartler, S.M. Nature 217, 750–751 (1968).

Empowering Proteomics

Katharine Gammon’s “A Machine to Capture Complexity” (Scientific American Worldview, 2013) drew attention to the power of mass spectrometry for improving our fundamental understanding of human health. Driven by innovation, this analytical technique has seen a spectacular rise in use since the invention of electrospray ionization in the 1980s—a “soft” or gentle ionization technique that, for the first time, allowed researchers to analyze biomolecules like never before. 

In my view, mass spectrometry is as much about breaking down complexity as it is about “capturing complexity.” And that was never more evident than at this year’s ProteoMMX 3.0 Symposium on quantitative proteomics held recently in Chester, England. 

As a science, proteomics is advancing rapidly, thanks to mass spectrometry. One scientist at the symposium showed how mass spectrometry has helped her study the mitochondrial protein content of cardiac cells as a biomarker of cardiac disease. To think that we are getting to the point of understanding which sets of mitochondrial proteins, and their comparative levels, are important enough to track over time as indicators of heart health is mind-blowing; it was the stuff of dreams just a few years ago. The research has captured the imagination—and funding—of the US National Institutes of Health and the American Heart Association to the tune of tens of millions of dollars.

Gammon’s article described one type of mass spectrometry. Today, fortunately for scientists (and for science), they have quite a range of choices available to them. Whether looking at entire proteomes or individual proteins, breaking down complexity is the task of a mass spectrometer. And not all mass spectrometers are created equal.

Take, for example, electron transfer dissociation (ETD). It is catching on as a technique for transferring electrons to a protein or peptide backbone and causing the peptide to fragment. Equipped with ETD, a mass spectrometer can provide a more complete and accurate picture of protein structure than previously possible. A recent paper describes the first use of ETD combined with a high-resolution mass spectrometer for the surface mapping of intact protein complexes.1 

Today, scientists in all fields have many more and better mass spectrometry options available to them than ever before. Continued innovation will bring to them new capabilities and higher performance.

» James Langridge
Director, Health Sciences
Waters Corporation
Milford, Massachusetts

1. Lermyte, F. et al. J. Am. Soc. Mass Spectrom. 25, 343–350 (2014). 

Science for the Suffering

In a letter to Scientific American Worldview, 2012, Annalisa Jenkins of Merck Serono discussed the work her company is doing to address unmet medical needs in Northeast Asian countries. Merck Serono, she wrote, will increase R&D spending in the Asia Pacific Region by 45 percent. This is gratifying and encouraging, and I applaud them for their initiatives. It also serves as a reminder of ongoing challenges in other areas of Asia and the world—finding treatments for neglected tropical diseases (NTDs), such as Dengue fever, hookworm, onchocerciasis (river blindness) and lymphatic filariasis (elephantiasis). More than one billion of the world’s poorest people—one sixth of the world’s population—are infected by at least one of many forms of NTD, and 149 countries and territories are affected by at least one NTD. Victims of these diseases lose, collectively, approximately 50 million years of life, and NTDs kill an estimated 534,000 people every year.

Typically spread by insects, contaminated water or soil, NTDs are a group of infectious diseases that most often appear in economically poor countries. They are debilitating and disfiguring and persist for years, even decades. They affect populations that cannot provide the economic incentives for research into new treatments and diagnostics. They are called neglected because they have been largely wiped out in the more developed parts of the world and persist only in the poorest, most marginalized communities and conflict areas. In addition to causing physical and emotional suffering, these diseases hamper a person’s ability to work, keep children out of school and prevent families and communities from economically thriving.

We have been studying these terrible diseases at New England Biolabs, where more than 30 years ago, our founder Don Comb formed a parasitology unit to apply molecular tools to help eradicate them. 

There has been progress. Many drug discovery companies and consortiums, such as DNDi (Drugs for Neglected Diseases Initiative), have contributed to the study of these diseases. Collaborations with them and funding from the US National Institutes of Health, the World Health Organization, the Bill & Melinda Gates Foundation and other worldwide sources have helped to move projects forward and translate potential results to human populations. 

Nevertheless, we have far to go. For example, evidence suggests resistance is developing to existing drugs for many veterinary filarial nematodes, as well as the treatments of lymphatic filariasis (a parasitic disease caused by roundworms). No new anti-filarial drugs have been marketed in more than 20 years. For this reason, we joined the Anti-Wolbachia Consortium, a worldwide network of industrial and academic laboratories studying disease biology and with the goal of improving current treatments by reducing the time frame and efficacy of current treatments.

We highly encourage other labs and drug development companies to contribute to the global community. Just as our medical brethren can provide first aid and serve in organizations such as Doctors Without Borders, our training, knowledge and experience endows us with the potential to discover treatments for those whose suffering has been neglected.

» Barton Slatko
Senior Scientist
Genome Biology Division
New England Biolabs
Ipswich, Massachusetts

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