novel research in sciences

Is novel research worth doing? Evidence from peer review at 49 journals

Affiliations.

• 1 School of Information, University of Michigan, Ann Arbor, MI 48109.
• 2 Laboratory for Innovation Science at Harvard, Harvard University, Cambridge, MA 02138.
• 3 Harvard Business School, Boston, MA 02163.
• 4 Digital, Data and Design Institute, Harvard University, Cambridge, MA 02138.
• PMID: 36395142
• PMCID: PMC9704701
• DOI: 10.1073/pnas.2118046119

There are long-standing concerns that peer review, which is foundational to scientific institutions like journals and funding agencies, favors conservative ideas over novel ones. We investigate the association between novelty and the acceptance of manuscripts submitted to a large sample of scientific journals. The data cover 20,538 manuscripts submitted between 2013 and 2018 to the journals Cell and Cell Reports and 6,785 manuscripts submitted in 2018 to 47 journals published by the Institute of Physics Publishing . Following previous work that found that a balance of novel and conventional ideas predicts citation impact, we measure the novelty and conventionality of manuscripts by the atypicality of combinations of journals in their reference lists, taking the 90th percentile most atypical combination as "novelty" and the 50th percentile as "conventionality." We find that higher novelty is consistently associated with higher acceptance; submissions in the top novelty quintile are 6.5 percentage points more likely than bottom quintile ones to get accepted. Higher conventionality is also associated with acceptance (+16.3% top-bottom quintile difference). Disagreement among peer reviewers was not systematically related to submission novelty or conventionality, and editors select strongly for novelty even conditional on reviewers' recommendations (+7.0% top-bottom quintile difference). Manuscripts exhibiting higher novelty were more highly cited. Overall, the findings suggest that journal peer review favors novel research that is well situated in the existing literature, incentivizing exploration in science and challenging the view that peer review is inherently antinovelty.

Keywords: bias; novelty; peer review; publishing.

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• Research Support, Non-U.S. Gov't
• Peer Review, Research*
• Periodicals as Topic*

• Harvard Business School →
• Faculty & Research →
• November 22, 2022
• Proceedings of the National Academy of Sciences

Is Novel Research Worth Doing? Evidence from Peer Review at 49 Journals

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Karim R. Lakhani

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Novel Research Designs

• First Online: 08 July 2021

Cite this chapter

• Anjali Wagle 2 ,
• Nino Isakadze 2 &
• Seth S. Martin 3  

629 Accesses

Innovative technologies such as mobile health (mHealth) and just-in-time adaptive interventions have created an opportunity to individualize health care. Yet, the evidence to support scaling of these innovative technologies has lagged behind the pace of technology advancement. This chapter examines consider current approaches to clinical evidence generation and how innovative research designs could drive precision medicine forward. While randomized controlled trials (RCTs) are currently considered the gold standard to inform practice, conventional RCTs can be costly and time intensive. This could hinder their usefulness when evaluating rapidly evolving technologies. As a result, a variety of novel study designs have evolved to help further individualize patient care and in some cases allow faster evidence generation. These new methods are expanded on within the chapter and include micro-randomized trials (MRTs), n-of-1, site-less design, and stepped wedge trials. Furthermore, we discuss study methodologies that are used to develop mHealth interventions such as patient centered participatory research and user centered design. Each of these research designs aim to propagate precision medicine by moving classic research techniques from population-averaged effects to those directly relevant to the individual, which is ideally where the future of medicine is headed.

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Bothwell LE, Podolsky SH. The emergence of the randomized. Controlled Trial. N Engl J Med. 2016;375(6):501–4.

Article   Google Scholar  

Carpenter D, Reputation and power: organizational image and pharmaceutical regulation at the FDA. Princeton University Press; 2010.

Google Scholar  

Greene JA, Podolsky SH. Reform, regulation, and pharmaceuticals—the Kefauver-Harris Amendments at 50. N Engl J Med. 2012;367(16):1481–3.

Article   CAS   Google Scholar  

Bothwell LE, et al. Assessing the gold standard-lessons from the history of RCTs. N Engl J Med. 2016;374(22):2175–81.

Schulz KF, Grimes DA. Allocation concealment in randomised trials: defending against deciphering. Lancet. 2002;359(9306):614–8.

Lin Y, Zhu M, Su Z. The pursuit of balance: an overview of covariate-adaptive randomization techniques in clinical trials. Contemp Clin Trials. 2015;45(Pt A):21–5.

Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics. 1975;31(1):103–15.

Stanley K. Design of randomized controlled trials. Circulation. 2007;115(9):1164–9.

Scott NW, et al. The method of minimization for allocation to clinical trials. A review. Control Clin Trials. 2002;23(6):662–74.

Altman DG, et al. The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med. 2001;134(8):663–94.

Randomised trial of intravenous atenolol among 16 027 cases of suspected acute myocardial infarction: ISIS-1. First International Study of Infarct Survival Collaborative Group. Lancet. 1986;2(8498):57–66.

Long-term effects of intravenous thrombolysis in acute myocardial infarction: final report of the GISSI study. Gruppo Italiano per lo Studio della Streptochi-nasi nell’Infarto Miocardico (GISSI). Lancet. 1987;2(8564):871–4.

Evans JG. Evidence-based and evidence-biased medicine. Age Ageing. 1995;24(6):461–3.

Naylor CD. Grey zones of clinical practice: some limits to evidence-based medicine. Lancet. 1995;345(8953):840–2.

Garfield FB, Garfield JM. Clinical judgment and clinical practice guidelines. Int J Technol Assess Health Care. 2000;16(4):1050–60.

Cabana MB, Powe NR, et al. Why don’t clinicians follow clinical practice guidelines? A framework for improvement. JAMA. 1999;282:1458–65.

Sonis J, et al. Applicability of clinical trial results to primary care. JAMA. 1998;280(20):1746.

Gurwitz JH, Col NF, Avorn J. The exclusion of the elderly and women from clinical trials in acute myocardial infarction. JAMA. 1992;268(11):1417–22.

Frieden TR. Evidence for health decision making—beyond randomized. Controlled Trials. N Engl J Med. 2017;377(5):465–75.

Liao P, et al. Sample size calculations for micro-randomized trials in mHealth. Stat Med. 2016;35(12):1944–71.

Klasnja P. Micro-randomized trials: an experimental design for developing just-in-time adaptive interventions. Health Psychol. 2015;34:1220–8.

Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med. 2004;10(8):789–99.

Kratchwill TR. Single subject research: strategies for evaluating change. Academic Press; 1978. p. 316.

Zucker DR, et al. Combining single patient (N-of-1) trials to estimate population treatment effects and to evaluate individual patient responses to treatment. J Clin Epidemiol. 1997;50(4):401–10.

Joy TR, Zou GY, Mahon JL. N-of-1 (single-patient) trials for statin-related myalgia. Ann Intern Med. 2014;161(7):531–2.

Breivik H, et al. Assessment of pain. Br J Anaesth. 2008;101(1):17–24.

Marcolino MS, et al. The impact of mHealth interventions: systematic review of systematic reviews. JMIR Mhealth Uhealth. 2018;6(1):

Gurman TA, Rubin SE, Roess AA. Effectiveness of mHealth behavior change communication interventions in developing countries: a systematic review of the literature. J Health Commun. 2012;17(Suppl 1):82–104.

Devi BR, et al. mHealth: an updated systematic review with a focus on HIV/AIDS and tuberculosis long term management using mobile phones. Comput Methods Prog Biomed. 2015;122(2):257–65.

Sanders L. An evolving map of design practice and design research. Interactions. 2008;XV(6).

Kelders SM, et al. Evaluation of a web-based lifestyle coach designed to maintain a healthy bodyweight. J Telemed Telecare. 2010;16(1):3–7.

Wanner M, et al. Comparison of trial participants and open access users of a web-based physical activity intervention regarding adherence, attrition, and repeated participation. J Med Internet Res. 2010;12(1):

van Gemert-Pijnen JE, et al. A holistic framework to improve the uptake and impact of eHealth technologies. J Med Internet Res. 2011;13(4):

Tippey KG, Weinger MB. User-centered design means better patient care. Biomed Instrum Technol. 2017;51(3):220–2.

Jessen S, Mirkovic J, Ruland CM. Creating gameful design in mhealth: a participatory co-design approach. JMIR Mhealth Uhealth. 2018;6(12):

Zachary WW, et al. Participatory design of a social networking app to support type II diabetes self-management in low-income minority communities. Proc Int Symp Hum Factors Ergon Healthc. 2017;6(1):37–43.

Lamberti MJ, Getz K. White paper: Profiles of new approaches to improving the efficiency and performance of pharmaceutical drug development. Tufts Center for the Study of Drug Development, Boston, MA; 2015.

Sertkaya A, et al. Key cost drivers of pharmaceutical clinical trials in the United States. Clin Trials. 2016;13(2):117–26.

Ross S, et al. Barriers to participation in randomised controlled trials: a systematic review. J Clin Epidemiol. 1999;52(12):1143–56.

Covington D, Veley V. The remote patient-centered approach in clinical research. Appl Clin Trials. 2015.

Dorsey ER, et al. Novel methods and technologies for 21st-century clinical trials: a review. JAMA Neurol. 2015;72(5):582–8.

Europe’s First Fully Remote Diabetes Trial.

ClinicalHealth Announces Successful Results for an Entirely Remote Online Clinical Trial. 2016.

Hirsch IB, et al. Incorporating site-less clinical trials into drug development: a framework for action. Clin Ther. 2017;39(5):1064–76.

Perez MV, et al. Large-scale assessment of a smartwatch to identify atrial fibrillation. N Engl J Med. 2019;381(20):1909–17.

Brown CA, Lilford RJ. The stepped wedge trial design: a systematic review. BMC Med Res Methodol. 2006;6:54.

Li YH, Mullette E, Brant JM. The stepped-wedge trial design: paving the way for cancer care delivery research. J Adv Pract Oncol. 2018;9(7):722–7.

PubMed   PubMed Central   Google Scholar  

Chapman AR, et al. High-sensitivity cardiac troponin and the universal definition of myocardial infarction. Circulation. 2020;141(3):161–71.

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Wagle, A., Isakadze, N., Martin, S.S. (2021). Novel Research Designs. In: Martin, S.S. (eds) Precision Medicine in Cardiovascular Disease Prevention. Springer, Cham. https://doi.org/10.1007/978-3-030-75055-8_7

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Bias against Novelty in Science: A Cautionary Tale for Users of Bibliometric Indicators

Research which explores unchartered waters has a high potential for major impact but also carries a higher uncertainty of having impact. Such explorative research is often described as taking a novel approach. This study examines the complex relationship between pursuing a novel approach and impact. Viewing scientific research as a combinatorial process, we measure novelty in science by examining whether a published paper makes first time ever combinations of referenced journals, taking into account the difficulty of making such combinations. We apply this newly developed measure of novelty to all Web of Science research articles published in 2001 across all scientific disciplines. We find that highly novel papers, defined to be those that make more (distant) new combinations, deliver high gains to science: they are more likely to be a top 1% highly cited paper in the long run, to inspire follow on highly cited research, and to be cited in a broader set of disciplines. At the same time, novel research is also more risky, reflected by a higher variance in its citation performance. In addition, we find that novel research is significantly more highly cited in “foreign” fields but not in its “home” field. We also find strong evidence of delayed recognition of novel papers and that novel papers are less likely to be top cited when using a short time window. Finally, novel papers typically are published in journals with a lower than expected Impact Factor. These findings suggest that science policy, in particular funding decisions which rely on traditional bibliometric indicators based on short-term direct citation counts and Journal Impact Factors, may be biased against “high risk/high gain” novel research. The findings also caution against a mono-disciplinary approach in peer review to assess the true value of novel research.

Earlier versions of this paper were presented at the Workshop on the Organization, Economics and Policy of Scientific Research, Turin; Institute for Research Information and Quality Assurance, Berlin; Max Planck Institute for Innovation and Competition, Munich; and the TIES seminar at the MIT Sloan School, Cambridge. The authors thank seminar participants and in particular Pierre Azoulay, Christian Catalini, Paul David, Lee Fleming, Alfonso Gambardella, Dietmar Harhoff, Sybille Hinze, Stefan Hornbostel, Jacques Mairesse, Fabio Montobbio, Henry Sauermann, Daniel Sirtes, Scott Stern, Mark Veugelers, and John Walsh for helpful comments. Financial support from KU Leuven (GOA/12/003) and the Research Foundation - Flanders (FWO, G.0825.12) is gratefully acknowledged. J. Wang also gratefully acknowledges a postdoctoral fellowship from FWO. Publication data are sourced from Thomson Reuters Web of Science Core Collection. The views expressed herein are those of the authors and do not necessarily reflect the views of the National Bureau of Economic Research.

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Public–private partnerships have typically been considered as a means of enabling research to be more responsive to changing social and global challenges, thereby accelerating innovation and allowing wider economic and social gains from joint investments between governments and the private sector. The main benefit of such schemes is that they facilitate the matching of the specialist scientific expertise of academics with the capabilities of industry scientists to translate scientific breakthroughs into therapeutic advances, all in the context of secure funding 1 . The main challenges of such approaches include the perception of academics that research in industry is driven by market forces rather than being led by the science, and concerns over ownership of intellectual property rights 1 .

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We acknowledge Diego Alvarez Garcia, GSK Argentina, Djalma Oper, GSK Uruguay and Fishawack Health for support in writing the article.

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Novel score validated for diagnosis of gastroesophageal reflux disease

by Lori Solomon

A novel high-resolution manometry (HRM) score can stratify the risk and severity of gastroesophageal reflux disease (GERD), according to a study published online March 27 in the UEG Journal .

Stefano Siboni, M.D., from IRCCS Policlinico San Donato in Milan, and colleagues built and externally validated a manometric score (Milan Score) to stratify the risk and severity of the disease in patients undergoing HRM for suspected GERD. The analysis included 295 consecutive patients undergoing HRM and pH-study for persistent typical or atypical GERD symptoms.

The researchers report that straight leg raise response and evaluating esophagogastric junction subtype 3 had the highest impact on the score (odds ratios, 18.20 and 3.87, respectively). The external validation cohort of 233 patients showed the model had a corrected Harrel c-index of 0.90. There was good calibration observed, with a model-fitting optimism adjusted calibration slope of 0.93 and an integrated calibration index of 0.07.

"A novel HRM score for GERD diagnosis has been validated," the authors write. "We anticipate the Milan Score to be a useful screening tool to predict pathologic GERD, to stratify disease severity, and eventually make the diagnostic pathway more efficient and GERD treatment more precise and personalized."

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'Mathematical microscope' reveals novel, energy-efficient mechanism of working memory that works even during sleep

UCLA Health researchers have discovered a mechanism that creates memories while reducing metabolic cost, even during sleep. This efficient memory occurs in a part of the brain that is crucial for learning and memory, and where Alzheimer's disease begins.

The discovery is published in the journal Nature Communications .

Does this sound familiar: You go to the kitchen to fetch something, but when you get there, you forget what you wanted. This is your working memory failing. Working memory is defined as remembering some information for a short period while you go about doing other things. We use working memory virtually all the time. Alzheimer's and dementia patients have working memory deficits and it also shows up in mild cognitive impairment (MCI). Hence, considerable effort has been devoted to understand the mechanisms by which the vast networks of neurons in the brain create working memory.

During working memory tasks, the outermost layer of the brain, known as the neocortex, sends sensory information to deeper regions of the brain, including a central region called the entorhinal cortex, which is crucial for forming memories. Neurons in the entorhinal cortex show a complex array of responses, which have puzzled scientists for a long time and resulted in the 2014 Nobel Prize in medicine, yet the mechanisms governing this complexity are unknown. The entorhinal cortex is where Alzheimer's disease begins forming.

"It's therefore critical to understand what kind of magic happens in the cortico-entorhinal network, when the neocortex speaks to the entorhinal cortex which turns it into working memory. It could provide an early diagnostic of Alzheimer's disease and related dementia, and mild cognitive impairment," said corresponding author Mayank Mehta, a neurophysicist and head of the W. M. Keck Center for Neurophysics and the Center for Physics of Life at UCLA.

To crack this problem, Mehta and his coauthors devised a novel approach: a "mathematical microscope."

In the world of physics, mathematical models are commonly used, from Kepler to Newton and Einstein, to reveal amazing things we have never seen or even imagined, such as the inner workings of subatomic particles and the inside of a black hole. Mathematical models are used in brain sciences too, but their predictions are not taken as seriously as in physics. The reason is that in physics, predictions of mathematical theories are tested quantitatively, not just qualitatively.

Such quantitatively precise experimental tests of mathematical theories are commonly believed to be unfeasible in biology because the brain is vastly more complex than the physical world. Mathematical theories in physics are very simple, involving very few free parameters and hence precise experimental tests. In contrast, the brain has billions of neurons and trillions of connections, a mathematical nightmare, let alone a highly precise microscope.

"To tackle this seemingly impossible challenge of devising a simple theory that can still explain the experimental of data of memory dynamics in vivo data with high precision, we hypothesized that cortico-entorhinal dialog, and memory magic, will occur even when the subjects are sleeping, or anesthetized," said Dr. Krishna Choudhary, the lead author of the study. "Just like a car behaves like a car when it's idling or going at 70 mph."

UCLA researchers then made another large assumption: the dynamics of the entire cortex and the entorhinal cortex during sleep or anesthesia can be captured by just two neurons. These assumptions reduced the problem of billions of neurons' interactions to just two only free variables -- the strength of input from the neocortex to entorhinal cortex and the strength of recurrent connections within the entorhinal cortex. While this makes the problem mathematically tractable, it raises the obvious question -- is it true?

"If we test our theory quantitatively on data in vivo, then these are just interesting mathematical games, not a solid understanding of memory-making magic," said Mehta.

The crucial experimental tests of this theory required sophisticated experiments by Dr. Thomas Hahn, a coauthor who is now professor at Basel University and a clinical psychologist.

"The entorhinal cortex is a complicated circuit. To really test the theory we needed experimental techniques that can not only measure the neural activity with high precision, but also determine the precise anatomical identity of the neuron," said Hahn.

Hahn and Dr. Sven Berberich, also a coauthor, measured the membrane potential of identified neurons from the entorhinal cortex in vivo, using whole cell patch clamp technique and then used anatomical techniques to identify the neuron. Simultaneously they measured the activity of the parietal cortex, a part of neocortex that sends inputs to the entorhinal cortex.

"A mathematical theory and sophisticated in vivo data are necessary and cool, but we had to tackle one more challenge -- how does one map this simple theory onto complex neural data?" said Mehta.

"This required a protracted period of development, to generate a 'mathematical microscope' that can directly reveal the inner workings of neurons as they make memory," said Choudhary. "As far as we know, this has not been done before."

The authors observed that like an ocean wave forming and then crashing on to a shoreline, the signals from the neocortex oscillate between on and off states in intervals while a person or animal sleeps. Meanwhile, the entorhinal cortex acted like a swimmer in the water who can move up when the wave forms and then down when it recedes. The data showed this and the model captured this as well. But using this simple match the model then took a life of its own and discovered a new type of memory state known as spontaneous persistent inactivity, said Mehta.

"It's as if a wave comes in and the entorhinal cortex said, 'There is no wave! I'm going to remember that recently there was no wave so I am going to ignore this current wave and not respond at all'. This is persistent inactivity" Mehta said. "Alternately, persistent activity occurs when the cortical wave disappears but the entorhinal neurons remember that there was a wave very recently, and continue rolling forward."

While many theories of working memory had shown the presence of persistent activity, which the authors found, the persistent inactivity was something that the model predicted and had never been seen before.

"The cool part about persistent inactivity is that it takes virtually no energy, unlike persistent activity, which takes a lot of energy," said Mehta, "even better, the combination of persistent activity and inactivity more than doubles the memory capacity while cutting down the metabolic energy cost by half."

"All this sounded too good to be true, so we really pushed our mathematical microscope to the limit, into a regime where it was not designed to work," said Dr. Choudhary. "If the microscope was right, it would continue working perfectly even in unusual situations."

"The math-microscope made a dozen predictions, not just about entorhinal but many other brain regions too. To our complete surprise, the mathematical microscope worked every time," Mehta continued. "Such near perfect match between the predictions of a mathematical theory and experiments is unprecedented in neuroscience.

"This mathematical model that is perfectly matched with experiments is a new microscope," Mehta continued. "It reveals something that no existing microscope could see without it. No matter how many neurons you have imaged, it would not have revealed any of this.

"In fact, metabolic shortcomings are a common feature of many memory disorders," said Mehta. Mehta's laboratory is now following up on this work to understand how complex working memory is formed, and what goes wrong in the entorhinal cortex during Alzheimer's disease, dementia and other memory disorders."

• Nervous System
• Psychology Research
• Alzheimer's Research
• Healthy Aging
• Neuroscience
• Intelligence
• Alzheimer's disease
• Limbic system
• Memory bias
• Memory-prediction framework
• Computational neuroscience

Story Source:

Materials provided by University of California - Los Angeles Health Sciences . Original written by Will Houston. Note: Content may be edited for style and length.

Journal Reference :

• Krishna Choudhary, Sven Berberich, Thomas T. G. Hahn, James M. McFarland, Mayank R. Mehta. Spontaneous persistent activity and inactivity in vivo reveals differential cortico-entorhinal functional connectivity . Nature Communications , 2024; 15 (1) DOI: 10.1038/s41467-024-47617-6

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The best new science fiction books of May 2024

A new Stephen King short story collection, an Ursula K. Le Guin reissue and a celebration of cyberpunk featuring writing from Philip K. Dick and Cory Doctorow are among the new science fiction titles published this month

By Alison Flood

A new short story collection from Stephen King, You Like It Darker, is out in May

Shane Leonard

Every month, I trawl through publishers’ catalogues so I can tell you about the new science fiction being released. And every month, I’m disappointed to see so much more fantasy on publishers’ lists than sci-fi. I know it’s a response to the huge boom in readers of what’s been dubbed “ romantasy ”, and I’m not knocking it – I love that sort of book too. But it would be great to see more good, hard, mind-expanding sci-fi in the offing as well.

In the meantime, there is definitely enough for us sci-fi fans to sink our teeth into this month, whether it’s a reissue of classic writing from Ursula K. Le Guin, some new speculative short stories from Stephen King or murder in space from Victor Manibo and S. A. Barnes.

Last month, I tipped Douglas Preston’s Extinction and Sofia Samatar’s The Practice, the Horizon, and the Chain as books I was looking forward to. I can report that they were both excellent: Extinction was a lot of good, clean, Jurassic Park -tinged fun, while Samatar’s offering was a beautiful and thought-provoking look at life on a generation ship.

The Language of the Night: Essays on writing, science fiction, and fantasy by Ursula K. Le Guin

There are few sci-fi and fantasy writers more brilliant (and revered) than Ursula K. Le Guin. This reissue of her first full-length collection of essays features a new introduction from Hugo and Nebula award-winner Ken Liu and covers the writing of The Left Hand of Darkness and A Wizard of Earthsea , as well as her advocacy for sci-fi and fantasy as legitimate literary mediums. I’ve read some of these essays but not all, and I won’t be missing this collection.

Nuclear War: A Scenario by Annie Jacobsen

This isn’t science fiction, not quite, but it is one of the best and most important books I have read for some time. It sees Jacobsen lay out, minute by minute, what would happen if an intercontinental ballistic missile hit Washington DC. How would the US react? What, exactly, happens if deterrence fails? Jacobsen has spoken to dozens of military experts to put together what her publisher calls a “non-fiction thriller”, and what I call the scariest book I have possibly ever read (and I’m a Stephen King fan; see below). We’re currently reading it at the New Scientist Book Club, and you can sign up to join us here .

Read an extract from Nuclear War: A scenario by Annie Jacobsen

In this terrifying extract from Annie Jacobsen’s Nuclear War: A Scenario, the author lays out what would happen in the first seconds after a nuclear missile hits the Pentagon

The Big Book of Cyberpunk (Vol 1 & 2)

Forty years ago, William Gibson published Neuromancer . Since then, it has entranced millions of readers right from its unforgettable opening line: “The sky above the port was the color of television, tuned to a dead channel…”. Neuromancer gave us the literary genre that is cyberpunk, and we can now welcome a huge, two-volume anthology celebrating cyberpunk’s best stories, by writers from Cory Doctorow to Justina Robson, and from Samuel R. Delaney to Philip K. Dick. I have both glorious-sounding volumes, brought together by anthologist Jared Shurin, on my desk (using up most of the space on it), and I am looking forward to dipping in.

You Like It Darker by Stephen King

You could categorise Stephen King as a horror writer. I see him as an expert chronicler of the dark side of small-town America, and from The Tommyknockers and its aliens to Under the Dome with its literally divisive trope, he frequently slides into sci-fi. Even the horror at the heart of It is some sort of cosmic hideousness. He is one of my favourite writers, and You Like It Darker is a new collection of short stories that moves from “the folds in reality where anything can happen” to a “psychic flash” that upends dozens of lives. There’s a sequel to Cujo , and a look at “corners of the universe best left unexplored”. I’ve read the first story so far, and I can confirm there is plenty for us sci-fi fans here.

Enlightenment by Sarah Perry

Not sci-fi, but fiction about science – and from one of the UK’s most exciting writers (if you haven’t read The Essex Serpent yet, you’re in for a treat). This time, Perry tells the story of Thomas Hart, a columnist on the Essex Chronicle who becomes a passionate amateur astronomer as the comet Hale-Bopp approaches in 1997. Our sci-fi columnist Emily Wilson is reviewing it for New Scientist ’s 11 May issue, and she has given it a vigorous thumbs up (“a beautiful, compassionate and memorable book,” she writes in a sneak preview just for you guys).

Ghost Station by S.A. Barnes

Dr Ophelia Bray is a psychologist and expert in the study of Eckhart-Reiser syndrome, a fictional condition that affects space travellers in terrible ways. She’s sent to help a small crew whose colleague recently died, but as they begin life on an abandoned planet, she realises that her charges are hiding something. And then the pilot is murdered… Horror in space? Mysterious planets? I’m up for that.

In Hey, Zoey, the protagonist finds an animatronic sex doll hidden in her garage

Shutterstock / FOTOGRIN

Hey, Zoey by Sarah Crossan

Hot on the heels of Sierra Greer’s story about a sex robot wondering what it means to be human in Annie Bot , the acclaimed young adult and children’s author Sarah Crossan has ventured into similar territory. In Hey, Zoey , Dolores finds an animatronic sex doll hidden in her garage and assumes it belongs to her husband David. She takes no action – but then Dolores and Zoey begin to talk, and Dolores’s life changes.

How to Become the Dark Lord and Die Trying by Django Wexler

Davi has tried to take down the Dark Lord before, rallying humanity and making the final charge – as you do. But the time loop she is stuck in always defeats her, and she loses the battle in the end. This time around, Davi decides that the best thing to do is to become the Dark Lord herself. You could argue that this is fantasy, but it has a time loop, so I’m going to count it as sci-fi. It sounds fun and lighthearted: quotes from early readers are along the lines of “A darkly comic delight”, and we could all use a bit of that these days.

Escape Velocity by Victor Manibo

It’s 2089, and there’s an old murder hanging over the clientele of Space Habitat Altaire, a luxury space hotel, while an “unforeseen threat” is also brewing in the service corridors. A thriller in space? Sounds excellent – and I’m keen to see if Manibo makes use of the latest research into the angle at which blood might travel following violence in space, as reported on by our New Scientist humour columnist Marc Abrahams recently.

The best new science fiction books of March 2024

With a new Adrian Tchaikovsky, Mars-set romance from Natasha Pulley and a high-concept thriller from Stuart Turton due to hit shelves, there is plenty of great new science fiction to be reading in March

In Our Stars by Jack Campbell

Part of the Doomed Earth series, this follows Lieutenant Selene Genji, who has been genetically engineered with partly alien DNA and has “one last chance to save the Earth from destruction”. Beautifully retro cover for this space adventure – not to judge a book in this way, of course…

The Downloaded by Robert J. Sawyer

Two sets of people have had their minds uploaded into a quantum computer in the Ontario of 2059. Astronauts preparing for the world’s first interstellar voyage form one group; the other contains convicted murderers, sentenced to a virtual-reality prison. Naturally, disaster strikes, and, yup, they must work together to save Earth from destruction. Originally released as an Audible Original with Brendan Fraser as lead narrator, this is the first print edition of the Hugo and Nebula award-winning Sawyer’s 26 th novel.

The Ferryman by Justin Cronin

Just in case you still haven’t read it, Justin Cronin’s gloriously dreamy novel The Ferryman , set on an apparently utopian island where things aren’t quite as they seem, is out in paperback this month. It was the first pick for the New Scientist Book Club, and it is a mind-bending, dreamy stunner of a read. Go try it – and sign up for the Book Club in the meantime!

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Environmental Science: Water Research & Technology

Antibiotic resistance response of activated sludge to sulfamethoxazole: insights from the intracellular and extracellular dna fractions †.

* Corresponding authors

a CRETUS, Department of Chemical Engineering, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Galicia, Spain E-mail: [email protected]

b Department of Biotechnology, Delft University of Technology, Delft, The Netherlands

c Department of Biotechnology and Food Science, Norwegian University of Science and Technology, Trondheim, Norway

In activated sludge, the antibiotic resistance genes (ARGs) can be present either in the intracellular (iDNA) or extracellular DNA fraction (exDNA). Recent advances in the exDNA extraction methodology allow a better profiling of the pool of ARGs. However, little is known about how stress conditions modify the distribution of ARGs between both DNA fractions. Here, we performed two batch tests for analyzing the effects of two different stress conditions, namely nutrient starvation and high concentrations of sulfamethoxazole (1, 10 and 150 mg L −1 ) in activated sludge. We tracked by qPCR the resulting relative abundances of four target genes, namely the universal 16S rRNA gene, the class 1 integron-integrase gene intI1 , and the sulfonamide resistance genes sul1 and sul2 in both the iDNA and exDNA fractions. In the exDNA pool, unlike starvation, which provoked a decrease of 1–2 log 10 [copies] per ng DNA in the concentration of sul1 and intI1 , the presence of sulfamethoxazole did not influence the abundances of sul1 and sul2 . However, high concentrations of sulfamethoxazole (150 mg L −1 ) selected for microorganisms harboring sul1 and, more remarkably, sul2 genes in their iDNA during their exponential growth phase. The abundances of intI1 and sul1 were positively correlated in the exDNA fraction ( r > 0.7), whereas no significant correlation ( p < 0.05) between the abundance of these two genes was found in the iDNA fraction of the sludge. High SMX concentrations influenced the abundance of ARGs in the iDNA; their abundance in the exDNA was influenced by nutrient limitations. Further studies should consider the profiling of exDNA fractions because of the relationship between ARGs and mobile genetic elements. Besides, the surveillance of antimicrobial resistance is encouraged in wastewater treatment plants facing high antibiotic concentrations.

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Antibiotic resistance response of activated sludge to sulfamethoxazole: insights from the intracellular and extracellular DNA fractions

M. Martínez-Quintela, D. Calderón-Franco, M. C. M. van Loosdrecht, S. Suárez, F. Omil and D. G. Weissbrodt, Environ. Sci.: Water Res. Technol. , 2024, Advance Article , DOI: 10.1039/D3EW00591G

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• Vaccines, Blood & Biologics
• Science & Research (Biologics)

Development of Assays of Defined Sensitivity for the Regulatory Management of Novel Cell Substrates

Andrew M. Lewis, MD

Office of Vaccines Research and Review Division of Viral Products Laboratory of DNA Viruses

[email protected]

Andrew Lewis is a Principal Investigator in the Laboratory of DNA Viruses. He received his M.D. degree from Duke University in 1961 and worked as a scientist at the National Institute of Allergy and Infectious Diseases from 1963 to 1994.  His work at the NIH focused on virology, the discovery of non-defective adenovirus-SV40 hybrids, and the ability of DNA viruses such as SV40 to induce neoplastic transformation of cells in tissue culture and cause tumors in rodents.  Due to the concerns over the possible risks associated with the non-defective adeno-SV40 hybrid viruses, he was an active participant in the Asilomar Conference in 1975 that focused on the possible risks posed by laboratory experimentation involving recombinant DNA.  He joined CBER, FDA in the Division of Viral Products in 1995 to focus on safety issues associated with the use of transformed cells as cell substrates for vaccine manufacture.  At CBER, Dr. Lewis first worked on the possible association between SV40 contamination of early polio vaccines and subsequent tumor development in humans, which had implications for the safety of continuous cell lines for viral vaccine manufacture.  He became Chief of the Laboratory or DNA Viruses in the late 1990s.  He and others initiated a program to study the tumorigenic potential of transformed cells used during the production of new vaccines. These data were presented at the FDA advisory committee meeting in 2000. This committee encouraged Dr. Lewis and his lab to pursue this project further to identify and characterize the basic biological processes that allow VERO cells to develop the capacity to form tumors.  The lab has continued these studies for the past 20 years and has developed what may represent a hypothetical model of neoplasia in tissue culture.

General Overview

Vaccines are an essential public health tool for controlling viral diseases. Viral vaccines are produced in living cells; when cells are used during vaccine manufacture, they are called cell substrates. The development of safe and effective viral vaccines requires that these cell substrates and the other materials used in the production of vaccines must be carefully characterized. There are a variety of types of cell substrates, including cells from embryonated eggs and cells from mammals as well as  other species grown in culture. Some cells used as cell substrates are immortalized (transformed into cancer-like cells), that is, they continually multiply so the culture never dies out. Cells from cultures of transformed cells have the potential to form tumors in animals (tumorigenic cell substrates). A major challenge to the safety of vaccines manufactured in transformed/tumorigenic cell substrates is contamination with infectious agents. Problems include cancer-causing viruses and genetic material (DNA) that might encode infectious agents or small microRNAs (miRNA) that might trigger neoplastic activity in the vaccine recipient. However, transformed cell substrates are important for the development of vaccines for HIV/AIDS, vaccines against annual and pandemic influenza, vaccines to protect against the new viruses that are producing epidemics ( e.g., Ebola, Zika, SARS-COV-2), and vaccines to protect against viral agents of bioterrorism. FDA reviewers must evaluate the safety issues posed by all cell substrate reagents used in the manufacture of viral vaccines. Regulatory evaluation of transformed cell substrates could be improved by a better understanding of the processes involved in cell transformation. We have developed a systematic approach to neoplastic transformation of cells in tissue culture, creating cell lines across the spectrum of neoplasia from normal cells to tumorigenic cells. We have carefully characterized these cells for their tumorigenicity in animals, and applied miRNA analysis, chromosome analysis, methylation analysis, and bioinformatics to study these models. In this way, our laboratory is beginning to understand the fundamentals of mammalian cell transformation, how transformed cells develop the ability to form tumors, and how these tumors actually develop. In collaboration with the Peden laboratory, we are developing ways to examine the possible risks that might be associated with the DNA from tumor-forming cell substrates, including: 1) the possibility of transferring cancer-causing activity (DNA) to vaccines, 2) the possibility of transferring infectious microorganisms to vaccines, and 3) the possibility that enzymes added during manufacturing may cause harmful DNA degradation/breakdown.

Scientific Overview

The current projects underway include: 1) understanding the process of neoplastic transformation in cells in tissue culture, and using this understanding to characterize the tumorigenic phenotypes expressed by neoplastic cell substrates, including the VERO line of African green monkey kidney cells and Madin-Darby canine kidney (MDCK) cells; and 2) evaluating the oncogenicity/infectivity of DNA from neoplastic cell substrates; Determining whether transformed cell substrates are tumorigenic requires injecting cells into immune-incompetent mice. The cell doses selected represent dose-response assays that includes both tumor-forming and non-tumor forming cell doses. Such assays quantitatively define fundamental traits that characterize the neoplastic cell tumorigenic phenotype (cell-dose trait and tumor-latency trait). Using cell lines characterized by dose-response assays, we are studying neoplastic processes leading to the development of the tumorigenic phenotype and evaluating mechanisms of tumor formation in animals. Understanding the nature of cell doses required for tumor formation has been a major challenge for decades. We hypothesized that tumorigenic cell doses represent the ratio of tumor-forming stem cells to stromal/accessory cells required for tumor formation in animals. We are therefore examining miRNA expression across a spectrum of cell lines that exhibit 4000-fold differences in numbers of cells required for tumor formation, and results are providing insights into mechanisms associated with such differences. These studies now provide a model for the systematic study of neoplastic transformation in tissue culture and the cell-culture reagents needed to study the details of this process. These reagents have allowed us to study chromosome alterations and patterns of miRNA expression associated with the neoplastic processes that occur during the passage of mammalian cells in tissue culture. Chromosome changes are fundamental to the process of neoplastic transformation. We have also found that patterns of expression of miRNAs are basic components of this process. Based these findings, 6 – 8 miRNAs appear to be biomarkers of the VERO cell tumorigenic phenotype. This observation may contribute to the regulatory management of neoplastic cell substrates by reducing the need for animal models to study tumorigenicity. Association of these biomarkers with VERO-cell tumorigenicity has been expanded by developing another tumorigenic line of African green monkey kidney (AGMK1-9T7) cells. These data have allowed us to identify some type of yet-to-be defined renal stem cells as the origin of AGMK cell lines. Based on these findings, we have developed a comprehensive hypothesis of tissue culture transformation. With the Peden laboratory, we are evaluating the oncogenic activity posed by DNA from neoplastic cell substrates and the role of the murine immune system in tumorigenicity/metastases. Activated H-ras and c-myc oncogenes are oncogenic in mice when injected together in different plasmids or when combined in the same plasmid. Less than a nanogram of plasmid DNA containing both oncogenes can induce tumors. These plasmid-mouse models allow the study of possible oncogenic activity associated with the DNA of neoplastic cell substrates, as well as evaluation of the impact of DNA degradation on the removal of oncogenic activity and the infectivity of cell DNA-containing retroviral genomes.

Publications

• PLoS One 2023 Dec 7;18(12):e0293406 GLI1+ perivascular, renal, progenitor cells: The likely source of spontaneous neoplasia that created the AGMK1-9T7 cell line. Lewis AM Jr, Foseh G, Tu W, Peden K, Akue A, KuKuruga M, Rotroff D, Lewis G, Mazo I, Bauer SR
• Biologicals 2023 Nov;84:101724 Evaluating the sensitivity of newborn rats and newborn hamsters to oncogenic DNA. Sheng-Fowler L, Tu W, Phy K, Macauley J, Lanning L, Lewis AM Jr, Peden K
• PLoS One 2022 Oct 24;17(10):e0275394 The AGMK1-9T7 cell model of neoplasia: evolution of DNA copy-number aberrations and miRNA expression during transition from normal to metastatic cancer cells. Lewis AM Jr, Thomas R, Breen M, Peden K, Teferedegne B, Foseh G, Motsinger-Reif A, Rotroff D, Lewis G
• Vaccine X 2019 Apr 11;(1):100004 Responsiveness to basement membrane extract as a possible trait for tumorigenicity characterization. Murata H, Omeir R, Tu W, Lanning L, Phy K, Foseh G, Lewis AM Jr, Peden K
• Vaccine 2017 Oct 4;35(41):5503-9 Assessment of potential miRNA biomarkers of VERO-cell tumorigenicity in a new line (AGMK1-9T7) of African green monkey kidney cells. Teferedegne B, Rotroff DM, Macauley J, Foseh G, Lewis G, Motsinger-Rief A, Lewis AM Jr
• Chromosome Res 2015 Dec;23(4):663-80 A novel canine kidney cell line model for the evaluation of neoplastic development: karyotype evolution associated with spontaneous immortalization and tumorigenicity. Omeir R, Thomas R, Teferedegne B, Williams C, Foseh G, Macauley J, Brinster L, Beren J, Peden K, Breen M, Lewis AM Jr