coronavirus evolution TN

Teacher Notes for “Coronavirus Evolution and the COVID-19 Pandemic”[footnoteRef:1] [1: By Dr. Ingrid Waldron, Department of Biology, University of Pennsylvania, 2021. These Teacher Notes and the related Student Handout are available at https://serendipstudio.org/exchange/bioactivities/coronavirusOrigin. ]

To begin this analysis and discussion activity, students explore two hypotheses about the origins of the new coronavirus that is causing the COVID-19 pandemic. First, students learn how mutations and natural selection can produce a spillover infection. Then, students use molecular evidence to evaluate the hypothesis that scientists used genetic engineering to produce the new coronavirus. Next, students analyze the contributions of mutation and natural selection to the development of the new coronavirus variants that are more contagious and/or can evade immune defenses. Finally, students propose policies to reduce the risk that even more dangerous variants could develop in the future.

You could use this activity to introduce coronaviruses and natural selection. However, some students may find it helpful to complete the following analysis and discussion activities before they begin this activity.

· “Coronaviruses – What They Are and How They Can Make You Sick” (includes an introduction to how coronaviruses replicate) (https://serendipstudio.org/exchange/bioactivities/coronavirusintro)

· “What is natural selection?” (https://serendipstudio.org/exchange/bioactivities/NaturalSelectionIntro).

If your students would benefit from an introduction to or a review of how RNA provides the instructions to make proteins, I recommend:

· the 5-minute video, “What Is DNA and How Does It Work?” (https://www.statedclearly.com/videos/what-is-dna/) or

· the analysis and discussion activity, “How Genes Can Cause Disease – Understanding Transcription and Translation” (https://serendipstudio.org/exchange/bioactivities/trans).

Learning Goals

In accord with the Next Generation Science Standards (NGSS)[footnoteRef:2]: [2: Quotations are from http://www.nextgenscience.org/sites/default/files/HS%20LS%20topics%20combined%206.13.13.pdf ]

· This activity helps students to prepare for Performance Expectation HS-LS4-3. “Apply concepts of statistics and probability to support explanations that organisms with an advantageous heritable trait tend to increase in proportion to organisms lacking this trait.”

· This activity helps students to understand the Disciplinary Core Ideas:

· LS4.B “Natural selection occurs only if there is both (1) variation in the genetic information between organisms in a population and (2) variation in the expression of that genetic information – that is, trait variation – that leads to differences in performance among individuals. The traits that positively affect survival are more likely to be reproduced, and thus are more common in the population. The traits that positively affect survival are more likely to be reproduced, and thus are more common in the population.”

· LS4.C “Natural selection leads to adaptation, that is, to a population dominated by organisms that are… well suited to survive and reproduce in a specific environment. That is, the differential survival and reproduction of organisms in a population that have an advantageous heritable trait leads to an increase in the proportion of individuals in future generations that have the trait into a decrease in the proportion of individuals that do not.”

· Students engage in the Scientific Practices:

· “Constructing Explanations. Apply scientific ideas, principles and/or evidence to provide an explanation of phenomena and solve design problems…”

· “Developing and Using Models. Develop and/or use a model (including mathematical and computational) to generate data to support explanations, predict phenomena, analyze systems, and/or solve problems.”

· This activity helps students to understand the Crosscutting Concept, “Stability and Change. Much of science deals with constructing explanations of how things change and how they remain stable.”

Instructional Suggestions and Biology Background

If your students are learning online, we recommend that they use the Google Doc version of the Student Handout available at https://serendipstudio.org/exchange/bioactivities/coronavirusOrigin. To answer questions 2a, 4 and 6, students can either print the relevant pages, draw on them and send pictures to you, or they will need to know how to modify a drawing online. To answer online, they can double-click on the relevant drawing in the Google Doc to open a drawing window. Then, they can use the editing tools to answer the questions.[footnoteRef:3] You may want to revise the GoogleDoc or Word document to prepare a version of the Student Handout that will be more suitable for your students; if you do this, please check the format by viewing the PDF. [3: To draw a shapeAt the top of the page, find and click Shape.Choose the shape you want to use.Click and drag on the canvas to draw your shape.To insert textAt the top of the page, click Insert.To place text inside a box or confined area, click Text Box and drag it to where you want it.Type your text.You can select, resize and format the word art or text box, or apply styles like bold or italics to the text.When you are done, click Save and Close.]

To maximize student participation and learning, I suggest that you have your students work individually or in pairs to complete each group of related questions and then have a class discussion after each group of questions. In each discussion, you can probe student thinking and help them develop a sound understanding of the concepts and information covered before moving on to the next group of related questions.

A key is available upon request to Ingrid Waldron (iwaldron@upenn.edu). The following paragraphs provide additional instructional suggestions and background information – some for inclusion in your class discussions and some to provide you with relevant background that may be useful for your understanding and/or for responding to student questions.

Where did the new coronavirus come from?

The novel coronavirus that is causing the current global pandemic is called SARS-CoV-2 because of its similarity to SARS-CoV, the coronavirus which caused an earlier, smaller outbreak of SARS = Severe Acute Respiratory Syndrome (mainly in Asia in 2002-2004). The disease caused by SARS-Cov-2 is called COVID-19. (CO stands for corona, VI stands for virus and D stands for disease; 19 stands for 2019, the year in which this disease was first identified.) As of February 27, 2021, the estimated number of COVID-19 deaths was 510,000 in the US and 2.5 million in the world (https://www.google.com/search?q=Estimated+deaths+worldwide+Covid+19&rlz=1C1GCEA_enUS862US862&oq=Estimated+deaths+worldwide+Covid+19&aqs=chrome..69i57.4118j0j7&sourceid=chrome&ie=UTF-8).

Question 1 should get students thinking about the driving question for this part of the activity. A class discussion of student answers will help you to understand their current knowledge, including any misconceptions they may have.

The recommended 9-minute video, “Where do new viruses come from?” (https://www.youtube.com/watch?v=NJLXdsO1GBI) is generally very accurate, but at one point the narrator incorrectly refers to the virus, rather than the disease, as COVID-19. As explained in the video, spillover infections (the transmission of a pathogen from one animal to another) have been responsible for multiple human diseases caused by viral infections, including HIV (human immunodeficiency virus), Ebola virus, West Nile virus, Zika virus, influenza A virus (H1N1), Middle East respiratory syndrome coronavirus (MERS-CoV), and the first SARS outbreak (SARS-CoV). Spillover infections are also called zoonotic diseases.

The coronavirus spike protein binds to a molecular receptor on the surface of cells in the nose, lungs, and multiple other parts of the body. This binding causes the spike protein to change shape in a way that draws the virus toward the cell so the viral envelope merges with the cell membrane; this allows the viral RNA to enter the cell. Coronavirus RNA serves as mRNA and the cell’s ribosomes translate the viral RNA to make viral proteins. The viral RNA is copied by a viral enzyme, RNA-dependent RNA polymerase (replicase in the figure below). The viral proteins and RNA assemble to form new viruses that are released from the infected cell, which typically dies. The viruses that are released can infect other body cells; they may be inactivated by the person’s immune system; or they can be spread by coughing, sneezing, shouting, singing, and breathing where they may infect other people.

(https://www.ncbi.nlm.nih.gov/books/NBK554776/bin/Covid__Replication.jpg)

The descriptions on page 2 of the Student Handout, together with questions 5-6, provide a simplified introduction to how mutation and natural selection contribute to spillover infections. It is unlikely that a single mutation would have such a dramatic effect as the H mutation in this hypothetical example. Instead, multiple rounds of more modest mutations and natural selection are probably required for most spillover events.

Mutations are caused by random errors in copying the viral RNA.[footnoteRef:4] Since the viral RNA comes from a virus that has been successful in infecting a cell and reproducing, most mutations will either have little or no effect on fitness or will reduce the fitness of the virus (corresponding to the N mutation in this hypothetical example). Even if a mutation results in a virus that can bind to molecules on the surface of the cells of a new host and the mutated virus comes in contact with the new host, the virus will need additional adaptations to be efficiently reproduced by the cells of the new host. This will only occur if random mutations provide the needed raw material and natural selection is able to accumulate genetic changes that result in a virus that is well adapted to reproduction inside the new host. Natural selection will also favor any mutations that contribute to the coronavirus’ ability to spread from person to person. Students may need to be reminded that mutation is random, but natural selection is not random. [4: The analysis and discussion activity, “How Genes Can Cause Disease – Understanding Transcription and Translation” (https://serendipstudio.org/exchange/bioactivities/trans), includes the example of a mutation that changes a single amino acid in the hemoglobin protein to cause sickle cell anemia. Another activity, "Mutations and Muscular Dystrophy" (https://serendipstudio.org/exchange/bioactivities/mutation), includes examples of additional types of mutation, including some mutations that have major effects on the dystrophin protein and some that have no effect on the amino acid sequence in the protein.]

As discussed on the top of page 3 of the Student Handout and in question 7, viral mutations are common, but most mutations do not result in spillover infections to humans. Spillover infections require the combination of an initial mutation that allows a virus to infect a human cell, contact between animal and human that allows the mutated virus to reach a human host, and subsequent mutations and natural selection that allow the virus to spread among humans. The history of spillover infections provides evidence that this rare combination of events has repeatedly occurred in the past, which is understandable when you consider the trillions of animal viruses and billions of people in the world (https://www.nationalgeographic.com/science/2020/04/factors-allow-viruses-infect-humans-coronavirus/).

The Student Handout does not discuss another source of genetic variation, called recombination. When two genetically different coronaviruses infect the same cell, recombination can combine parts of the RNA from these two coronaviruses to produce a coronavirus with a new combination of mutations. After more than a decade of research on the origins of the 2002-2004 SARS outbreak, scientists identified a cave where many horseshoe bats roosted; the coronaviruses that infected these bats had RNA segments that were very similar to RNA segments in the coronavirus that caused this SARS outbreak. These scientists found evidence of frequent recombination of RNA segments from different coronaviruses, and they have argued that recombination in bat coronaviruses probably contributed to the origin of the SARS-CoV virus that caused the 2002-2004 SARS outbreak (https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006698). Additional evidence indicates that this bat coronavirus caused a spillover infection in civets which caused the spillover infection in humans.

Question 8 (and the introductory video) may prompt students to inquire about the effectiveness of travel restrictions to stop or slow the spread of COVID-19 and similar pandemics. The available evidence suggests that border closings can effectively reduce infection rates, but only if they are begun promptly when a new coronavirus emerges and if they are combined with other measures such as testing for infections, contact tracing, and strict quarantine of arriving travelers and any infected individuals (https://www.cochrane.org/CD013717/PUBHLTH_can-travel-related-control-measures-contain-spread-covid-19-pandemic; https://www.nature.com/articles/d41586-020-03605-6).

One way that people are exposed to bat coronaviruses is that children or adults may enter bat roosting sites where they may breathe in dust with coronaviruses from bat guano and urine. People are exposed to pangolin coronaviruses when pangolins are illegally sold for meat or use in traditional medicine.

The evidence that is presented on the bottom half of page 3 of the Student Handout is derived from “The proximal origin of SARS-CoV-2” (https://www.nature.com/articles/s41591-020-0820-9). This evidence provides the basis for a strong argument against the hypothesis that scientists purposely developed SARS-CoV-2 to cause a pandemic. However, this evidence is less persuasive against the hypothesis that SARS-CoV-2 resulted from an accidental release from a laboratory that was doing research on bat coronaviruses. (https://www.nytimes.com/2021/03/04/health/covid-virus-origins.html; https://www.washingtonpost.com/world/asia_pacific/coronavirus-who-china-investigation-wuhan/2021/02/09/2af3c44c-6a79-11eb-a66e-e27046e9e898_story.html; https://www.sciencemag.org/news/2020/07/trump-owes-us-apology-chinese-scientist-center-covid-19-origin-theories-speaks-out; https://www.sciencemag.org/sites/default/files/Shi%20Zhengli%20Q%26A.pdf)

In summary, the weight of the evidence indicates that SARS-CoV-2 arose through mutation, recombination, and natural selection of coronaviruses that originated in bats (https://advances.sciencemag.org/content/6/27/eabb9153; https://www.cell.com/trends/ecology-evolution/fulltext/S0169-5347(20)30348-7). However, many specifics are currently unknown. To gain more information about the origin of SARS-CoV-2, scientists will continue to:

· study coronaviruses in bats, pangolins, and other possible intermediate hosts

· search for more information about the earliest human COVID-19 infections.

It would also be helpful to have more information about the types of coronavirus research at the Wuhan Institute of Virology.[footnoteRef:5] (https://www.nature.com/articles/d41586-021-00502-4; https://www.nature.com/articles/d41586-020-01541-z; https://www.nytimes.com/2020/07/08/health/coronavirus-origin-china-lucey.html) [5: Notice that scientists have identified the probable origin of SARS-CoV, but there is much more uncertainty about the origin of SARS-CoV-2. This illustrates the Nature of Science principles that science is a process that takes time and scientific findings may have varying degrees of certainty and uncertainty. If you want more information on this research, I recommend “How China’s ‘Bat Woman’ Hunted down Viruses from SARS to the New Coronavirus” (https://www.scientificamerican.com/article/how-chinas-bat-woman-hunted-down-viruses-from-sars-to-the-new-coronavirus1/).]

You may want to add the following question to page 3 of the Student Handout.

Researchers have made several recommendations for preventing new spillover infections in humans. These recommendations include:

· Reduce human contact with wild animals.

· Regularly test the blood of people who are exposed to viruses in bats or other animals to detect exposure to any new or unusual viruses and take prompt action to prevent spread of these viruses.

· Monitor hospital patients to detect clusters of cases with unusual symptoms that may indicate a new spillover infection and act promptly to prevent wider spread of any new infectious disease.

What are the pros and cons of these recommendations?

The strategies recommended in this question would reduce the likelihood of a future pandemic. However, these strategies would require a substantial investment of resources. Also, past experience suggests that many people may be reluctant to comply with the recommended behavioral changes.

How has the coronavirus changed during the COVID-19 pandemic?

Many of the estimated 113 million known cases of COVID-19 have been confirmed by testing for coronavirus RNA in a sample collected from the nose (or saliva). For some of these samples, scientists have checked the sequence of the nearly 30,000 nucleotides in the RNA of the coronavirus. Scientists have found lots of variation in the nucleotide sequence, but research has focused on a relatively small number of mutations that have become widespread. Mutations refer to changes in the nucleotide sequence relative to the original strain of coronavirus that spread around the world in late 2019 and very early 2020.

Page 4 of the Student Handout analyzes how one mutation spread worldwide in the first half of 2020. The graph of the spread of the G mutation in question 10 is based on sequencing 52,292 samples worldwide during the first half of 2020 (https://media.nature.com/original/magazine-assets/d41586-020-02544-6/d41586-020-02544-6.pdf). The scientific name of the G mutation is D614G because it results in the amino acid glycine (G) instead of aspartic acid (D) in the 614th amino acid position of the spike protein. Molecular evidence, cell experiments, and epidemiological evidence indicate that this mutation makes it easier for the coronavirus to enter respiratory system cells and thus increases the transmission of coronaviruses from person to person.

The figure in the bottom half of page 4 of the Student Handout shows an unrealistically regular spread of coronavirus infections. The actual spread of coronavirus infections shows much more variation. On the one hand, many infected people don’t pass their coronavirus infection to anyone else. At the other extreme, superspreader events, where a single infected person infects many other people, have played a significant role in the spread of coronavirus infections (https://www.nature.com/articles/d41586-021-00460-x). Notice that natural selection favors mutations that increase reproduction as well as mutations that decrease mortality.

The last page of the Student Handout focuses on three variants that have caused the most concern in January and February 2021 (https://www.nytimes.com/interactive/2021/health/coronavirus-variant-tracker.html). A variant is a group of viruses that share the same set of inherited mutations and have become relatively common in a region or country.

The figure below shows the spread of the B.1.351 variant (also called 20H/501Y.V.2) in South Africa. This variant has eight mutations in the spike protein gene, including:

· N501Y, which helps to make this variant more contagious, and

· E484K and K417N, which decrease the effectiveness of immune defenses that developed after an initial infection with the original strain or after vaccination with a vaccine developed against the original strain. (https://www.livescience.com/south-african-coronavirus-variant-faq.html; https://www.washingtonpost.com/health/2021/02/05/virus-variant-reinfection-south-africa/)

(The Y axis extends from 0% to 100% of the samples of coronavirus, and the different colors correspond to different variants; https://nextstrain.org/ncov/global?f_country=South%20Africa)

The variant that was first detected in Brazil (P.1) has 21 mutations, including at least three that were observed in the variant that was first detected in South Africa (N501Y, E484K and K417N/T). These mutations increased the rate of transmission of coronavirus infections and decreased the effectiveness of immune defenses developed during earlier infections. Because immune defenses were less effective against the P.1 variant, this variant was able to infect individuals who had already been infected once; this characteristic was particularly favored by natural selection in the city of Manaus where roughly three-quarters of the residents had already had COVID-19 by October 2020. In Manaus, the P.1 variant increased from 0% to 87% of coronavirus samples in just eight weeks. Scientists have estimated that the P.1 variant is 1.4-2.2 times more transmissible than the previously circulating form of the virus. (https://www.nytimes.com/2021/03/01/health/covid-19-coronavirus-brazil-variant.html)

The variant that was first detected in the UK (B.1.1.7) has multiple mutations, including the N501Y mutation found in the variants first detected in South Africa and Brazil. Also, the E484K mutation has recently been found in some cases of the UK variant (https://www.newscientist.com/article/2266429-uk-coronavirus-variant-gets-nastier-as-south-african-variant-spreads/; https://www.cdc.gov/mmwr/volumes/70/wr/mm7003e2.htm). The fact that the same mutations are found in variants that developed independently indicates that natural selection favors coronavirus variants that have these mutations, e.g., because they increase transmission and/or decrease the effectiveness of immune defenses. This is an example of convergent evolution, a more general phenomenon that has occurred frequently; a familiar example is the wide, thin shape of the wings of birds, bats and insects.

Recent evidence indicates that the variant first detected in the UK increases the risk of dying of COVID-19 in two ways:

· The risk of infection is increased because the rate of transmission of coronavirus infections is increased by roughly 50% for this variant.

· The risk that a coronavirus infection will result in death appears to be ~30-50% higher for this variant. (https://www.nature.com/articles/d41586-021-00299-2)

This more transmissible coronavirus variant is currently spreading rapidly in the US (https://www.nytimes.com/interactive/2021/03/06/us/coronavirus-variant-sequencing.html; https://www.washingtonpost.com/health/ukvariant-coronavirus-us-spread/2021/02/07/a197dbc2-680a-11eb-8468-21bc48f07fe5_story.html). The figure below shows that the number of coronavirus infections in the UK increased during December as this variant was spreading widely. Although this more contagious variant continued to spread in the UK in January, there was a sharp decrease in cases after the UK government carried out a vigorous vaccination campaign and instituted stricter limitations on when and how people could leave home and interact in person with people outside their household (https://www.gov.uk/guidance/national-lockdown-stay-at-home). The increase and subsequent decrease in cases was also influenced by holiday travel and get-togethers.

(https://www.worldometers.info/coronavirus/country/uk/)

Multiple additional mutations and variants have been observed and are expected in the future as the coronavirus continues to evolve. For example, a variant that appears to be more transmissible has been spreading widely in California (https://www.nytimes.com/2021/02/23/health/coronavirus-california-variant.html).

The emergence of new mutations and variants has been facilitated by the very large number of coronavirus infections and two additional factors. When a substantial part of the population has already been infected with the original strain or vaccinated against the original strain, then the ability to evade immune defenses against the original strain has a bigger selective advantage. Also, it appears that new variants with multiple mutations may evolve during prolonged coronavirus infections in an immunocompromised individual who has been treated with antibodies from the blood of people who have recovered from coronavirus infections.

Follow-Up Activities and Additional Resources

COVID-19 Vaccines – How do they work?

https://serendipstudio.org/exchange/bioactivities/coronavirusvaccine

Students begin by proposing a hypothesis to explain why most people who have had COVID-19 or have been vaccinated do not become sick if they are exposed to the coronavirus in the future. Students analyze how the adaptive immune system responds to a coronavirus infection and how this response differs after a first vs. second exposure to coronavirus. Then, students analyze the body’s responses to an RNA vaccine and revise their hypothesis about how a vaccine protects against illness. Finally, students use reliable sources to investigate their questions about COVID-19 vaccines.

Resources for Teaching about Coronavirus

https://serendipstudio.org/exchange/bioactivities/coronavirus

This webpage has compiled information about learning activities and other resources for teaching high school biology students about the coronavirus and COVID-19.

If your students have additional questions about the novel coronavirus and the COVID-19 pandemic, you may want to encourage them to research these questions using the following sources of reliable information.

· Coronavirus (COVID-19) (https://www.cdc.gov/coronavirus/2019-ncov/index.html)

· Science (https://www.sciencenews.org/editors-picks/2019-novel-coronavirus-outbreak)

· New York Times (https://www.nytimes.com/news-event/coronavirus)

· FAS COVID-19 – Ask a Scientist (https://covid19.fas.org/)

For additional information and learning activities about natural selection, see “Resources for Teaching and Learning about Evolution” (https://serendipstudio.org/exchange/bioactivities/evolrec).

Sources for Student Handout Figure

· Figure of coronavirus structure, adapted from https://viralzone.expasy.org/resources/nCoV_SARS_virion.png

· Figure of translation and mutation, adapted from https://i.pinimg.com/564x/1d/6b/e9/1d6be9580a00ace750b472953a2bd77f--point-mutation-ap-biology.jpg

· Figure of bat, pangolin and humans, adapted from https://news.cgtn.com/news/7a416a4d3245444f7763444f3163544e7951444f31457a6333566d54/img/2884c659bdd747f9b3374d9d6e76988d/2884c659bdd747f9b3374d9d6e76988d.jpeg

· Figure of trends in G mutation, adapted from https://www.nature.com/articles/d41586-020-02544-6

Other figures were made by the author.

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