Philosophers argue that scientific conclusions need not be accurate, justified, or believed by their authors

A remarkable paper has just been posted to a philosophy of science preprint website. (It will be published in Synthase.) Like many papers in this field it's difficult to read and the logic is obtuse but the bottom line is that scientists don't really need to be held to the old standards that we scientists used to think are essential.

Dang, Haixin and Bright, Liam Kofi (2021) Scientific Conclusions Need Not Be Accurate, Justified, or Believed by their Authors. PhilSci Archive {PDF]

We argue that the main results of scientific papers may appropriately be published even if they are false, unjustified, and not believed to be true or justified by their author. To defend this claim we draw upon the literature studying the norms of assertion, and consider how they would apply if one attempted to hold claims made in scientific papers to their strictures, as assertions and discovery claims in scientific papers seem naturally analogous. We first use a case study of William H. Bragg’s early 20th century work in physics to demonstrate that successful science has in fact violated these norms. We then argue that features of the social epistemic arrangement of science which are necessary for its long run success require that we do not hold claims of scientific results to their standards. We end by making a suggestion about the norms that it would be appropriate to hold scientific claims to, along with an explanation of why the social epistemology of science—considered as an instance of collective inquiry—would require such apparently lax norms for claims to be put forward.

How do you explain evolution to non-experts?

I spent a lot of time explaining evolution in my book. The goal is to educate readers to the level where they can understand the drift-barrier hypothesis and why slightly deleterious mutations can accumulate in species with small populations. This requires some knowledge of random genetic drift and some knowledge of Neutral Theory and Nearly-Neutral Theory. The emphasis is on population genetics as the most important way of understanding evolution.

You can't understand genomes and junk DNA unless you have a firm understanding of evolution. In fact, you can't make sense of anything about genes and gene expression without such knowledge ... what the heck, nothing in all of biology makes sense if you don't know about evolution.

My approach hasn't been copied by popular websites. They usually misrepresent evolution by presenting it as adaptation; natural selection is the only game in town. I'll put in a link to Francis Collins describing evolution in truly bizarre narration but my question for Sandwalk readers is whether this is useful or not. Is it better to dumb down evolution on the NIH: National Huamn Genome Website [Evolution] or is this a bad idea?

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Should we teach genomics and evolution to medical students?

Rama Singh,¹ a biology professor at McMaster Universtiy in Hamilton (Ontario, Canada) has just published an interesting article on The Conversation website. It's about Medical schools need to prepare doctors for revolutionary advances in genetics. You can read the full article yourself but let me highlight the last few paragraphs to start the discussion.

Future physicians will be part of health networks involving medical lab technicians, data analysts, disease specialists and the patients and their family members. The physician would need to be knowledgeable about the basic principles of genetics, genomics and evolution to be able to take part in the chain of communication, information sharing and decision-making process.

This would require a more in-depth knowledge of genomics than generally provided in basic genetics courses.

Much has changed in genetics since the discovery of DNA, but much less has changed how genetics and evolution are taught in medical schools.

In 2013-14 a survey of course curriculums in American and Canadian medical schools showed that while most medical schools taught genetics, most respondents felt the amount of time spent was insufficient preparation for clinical practice as it did not provide them with sufficient knowledge base. The survey showed that only 15 per cent of schools covered evolutionary genetics in their programs.

A simple viable solution may require that all medical applicants entering medical schools have completed rigorous courses in genetics and genomics.

Here's the problem. I've just finished research on a book about modern evolution and genomics so I think I know a little bit about the subject. I'm also on the editorial board of a journal that publishes research on biochemistry and molecular biology education. I've written a biochemistry textbook and I have far too many years of experience trying to teach this material to graduate students and undergraduates at the University of Toronto. I can safely say that we (university teachers) have done a horrible job of teaching evolution and genomics to our students. We have turned out an entire generation of students who don't understand modern molecular evolution and don't understand what's in your genome.

What this means is that there's an extremely small pool of students who have completed "rigorous courses in genetics and genomics." Nobody will be able to apply to medical school. I doubt that we could teach this material to medical students with or without the appropriate background.

But you don't have to take my word for it. Some people have tried to teach this material to health science workers so we can see how it's working at that level. Take a look at the The Genomics Education Programme supported by the NHS in the United Kingdom. They have a series of short videos and longer lessons that are designed to educate health care specialists. Here's the blurb that defines their objective.

Rapid advances in technology and understanding mean that genomics is now more relevant than ever before. As genomics increasingly becomes a part of mainstream NHS care, all healthcare professionals, and not just genomics specialists, need to have a good understanding of its relevance and potential to impact the diagnosis, treatment and management of people in our care.

In 2014, Health Education England (HEE) launched a four-year £20 million Genomics Education Programme (GEP) to ensure that our 1.2 million-strong NHS workforce has the knowledge, skills and experience to keep the UK at the heart of the genomics revolution in healthcare.

Funding for the programme has since been extended to enable us to continue our work in providing co-ordinated national direction of education and training in genomics and developing resources for a wide range of professionals.

They describe genes as 'coding' genes that build proteins. There's no mention of noncoding genes. The define a genome as "both genes (coding) and non-coding DNA." They also say that your genome is all of the DNA in our cells (46 chromosomes, 23 pairs). I don't see anything in their education packages that covers modern molecular evolution. In one of the packages they say,

The term ‘junk DNA’ has been used since the 1970s to describe non-coding regions of the genome, but today it is considered inaccurate and misleading. The term ‘junk’ suggests that 98% of the genome has no use, but in recent years, studies and projects have used advances in technology to shed light on these regions and have come to different conclusions about how much of the genome has a biological function.

Here's a link to a short video called What is a genome?. I recommend that you watch it to see the level that these experts think is suitable for health care professionals in the UK and to see the level of expertise of those who made the video. This is what seven years of work by experts and £20 million will get you.

All of this tells me that teaching genomics and evolution to medical students is going to be a lot more difficult than Rama Singh imagines. Not only would we have to counter several years of misinformation but we would have to rely on teachers who probably don't understand either topic.

Let's start by teaching these things correctly to biology and biochemistry majors. That's going to be hard enough for now.

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1. Full displosure: Rama and I shared an NSERC grant in 1981 on genetic variation in Drosophila.

SARS-CoV-2 mRNA vaccines: RNA + lipid nanoparticles

The new mRNA vaccines are the result of extensive research over the past thirty years or so. They are marvels of technological innovation but probably not just for the reasons you imagine. The basics of therapeutic mRNA synthesis have been around for about ten years but the problem was how to get the RNA into cells. That requires specialized lipid nanoparticles and making those has been the most recent technological advance. A lot of this research was done in Canada. I found a nice paper (Buschmann et al., 2021) that covers this research and I'll summarize the important points for those of you don't have time to read it.

The mRNA

Normal messenger RNA is susceptable to nuleases and is not readily taken up by human cells. In addition, it elicits an innate immune response that results in supression of translation through phosphorylation of eIF2a. The immune response can be blocked by incorporating modified nucleotides than are not recognized by the various receptors that stimulate the normal response. This was discovered over ten years ago. These modified nucleotides, such as N1-methylpseudouridine, were used to make the SAR-CoV-2 vaccine.

On the accuracy of genomics in detecting disease variants

Several diseases, such as cancers, are caused by the presence of deleterious alleles that affect the function of a gene. In the case of cancer, most of the mutations are somatic cell mutations—mutations that have occurred after fertilization. These mutations will not be passed on to future generations. However, there are some variants that are present in the germline and these will be inherited. A small percentage of these variants will cause cancer directly but most will just indicate a predisposition to develop cancer.

There are a host of other diseases that have a genetic component and the responsible alleles can also be present in the germline or due to somatic cell mutations.

Over the past fifty years or so there has been a lot of hype associated with the latest technological advances and the ability to detect deleterious germline mutations. The general public has been repeatedly told that we will soon be able to identify all disease-causing alleles and this will definitely lead to incredible medical advances in treating these diseases. Just yesterday, for example, I posted an article on predictions made by The National Genome Research Institute (USA) who predicts that by 2030,

The clinical relevance of all encountered genomic variants will be readily predictable, rendering the diagnostic designation ‘variant of uncertain significance (VUS)’ obsolete.

Similar predictions, in various forms, were made when the human genome project got under way and at various time afterword. First there was the 1000 genomes project then there was the 100,000 genome project and, of course, ENCODE. The problem is that genomics hasn't lived up to these expectations and there's a very good reason for that: it's because the problem is a lot more difficult than it seems.

One of the Facebook groups that I follow (Modern Genetics & Technology)¹ alerted me to a recent paper in JAMA that addressed the problem of genomics accuracy and the prediction of pathogenic variants. I'm posting the complete abstract so you can see the extent of the problem.

AlDubayan, S.H., Conway, J.R., Camp, S.Y., Witkowski, L., Kofman, E., Reardon, B., Han, S., Moore, N., Elmarakeby, H. and Salari, K. (2020) Detection of Pathogenic Variants With Germline Genetic Testing Using Deep Learning vs Standard Methods in Patients With Prostate Cancer and Melanoma. JAMA 324:1957-1969. [doi: 10.1001/jama.2020.20457]

Importance Less than 10% of patients with cancer have detectable pathogenic germline alterations, which may be partially due to incomplete pathogenic variant detection.

Objective To evaluate if deep learning approaches identify more germline pathogenic variants in patients with cancer.

Design Setting, and Participants A cross-sectional study of a standard germline detection method and a deep learning method in 2 convenience cohorts with prostate cancer and melanoma enrolled in the US and Europe between 2010 and 2017. The final date of clinical data collection was December 2017.

Exposures Germline variant detection using standard or deep learning methods.

Main Outcomes and Measures The primary outcomes included pathogenic variant detection performance in 118 cancer-predisposition genes estimated as sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The secondary outcomes were pathogenic variant detection performance in 59 genes deemed actionable by the American College of Medical Genetics and Genomics (ACMG) and 5197 clinically relevant mendelian genes. True sensitivity and true specificity could not be calculated due to lack of a criterion reference standard, but were estimated as the proportion of true-positive variants and true-negative variants, respectively, identified by each method in a reference variant set that consisted of all variants judged to be valid from either approach.

Results The prostate cancer cohort included 1072 men (mean [SD] age at diagnosis, 63.7 [7.9] years; 857 [79.9%] with European ancestry) and the melanoma cohort included 1295 patients (mean [SD] age at diagnosis, 59.8 [15.6] years; 488 [37.7%] women; 1060 [81.9%] with European ancestry). The deep learning method identified more patients with pathogenic variants in cancer-predisposition genes than the standard method (prostate cancer: 198 vs 182; melanoma: 93 vs 74); sensitivity (prostate cancer: 94.7% vs 87.1% [difference, 7.6%; 95% CI, 2.2% to 13.1%]; melanoma: 74.4% vs 59.2% [difference, 15.2%; 95% CI, 3.7% to 26.7%]), specificity (prostate cancer: 64.0% vs 36.0% [difference, 28.0%; 95% CI, 1.4% to 54.6%]; melanoma: 63.4% vs 36.6% [difference, 26.8%; 95% CI, 17.6% to 35.9%]), PPV (prostate cancer: 95.7% vs 91.9% [difference, 3.8%; 95% CI, –1.0% to 8.4%]; melanoma: 54.4% vs 35.4% [difference, 19.0%; 95% CI, 9.1% to 28.9%]), and NPV (prostate cancer: 59.3% vs 25.0% [difference, 34.3%; 95% CI, 10.9% to 57.6%]; melanoma: 80.8% vs 60.5% [difference, 20.3%; 95% CI, 10.0% to 30.7%]). For the ACMG genes, the sensitivity of the 2 methods was not significantly different in the prostate cancer cohort (94.9% vs 90.6% [difference, 4.3%; 95% CI, –2.3% to 10.9%]), but the deep learning method had a higher sensitivity in the melanoma cohort (71.6% vs 53.7% [difference, 17.9%; 95% CI, 1.82% to 34.0%]). The deep learning method had higher sensitivity in the mendelian genes (prostate cancer: 99.7% vs 95.1% [difference, 4.6%; 95% CI, 3.0% to 6.3%]; melanoma: 91.7% vs 86.2% [difference, 5.5%; 95% CI, 2.2% to 8.8%]).

Conclusions and Relevance Among a convenience sample of 2 independent cohorts of patients with prostate cancer and melanoma, germline genetic testing using deep learning, compared with the current standard genetic testing method, was associated with higher sensitivity and specificity for detection of pathogenic variants. Further research is needed to understand the relevance of these findings with regard to clinical outcomes.

It's really difficult to understand this paper since there are many terms that I'd have to research more thoroughly; for example, does "germline whole-exon sequencing" mean that only sperm or egg DNA was sequenced and that every single exon in the entire genome was sequenced? Were exons in noncoding genes also sequenced?

I found it much more useful to look at the accompanying editorial by Gregory Feero.

Feero, W.G. (2020) Bioinformatics, Sequencing Accuracy, and the Credibility of Clinical Genomics. JAMA 324:1945-1947. [doi: 10.1001/jama.2020.19939]

Ferro explains that the main problem is distinguishing real pathogenic variants from false positives and this can only be accomplished by first sequencing and assembling the DNA and then using various algorithms to focus on important variants. Then there's the third step.

The third step, which often requires a high level of clinical expertise, sifts through detected potentially deleterious variations to determine if any are relevant to the indication for testing. For example, exome sequencing ordered for a patient with unexplained cardiomyopathy might harbor deleterious variants in the BRCA1 gene which, while a potentially important incidental finding, does not provide a plausible molecular diagnosis for the cardiomyopathy. The complexity of the bioinformatics tools used in these 3 steps is considerable.

It's that third step that's analyzed in the AlDubayan et al. paper and one of the tools used is a deep-learning (AI) algorithm. However, the training of this algorithm requiries considerable clinical expertise and testing it requires a gold standard set of variants to serve as an internal control. As you might have guessed, that gold standard doesn't exist because the whole point of the genomics is to identify perviously unknown deleterious alleles.

Ferro warns us that "clinical genome sequencing remains largely unregulated and accuracy is highly dependant on the expertise of individual testing laboratories." He concludes that genomics still has a long way to go.

The genomics community needs to act as a coherent body to ensure reproducibility of outcomes from clinical genome or exome sequencing, or provide transparent quality metrics for individual clinical laboratories. Issues related to achieving accuracy are not new, are not limited to bioinformatics tools, and will not be surmounted easily. However, until analytic and clinical validity are ensured, conversations about the potential value that genome sequencing brings to clinical situations will be challenging for clinical centers, laboratories that provide sequencing services, and consumers. For the foreseeable future, nongeneticist clinicians should be familiar with the quality of their chosen genome-sequencing laboratory and engage expert advice before changing patient management based on a test result.

I'm guessing that Gregory Feero doesn't think that in nine years (2030) "The clinical relevance of all encountered genomic variants will be readily predictable."

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1. I do NOT recommend this group. It's full of amateurs who resist leaning and one of it's main purposes is to post copies of pirated textbooks in its files. The group members get very angry when you tell them that what they are doing is illegal!

Bold predictions for human genomics by 2030

After spending several years working on a book about the human genome I've come to the realization that the field of genomics is not delivering on its promise to help us understand what's in your genome. In fact, genomics researchers have by and large impeded progress by coming up with false claims that need to be debunked.

My view is not widely shared by today's researchers who honestly believe they have made tremendous progress and will make even more as long as they get several billion dollars to continue funding their research. This view is nicely summarized in a Scientific American article from last fall that's really just a precis of an article that first appeared in Nature. The Nature article was written by employees of the National Human Genome Research Institute (NHGRI) at the National Institutes of Health in Bethesda, MD, USA (Green et al., 2020). Its purpose is to promote the work that NHGRI has done in the past and to summarize its strategic vision for the future. At the risk of oversimplifying, the strategic vision is "more of the same."

Green, E.D., Gunter, C., Biesecker, L.G., Di Francesco, V., Easter, C.L., Feingold, E.A., Felsenfeld, A.L., Kaufman, D.J., Ostrander, E.A. and Pavan, W.J. and 20 others (2020) Strategic vision for improving human health at The Forefront of Genomics. Nature 586:683-692. [doi: 10.1038/s41586-020-2817-4]

Starting with the launch of the Human Genome Project three decades ago, and continuing after its completion in 2003, genomics has progressively come to have a central and catalytic role in basic and translational research. In addition, studies increasingly demonstrate how genomic information can be effectively used in clinical care. In the future, the anticipated advances in technology development, biological insights, and clinical applications (among others) will lead to more widespread integration of genomics into almost all areas of biomedical research, the adoption of genomics into mainstream medical and public-health practices, and an increasing relevance of genomics for everyday life. On behalf of the research community, the National Human Genome Research Institute recently completed a multi-year process of strategic engagement to identify future research priorities and opportunities in human genomics, with an emphasis on health applications. Here we describe the highest-priority elements envisioned for the cutting-edge of human genomics going forward—that is, at ‘The Forefront of Genomics’.

What's interesting are the predictions that the NHGRI makes for 2030—predictions that were highlighted in the Scientific American article. I'm going to post those predictions without comment other than saying that I think they are mostly bovine manure. I'm interested in hearing your comments.

Bold predictions for human genomics by 2030

Some of the most impressive genomics achievements, when viewed in retrospect, could hardly have been imagined ten years earlier. Here are ten bold predictions for human genomics that might come true by 2030. Although most are unlikely to be fully attained, achieving one or more of these would require individuals to strive for something that currently seems out of reach. These predictions were crafted to be both inspirational and aspirational in nature, provoking discussions about what might be possible at The Forefront of Genomics in the coming decade.

1. Generating and analysing a complete human genome sequence will be routine for any research laboratory, becoming as straightforward as carrying out a DNA purification.
2. The biological function(s) of every human gene will be known; for non-coding elements in the human genome, such knowledge will be the rule rather than the exception.
3. The general features of the epigenetic landscape and transcriptional output will be routinely incorporated into predictive models of the effect of genotype on phenotype.
4. Research in human genomics will have moved beyond population descriptors based on historic social constructs such as race.
5. Studies that involve analyses of genome sequences and associated phenotypic information for millions of human participants will be regularly featured at school science fairs.
6. The regular use of genomic information will have transitioned from boutique to mainstream in all clinical settings, making genomic testing as routine as complete blood counts.
7. The clinical relevance of all encountered genomic variants will be readily predictable, rendering the diagnostic designation ‘variant of uncertain significance (VUS)’ obsolete.
8. An individual’s complete genome sequence along with informative annotations will, if desired, be securely and readily accessible on their smartphone.
9. Individuals from ancestrally diverse backgrounds will benefit equitably from advances in human genomics.
10. Breakthrough discoveries will lead to curative therapies involving genomic modifications for dozens of genetic diseases.

I predict that nine years from now (2030) we will still be dealing with scientists who think that most of our genome is functional; that most human protein-coding genes produce many different proteins by alternative splicing; that epigenetics is useful; that there are more noncoding genes than protein-coding genes; that the leading scientists in the 1960 and 70s were incredibly stupid to suggest junk DNA; that almost every transcription factor binding site is biologically relevant; that most transposon-related sequences have a mysterious (still unknown) function; that it's still a mystery why humans are so much more complex than chimps; and that genomics will eventually solve all problems by 2040.

Why in the world, you might ask, would we still be dealing with issues like that? Because of genomics.

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"Dark matter" as an argument against junk DNA

Opponents of junk DNA have been largely unsuccessful in demonstrating that most of our genome is functional. Many of them are vaguely aware of the fact that "no function" (i.e. junk) is the default hypothesis and the onus is on them to come up with evidence of function. In order to shift, or obfuscate, this burden of proof they have increasingly begun to talk about the "dark matter" of the genome. The idea is to pretend that most of the genome is a complete mystery so that you can't say for certain whether it is junk or functional.

One of the more recent attempts appears in the "Journal Club" section of Nature Reviews Genetics. It focuses on repetitive DNA.

Before looking at that article, let's begin by summarizing what we already know about repetitive DNA. It includes highly repetitive DNA consisting of mutliple tandem repeats of short sequences such as ATATATATAT... or CGACGACGACGA ... or even longer repeats. Much of this is located in centromeric regions of the chromosome and I estimate that functional highly repetitve regions make up about 1% of the genome.[see Centromere DNA and Telomeres]

The other part of repetitive DNA is middle repetitive DNA, which is largely composed of transposons and endogenous viruses, although it includes ribosomal RNA genes and origins of replication. Most of these sequences are dispersed as single copies throughout the genome. It's difficult to determine exactly how much of the genome consists of these middle repetitive sequences but it's certainly more than 50%.

Almost all of the transposon- and virus-related sequences are defective copies of once active transposons and viruses. Most of them are just fragments of the originals. They are evolving at the neutral rate so they look like junk and they behave like junk.¹ That's not selfish DNA because is doesn't transpose and it's not "dark matter." These fragments have all the characterstics of nonfunctional junk in our genome.

We know that the C-value paradox is mostly explained by differing amounts of repetitive DNA in different genomes and this is consistent with the idea that they are junk. We know that less that 10% of our genome is conserved and this fits in with that conclusion. Finally, we know that genetic load arguments indicate that most our genome must be impervious to mutation. Combined, these are all powerful bits of evidence and logic in favor of repetitive sequences being mostly junk DNA.

Now let's look at what Neil Gemmell says in this article.

Gemmell, N.J. (2021) Repetitive DNA: genomic dark matter matters. Nature Reviews Genetics:1-1. [doi: 10.1038/s41576-021-00354-8]

"Repetitive DNA sequences were found in hundreds of thousands, and sometimes millions, of copies in the genomes of most eukaryotes. while widespread and evolutionarily conserved, the function of these repeats was unknown. Provocatively, Britten and Kohne concluded 'a concept that is repugnant to us is that about half of the DNA of higher organisms is trivial or permanently inert.'”"

That's from Britten and Kohne (1968) and it's true that more than 50 years ago those workers didn't like the idea of junk DNA. Britten argued that most of this repetitive DNA was likely to be involved in regulation. Gemmell goes on to describe centromeres and telomeres and mentions that most repetitive DNA was thought to be junk.

"... the idea that much of the genome is junk, maintained and perpetuated by random chance, seemed as broadly unsatisfactory to me as it had to the original authors. Enthralled by the mystery of why half our genome is repetitive DNA, I have followed this field ever since."

Gemmell is not alone. In spite of all the evidence for junk DNA, the majority of scientists don't like the fact that most of our genome is junk. Here's how he justifies his continued skepticism.

"But it was not until the 2000s, as full eukaryotic genome sequences emerged, that we discovered that the repetitive non-coding regions of our genome harbour large numbers of promoters, enhancers, transcription factor binding sites and regulatory RNAs that control gene expression. More recently, the importance of repetitive DNA in both structural and regulatory processes has emerged, but much remains to be discovered and understood. It is time to shine further light on this genomic dark matter."

This appears to be the ENCODE publicity campaign legacy rearing its ugly head once more. Most Sandwalk readers know that the presence of transcription factor binding sites, RNA polymerase binding sites, and junk RNA is exactly what one would predict from a genome full of defective transposons. Most of us know that a big fat sloppy genome is bound to contain millions of spurious binding sites for transcription factors so this says nothing about function.

Apparently Gemmell's skepticism doesn't apply to the ENCODE results so he still thinks that all those bits and pieces of transposons are mysterious bits of dark matter that could be several billion base pairs of functional DNA. I don't know what he imagines they could be doing.

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Photo Credit: The photo shows human chromosomes labelled with a telomere probe (yellow), from Christoher Counter at Duke University.

1. In my book, I cover this in a section called "If it walks like a duck ..." It's a form of abductive reasoning.

Britten, R. and Kohne, D. (1968) Repeated Sequences in DNA. Science 161:529-540. [doi: 10.1126/science.161.3841.529]

Off to the publisher!

The first draft of my book is ready to be sent to my publisher.

Text by Laurence A. Moran

Cover art and figures by Gordon L. Moran

• 11 chapters
• 112,000 words (+ preface and glossary)
• about 370 pages (estimated)
• 26 figures
• 305 notes
• 400 references

©Laurence A. Moran

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I think I'll skip this meeting

I just received an invitation to a meeting ...

On behalf of the international organizing committee, we would like to invite you to a conference to be held in Neve Ilan, near Jerusalem, from 4-8 October 2021, entitled ‘Potential and Limitations of Evolutionary Processes’. The main goal of this interdisciplinary, international conference is to bring together scientists and scholars who hold a range of viewpoints on the potential and possible limitations of various undirected chemical and biological processes.

The conference will include presentations from a broad spectrum of disciplines, including chemistry, biochemistry, biology, origin of life, evolution, mathematics, cosmology and philosophy. Open-floor discussion will be geared towards delineating mechanistic details, with a view to discussing in such a way that speakers and participants feel comfortable expressing different opinions and different interpretations of the data, in the spirit of genuine academic inquiry.

I'm pretty sure I got this invite because I attended the Royal Society Meeting on New trends in evolutionary biology: biological, philosophical and social science perspectives back in 2016. That meeting was a big disappointment because the proponents of extending the modern synthesis didn't have much of a case [Kevin Laland's new view of evolution].

I was curious to see what kind of followup the organizers of this new meeting were planning so I checked out the website at: Potential and Limitations of Evolutionary Processes. Warning bells went off immediately when I saw the list of topics.

• Fine-Tuning of the Universe
• The Origin of Life
• Origin & Fine-Tuning of the Genetic Code
• Origin of Novel Genes
• Origin of Functional Islands in Protein Sequence Space
• Origin of Multi-Component Molecular Machines
• Fine-Tuning of Molecular Systems
• Fine-Tuning in Complex Biological Systems
• Evolutionary Waiting Times
• History of Life & Comparative Genomics

This is a creationist meeting. A little checking shows that three of the four organizers, Russ Carlson, Anthony Futerman, and Siegfried Scherer, are creationists. (I don't know about the other organizer, Joel Sussman, but in this case guilt by association seems appropriate.)

I don't think I'll book a flight to Israel.

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Happy St. Patrick's Day!

Happy St. Patrick's Day! These are my great-grandparents Thomas Keys Foster, born in County Tyrone on September 5, 1852 and Eliza Ann Job, born in Fintona, County Tyrone on August 18, 1852. Thomas came to Canada in 1876 to join his older brother, George, on his farm near London, Ontario, Canada. Eliza came the following year and worked on the same farm. Thomas and Eliza decided to move out west where they got married in 1882 in Winnipeg, Manitoba, Canada.

The couple obtained a land grant near Salcoats, Saskatchewan, a few miles south of Yorkton, where they build a sod house and later on a wood frame house that they named "Fairview" after a hill in Ireland overlooking the house where Eliza was born. That's where my grandmother, Ella, was born.

Other ancestors in this line came from the adjacent counties of Donegal (surname Foster) and Fermanagh (surnames Keys, Emerson, Moore) and possibly Londonderry (surname Job).

One of the cool things about studying your genealogy is that you can find connections to almost everyone. This means you can celebrate dozens of special days. In my case it was easy to find other ancestors from England, Scotland, Netherlands, Germany, France, Spain, Poland, Lithuania, Belgium, Ukraine, Russia, and the United States. Today, we will be celebrating St. Patrick's Day. It's rather hectic keeping up with all the national holidays but somebody has to keep the traditions alive!

It's nice to have an excuse to celebrate, especially when it means you can drink beer. However, I would be remiss if I didn't mention one little (tiny, actually) problem. Since my maternal grandmother is pure Irish, I should be 25% Irish but my DNA results indicate that I'm only 4% Irish. That's probalby because my Irish ancestors were Anglicans and were undoubtedly the descendants of settlers from England, Wales, and Scotland who moved to Ireland in the 1600s. This explains why they don't have very Irish-sounding names.

I don't mention this when I'm in an Irish pub.

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Is science the only way of knowing?

Most of us learned that science provides good answers to all sort of questions ranging from whether a certain drug is useful in treating COVID-19 to whether humans evolved from primitive apes. A more interesting question is whether there are any limitations to science or whether there are any other effective ways of knowing. The question is related to the charge of "scientism," which is often used as a pejorative term to describe those of us who think that science is the only way of knowing.

I've discussed these issue many times of this blog so I won't rehash all the arguments. Suffice to say that there are two definitions of science; the broad definition and the narrow one. The narrow definition says that science is merely the activity carried out by geologists, chemists, physicists, and biologists. Using this definition it would be silly to say that science is the only way of knowing. The broad definition can be roughly described as: science is a way of knowing that relies on evidence, logic (rationality), and healthy skepticism.

The broad definition is the one preferred by many philosophers and it goes something like this ...

Unfortunately neither "science" nor any other established term in the English language covers all the disciplines that are parts of this community of knowledge disciplines. For lack of a better term, I will call them "science(s) in the broad sense." (The German word "Wissenschaft," the closest translation of "science" into that language, has this wider meaning; that is, it includes all the academic specialties, including the humanities. So does the Latin "scientia.") Science in a broad sense seeks knowledge about nature (natural science), about ourselves (psychology and medicine), about our societies (social science and history), about our physical constructions (technological science), and about our thought construction (linguistics, literary studies, mathematics, and philosophy). (Philosophy, of course, is a science in this broad sense of the word.)

Sven Ove Hanson "Defining Pseudoscience and Science" in Philosophy of Pseudescience: Reconsidering the Demarcation Problem.

The bad news from Ghent

A group of scientists, mostly from the University of Ghent¹ (Belgium), have posted a paper on bioRxiv.

Lorenzi, L., Chiu, H.-S., Cobos, F.A., Gross, S., Volders, P.-J., Cannoodt, R., Nuytens, J., Vanderheyden, K., Anckaert, J. and Lefever, S. et al. (2019) The RNA Atlas, a single nucleotide resolution map of the human transcriptome. bioRxiv:807529. [doi: 10.1101/807529]

The human transcriptome consists of various RNA biotypes including multiple types of non-coding RNAs (ncRNAs). Current ncRNA compendia remain incomplete partially because they are almost exclusively derived from the interrogation of small- and polyadenylated RNAs. Here, we present a more comprehensive atlas of the human transcriptome that is derived from matching polyA-, total-, and small-RNA profiles of a heterogeneous collection of nearly 300 human tissues and cell lines. We report on thousands of novel RNA species across all major RNA biotypes, including a hitherto poorly-cataloged class of non-polyadenylated single-exon long non-coding RNAs. In addition, we exploit intron abundance estimates from total RNA-sequencing to test and verify functional regulation by novel non-coding RNAs. Our study represents a substantial expansion of the current catalogue of human ncRNAs and their regulatory interactions. All data, analyses, and results are available in the R2 web portal and serve as a basis to further explore RNA biology and function.

They spent a great deal of effort identifying RNAs from 300 human samples in order to construct an extensive catalogue of five kinds of transcripts: mRNAs, lncRNAs, antisenseRNAs, miRNAs, and circularRNAs. The paper goes off the rails in the first paragraph of the Results section where they immediately equate transcripts wiith genes. They report the following:

• 19,107 mRNA genes (188 novel)
• 18,387 lncRNA genes (13,175 novel)
• 7,309 asRNA genes (2,519 novel)
• 5,427 miRNAs
• 5,427 circRNAs

Is science a social construct?

Richard Dawkins has written an essay for The Spectator in which he says,

"[Science is not] a social construct. It’s simply true. Or at least truth is real and science is the best way we have of finding it. ‘Alternative ways of knowing’ may be consoling, they may be sincere, they may be quaint, they may have a poetic or mythic beauty, but the one thing they are not is true. As well as being real, moreover, science has a crystalline, poetic beauty of its own.

The essay is not particularly provocative but it did provoke Jerry Coyne who pointed out that, "The profession of science" can be contrued as a social construct. In this sense Jerry is agreeing with his former supervisor, Richard Lewontin¹ who wrote,

"Science is a social institution about which there is a great deal of misunderstanding, even among those who are part of it. We think that science is an institution, a set of methods, a set of people, a great body of knowledge that we call scientific, is somehow apart from the forces that rule our everyday lives and tha goven the structure of our society... The problems that science deals with, the ideas that it uses in investigating those problems, even the so-called scientific results that come out of scientific investigation, are all deeply influenced by predispositions that derive from the society in which we live. Scientists do not begin life as scientists after all, but as social beings immersed in a family, a state, a productive structure, and they view nature through a lens that has been molded by their social structure."

Coincidently, I just happened to be reading Science Fictions an excellent book by Stuart Ritchie who also believes that science is a social construct but he has a slighly different take on the matter.

"Science has cured diseases, mapped the brain, forcasted the climate, and split the atom; it's the best method we have of figuring out how the universe works and of bending it to our will. It is, in other words, our best way of moving towards the truth. Of course, we might never get there—a glance at history shows us hubristic it is to claim any facts as absolute or unchanging. For ratcheting our way towards better knowledge about the world, though, the methods of science is as good as it gets.

But we can't make progress withthose methods alone. It's not enough to make a solitary observation in your lab; you must also convince other scientists that you've discovered something real. This is where the social part comes. Philosophers have long discussed how important it is for scientists to show their fellow researchers how they came to their conclusions.

Dawkins, Coyne, Lewontin, and Ritchie are all right in different ways. Dawkins is talking about science as a way of knowing, although he restricts his definition of science to the natural sciences. The others are referring to the practice of science, or as Jerry Coyne puts it, the profession. It's true that the methods of science are the best way we have to get at the truth and it's true that the way of knowing is not a social construct in any meanigful sense.

Jerry Coyne is right to point out that the methods are employed by human scientists (he's also restricting the practice of science to scientists) and humans are fallible. In that sense, the enterprise of (natural) science is a social construct. Lewontin warns us that scientists have biases and prejudices and that may affect how they do science.

Ritchie makes a diffferent point by emphasizing that (natural) science is a collective endeavor and that "truth" often requires a consensus. That's the sense in which science is social. This is supposed to make science more robust, according to Ritchie, because real knowledge only emerges after carefull and skeptical scrutiny by other scientists. His book is mostly about how that process isn't working and why science is in big trouble. He's right about that.

I think it's important to distinguish between science as a way of knowing and the behavior and practice of scientists. The second one is affected by society and its flaws are well-known but the value of science as way of knowing can't be so easily dismissed.

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1. The book is actually a series of lectures (The Massey Lectures) that Lewontin gave in Toronto (Ontario, Canada) in 1990. I attended those lectures.

The 20th anniversary of the human genome sequence: 6. Nature doubles down on ENCODE results

Nature has now published a series of articles celebrating the 20th anniversary of the publication of the draft sequences of the human genome [Genome revolution]. Two of the articles are about free access to information and, unlike a similar article in Science, the Nature editors aren't shy about mentioning an important event from 2001; namely, the fact that Science wasn't committed to open access.

By publishing the Human Genome Project’s first paper, we worked with a publicly funded initiative that was committed to data sharing. But the journal acknowledged there would be challenges to maintaining the free, open flow of information, and that the research community might need to make compromises to these principles, for example when the data came from private companies. Indeed, in 2001, colleagues at Science negotiated publishing the draft genome generated by Celera Corporation in Rockville, Maryland. The research paper was immediately free to access, but there were some restrictions on access to the full data.

The 20th anniversary of the human genome sequence: 5. 90% of our genome is junk

This is the fifth (and last) post in celebration of the 20th anniversary of publishing the draft sequence. The first four posts dealt with: (1) the way Science chose to commemorate the occasion [Access to the data]; (2) finishing the sequence; (3) the number of genes; and (4) the amount of functional DNA in the genome.

Back in 2001, knowledgeable scientists knew that most of the human genome is junk and the sequence confirmed that knowledge. Subsequent work on the human genome over the past 20 years has provided additional evidence of junk DNA so that we can now be confident that something like 90% of our genome is junk DNA. Here's a list of data and arguments that support that claim.

The 20th anniversary of the human genome sequence: 4. Functional DNA in our genome

We know a lot more about the human genome than we did when the draft sequences were published 20 years ago. One of the most important discoveries is the recognition and extent of true functional sequences in the genome. Genes are one example of such functional sequence but only a minor component (about 1.4%). Most of the functional regions of the genome are not genes.

Here's a list of functional DNA in our genome other than the functional part of genes.

• Centromeres: There are 24 different centromeres and the average size is four million base pairs. Most of this is repetitive DNA and it adds up to about 3% of the genome. The total amount of centromeric DNA ranges from 2%-10% in different individuals. It's unlikely that all of the centromeric DNA is essential; about 1% seems to be a good estimate.
• Telomeres: Telomeres are repetivie DNA sequences at the ends of chromosomes. They are required for the proper replication of DNA and they take up about 0.1% of the genome sequence.
• Origins of replication: DNA replication begins at origins of replication. The size of each origin has not been established with certainlty but it's safe to assume that 100 bp is a good estimate. There are about 100,000 origin sequences but it's unlikely that all of them are functional or necessary. It's reasonable to assume that only 30,000 - 50,000 are real origins and that means 0.3% of the genome is devoted to origins of replication.
• Regulatory sequences: The transcription of every gene is controlled by sequences that lie outside of the genes, usually at the 5′ end. The total amount of regulatory sequence is controversial but it seems reasonable to assume about 200 bp per gene for a total of five million bp or less than 0.2% of the genome (0.16%). The most extreme claim is about 2,400 bp per gene or 1.8% of the genome.
• Scaffold attachment regions (SARs): Human chromatin is organized into about 100,000 large loops. The base of each loop consists of particular proteins bound to specific sequences called anchor loop sequences. The nomenclature is confusing; the original term (SAR) isn't as popular today as it was 35 years ago but that doesn't change the fact that about 0.3% of the genome is required to organize chromatin.
• Transposons: Most of the transposon-related sequencs in our genome are just fragments of defective transposons but there are a few active ones. They account for only a tiny fraction of the genome.
• Viruses: Functional virus DNA sequences account for less than 0.1% of the genome.

If you add up all the functional DNA from this list, you get to somewhere between 2% and 3% of the genome.

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Image credit: Wikipedia.

The 20th anniversary of the human genome sequence: 3. How many genes?

This week marks the 20th anniversary of the publication of the first drafts of the human genome sequence. Science choose to celebrate the achievement with a series of articles that had little to say about the scientific discoveries arising out of the sequencing project; one of the articles praised the opennesss of sequence data without mentioning that the journal had violated its own policy on openness by publishing the Celera sequence [The 20th anniversary of the human genome sequence: 1. Access to the data and the complicity of Science].

I've decided to post a few articles about the human genome beginning with one on finishing the sequence. In this post I'll summarize the latest data on the number of genes in the human genome.

The 20th anniversary of the human genome sequence: 2. Finishing the sequence

It's been 20 years since the first drafts of the human genome sequence were published. These first drafts from the International Human Genome Project (IHGP) and Celera were far from complete. The IHGP sequence covered about 82% of the genome and it contained about 250,000 gaps and millions of sequencing errors.

Celera never published an updated sequences but IHPG published a "finished" sequence in October 2004. It covered about 92% of the genome and had "only" 300 gaps. The error rate of the finished sequence was down to 10^-5.

International Human Genome Sequencing Consortium (2004) Finishing the euchromatic sequence of the human genome. Nature 431:931-945. doi: 10.1038/nature03001

We've known for many decades that the correct size of the human genome is close to 3,200,000 kb or 3.2 Gb. There's isn't a more precise number because different individuals have different amounts of DNA. The best average estimate was 3,286 Gb based on the sequence of 22 autosomes, one X chromosome, and one Y chromosome (Morton 1991). The amount of actual nucleotide sequence in the latest version of the reference genome (GRCh38.p13) is 3,110,748,599 bp and the estimated total size is 3,272,116,950 bp based on estimating the size of the remaining gaps. This means that 95% of the genome has been sequenced. [see How much of the human genome has been sequenced? for a discussion of what's missing.]

Recent advances in sequencing technology have produced sequence data covering the repetitive regions in the gaps and the first complete sequence of a human chromosome (X) was published in 2019 [First complete sequence of a human chromosome]. It's now possible to complete the human genome reference sequence by sequencing at least one individual but I'm not sure that the effort and the expense are worth it.

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Image credit the figure is from Miga et al. (2019)

Miga, K.H., Koren, S., Rhie, A., Vollger, M.R., Gershman, A., Bzikadze, A., Brooks, S., Howe, E., Porubsky, D., Logsdon, G.A. et al. (2019) Telomere-to-telomere assembly of a complete human X chromosome. Nature 585:79-84. [doi: 10.1038/s41586-020-2547-7]

Morton, N.E. (1991) Parameters of the human genome. Proceedings of the National Academy of Sciences 88:7474-7476. [doi: 10.1073/pnas.88.17.7474]

The 20th anniversary of the human genome sequence: 1. Access to the data and the complicity of Science

The first drafts of the human genome sequence were published 20 years ago. The paper from the International Human Genome Project (IHGP) was published in Nature on Febuary 15, 2001 and the paper from Celera was published in Science on February 16, 2001.

The original agreement was to publish both papers in Science but IHGP refused to publish their sequence in that journal when it choose to violate its own policy by allowing Celera to restrict access to its data. I highly recommend James Shreeve's book The Genome War for the history behind these publications. It paints an accurate, but not pretty, picture of science and politics.

Lander, E., Linton, L., Birren, B., Nusbaum, C., Zody, M., Baldwin, J., Devon, K., Dewar, K., Doyle, M., FitzHugh, W., Funke, R., Gage, D., Harris, K., Heaford, A., Howland, J., Kann, L., Lehoczky, J., LeVine, R., McEwan, P., McKernan, K., Meldrim, J., Mesirov, J., Miranda, C., Morris, W., Naylor, J., Raymond, C., Rosetti, M., Santos, R., Sheridan, A. and Sougnez, C. (2001) Initial sequencing and analysis of the human genome. Nature 409:860-921. doi: 10.1038/35057062

Venter, J., Adams, M., Myers, E., Li, P., Mural, R., Sutton, G., Smith, H., Yandell, M., Evans, C., Holt, R., Gocayne, J., Amanatides, P., Ballew, R., Huson, D., Wortman, J., Zhang, Q., Kodira, C., Zheng, X., Chen, L., Skupski, M., Subramanian, G., Thomas, P., Zhang, J., Gabor Miklos, G., Nelson, C., Broder, S., Clark, A., Nadeau, J., McKusick, V. and Zinder, N. (2001) The sequence of the human genome. Science 291:1304 - 1351. doi: 10.1126/science.1058040

On the importance of controls

When doing an exeriment, it's important to keep the number of variables to a minimum and it's important to have scientific controls. There are two types of controls. A negative control covers the possibility that you will get a signal by chance; for example, if you are testing an enzyme to see whether it degrades sugar then the negative control will be a tube with no enzyme. Some of the sugar may degrade spontaneoulsy and you need to know this. A positive control is when you deliberately add something that you know will give a positive result; for example, if you are doing a test to see if your sample contains protein then you want to add an extra sample that contains a known amount of protein to make sure all your reagents are working.

Lots of controls are more complicated than the examples I gave but the principle is important. It's true that some experiments don't appear to need the appropriate controls but that may be an illusion. The controls might still be necessary in order to properly interpret the results but they're not done because they are very difficult. This is often true of genomics experiments.

What do believers in epigenetics think about junk DNA?

I've been writing some stuff about epigenetics so I've been reading papers on how to define the term [What the heck is epigenetics? ]. Turns out there's no universal definition but I discovered that scientists who write about epigenetics are passionate believers in epigenetics no matter how you define it. Surprisingly (not!), there seems to be a correlation between belief in epigenetics and other misconceptions such as the classic misunderstanding of the Central Dogma of Molecular Biology and rejection of junk DNA [The Extraordinary Human Epigenome]

Here's an illustraton of this correlation from the introduction to a special issue on epigenetics in Philosophical Transactions B.

Ganesan, A. (2018) Epigenetics: the first 25 centuries, Philosophical Transactions B. 373: 20170067. [doi: 10.1098/rstb.2017.0067]

Epigenetics is a natural progression of genetics as it aims to understand how genes and other heritable elements are regulated in eukaryotic organisms. The history of epigenetics is briefly reviewed, together with the key issues in the field today. This themed issue brings together a diverse collection of interdisciplinary reviews and research articles that showcase the tremendous recent advances in epigenetic chemical biology and translational research into epigenetic drug discovery.

In addition to the misconceptions, the text (see below) emphasizes the heritable nature of epigenetic phenomena. This idea of heritablity seems to be a dominant theme among epigenetic believers.

A central dogma became popular in biology that equates life with the sequence DNA → RNA → protein. While the central dogma is fundamentally correct, it is a reductionist statement and clearly there are additional layers of subtlety in ‘how’ it is accomplished. Not surprisingly, the answers have turned out to be far more complex than originally imagined, and we are discovering that the phenotypic diversity of life on Earth is mirrored by an equal diversity of hereditary processes at the molecular level. This lies at the heart of modern day epigenetics, which is classically defined as the study of heritable changes in phenotype that occur without an underlying change in genome sequence. The central dogma's focus on genes obscures the fact that much of the genome does not code for genes and indeed such regions were derogatively lumped together as ‘junk DNA’. In fact, these non-coding regions increase in proportion as we climb up the evolutionary tree and clearly play a critical role in defining what makes us human compared with other species.

At the risk of bearting a dead horse, I'd like to point out that the author is wrong about the Central Dogma and wrong about junk DNA. He's right about the heritablitly of some epigenetic phenomena such as methylation of DNA but that fact has been known for almost five decades and so far it hasn't caused a noticable paradigm shift, unless I missed it [Restriction, Modification, and Epigenetics].

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Mouse traps Michael Denton

Michael Denton is a New Zealand biochemist, a Senior Fellow at the Discovery Institute, and the author of two Intelligent Design Creationist books: Evolution: A Theory in Crisis (1985) and Nature's Destiny (1998).

He has just read Michael Behe's latest book and he (Denton) is impressed [Praise for Behe’s Latest: “Facts Before Theory”]:

Behe brings out more forcibly than any other author I have recently read just how vacuous and biased are the criticisms of his work and of the ID position in general by so many mainstream academic defenders of Darwinism. And what is so telling about his many wonderfully crafted responses to his Darwinian critics is that it is Behe who is putting the facts before theory while his many detractors — Kenneth Miller, Jerry Coyne, Larry Moran, Richard Lenski, and others — are putting theory before the facts. In short, this volume shows that it is Behe rather than his detractors who is carefully following the evidence.

I don't know what planet Michael Denton is living on—probably the same one as Michael Behe—but let's make one thing clear about facts and evidence. Behe's entire argument is based on the "fact" that he can't see how Darwin's theory of natural selection can account for the evolution of complex features: therefore god(s) must have done it. This is NOT putting facts before theory and it is NOT carefully following the evidence.

It's just a somewhat sophisticated version of god of the gaps based on Behe's lack of understanding of the basic mechanisms of evolution.

(See, Of mice and Michael, where I explain why Michael Behe fails to answer my critique of The Edge of Evolution.)

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Of mice and Michael

Michael Behe has published a book containing most of his previously published responses to critics. I was anxious to see how he dealt with my criticisms of The Edge of Evolution but I was disappointed to see that, for the most part, he has just copied excerpts from his 2014 blog posts (pp. 335-355).

I think it might be worthwhile to review the main issues so you can see for yourself whether Michael Behe really answered his critics as the title of his most recent book claims. You can check out the dueling blog posts at the end of this summary to see how the discussion evolved in real time more than four years ago.

Many Sandwalk readers participated in the debate back then and some of them are quoted in Behe's book although he usually just identifies them as commentators.

My Summary

Michael Behe has correctly indentified an extremely improbably evolution event; namely, the development of chloroquine resistance in the malaria parasite. This is an event that is close to the edge of evolution, meaning that more complex events of this type are beyond the edge of evolution and cannot occur naturally. However, several of us have pointed out that his explanation of how that event occurred is incorrect. This is important because he relies on his flawed interpretation of chloroquine resistance to postulate that many observed events in evolution could not possibly have occurred by natural means. Therefore, god(s) must have created them.

In his response to this criticism, he completely misses the point and fails to understand that what is being challenged is his misinterpretation of the mechanisms of evolution and his understanding of mutations.

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The main point of The Edge of Evolution is that many of the beneficial features we see could only have evolved by selecting for a number of different mutations where none of the individual mutations confer a benefit by themselves. Behe claims that these mutations had to occur simultaneously or at least close together in time. He argues that this is possible in some cases but in most cases the (relatively) simultaneous occurrence of multiple mutations is beyond the edge of evolution. The only explanation for the creation of these beneficial features is god(s).

Using modified nucleotides to make mRNA vaccines

The key features of the mRNA vaccines are the use of modified nucleotides in their synthesis and the use of lipid nanoparticles to deliver them to cells. The main difference between the Pfizer/BioNTech vaccine and the Moderna vaccine is in the delivery system. The lipid vescicules used by Moderna are somewhat more stable and the vaccine doesn't need to be kept constantly at ultra-low temperatures.

Both vaccines use modified RNAs. They synthesize the RNA using modified nucleotides based on variants of uridine; namely, pseudouridine, N¹-methylpseudouridine and 5-methylcytidine. (The structures of the nucleosides are from Andries et al., 2015).) The best versions are those that use both 5-methylcytidine and N¹-methylpseudouridine.

I'm not an expert on these mRNAs and their delivery systems but the way I understand it is that regular RNA is antigenic—it induces antibodies against it, presumably when it is accidently released from the lipid vesicles outside of the cell. The modified versions are much less antigenic. As an added bonus, the modified RNA is more stable and more efficiently translated.

Two of the key papers are ...

Andries, O., Mc Cafferty, S., De Smedt, S.C., Weiss, R., Sanders, N.N. and Kitada, T. (2015) "N1-methylpseudouridine-incorporated mRNA outperforms pseudouridine-incorporated mRNA by providing enhanced protein expression and reduced immunogenicity in mammalian cell lines and mice." Journal of Controlled Release 217: 337-344. [doi: 10.1016/j.jconrel.2015.08.051]

Pardi, N., Tuyishime, S., Muramatsu, H., Kariko, K., Mui, B.L., Tam, Y.K., Madden, T.D., Hope, M.J. and Weissman, D. (2015) "Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes." Journal of Controlled Release 217: 345-351. [doi: 10.1016/j.jconrel.2015.08.007]

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Why is the Central Dogma so hard to understand?

The Central Dogma of molecular biology states ...

... once (sequential) information has passed into protein it cannot get out again (F.H.C. Crick, 1958).

The central dogma of molecular biology deals with the detailed residue-by-residue transfer of sequential information. It states that such information cannot be transferred from protein to either protein or nucleic acid (F.H.C. Crick, 1970).

This is not difficult to understand since Francis Crick made it very clear in his original 1958 paper and again in his 1970 paper in Nature [see Basic Concepts: The Central Dogma of Molecular Biology]. There's nothing particularly complicated about the Central Dogma. It merely states the obvious fact that sequence information can flow from nucleic acid to protein but not the other way around.

So, why do so many scientists have trouble grasping this simple idea? Why do they continue to misinterpret the Central Dogma while quoting Crick? I seems obvious that they haven't read the paper(s) they are referencing.

I just came across another example of such ignorance and it is so outrageous that I just can't help sharing it with you. Here's a few sentences from a recent review in the 2020 issue of Annual Reviews of Genomics and Human Genetics (Zerbino et al., 2020).

Once the role of DNA was proven, genes became physical components. Protein-coding genes could be characterized by the genetic code, which was determined in 1965, and could thus be defined by the open reading frames (ORFs). However, exceptions to Francis Crick's central dogma of genes as blueprints for protein synthesis (Crick, 1958) were already being uncovered: first tRNA and rRNA and then a broad variety of noncoding RNAs.

I can't imagine what the authors were thinking when they wrote this. If the Central Dogma actually said that the only role for genes was to make proteins then surely the discovery of tRNA and rRNA would have refuted the Central Dogma and relegated it to the dustbin of history. So why bother even mentioning it in 2020?

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Crick, F.H.C. (1958) On protein synthesis. Symp. Soc. Exp. Biol. XII:138-163. [PDF]

Crick, F. (1970) Central Dogma of Molecular Biology. Nature 227, 561-563. [PDF file]

Zerbino, D.R., Frankish, A. and Flicek, P. (2020) "Progress, Challenges, and Surprises in Annotating the Human Genome." Annual review of genomics and human genetics 21:55-79. [doi: 10.1146/annurev-genom-121119-083418]

On the misrepresentation of facts about lncRNAs

I've been complaining for years about how opponents of junk DNA misrepresent and distort the scientific literature. The same complaints apply to the misrepresentation of data on alternative splicing and on the prevalence of noncoding genes. Sometimes the misrepresentation is subtle so you hardly notice it.

I'm going to illustrate subtle misrepresentation by quoting a recent commentary on lncRNAs that's just been published in BioEssays. The main part of the essay deals with ways of determining the function of lncRNAs with an emphasis on the sructures of RNA and RNA-protein complexes. The authors don't make any specific claims about the number of functional RNAs in humans but it's clear from the context that they think this number is very large.

Undergraduate education in biology: no vision, no change

I was looking at the Vision and Change document the other day and it made me realize that very little has changed in undergraduate education. I really shouldn't be surprised since I reached the same conclusion in 2015—six years after the recommendations were published [Vision and Change] [Why can't we teach properly?].

The main recommendations of Vision and Change are that undergraduate education should adopt the proven methods of student-centered education and should focus on core concepts rather than memorization of facts. Although there has been some progress, it's safe to say that neither of these goals have been achieved in the vast majority of biology classes, including biochemistry and molecular biology classes.

Things are getting even worse in this time of COVID-19 because more and more classes are being taught online and there seems to be general agreement that this is okay. It is not okay. Online didactic lectures go against everything in the Vision and Change document. It may be possible to develop online courses that practice student-centered, concept teaching that emphasizes critical thinking but I've seen very few attempts.

Here are a couple of quotations from Vision and Change that should stimulate your thinking.

Traditionally, introductory biology [and biochemistry] courses have been offered as three lectures a week, with, perhaps, an accompanying two- or three-hour laboratory. This approach relies on lectures and a textbook to convey knowledge to the student and then tests the student's acquisition of that knowledge with midterm and final exams. Although many traditional biology courses include laboratories to provide students with hands-on experiences, too often these "experiences" are not much more than guided exercises in which finding the right answer is stressed while providing students with explicit instructions telling them what to do and when to do it.

"Appreciating the scientific process can be even more important than knowing scientific facts. People often encounter claims that something is scientifically known. If they understand how science generates and assesses evidence bearing on these claims, they possess analytical methods and critical thinking skills that are relevant to a wide variety of facts and concepts and can be used in a wide variety of contexts.”

National Science Foundation, Science and Technology Indicators, 2008

If you are a student and this sounds like your courses, then you should demand better. If you are an instructor and this sounds like one of your courses then you should be ashamed; get some vision and change [The Student-Centered Classroom].

Although the definition of student-centered learning may vary from professor to professor, faculty generally agree that student-centered classrooms tend to be interactive, inquiry-driven, cooperative, collaborative, and relevant. Three critical components are consistent throughout the literature, providing guidelines that faculty can apply when developing a course. Student-centered courses and curricula take into account student knowledge and experience at the start of a course and articulate clear learning outcomes in shaping instructional design. Then they provide opportunities for students to examine and discuss their understanding of the concepts presented, offering frequent and varied feedback as part of the learing process. As a result, student-centered science classrooms and assignments typically involve high levels of student-student and student-faculty interaction; connect the course subject matter to topics students find relevant; minimize didactic presentations; reflect diverse views of scientific inquiry, including data presentation, argumentation, and peer review; provide ongoing feedback to both the student and professor about the student's learning progress; and explicitly address learning how to learn.

This is a critical time for science education since science is under attack all over the world. We need to make sure that university students are prepared to deal with scientific claims and counter-claims for the rest of their lives after they leave university. This means that they have to be skilled at critical thinking and that's a skill that can only be taught in a student-centered classroom where students can practice argumentation and learn the importance of evidence. Memorizing the enzymes of the Krebs Cycle will not help them understand climate change or why they should wear a mask in the middle of a pandemic.

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On the importance of random genetic drift in modern evolutionary theory

The latest issue of New Scientist has a number of articles on evolution. All of them are focused on extending and improving the current theory of evolution, which is described as Darwin's version of natural selection [New Scientist doesn't understand modern evolutionary theory].

Most of the criticisms come from a group who want to extend the evolutionary synthesis (EES proponents). Their main goal is to advertise mechanisms that are presumed to enhance adaptation but that weren't explicitly included in the Modern Synthesis that was put together in the late 1940s.

One of the articles addresses random genetic drift [see Survival of the ... luckiest]. The emphasis in this short article is on the effects of drift in small populations and it gives examples of reduced genetic diversity in small populations.