Siddhartha Mukherjee tries to correct his book

There are lots of things wrong with Mukherjee's best-selling book The Gene. I've listed a few things that I know about [What is a "gene" and how do genes work according to Siddhartha Mukherjee?]. Others have come up with different problems.

The biggest problem is that Mukherjee misrepresents the current state of knowledge in genetics, biochemistry, and molecular biology. His misleads his readers by promoting silly viewpoints that conflict with the consensus view. He doesn't mention that there are other views that are well supported by tons of scientific evidence.

The best example is regulation of gene expression. He fails to explain the standard textbook understanding of transcriptional regulation by transcription factors—a view that's solidly backed by decades of work in biochemistry, developmental genetics, molecular biology, and genomics. Instead, he promotes a flaky epigenetic theory that, according to him, threatens to overthrow Darwinian evolution.

The most important thing about nature according to Bill Martin

My friend and colleague, Alex Palazzo, alerted me to an interview of Bill Martin published in the July 11, 2016 issue of Current Biology [Bill Martin]. I loved all his answers—Bill Martin is one of my scientific heroes—but his answer to the last question was particularly insightful. The question was, "What’s the single most important thing that you have come to realize about nature?"

His answer was ....

Life is an exergonic chemical reaction. It’s the energy releasing redox reaction at the core of metabolism that makes life run, and throughout all of life’s history it is one and the same reaction that has been running in uninterrupted continuity from life’s onset. Everything else is secondary, manifestations of what is possible when the energy is harnessed to make genes that pass the torch.

I'm a biochemist so you might think I'm a little bit biased but let me tell you why this answer is so important.

You are junk

There's an article about junk DNA in the latest issue of New Scientist (July 27, 2016) [You are junk: Why it’s not your genes that make you human]. I've already discussed the false meme at the beginning of the article [False history and the number of genes: 2016]. Now it's time to look at the main argument.

The subtitle is ...

Genes make proteins make us – that was the received wisdom. But from big brains to opposable thumbs, some of our signature traits could come from elsewhere.

You can see where this is going. You start with a false paradigm, "Genes make proteins make us," then proceed to refute it. This is called "paradigm shafting."¹

False history and the number of genes: 2016

There's an article about junk DNA in the latest issue of New Scientist. The title is: You are junk: Why it’s not your genes that make you human. The author is Colin Barras, a science writer from Michigan with a Ph.D. in paleontology.

He begins with .....

IT WAS a discovery that threatened to overturn everything we thought about what makes us human. At the dawn of the new millennium, two rival teams were vying to be the first to sequence the human genome. Their findings, published in February 2001, made headlines around the world. Back-of-the-envelope calculations had suggested that to account for the sheer complexity of human biology, our genome should contain roughly 100,000 genes. The estimate was wildly off. Both groups put the actual figure at around 30,000. We now think it is even fewer – just 20,000 or so.

"It was a massive shock," says geneticist John Mattick. "That number is tiny. It’s effectively the same as a microscopic worm that has just 1000 cells."

What is "THE" theory of evolution?

I wish people would stop referring to "THE" Theory of Evolution. What they really mean, of course, is "The Theory of Natural Selection"—part of modern evolutionary theory. There's no question about the importance of natural selection and the major contribution of Charles Darwin in discovering it and promoting it to the general public. However, in 2016 there's a lot more to evolutionary theory than just natural selection and the public needs to know this. Many scientists need to know this.

There's also no debate about Darwin's contribution to promoting the evidence of evolution and descent with modification. He made a brilliant case for evolution in his books. Subsequent discoveries have demonstrated beyond a reasonable doubt that modern life is the product of billions of years of evolution. Descent with modification is a scientific fact. The fact that evolution has occurred is not a theory. It is not a "theory" that humans and the other apes have descended form a common ancestor ... it is a fact [Evolution Is a Fact and a Theory].

We perpetuate confusion in the minds of the general public if we don't make it abundantly clear that modern evolution theory is not about whether evolution occurred and it's not just about natural selection.

I was prompted to write this blog post by a recent article in New Scientist: Darwin’s discovery: The remarkable history of evolution.¹ The author is John van Wyhe of the National University of Singapore. He is a historian of science with a special interest in Charles Darwin and Alfred Russel Wallace.

The article contains a box that says ...

Evolution in a nutshell

Darwin’s and Wallace’s theory of evolution maintains that new species are descended from earlier ones. This long-term process happens because all organisms vary. The tiny variations are naturally “selected” by virtue of whether or not they help an organism to survive the brutal struggle for existence in nature. Many are born, but few survive; fortuitous variations are preferentially passed on. This process of endless filtering works to adapt organisms to their environment.

This is misleading in two ways. First, it states that common descent is part of the the theory of evolution. Second, it only talks about natural selection as a mechanism of evolution.

We wish to question a deeply engrained habit of thinking among students of evolution. We call it the adaptationist programme, or the Panglossian paradigm.

S.J. Gould & R.C. Lewontin (1979) p. 584Fortunately, the main body of the article is quite a bit better. Here's what John van Wyhe actually says about evolution.

Despite its baptism of fire, On the Origin of Species almost single-handedly convinced the international scientific community that evolution was a fact. In his 1889 book Darwinism, Wallace wrote of the revolution Darwin effected: "this totally unprecedented change in public opinion has been the result of the work of one man, and was brought about in the short space of twenty years!"

The theory of evolution has come a long way since. Today we think of it in terms of genes and DNA, but Darwin and Wallace had no idea of their existence. It was only in the 1930s and 1940s that genetics was incorporated into evolutionary theory. Even now, new discoveries are shaking up our understanding, but at the core of the modern theory remains Darwin’s idea of descent with modification.

Today evolution has many critics outside the scientific community, especially in the US, where a significant percentage of the population are creationists. What is forgotten is that the scientific debate over evolution was over by the 1870s and has never again been a matter of serious dispute.

Darwin showed that evolution is a fact and it's good that van Wyhe made this point in a article aimed at the general public. It's not good when he says "the core of the modern theory remains Darwin’s idea of descent with modification."

It's not good that he still refers to "THE" theory of evolution instead of "evolutionary theory," which encompasses all kinds of things other than natural selection.

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1. The title in the print edition is: "The Evolution Revolution."

The seven biggest problems in science

Here's an interesting article about the biggest problems in (American) science: The 7 biggest problems facing science, according to 270 scientists. Most of them apply to science in other countries.

I've added brief comments under six of the headings. Those are MY opinions, not necessarily those of the authors. The comment under #6 is a direct quote from the article.

1. Academia has a huge money problem.
   There's not enough money to do high quality science, especially basic science.
2. Too many studies are poorly designed. Blame bad incentives.
   Some experiments are poorly designed. All scientists are under pressure to make their results seem important.
3. Replicating results is crucial. But scientists rarely do it.
   Replication is important—especially in medical studies—but I think this problem is exaggerated.
4. Peer review is broken.
   The system (peer review) isn't working well. That doesn't mean there's a better system.
5. Too much science is locked behind paywalls.
   This was never a problem in the past when you had to go to the library to read science journals. You could photocopy whatever you wanted. Now it's a problem because we want instant access from our laptops.
6. Science is poorly communicated to the public.
   "But not everyone blamed the media and publicists alone. Other respondents pointed out that scientists themselves often oversell their work, even if it's preliminary, because funding is competitive and everyone wants to portray their work as big and important and game-changing.
   
   'You have this toxic dynamic where journalists and scientists enable each other in a way that massively inflates the certainty and generality of how scientific findings are communicated and the promises that are made to the public,' writes Daniel Molden, an associate professor of psychology at Northwestern University. 'When these findings prove to be less certain and the promises are not realized, this just further erodes the respect that scientists get and further fuels scientists desire for appreciation.'"
7. Life as a young academic is incredibly stressful.
   This is not just a problem for my younger colleagues. It affects all of us. It affects morale in an academic department and it affects the way science is done.

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Bastille Day

Today is the Fête Nationale in France known also as "le quatorze juillet" or Bastille Day.

This is the day in 1789 when French citizens stormed and captured the Bastille—a Royalist fortress in Paris. It marks the symbolic beginning of the French revolution although the real beginning is when the Third Estate transformed itself into the National Assembly on June 17, 1789 [Tennis Court Oath].

Ms. Sandwalk and I visited the site of the Bastille (Place de la Bastille) when we were in Paris in 2008. There's nothing left of the former castle but the site still resonates with meaning and history.

One of Ms Sandwalk's ancestors, William Playfair witnessed the storming of the Bastille.

In honor of the French national day I invite you to sing the French national anthem, La Marseillaise. An English translation is provided so you can see that La Marseillaise is truly a revolutionary call to arms. (A much better translation can be found here.)

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Check out Uncertain Principles for another version of La Marseillaise—this is the famous scene in Casablanca.

Reposted from 2009.

A genetics professor who rejects junk DNA

Praveen Sethupathy is a genetics professor at the University of North Carolina in Chapel Hill, North Carolina, USA.

He explains why he is a Christian and why he is "more than his genes" in Am I more than my genes? Faith, identity, and DNA.

Here's the opening paragraph ...

The word “genome” suggests to many that our DNA is simply a collection of genes from end-to-end, like books on a bookshelf. But it turns out that large regions of our DNA do not encode genes. Some once called these regions “junk DNA.” But this was a mistake. More recently, they have been referred to as the “dark matter” of our genome. But what was once dark is slowly coming to light, and what was once junk is being revealed as treasure. The genome is filled with what we call “control elements” that act like switches or rheostats, dialing the activation of nearby genes up and down based on whatever is needed in a particular cell. An increasing number of devastating complex diseases, such as cancer, diabetes, and heart disease, can often be traced back, in part, to these rheostats not working properly.

Science journal tries to fix problems with transparency and trustworthiness

The editors of Science recognize that they have a problem. They aren't very transparent or trustworthy. This is true. These same editors have been guilty of publishing and promoting lots of poor quality science over the past few years. Three examples come to mind ...

• Arseniclife: Science published a ridiculous claim that arsenic could replace phosphorus in DNA. That paper has been refuted but never retracted.
• Ardipithicus ramidus: Science fell for the authors' hype.
• ENCODE: Science falls for the hype promoted by ENCODE leaders. Editorial and feature writers announce the death of junk DNA

Don't worry. The editors have been working hard to fix the problem. After a year of study they announce their solution in the June 3, 2016 issue in the lead editorial: Taking up TOP. The author is the current Editor-in-Chief, Marcia McNutt.

She begins with ...

Nearly 1 year ago, a group of researchers boldly suggested that the standards for research quality, transparency, and trustworthiness could be improved if journals banded together to adopt eight standards called TOP (Transparency and Openness Promotion).* Since that time, more than 500 journals have been working toward their implementation of TOP. The editors at Science have held additional retreats and workshops to determine how best to adapt TOP to a general science journal and are now ready to announce our new standards, effective 1 January 2017.

So, what is TOP and how is it going to make Science more trustworthy? Does it involve firing some well-known writers and editors? Does it involve better reviewers?

Nope. TOP is just a way of making sure that raw data is available to other researchers.

... we believe the benefits of requiring the availability of data, code, and samples on which the authors' interpretations rest are worth the effort in compliance (and in some cases in adjusting data ownership expectations), while acknowledging that some special circumstances will require exemptions. This practice increases transparency, enables reproducibility, promotes data reuse, and is increasingly in line with funder mandates. We are also requiring the citation of all data, program code, and other methods not contained in the paper, using DOIs (digital object identifiers), journal citations, or other persistent identifiers, for the same reason. Citations reward those who originated the data, samples, or code and deposited them for reuse. Such a policy also allows accurate accounting for exactly which specific data, samples, or code were used in a given study.

That's not going to fix the main problem.

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Nature journal tries to fix the problem of a scientific literature that's too complex to understand

I recently posted some thoughts on the complexity of the scientific literature noting that many papers are simply too difficult to understand. This includes papers that are well within my areas of interest [How to read the scientific literature? and The scientific literature is becoming more complex].

Nature journal recognizes that there's a problem. A few weeks ago (June 16, 2016) they published a brief comment on Nature distilled.

They begin by describing the problem ...

Any journal that tries to publish the most important results that it is sent, in all fields of science, will run into the same problem. Every bit of our output, we hope, is useful and interesting to somebody somewhere. But even the most optimistic of our editors would concede that the pool of readership for each of these specific advances is only a small subsection of our audience, professional researchers included. To the outside world, science is science. To those who read Nature, science is a multiplicity of specialisms — and specialists.

We know that most of you are specialists, and that you don’t read most of what we present to you. You’re busy people. It is hard enough to follow the literature that you need to read. Even the titles of research papers in an unfamiliar field can look incomprehensible. But if you’re anything like us, one reason you got into science in the first place was curiosity about the world — and not just the tiny piece of it that you now focus on. Wouldn’t it be useful and interesting to keep better track of the rest? Or at least, the rest that is published in Nature, and therefore already judged to be important?

Let's make one thing clear. It's not just the complexity of a paper that's the problem and it's not just that the science isn't explained in easy to understand sentences. There's also the more serious problem of content. Sometimes the papers are hard to understand because the significance of the results is exaggerated and its importance is not placed in proper context.

The ENCODE papers are good examples of this problem. It wasn't easy to understand that they did but, more importantly, it wasn't easy to understand the significance of their results because the authors didn't explain their results very well. They made unsubstantiated claims.

Here's how Nature hopes to fix the problems they identified.

We think so, and this week we begin an experiment to see how many of you agree. We have revisited 15 recently published Nature papers and asked the authors to produce two-page summaries of each. The summaries remain technical — these are not articles suitable for the popular press — but they try to communicate both the research advance and why it matters. The authors of these papers have been enthusiastic — they want the broadest possible readership — and we thank them for their cooperation. Now we want to know what you think. The first three summaries are published online this week (see go.nature.com/1uhcy3x). The rest will be released in the coming weeks. Please take a look. Be brave — pick a topic that you expect to struggle with — and then fill in the online survey to let us know what you think. The rest will be released in the coming weeks. Please take a look. Be brave — pick a topic that you expect to struggle with — and then fill in the online survey to let us know what you think.

I looked at two papers that were about biology and I didn't think the summaries added anything to my understanding. That's partly because the papers weren't that hard to understand in the first place if you were just satisfied with knowing what they did.

Both papers raised lots of questions in my mind about the biological significance of the studies and whether they were accurate and reproducible. The author summaries didn't help much. [Non-coding recurrent mutations in chronic lymphocytic leukaemia and DNA-dependent formation of transcription factor pairs alters their binding specificity].

If the scientific literature is difficult to understand, and it is, then there's a problem with the authors. They aren't able to explain what they did in a reasonable manner and they aren't able to place their work in a proper context so we can evaluate the significance of the result. Asking them to try again (and doubling their citations) is probably not going to help.

The ENCODE authors couldn't do it.

It's a lot like asking the fox to guard the henhouse.

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What is a "gene" and how do genes work according to Siddhartha Mukherjee?

It's difficult to explain fundamental concepts of biology to the average person. That's why I'm so interested in Siddhartha Mukherjee's book "The Gene: an intimate history." It's a #1 bestseller so he must be doing something right.

My working definition of a gene is based on a blog post from several years ago [What Is a Gene?].

A gene is a DNA sequence that is transcribed to produce a functional product.

This covers two types of genes: those that eventually produce proteins (polypeptides); and those that produce functional noncoding RNAs. This distinction is important when discussing what's in our genome.

Paradigm shifting at the Royal Society meeting in November

Suzan Mazur has been making a name for herself by promoting the overthrow of modern evolutionary theory. She began with a lot of hype about the Alternberg 16 back in 2008 and continued with a series of interviews of prominent evolutionary biologists.

Now she's focused on the upcoming meeting in November as another attempt to shift paradigms [see New Trends in Evolutionary Biology: The Program]. She's not entirely wrong. Many of the people involved in those meeting see themselves as paradigm shifters.

TED-Ed misrepresents epigenetics

TED-Ed is the educational arm of TED. Here's what TED says about itself and about TED-Ed ...

TED believes passionately that ideas have the power to change attitudes, lives, and ultimately, the world. This underlying philosophy is the driving force behind all of TED’s endeavors, including the TED Conferences, TEDx, TED Books, the TED Fellows Program, and the TED Open Translation Project. With this philosophy in mind, and with the intention of supporting teachers and sparking the curiosity of learners around the world, TED-Ed was launched in 2012.

TED-Ed is TED’s youth and education initiative. TED-Ed’s mission is to spark and celebrate the ideas of teachers and students around the world. Everything we do supports learning — from producing a growing library of original animated videos , to providing an international platform for teachers to create their own interactive lessons, to helping curious students around the globe bring TED to their schools and gain presentation literacy skills, to celebrating innovative leadership within TED-Ed’s global network of over 250,000 teachers. TED-Ed has grown from an idea worth spreading into an award-winning education platform that serves millions of teachers and students around the world every week.

The scientific literature is becoming more complex

A recent paper by Cordero et al. (2016) looked at the biological scientific literature in 1993, 2003, and 2013. They found that the average publishable unit (APU) almost doubled in twenty years. There were substantial increases in the number of tables & figures and the number of panels per figure. The number of pages increased as did the number of references and the number of authors.

I agree that papers are becoming more complex and more difficult to understand for the average scientist; especially those outside of the specific field of study. The authors of this study point out a number of problems with this increase. I'd like to highlight one of them.

With respect to the number of authors, they say,

Concomitantly, with the increase in information density we note a significant increase in the number of authors per article that also correlated with the average IF of the journal. Since the famous de Solla Price predictions [38], trends toward an increasing number of authors per publication have been widely documented [23,39–44]. Such a trend of increasing collaboration could be explained by the causes suggested above for the growth of information density. The costs associated with the generation of cutting-edge scientific information, the funding restrictions, and the associated risks in scientific publishing in a “winner-take-all” reward system [45] may motivate scientists to team-up, pool resources and fractionate the risks through co-authoring. Also, the increasing complexity of scientific research has resulted in greater specialization of scientists [46], which in turn suggests that the inclusion of additional techniques requires the recruitment of additional investigators to provide that data and thus serve as co-authors. This trend could have both positive and negative consequences. Increased interaction between scientists in diverse fields could translate into greater communication and the possibility for advances at the interfaces of different disciplines. On the other hand, an increase in the number of authors, some of whom bring highly specialized knowledge, could result in reduced supervision of larger groups, and less responsibility per author for the final product and reduced integration of data.

I think the major consequence is the lack of responsibility of individual authors in a multi-author study. With increased specialization, there are fewer and fewer authors who see the big picture and who are capable of integrating the results from several subspecialties. The fact that the studies include work from several highly specialized techniques that only a few people understand also makes it harder for the average reader to evaluate the paper.

It's likely, in my opinion, that many of the authors on the paper don't fully understand the techniques being used by their colleagues. This is a big change from the science I grew up with.

Cordero et al. are worried about the possibility of fraud.

The growth in authors brings with it the concerns about the possibility that as more authors are added, there is an increased likelihood of some individuals with reduced integrity and capable of misconduct joining the group. In this regard, we note that the inclusion of one individual who has been accused of misconduct in numerous studies has led to dozens of retractions of scientific publications.

This is a very real danger but I think that outright fraud is not a significant worry. What concerns me more is the tendency to gloss over the limitations and possible misinterpretations of complex data analyses. The specialist who performs these analyses probably doesn't intend to misrepresent or exaggerate the significance of the result; it's just that they have become so used to using a particular technique (i.e. a software package) that they have forgotten those limitations. They don't communicate them to their colleagues who, because they don't understand the technique, don't realize there's a problem.

Cordero et al. summarize their results ....

In summary, our study documents a change in the literature of the biological sciences toward publications with more data over time. The causes for these trends are complex and probably include increasing experimental options and changes to the culture of science. At first glance, this data could be interpreted as a cultural change opposite to data fragmentation practices. However, it is also possible that an increase in publication density can still occur over a ‘salami slicing’ culture if the publication unit to be segregated is larger to begin with, as the result of technological improvements and increasing numbers of scientific authors. The benefits and debits of this trend for the scientific process are uncertain at this time but it is clear that there have been major changes to the nature of scientific publications in the past two decades that are likely to have major repercussions in all aspects of the scientific enterprise.

I think they're on to something.

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Cordero, R. J., de León-Rodriguez, C. M., Alvarado-Torres, J. K., Rodriguez, A. R., and Casadevall, A. (2016). Life Science’s Average Publishable Unit (APU) Has Increased over the Past Two Decades. PloS one, 11(6), e0156983. [doi: 10.1371/journal.pone.0156983]

How to read the scientific literature?

Science addressed the problem of How to (seriously) read a scientific paper by asking a group of Ph.D. students, post-docs, and scientists how they read the scientific literature. None of the answers will surprise you. The general theme is that you read the abstract to see if the work is relevant then skim the figures and the conclusions before buckling down to slog through the entire paper.

None of the respondents address the most serious problems such as trying to figure out what the researchers actually did while not having a clue how they did it. Nor do they address the serious issue of misleading conclusions and faulty logic.

I asked on Facebook whether we could teach undergraduates to read the primary scientific literature. I'm skeptical since I believe it takes a great deal of experience to be able to profitably read recent scientific papers and it takes a great deal of knowledge of fundamental concepts and principles. We know from experience that many professional scientists can be taken in by papers that are published in the scientific literature. Arseniclife is one example and the ENCODE papers published in September 2012 are another. If professional scientists can be fooled, how are we going to teach undergraduates to be skeptical?