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Showing posts with label Biochemistry. Show all posts
Showing posts with label Biochemistry. Show all posts

Saturday, July 30, 2016

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.

Sunday, July 10, 2016

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.

Thursday, April 28, 2016

Fun and games with Otangelo Grasso about photosynthesis

Otangelo Grasso just posted another one of his screeds. This time it's on photosynthesis. All of his "essays' conform to the same pattern. He looks for some complex set of biochemical reactions, usually in complex animals, then claims that it couldn't possibly have evolved because the whole thing is irreducibly complex according to his understanding of biochemistry and evolution.

It's a classic argument from ignorance.

In this case it's photosynthesis in flowering plants. He posted this figure from the Kegg database ....


Then he says,
In photosynthesis , 26 protein complexes and enzymes are required to go through the light and light independent reactions, a chemical process that transforms sunlight into chemical energy, to get glucose as end product , a metabolic intermediate for cell respiration. A good part of the protein complexes are uniquely used in photosynthesis. The pathway must go all the way through, and all steps are required, otherwise glucose is not produced. Also, in the oxygen evolving complex, which splits water into electrons, protons, and CO2, if the light-induced electron transfer reactions do not go all the five steps through, no oxygen, no protons and electrons are produced, no advanced life would be possible on earth. So, photosynthesis is a interdependent system, that could not have evolved, since all parts had to be in place right from the beginning. It contains many interdependent systems composed of parts that would be useless without the presence of all the other necessary parts. In these systems, nothing works until all the necessary components are present and working. So how could someone rationally say, the individual parts, proteins and enzymes, co-factors and assembly proteins not present in the final assemblage, all happened by a series of natural events that we can call ad hoc mistake "formed in one particular moment without ability to consider any application." , to then somehow interlink in a meaningful way, to form electron transport chains, proton gradients to " feed " ATP synthase nano motors to produce ATP , and so on ? Such independent structures would have not aided survival. Consider the light harvesting complex, and the electron transport chain, that did not exist at exactly the same moment--would they ever "get together" since they would neither have any correlation to each other nor help survival separately? Repair of PSII via turnover of the damaged protein subunits is a complex process involving highly regulated reversible phosphorylation of several PSII core subunits. If this mechanism would not work starting right from the beginning, various radicals and active oxygen species with harmful effects on photosystem II (PSII) would make it cease to function. So it seems that photosynthesis falsifies the theory of evolution, where all small steps need to provide a survival advantage.
I responded on Facebook, pointing out that the cytochrome bc complex and ATP synthase pre-date photosynthesis [Facebook: Photosynthesis]. I also pointed out that there are many living species that use only simpler versions of photsystem I or only photosystem II to carry out photosynthesis [e.g. A Simple Version of Photosynthesis]. Those nasty little facts don't seem to fit with his claim that, "In these systems, nothing works until all the necessary components are present and working."

I probably should have known better. Otangelo Grasso's standard response to such criticism is to avoid dealing directly with his false statements and shift the goalposts on to some other topic. He then posts all kinds of links to websites that seem to back up his claims even if they have nothing to do with the criticisms. You can see him at work on the Facebook thread.

It's pretty frustrating. I probably shouldn't respond to kooks, especially those who think they are experts in biochemistry.


Tuesday, March 22, 2016

How do you characterize these scientists?

We've been having a discussion on another thread about ID proponents. Are some of them acting in good faith or are they all lying and deceiving their followers?

I have similar problems about many scientists. I've been reading up on pervasive transcription and the potential number of genes for noncoding, functional, RNAs in the human genome. As far as I can tell, there are only a few hundred examples that have any supporting evidence. There are good scientific reasons to believe that most of the detected transcripts are junk RNA produced as the result of accidental, spurious, transcription.

There are about 20,000 protein-coding genes in the human genome. I think it's unlikely that there are more than a few thousand genes for functional RNAs for a total of less than 25,000 genes.

Here's one of the papers I found.
Guil, S. and Esteller, M. (2015) RNA–RNA interactions in gene regulation: the coding and noncoding players. Trends in Biochemical Sciences 40:248-256. [doi: 10.1016/j.tibs.2015.03.001]
Trends in Biochemical Sciences is a good journal and this is a review of the field by supposed experts. The authors are from the Department of Physiological Sciences II at the University of Barcelona School of Medicine in Barcelona, Catalonia, Spain. The senior author, Manel Esteller, has a Wikipedia entry [Manel Esteller].

Here's the first paragraph of the introduction.
There are more genes encoding regulatory RNAs than encoding proteins. This evidence, obtained in recent years from the sum of numerous post-genomic deep-sequencing studies, give a good clue of the gigantic step we have taken from the years of the central dogma: one gene gives rise to one RNA to produce one protein.
The first sentence is not true by any stretch of the imagination. The best that could be said is that there "may" be more genes for regulatory RNAs (> 20,000) but there's no strong consensus yet. Since the first sentence is an untruth, it follows that it is incorrect to say that the evidence supports such a claim.

It's also untrue to distort the real meaning of the Central Dogma of Molecular Biology, which never said that all genes have to encode proteins. The authors don't understand the history of their field in spite of the fact they are writing a review of that field.

Here's the problem. Are these scientists acting in good faith when they say such nonsense? Does acting in "good faith" require healthy criticism and critical thinking or is "honesty" the only criterion? The authors are clearly deluded about the controversy since they assume that it has been resolved in favor of their personal biases but they aren't lying. Can we distinguish between competent science and bad science based on such statements? Can we say that these scientists are incompetent or is that too harsh?

Furthermore, what ever happened to peer review? Isn't the system supposed to prevent such mistakes?


Wednesday, March 09, 2016

University of Toronto post-doc shares lab notes

The University of Toronto publicity department is making a big deal of Rachel Harding. She's a post-doc in the Structural Genomics Consortium (SGC). She works on Huntington's disease.

Here's the link to the press release and the first few paragraphs [Researcher is an Open Book: First to Share Lab Notes in Real Time].

Faculty of Medicine researcher Rachel Harding will be the first known biomedical researcher to welcome the world to review her lab notes in real time. The post-doctoral fellow with U of T’s Structural Genomics Consortium (SGC) is also explaining her findings to the general public through her blog. She hopes her open approach will accelerate research into Huntington’s disease.

“This should drive the process faster than working alone,” Harding says. “By sharing my notes, I hope that other scientists will critique my work, collaborate and share data in the early stages of research.” Her research at SGC is funded by CHDI Foundation, a non-profit drug-development organization exclusively dedicated to Huntington’s disease. Both organizations aim to accelerate research by making it open and collaborative.

Her approach is intended to leverage the experience of a community of scientists. Individual researchers often still work in relative isolation and then publish only their positive discoveries, usually years after the experiments were actually done. Thus, scientists often pursue similar ideas in parallel and miss many opportunities to learn from each other’s mistakes.

She has started by publishing raw data and play-by-play details of her first effort on the CERN open digital repository Zenodo. She also posts regular updates on her blog Lab Scribbles, where she includes an experimental summary written in lay terms.

It's been over 35 years since I first starting thinking and talking about electronic (computerized) lab notes1 and it's been over twenty years since I first heard discussions about putting them online. I seriously doubt that Rachel Harding is the first biomedical researcher to put lab notes on the web. I'm also very skeptical about her keeping up the practice for very long.

Not only is it boring and tedious to write your lab notes in a word processing program but it's kinda embarrassing to post everything you do in the lab. At least it would have been for me. I made lots of mistakes and there are lots of R-rated words and phrases in my notes.

Let's keep an eye on this experiments to see how it goes. So far there are four items on the Zenodo website. The first is a Word document containing a few brief notes from Jan. 6, 7, 9, 11 and 25. There are brief notes posted on Feb. 6 and two on Feb. 11. I hope this isn't the extent of her lab notes.

The blog is Lab Scribbles. There are a few posts. It's interesting but I'm not sure anyone is going to read it even if you're interested in Huntington's.

Has anyone else experimented with open lab notes?


1. I still have a few floppy disks with those attempts from about 1981. Unfortunately, I don't have a machine that can read them.

Tuesday, February 09, 2016

Junk DNA doesn't exist according to "Conceptual Revolutions in Science"

The blog "Conceptual Revolutions in Science" only publishes "evidence-based, paradigm-shifting scientific news" according to their home page.

The man behind the website is Adam B. Dorfman (@DorfmanAdam). He has an MBA from my university and he currently works at a software company. Here's how he describes himself on the website.

Saturday, February 06, 2016

A DNA quiz

Jerry Coyne discovered a Quiz on DNA. He calls is a so-so quiz on DNA. He says that one question is really, really, dumb. I disagree, I think there are several dumb questions.

I tried it and got a score of 19/19 in just under four minutes. This is misleading since you have to get every question right before continuing on to the next question. I had to anticipate what the authors wanted in order to proceed.

Try the quiz yourself before reading any further. There are spoilers below!

Thursday, January 28, 2016

Where did the glucose come from?

Currently there are two distinct views on the origin of life. The majority of scientists think that life arose in a prebiotic soup of complex organic molecules. Most of them think this "warm little pond" was the ocean (!) and most of them have bought into the stories about asteroids and comets delivering complex organic molecules to create a soup of amino acids and sugars. Presumably, all the earliest forms of life had to do was to join together the amino acids to make proteins and hook up the nucleotides to make RNA. The energy for these reactions was derived from breaking down all the glucose in the sweet ocean.

Friday, January 22, 2016

An undergraduate biochemistry lecture converts an atheist to Christianity

I'm reading Creation or Evolution: Do we have to choose? by Denis Alexander in preparation for our discussion next Friday at Wycliffe College on the University of Toronto downtown campus [Discussing the conflict between science and religion with Denis Alexander].

Denis Alexander is a biochemist at the University of Cambridge (UK). I thought I'd share one of the stories in his book.
At the church I attend in Cambridge we baptised an undergraduate in the natural sciences who had come to a personal, saving faith in Christ from a completely atheistic background. As is usual in our church, just before being baptised she explained publicly to the whole congregation how she had become a Christian, telling us she had become convinced there must be a God while sitting through a standard biochemistry lecture, hearing the amazing story of how two meters (about six feet) of DNA are packaged into a single cell. Of course the lecturer was not talking in religious terms at all, but she described to us how the beauty of that engineering feat overwhelmed her as she listened, giving her the deep intuition there must be a God, so leading her onward in he personal pilgrimage to put her trust in this creator God through Christ. Truly natural theology at work!
That got me thinking. I've been describing chromatin and packing in my textbooks since the first version in 1987. There must have been several hundred thousand students who have read my descriptions since then.

I wonder how many I've converted?


Tuesday, December 15, 2015

How many different proteins are made in a typical human cell?

There are about 20,000 protein-coding genes in the human genome. Protein products for about 18,000 of these genes have been detected in at least one human tissue (Kim et al, 2015; Wilhelm et al., 2015) [see How many proteins do humans make?].

About 10,000 of these proteins are present in all cells (Wilhelm et al., 2015) and somewhere between 1500 and 2000 are derived from genes that are essential in the average human cell (Blomen et al., 2015; Wang et al, 2015; Hart et al., 2015) [see How many human protein-coding genes are essential for cell survival?].

Let's assume there are about 10,000 protein-coding genes that are expressed in a typical human cell. Does this mean that there are only 10,000 different proteins in those cells? The answer is "no" but the differences are often subtle. The activities of some proteins, for example, are regulated by covalent modification so a typical cell will contain different versions of the protein: some are modified and some are not (e.g. phosphorylated and non-phosphorylated). These would be genuine versions of different proteins although you probably wouldn't want to make a fuss about it.

In some cases, there are various intermediates produced during protein synthesis. For example, some proteins destined for the mitochondria have an N-terminal tag that's cleaved when the proteins reach their destination. There are two different versions of the protein but, again, this isn't really a big deal. We should really only count the steady-state, terminal, stage of processing and modification.

Similarly, there are proteins that are glycosylated in various ways and cells will always contain intermediates including non-glycosylated versions that have just entered the ER. These don't count as different versions of the protein.

Some genes are alternatively spliced to give proteins that have different internal amino acid sequences. These are genuinely different proteins produced from the same gene.

If you add up all the genuinely different versions of proteins produced from 10,000 protein-coding genes, how many proteins are present in a typical human cell?

Here's a standard answer given in a recent news article in Nature (Savage, 2015)
The human body contains roughly 20,000 genes that are capable of producing proteins. Each gene can produce multiple forms of a protein, and these in turn can be decorated with several post-translational modifications: they can have phosphate or methyl groups attached, or be joined to lipids or carbohydrates, all of which affect their function. “The number of potential molecules you can make from one gene is huge,” says Bernhard Küster, who studies proteomics at the Technical University of Munich in Germany. “It's very hard to estimate, but I wouldn't be surprised to have in one cell type 100,000 or more different proteins.”
I suspect that Küster is one of those scientists who think that almost all human protein-coding genes are alternatively spliced to yield several different proteins in each cell. He has to imagine that there are, on average, ten different versions of a protein produced from each gene that's expressed in a typical cell.

That means ten different versions of each of the subunits of pyruvate dehydrogenase and RNA polymerase. It means ten different versions of triose phosphate isomerase and each of the ribosomal proteins. There should be ten different versions of actin and ten different versions of cytochrome c.

This seems very unlikely to me.

Discuss.

(There may be a few genes that have thousands of different variants, although I'm skeptical. In that case there may be 100,000 different proteins in a human cell but surely this is misleading even if it's accurate?)


Blomen, V.A., Májek, P., Jae, L.T., Bigenzahn, J.W., Nieuwenhuis, J., Staring, J., Sacco, R., van Diemen, F.R., Olk, N., and Stukalov, A. (2015) Gene essentiality and synthetic lethality in haploid human cells. Science, 350:1092-1096. [doi: 10.1126/science.aac7557 ]

Hart, T., Chandrashekhar, M., Aregger, M., Steinhart, Z., Brown, K.R., MacLeod, G., Mis, M., Zimmermann, M., Fradet-Turcotte, A., and Sun, S. (2015) High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities. Cell 163:1515-1526. [doi: 10.1016/j.cell.2015.11.015]

Kim, M.-S., Pinto, S.M., Getnet, D., Nirujogi, R.S., Manda, S.S., Chaerkady, R., Madugundu, A.K., Kelkar, D.S., Isserlin, R., Jain, S., Thomas, J.K., Muthusamy, B., Leal-Rojas, P., Kumar, P., Sahasrabuddhe, N.A., Balakrishnan, L., Advani, J., George, B., Renuse, S., Selvan, L.D.N., Patil, A.H., Nanjappa, V., Radhakrishnan, A., Prasad, S., Subbannayya, T., Raju, R., Kumar, M., Sreenivasamurthy, S.K., Marimuthu, A., Sathe, G.J., Chavan, S., Datta, K.K., Subbannayya, Y., Sahu, A., Yelamanchi, S.D., Jayaram, S., Rajagopalan, P., Sharma, J., Murthy, K.R., Syed, N., Goel, R., Khan, A.A., Ahmad, S., Dey, G., Mudgal, K., Chatterjee, A., Huang, T.-C., Zhong, J., Wu, X., Shaw, P.G., Freed, D., Zahari, M.S., Mukherjee, K.K., Shankar, S., Mahadevan, A., Lam, H., Mitchell, C.J., Shankar, S.K., Satishchandra, P., Schroeder, J.T., Sirdeshmukh, R., Maitra, A., Leach, S.D., Drake, C.G., Halushka, M.K., Prasad, T.S.K., Hruban, R.H., Kerr, C.L., Bader, G.D., Iacobuzio-Donahue, C.A., Gowda, H., and Pandey, A. (2014) A draft map of the human proteome. Nature, 509:575-581. [doi: 10.1038/nature13302]

Savage, N. (2015) High-protein research. Nature 527:S6-S7. [doi: 10.1038/527S6a]

Wang, T., Birsoy, K., Hughes, N.W., Krupczak, K.M., Post, Y., Wei, J.J., Lander, E. S., and Sabatini, D.M. (2015) Identification and characterization of essential genes in the human genome. Science, 350:1096-1101. [doi: 10.1126/science.aac7041]

Wilhelm, M., Schlegl, J., Hahne, H., Gholami, A.M., Lieberenz, M., Savitski, M.M., Ziegler, E., Butzmann, L., Gessulat, S., Marx, H., Mathieson, T., Lemeer, S., Schnatbaum, K., Reimer, U., Wenschuh, H., Mollenhauer, M., Slotta-Huspenina, J., Boese, J.-H., Bantscheff, M., Gerstmair, A., Faerber, F., and Kuster, B. (2014) Mass-spectrometry-based draft of the human proteome. Nature, 509:582-587. [doi: 10.1038/nature13319]

Sunday, November 29, 2015

Motoo Kimura calculates a biochemical mutation rate in 1968

I recently had occasion to re-read a paper by Motoo Kimura from 1968. (Kimura, 1968). I noticed, for the first time, that he estimates a mutation rate based on his understanding of the error rate of DNA replication. He also makes a comment about creationists.

Remember, this was in 1968 and we didn't know as much then as we do now. Kimura took note of the fact that evolutionary trees based on comparing amino acid sequences gave rates of amino acid substitutions that seemed far too high. His conclusion is in the abstract.

Friday, November 20, 2015

Different kinds of pseudogenes: Polymorphic pseudogenes

There are three main kinds of pseudogenes: processed pseudogenes, duplicated pseudogenes, and unitary pseudogenes [Different kinds of pseudogenes - are they really pseudogenes?].

There's one sub-category of pseudogenes that deserves mentioning. It's called "polymorphic pseudogenes." These are pseudogenes that have not become fixed in the genome so they exist as an allele along with the functional gene at the same locus. Some defective genes might be detrimental, representing loss-of-function alleles that compromise the survival of the organism. Lots of genes for genetic diseases fall into this category. That's not what we mean by polymorphism. The term usually applies to alleles that have reached substantial frequency in the population so that there's good reason to believe that all alleles are about equal with respect to natural selection.

Polymorphic pseudogenes can be examples of pseudogenes that are caught in the act of replacing the functional gene. This indicates that the functional gene is not under strong selection. For example, a newly formed processed pseudogene can be polymorphic at the insertion site and newly duplicated loci may have some alleles that are still functional and others that are inactive. The fixation of a pseudogene takes a long time.

Different kinds of pseudogenes: Unitary pseudogenes

The most common types of pseudogenes are processed pseudogenes and those derived from gene duplication events [duplicated pseudogenes].

The third type of pseudogene is the "unitary" pseudogene. Unitary pseudogenes are genes that have no parent gene. There is no functional gene in the genome that's related to the pseudogene.

Unitary psedogenes arise when a normally functional gene becomes inactivated by mutation and the loss of function is not detrimental to the organism. Thus, the mutated, inactive, gene can become fixed in the population by random genetic drift.

The classic example is the gene for L-glucono-γ-lactone oxidase (GULO), a key enzyme in the synthesis of vitamin C (L-ascorbate, ascorbic acid). This gene is functional in most vertebrate species because vitamin C is required as a cofactor in several metabolic reactions; notably, the processing of collagen [Vitamin C]. This gene has become inactive in primates so primates cannot synthesize Vitamin C and must obtain it from the food they eat.

A pseudogene can be found at the locus for the L-glucono-γ-lactone oxidase gene[GULOP = GULO Pseudogene]. It is a highly degenerative pseudogene with multiple mutations and deletions [Human GULOP Pseudogene]


This is a unitary pseudogene. Unitary pseudogenes are rare compared to processed pseudogenes and duplicated pseudogenes but they are distinct because they are not derived from an existing, functional, parent gene.

Note: Intelligent design creationists will go to great lengths to discredit junk DNA. They will even attempt to prove that the GULO pseudogene is actually functional. Jonathan Wells devoted an entire chapter in The Myth of Junk DNA to challenging the idea that the GULO pseudogene is actually a pseudogene. A few years ago, Jonathan McLatchie proposed a mechanism for creating a functional enzyme from the bits and pieces of the human GULOP pseudogene but that proved embarrasing and he retracted [How IDiots Would Activate the GULO Pseudogene] Although some scientists are skeptical about the functionality of some pseudogenes, they all accept the evidence showing that most psuedogenes are nonfunctional.


Different kinds of pseudgogenes: Duplicated pseudogenes

Of the three different kinds of pseudogenes, the easiest kind of pseudogene formation to understand is simple gene duplication followed by inactivation of one copy. [see: Processed pseudogenes for another type]

I've assumed, in the example shown below, that the gene duplication event happens by recombination between sister chromosomes when they are aligned during meiosis. That's not the only possibility but it's easy to understand.

These sorts of gene duplication events appear to be quite common judging from the frequency of copy number variations in complex genomes (Redon et al., 2006; MacDonald et al., 2013).


Wednesday, November 18, 2015

Different kinds of pseudogenes: Processed pseudogenes

Let's look at the formation of a "processed" pseudogene. They are called "processed" because they are derived from the mature RNA produced by the functional gene. These mature RNAs have been post-transcriptionally processed so the pseudogene resembles the RNA more closely than it resembles the parent gene.

This is most obvious in the case of processed pseudogenes derived from eukaryotic protein-coding genes so that's the example I'll describe first.

In the example below, I start with a simple, hypothetical, protein-coding gene consisting of two exons and a single intron. The gene is transcribed from a promoter (P) to produce the primary transcript containing the intron. This primary transcript is processed by splicing to remove the intron sequence and join up the exons into a single contiguous open reading frame that can be translated by the protein synthesis machinery (ribosomes plus factors etc.).1 [See RNA Splicing: Introns and Exons.]

Different kinds of pseudogenes - are they really pseudogenes?

I define a gene as "DNA sequence that is transcribed to produce a functional product" [What Is a Gene? ]. Genes can encode proteins or the final product can be a functional RNA other than mRNA.

A pseudogene is a broken gene that cannot produce a functional RNA. They are called "pseudogenes" because they resemble active genes but carry mutations that have rendered them nonfunctional. The human genome contains about 14,000 pseudogenes related to protein-coding genes according to the latest Ensembl Genome Reference Consortium Human Genome build [GRCh38.p3]. There's some controversy over the exact number but it's certainly in that ballpark.1

The GENCODE Pseudogene Resource is the annotated database used by Ensembl and ENCODE (Pei et al. 2012).

There are an unknown number of pseudogenes derived from genes for noncoding functional RNAs. These pseudogenes are more difficult to recognize but some of them are present in huge numbers of copies. The Alu elements in the human genome are derived from 7SL RNA and there are similar elements in the mouse genome that are derived from tRNA genes.

There are three main classes of pseudogenes and one important subclass. The categories apply to pseudogenes derived from protein-coding genes and to those derived from genes that specify functional noncoding RNAs. I'm going to describe each of the categories in separate posts. I'll mostly describe them using a protein-coding gene as the parent.

1. Processed pseudogenes [Processed pseudogenes ]
2. Duplicated pseudogenes [Duplicated pseudogenes ]
3. Unitary pseudogenes [Unitary Pseudogenes]
4. subclass: Polymorphic pseudogenes [Polymorphic Pseudogenes]

Friday, November 13, 2015

The 2015 Nobel Prize in Chemistry: was the history of the discovery of DNA repair correct?

... those ignorant of history are not condemned to repeat it; they are merely destined to be confused.

Stephen Jay Gould
Ontogeny and Phylogeny (1977)
Back when the Nobel Prize in Chemistry was announced I was surprised to learn that it was for DNA repair but Phil Hanawalt wasn't a winner. I blogged about it on the first day [Nobel Prize for DNA repair ].

I understand how difficult it is to choose Nobel Laureates in a big field where a great many people make a contribution. That doesn't mean that the others should be ignored but that's exactly what happened with the Nobel Prize announcement [The Nobel Prize in Chemsitry for 2015].
In the early 1970s, scientists believed that DNA was an extremely stable molecule, but Tomas Lindahl demonstrated that DNA decays at a rate that ought to have made the development of life on Earth impossible. This insight led him to discover a molecular machinery, base excision repair, which constantly counteracts the collapse of our DNA.
Maybe it's okay to ignore people like Phil Hanawalt and others who worked out mechanisms of DNA repair in the early 1960s but this description pretends that DNA repair wasn't even discovered until ten years later.

I published links to all the papers from the 1960s in a follow-up post [Nature publishes a misleading history of the discovery of DNA repair ].

By that time I was in touch with David Kroll who was working on an article about the slight to early researchers. He had already spoken to Phil Hanawalt and discovered that he (Hanawalt) wasn't too upset. Phil is a really, really nice guy. It would be shocking if he expressed disappointment or bitterness about being ignored. I'll do that for him!

The article has now been published: This Year’s Nobel Prize In Chemistry Sparks Questions About How Winners Are Selected.

Read it. It's very good.


Friday, November 06, 2015

The cost of a new gene

Let's think about the biochemical cost associated with adding some new piece of DNA to an existing genome. Michael Lynch has been thinking about this for a long time. He notes that there certainly IS a cost (burden) because the new bit of DNA has to be replicated. That means extra nucleotides have to be synthesized and polymerized every time a cell replicates.

This burden might seem prohibitive for strict adaptationists1 since everything that's detrimental should be lost by negative selection. Lynch, and others, ague that the cost is usually quite small and if it's small enough the detrimental effect might be below the threshold that selection can detect. When this happens, new stretches of DNA become effectively neutral (nearly neutral) and they can be fixed in the genome by random genetic drift.

The key parameter is the size of the population since the power of selection increases as the population size increases. Populations with large numbers of individuals (e.g. more than one million) can respond to the small costs/burdens and eliminate excess DNA whereas populations with smaller numbers of individuals cannot.

Monday, November 02, 2015

Evolution as a foundational concept in biochemistry and molecular biology

The American Society for Biochemistry and Molecular Biology (ASBMB) has been promoting a new way of teaching undergraduate courses. The idea is to concentrate on fundamental principles and concepts rather than on trivial details. The various working groups came up with a list of these fundamental concepts under five main headings: Evolution; Matter and Energy Transformation; Homeostasis; Macromolecular Structure & Function; and Biological Information.

I've discussed the concepts before [ASBMB Core Concepts]. There are problems.

Various committees continue to meet in order to build a "concept inventory" to guide the new curriculum. There have been a series of workshops organized around the main themes. The participants in the workshops are, for the most part, teachers at small universities and colleges. They have lots of experience teaching undergraduate courses but they aren't necessarily experts in the subject material.

I saw this clearly when I attended a session at the last Experimental Biology meeting in Boston last April. The purpose of the meeting was to review the major concepts in Evolution and Homeostasis. I met a great deal of resistance from the workshop leaders when I tried to explain the concepts of neutral alleles and random genetic drift and show them why they were so important when comparing sequences and constructing phylogenetic trees.
INTEGRATING EVOLUTION AND HOMEOSTASIS WITH THE CORE CONCEPTS OF BIOCHEMISTRY AND MOLECULAR BIOLOGY
Symposium Tues. 9:45 am Boston Convention & Exhibition Center, room 256

Chaired: E. Bell

9:45 RCN-UBE: Integrating Evolution and Homeostasis with the Core Concepts of Biochemistry and Molecular Biology J.E. Bell, A. Aguanno, P. Mertz, M. Johnson and K.M. Fox. Univ. of Richmond, Union Col., NY, Univ. of Alabama, St Mary’s Col. of Maryland and Marymount Manhattan. (559.2)

Presenters:
Small Group Work: Integrating Evolution and Homeostasis into the Core Concepts E. Bell, Univ. of Richmond A. Aguanno, Marymount Manhattan Col.

Group Discussion on Core Concept integration with Homeostasis A. Aguanno, Marymount Manhattan Col.

Small Group Work: Question Development Involving Evolution and Homeostasis M. Johnson, Univ. of Alabama

Group Presentations and Discussion on Question Implementation K. Fox. Union Col.
This same group has published some of their findings in the July/August issue of the education journal, Biochemistry and Molecular Biology Education (BAMBED)1 (Aguanno et al. 2015).

Here are the learning objectives they have developed under the "Evolution" concept.
  • central importance of the theory of evolution
  • Darwin's theory of evolution
  • process of natural selection
  • evidence for the theory of evolution
  • molecular basis of natural selection
I really think this misses the boat in a biochemistry context where molecular evolution plays such an important role. It will be hard to discuss genome organization and junk DNA, for example, if students don't know about population genetics and random genetic drift. It will be hard to explain (correctly) why different proteins in different species have different amino acid sequences if students don't know about neutral alleles.

I pointed this out to the authors at the meeting and stimulated a discussion about these concepts. The authors, and the other teachers in the room, were pretty certain that the differences in amino acid sequences were all due to natural selection. Most of them had never heard of random genetic drift.

The problem here is that the learning objectives and the "capstone experiences" are being developed by teachers who don't really understand evolution. It is assumed that the best people to work on the new curriculum are experienced teachers but that's demonstrably false. (It applies to the other concepts as well.)

It turns out that biochemistry professors are not as knowledgeable about core concepts as you might imagine.

The authors surveyed 161 teachers in 143 institutions across the USA to find out what are the most important concepts in a biochemistry and//or molecular biology course.

The results, right, indicate that less than 8% of the respondents thought that evolution was an important concept.

This could be due, in part, to the fact that biochemistry courses are often taught by professors who are members of a chemistry department but no matter what the explanation it looks like we have a lot of work ahead of us if we are going to convince our colleagues to make evolution a core concept.

I'm pretty sure that many of the people who teach our introductory biochemistry courses at the University of Toronto don't see evolution as a core concept and don't understand modern evolutionary theory.


1. Disclaimer: I am on the editorial board of that journal.

Aguanno, A., Mertz, P., Martin, D., and Bell, E. (2015) A National Comparison of Biochemistry and Molecular Biology Capstone Experiences. BAMBED 43:223-232. [doi: 10.1002/bmb.20869]

Sunday, November 01, 2015

More stupid hype about lncRNAs

I've just posted an article about a group of scientists at UCLA who claimed to have discovered 3,000 new genes in the human genome [3,000 new genes discovered in the human genome - dark matter revealed].

They did no such thing. What they discovered was about 3,000 previously unidentified transcripts expressed at very low levels in human B cells and T cells. They declared that these low-level transcripts are lncRNAs and they assumed that the complementary DNA sequences were genes. Their actual result identifies 3,000 bits of the genome that may or may not turn out to be genes. They are PUTATIVE genes.

None of that deterred Karen Ring who blogs at The Stem Cellar: The Official Blog of CIRM, California's Stem Cell Agency. Her post on this subject [UCLA Scientists Find 3000 New Genes in “Junk DNA” of Immune Stem Cells] begins with ...