Life is a Struggle...to define.

There was an interesting blog post on a recent meeting of the AAAS - the organization that publishes Science magazine, that you might've missed since it came out on Valentine's Day. But one of the questions that scientists had gathered to address was "If we came across alien life, would we even know it was alive?"

It's an interesting question that emphasizes that we are good at looking for what we already know, and struggle somewhat to define how to look for something we haven't found yet. While this obviously applies to the search for extraterrestrial life in strange places like the hydrocarbon seas of Titan, it also applies to "The Shadow Biosphere" that represents life on earth that we haven't yet discovered.  While the term Shadow Biosphere refers to Life of a fundamentally different nature than DNA-based life, it's worth pointing out that plenty of strange DNA-based life has only been discovered recently: Annamox bacteria, novel microbial communities deep in the ocean and even new viruses of unusual size.

This highlights the fact that when it comes to defining Life, we are best to admit that the definition may change and when it does it will likely be from someone figuring out how to find something super cool.

More on this topic and the origin of life:

1 The cellular/acellular divide
2 Magma oceans and marauding asteroids
3 The First Language
4 The Singularity (x 3)
5 To Catch a Predator

Is Google responsible for telling the truth?

Wanted: A truth engine

You might have noticed that when you do a search on Google, you don't always get the same format of results. Sometimes you'll see Ads first, or a local map, or a Flashcard-looking-thing like this:

This is a fairly good, quick--and true--description of thermodynamics. And Google was smart enough to know that I wasn't looking to buy a really snazzy, dynamic thermos. So good job on that one. However, the next result isn't quite as good:

Ah, so here the movie "Gravity" takes full precedence over the scientific concept, Gravity. It's a good movie, I liked the bit with the bookcases and all*, but to me Google fails here to provide truth before advertising. If you type in "gravity definition" then you get the truth about the concept Gravity. 

Google’s search algorithms are somewhat explained here, and if nothing else it makes you realize that the process of filtering out the spam websites is, by itself, a hugely daunting task that Google does a great job with. After the Spam has been filtered then Google has an important decision to make on what to show first: Ads, Popularity, Truth? It makes a big difference what is shown first, and these 3 categories can have totally different top hits. 

After talking with a friend that used to work at Google, he brought up the point that displaying websites with factual information (Truth first) might be perceived by government regulatory agencies as a form of bias. As in, truth might be perceived differently by different people. Nonetheless, since I’m often searching for sciencey stuff -- fact-driven webpages with good summaries and links to research studies -- it's frustrating when Google thinks I'm shopping for lingerie (Wait, that's Facebook that thinks I always want lingerie, they seem to be even further behind the curve). 

But it’s hard to know how all the different search filters play out unless you test how google responds to different searches. Here's two more sad examples: 

When you search for “Evolution” the factual blurb doesn’t pop up and the top results include some conspicuous results. Why not a quick definition here?

Evolution: Populations change over time. 

Would this 4 word definition be so traumatic to display? I somehow think the internet would survive. And I find it strange that no "knowledge card" pops up. 

Here's one more peculiar one:

Aside from the poor sentence structure in the definition for "GMOs" the knowledge card includes a picture of a lime photoshopped with an apple. This is not a GMO or any living organism, just a fabricated image. Here again Google could do much to improve. 

So, that's why it would be great to have a truth engine, a way to distinguish facts from opinions. I’m looking forward to having a button next to “I'm feeling lucky” that says, “I'm feeling truthy” or “I can handle the truth” or some other pithy remark. I have hopes that there are enough sciency-oriented people at Google that they will get there eventually.   

*EDIT: Apparently I was thinking of "Interstellar" when I wrote this. "Gravity" is the one where astronauts are doing Satellite repairs and such. My bad. 

The Laws of Genetics

The Mendelian Laws of Genetics are really peculiar. They’re ubiquitous in textbooks on genetics, as it would seemingly be very important to clearly state what the basic, underlying principles are for the subject. But there are several problems with Mendel’s Laws. The first issue is that Mendel did not actually try to claim that what he was studying were fundamental laws of nature that would apply to all organisms  (see On the Origins of the Mendelian Laws – good title). Instead, they were inferred from Mendel’s work on pea plants and codified by later geneticists into law. According to the above source, they first appeared in the form of “Two Mendelian Laws” in the writings of Thomas Morgan. So, they might more properly be called ‘Morgan’s Laws’ or just ‘The Laws of Genetics’. 

Next up is how many laws there should be, I thought I was pushing the envelope when I first taught students that they should consider a 3^rd law (The Law of Dominance) to best understand Mendelian genetics. But if you look around several others also use this third law, even though the 3^rd law is not often attributed to Mendel because it had been shown by others before him. But, if we’re just considering fundamental “Laws of Genetics” rather than “Things Mendel Wrote First,” then this 3^rd Law on Dominant vs. Recessive traits is really quite useful.  

Which brings us to the final issue – usefulness. For something to be called a “Law” one would hope that it describes something that is always true. Both of the 2 classic Mendelian Laws have situations where they do not hold true. It doesn’t mean they’re wrong, it’s just that they don’t always apply.

So what we have with “Mendel’s Laws” are a small set of dubiously named, non-comprehensive and not always applicable rules. It's important to note that this is not a rare footnote – these are rules that every Genetics student learns!! As an avid board game player, I very much like for the rules to be written out clearly.

So, here’s an updated list of Genetics Laws according to no one but me. The only criterion being that they are unique concepts that are fundamental to genetics. 

So, here are 12 fundamental principles of genetics, that every genetics student should be familiar with.

The Mendelian Laws

   1) Segregation.

   2) Independent Assortment.

   3) Dominance.

The Central Dogma Laws

   4) Information Storage. 

   5) Chemical Language.

   6) DNA Repair.

The Molecular Genetics Laws

   7) Regulation.

   8) Modulation. 

   9) Epigenetics.

 The Population Genetics Laws
  10) Gene Duplication.
  11) Horizontal Gene Transfer.

  12) The Law of Evolution

The Mendelian Laws

Mitotic spindles (green) segregate chromosomal DNA (blue).
Microtubule proteins connect to chromosomes through kinetochores (red)

1) The Law of Segregation. There are two copies of each genetic unit (genes). Parents produce gametes with half the total number of genes. Offspring receive one copy of each gene from each parent, so that they also have two copies of each gene.

Caveat: This is true for all diploid organisms with a sexual life cycle. It is not true for haploid, triploid, tetraploid, hexaploid, etc organisms. Similar but not identical rules apply. For instance, haploid organisms receive one copy of each gene from a single haploid parent. Some organisms can switch between sexual and asexual reproduction, giving further complexity. 

 

Siblings are rarely identical, due to the combination of Laws 1 and 2.

2) The Law of Independent Assortment. Each genetic unit is inherited independently such that offspring show a combination of traits rather than showing all of the traits of one parental phenotype over the other. 

T. Morgan's initial hypothesis of chromosomal
recombination to explain genetic linkage.

Caveat: This is true for all traits that are on separate chromosomes or are very distant from each other on the same chromosome. This is not always true, as some genes are located very close to each other on the same chromosome. Two such genes are “linked” and will most often be transmitted to offspring together at a higher frequency than independent assortment would predict due to the spatial constraints of recombination.
 

3) Dominance. Each gene can potentially have several variants, or alleles. The character of these variants can be described as either dominant or recessive. Dominant traits are observed under two conditions: when there are two copies of the dominant allele (homozygous dominant) or when there is only one copy of the dominant allele (heterozygous state). Recessive traits are only observed when there are two copies of the recessive allele (homozygous recessive). Dominance was critical to Mendel's work but not discovered by Mendel, so this is sometimes not listed as a Mendelian Law. Nonetheless, it is essential to experimental observation of Laws 1 and 2.

Caveat: There are several situations that complicate the Law of Dominance. For example, co-dominance can occur, such as A and B blood types (both are dominant over blood type O). Incomplete dominance can occur, such as wavy hair (curly hair is dominant but does not express at the same high levels in heterozygotes). Importantly, dominance is often caused by functional genetic variants (alleles), while recessive traits are often due to non-functional alleles.  

The ABO blood types can be explained through phenotypic expression
of cell surface molecules A and B. O is the lack of either molecule.  

The Central Dogma Laws

These laws summarize what is often called The Central Dogma, which describes the basic molecular understanding of genetics that came from the work of Watson, Crick, Franklin, Brenner, Nirenberg, Khorana, Lindahl, Modrich, Sancar, etc. These laws stem from the discovery of DNA and that all cells share a molecular architecture for DNA, RNA and protein synthesis.

4) Information Storage.  Complementary strands of DeoxyriboNucleic Acid polymers (DNA) store information and are the genetic material responsible for the inheritance of traits from parent to offspring. DNA polymers are made by DNA polymerase enzymes that “read” a template strand and synthesize a complementary strand. DNA polymerases make mistakes with predictable frequency (see #9 Law of Repair). Replication of DNA occurs prior to cell division and results in two new helices of double stranded DNA (dsDNA), each double helix containing one old and one new strand of DNA. All of the genetic material of an individual is carried within cells on one or more chromosome(s), with all of the material together called a genome. 

Double helical ball and stick model of the B form of DNA, showing the major
and minor grooves. DNA consists of only 5 elements (C, O, P, N and H) and four distinct
nucleotides: the single ring pyrimidines (T, C) and double ring purines (A, G).

Caveat: While double stranded DNA (dsDNA) is the primary genetic material, there are some exceptions, such as single stranded (ssDNA) or RNA viruses.  RNA, rather than DNA, may have been the primary genetic material at the very beginning of life on planet earth. Also, several artificial genetic materials have been produced, so it is important to note that there is nothing magical about DNA. However, relative to RNA, DNA is more stable and understanding of DNA is critical to understanding of genetic variation, expression and evolution.

Note: I didn’t re-number the Laws, but if I had this Law on Information Storage would be Law #1. Understanding DNA, how it carries information and how fragile DNA is (see law #6) are really the most fundamental concepts in genetics.  

5) Chemical Language. DNA carries information in a language that can be interpreted and translated by the cell. One gene may code for one (or more) gene product(s). Gene products include functional RNAs as well as proteins. Each DNA gene sequence codes for an RNA of complementary sequence that can be formed by RNA polymerase enzymes. Most RNAs (but not all) then serve as a template for translation by ribosomes (amino acid polymerizing enzymes) into proteins that are 1/3 the sequence length of the RNA message due to the triplet organization of the genetic code. Thus, 1200 units of DNA sequence will yield 1200 units of RNA sequence, but only 400 units of protein sequence. Because of the cellular hierarchy of DNA to RNA to protein, mistakes in RNA or protein synthesis are less consequential than mistakes in DNA synthesis.

The ancient and mysterious ribosome is central to translating two chemical languages,
from RNA nucleotides to amino acids for proteins. 

Caveat: This processing of information holds true across all organisms. However, some RNAs can be translated into multiple proteins through multicistronic (many gene) messages or through RNA exon shuffling. Some mechanisms (like latent retroviruses) turn RNA information into DNA. 

DNA repair relies on many mechanisms and
it's essential for all cells, every day.

6) Repair. DNA polymers are fragile and subjected to a ceaseless assault of damaging events from external and internal sources. The fragility of DNA guarantees that DNA will change over time. Because cells have been subject to damage throughout the history of life, cells are prepared for this battle. The vast majority of damaging events are faithfully repaired by an overlapping cadre of DNA repair enzymes. A rare, but predictable fraction of damaging events will result in repairs that change the sequence of DNA. 

More: Sequence changes through repair, along with DNA polymerase errors during replication, are collectively called mutations. Non-lethal mutations are preserved in the genetic memory and become part of the natural variation that exists from organism to organism. Some mutations make cells sick, and some sick cells replicate uncontrollably -- this is the genetics of Cancer.  

But most damage is repaired. Most mutations are silent (no functional change in gene products or expression). Some mutations cause a loss of function. For instance, blue eye color is a variant that was caused by a loss of function mutation. Some mutations cause a gain of function. Gain of function can occur through duplication events or changes in regulatory sub-regions. 

The Molecular Genetics Laws

These laws go into concepts that are critical to genetics but describe phenomena that occur below the level of the genetic unit envisioned by Mendel. In addition, these principles are not intuitively obvious from the Central Dogma above. But further studies into the molecular nature of genetics revealed the importance of gene regulation, the modular functions of domains and the impact of epigenetic modification of chromosomes.

7) Regulation. Genetic units consist of a regulatory region called a promoter and a coding region. Mendel's original units of inheritance can be broken down to these two critical sub-regions. The regulatory sub-regions function as an on/off switch and are usually found directly in front of coding regions. These on/off switches allow for finely tuned control of gene expression and traits. Without a promoter, a gene’s coding sequence can not be turned into a useful product through the successive actions of RNA polymerase and Ribosomes.

Regulatory sequences (promoters) can be studied with reporter proteins, such as GFP. 

Caveat: While I can’t think of any exceptions to this rule, it’s worth noting that regulation and regulatory regions can get very complicated and involve regions that are not within close proximity to the coding region.

8) Modulation. While a gene is a unit of inheritance, each gene coding sequence is often a conglomeration of multiple functional subunits. Just like Legos can be taken apart and reassembled in to a new overall structure, proteins have a modular structure and protein domains yield new functions when organized differently. Modulation also occurs at the RNA level, mostly through the presence of exon (expressed) and intron (removed) sequences. New organization of modules can occur through DNA editing (recombination), through RNA editing (Exon shuffling), or through protein editing (proteolysis events and other protein modifications).

Protein domain structure from N-terminus to C-terminus.

More: Recombination of DNA plays a critical role in genetic variation (see gene linkage in the 2^nd Law) and is also critical for the human adaptive immune system and production of antibodies. Exon shuffling (also called alternative splicing) allows one gene sequence to code for many different proteins and plays a critical role in the development of different cell types. For instance, muscle cells, brains cells and skin cells can each produce their own distinct version of a protein from the same original DNA gene sequence. Proteolysis (breaking of proteins) can change, remove or split protein modules, but otherwise modules remain fixed within a given protein sequence.  

9) Epigenetic Inheritance. Gene expression can also be altered without sequence-altering mutations. Modification of genes and proteins through processes such as methylation of DNA, can lead to changes in gene expression. The impact of these changes can be fleeting--less than a second as gene expression is finely tuned to the needs of the cell or it can have a lasting impact. Methylation of gene regulatory sub-regions can be passed from parent to offspring, impacting the traits of the offspring without a permanent genetic alteration.

The Population Genetics Laws

These laws covers concepts related to genetics across populations. Populations change over time and these changes have genetic underpinnings. From the birth of new genes through gene duplication to the vertical and horizontal modes of transfer to the variations in individuals that lead to micro- and macro-evolution, the population genetics laws describe how genetic principles apply to speciation and extinction.  

Duplication of the
region in blue.

10) Gene Duplication.  Some processes cause promoters, genes or larger regions to duplicate. These duplicated regions cost little to the organism in terms of energy, but provide the raw material for variation and adaptation to new functions. After the duplication event, each copy will accrue sequence variants (mutations) at different times and in different locations. Their histories diverge, but genes with a common ancestral origin can be detected through the presence of homology -- sequence and structural similarity due to a shared ancestry.

11) Horizontal Transfer.  Genes can be transferred vertically from parent to offspring or horizontally between two organisms. Genes transferred vertically from parent to offspring are subject to the first and second laws, but genes transferred horizontally are not.  Horizontal transfer occurs through one of three mechanisms –transformation (free DNA to cell), conjugation (cell to cell), and transduction (virus to cell). These 3 processes are more rare than vertical transfer but have a tremendous impact.
 

The easiest of these 3 processes to see happen in everyday life is transduction. It happens every time you get sick due to a viral infection. Viruses have to inject their genetic material into cells in order to replicate. For the recipient cell, this is new genetic information. This horizontal process can sometimes kill the recipient cell, but in other cases the injected genetic material can become incorporated in the recipient cell's genome. This is called a latent or lysogenic state.

Cell-cell transfer (conjugation) can also occur, in particular this is a method of genetic exchange in bacteria. However, cell-cell transfer of DNA is also an essential step in sexual life cycles -- it's what happens during fertilization, where DNA from a sperm cell is transferred to an egg cell to form a zygote. Transformation is the most rare, it's the uptake and incorporation of DNA to a cell from the environment. It's also the natural process that can be utilized for in vitro fertilization and cloning.

Important note on GMOs: Genetic modification of organisms through the natural processes of horizontal transfer outlined here happens in nature. Selecting for a new organism with directed genetics is therefore just as natural as selecting for a new organism by deducing genotype through assessing the phenotypes and subsequent breeding. The difference is one of precision -- it's like performing surgery with a laser instead of a hacksaw. 

11) The Law of Evolution. Populations change over time through four processes (1) Genetic drift, random fluctuations in gene frequency from generation to generation, (2) Gene flow, the movement of genes between two otherwise distinct populations. (3) Mutation (see Law #9) and (4) Selection, pressures from environmental (or anthropogenic) forces that impact reproduction and/or survival. 

Genetic drift shown through changing distributions in phenotypes across generations.

Note: It’s quite possible that this section on populations deserves to be expanded to include others concepts: sexual v. asexual reproduction, the impact of gene loss, death and extinction, population diversity and stable ecosystem formation, the interactions of genes and memes in social species, vaccination and herd immunity, & etc. For now, let’s just say that evolution is a broad enough topic to be its own subject and this last law is here as a connector between genetics and a discussion of evolution.