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Monthly Archives: November 2013

I Think… but I do not Know

Darwin, wrote in his ‘B’ notebook in 1837,

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And in one instant transformed the way that we all think about life on earth. This simple diagram unified science. It captured Linnaeus’ nomenclature and married it to the fossil progressions that geologist the world over were seeing in the rocks. It redefined how we understand species and laid the framework for a new view of life as being all related at some level, with some organisms sharing more characteristics with their closer relatives and less with those more distant. It allowed scientists more than a hundred years later to recognize that the biochemical foundations of bacteria and yeast and drosophila and humans were all the same. Because we are fundamentally one family. There was no need to identify a genetic code for each species. Instead, we share a common (universal) code of DNA triplets each calling for an Amino Acid in building proteins.

However, there has been a lot of thought about what it really does mean to be a species. Darwin’s book, The Origin of Species, addresses just this point. I raise this question on the first day of my general biology class and my microbiology class. In general biology we eventually rest on the idea that, at least in the larger plants and animals we are used to encountering – and will discuss in the course of our class, the ability to mate with, and produce fertile offspring from is necessary and sufficient to group two animals into the same species. Of course the mule comes up as a near exception necessitating the ‘produce fertile offspring’ clause, but this is a definition we can accept. In microbiology, we are forced, by the nature of the organisms we study, to discard that convenient description. Many micro-organisms replicate asexually and are capable of transferring genes horizontally.

thrashing fish
knowing they’re in a bucket
and not knowing

          -Issa 1819

In the November 1 issue of The Scientist, Axel G. Rossberg, Tim Rogers, and Alan J. McKane tackle the very existence of ‘species.’ Therein, they acknowledge the fact that we use the concept of ‘species’ for our own convenience and consider the possibility (or rater, probability) that the very idea of species delineation may be artificial. The article looks into the variety of life and how the definition must change depending upon the organisms in question and makes us face the assumptions we often take for granted. Click on ‘The Scientist’ below to see the full article.

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                Link to the article in The Scientist

 
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Posted by on November 27, 2013 in Uncategorized

 

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Fred Sanger: the giant of genomics

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There was always something peaceful and satisfying about sitting with a well done sequencing gel / film and deciphering a gene.

We say goodbye to Fred Sanger, who died last week at age 95. Sanger is best known for the DNA sequencing method that bears his name. His process utilized dideoxyribonucleotides and PCR-like amplification of fragments. An animation of this sequencing method illustrates the principle.
http://www.dnalc.org/resources/3d/29-sanger-sequencing.html

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Last week, the biochemist Dr Fred Sanger died at the age of 95. He made an enormous contribution to research throughout the fields of biology and medicine, and we were all sad to hear the news.

Dr Sanger is best know for the breakthroughs that earned him two Nobel prizes: the development first of methods for determining the sequence of the amino acid building blocks in proteins, and later of the ‘Sanger method’ for sequencing DNA. He was not a cancer researcher — he tested his protein sequencing method on the hormone insulin, and applied his DNA sequencing method to simple viruses — but the methods that he devised have enabled a revolution in our understanding of diseases like cancer. Sanger sequencing…

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Posted by on November 25, 2013 in Uncategorized

 

Cellular robotics? A cute video summarizing cellular functions from TedEd

Check out this video. I think I like it, but I’m not positive yet. It’s so well done that I’m kind of taken by the aesthetics, however, I’m not sure that this makes cell biology easier to understand. What’s your opinion?

 
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Posted by on November 25, 2013 in Uncategorized

 

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Immunology’s ‘dihybrid cross’ : Antibody response to different antigens

The progress of infection can be summarized as a pathogen going through a series of steps:

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Progress of Infection

The first three steps, ‘Portal of Entry’, through ‘Surviving Host Defences’ encapsulates all of the immune response. Some key events in the immunity are inflammation and the innate  response, antigen processing and presentation, adaptive immunity and memory.

Several of these topics I’ve described here before including an outline of the development of lymphocytes (B and T Cells – sorry NK Cells) in an article here. The activation of B cells here, immunological memory in several places including here.  Some of these topics I have yet to address (e.g. a good discussion of inflammation), and others (e.g. antigen processing and presentation) have been buried in other posts (see my lymphocyte development, B cell Activation or this post on Transmissible tumors). 

This time, I thought I’d prevent a sketch of the humoral immune response and how this illustrates, like Mendel’s traits in a dihybrid cross, that each immune reaction is ‘independent’. A typical immune response is outlined below showing the development of antibodies following a primary response and then a more rapid and robust secondary response. If we want to compare this response to Mendel’s monohybrid cross, we can see the same response for antigen after antigen just as Mendel saw the same pattern of inheritance for any single trait he observed.

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Response to a single antigen

 

Before we had the ability to ‘see’ this response on a molecular level, we could see its effects on people. Those who previously contracted a disease did not contract that same disease a second time. This immunological memory is the basis for vaccination, where we separate the disease-causing agent from the immunological memory-inducing agent for any given pathogen and then use only the later to vaccinate.

However, Mendel continued to examine traits and how they were inherited individually (i.e. the inheritance of one trait had no bearing on the inheritance of another). He called this independent assortment. Is there a similar experiment that can be done to show ‘independent immunity’?

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Response to two antigens independently

Borrowing a figure from Abul Abbas’ text on Cellular and Molecular Immunology, we see  that the response to one antigen has no bearing on the body’s response to a second, unique antigen. Like Mendel’s dihybrid crosses, the response to two antigens is, indeed, independent. (Note, the serum titer in this graph falls much lower than that in the first illustration – this second curve is more representative for real responses. Regardless, the antibody titer for a secondary response remains higher than that of the primary response.)

The primary response to antigen B is identical to the primary response to antigen A. The secondary response to antigen A results in a more rapid, robust response and eventually levels out to a higher steady-state of serum antibody.

To extend the analogy just a bit further, one might ask if there is such a thing in immunology that parallels the ‘linked genes’ of inheritance?

In fact, there is. The world’s first vaccine, developed by Edward Jenner in 1796, involved the use of cowpox pus to induce protective immunity to both cowpox and the related virus, smallpox. This seems to violate our rule of independent immunity, just as the Morgan lab found that genes for body color and wing formation were found to be inherited together in fruit flies, thus violating the Law of Independent Assortment (of alleles).

In the case of cowpox and smallpox, this comes from the similarity in antigens made by each of these viruses. That is, the cowpox antigens the body generates an immune response against are NOT (ENTIRELY) UNIQUE from antigens found in smallpox. When the vaccinated individual is challenged with smallpox, antibodies created to defend against a secondary challenge with cowpox react to the smallpox antigens as if this was a secondary response directed against smallpox.

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Primary reaction to Cowpox antigen (A) is used for vaccination. Secondary reaction to Smallpox antigen (A’) upon challenge.

 
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Posted by on November 25, 2013 in Uncategorized

 

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A thoughtful article on the use and abuse of antibiotics

ImageEarlier today, I found this well written article on the era of antibiotics by Maryn McKenna (Published November 20, 2013). While I’m not sure I agree with everything in it – and have been spending time tracking down some publications to support or refute some data cited here (particularly in regards to the use of antibiotics in agricultural animals), the  summary of how antibiotics were first discovered and used and how researchers including Flemming feared an end of antibiotic usefulness, paints a vivid portrait of the problem at hand.

While we might typically think of antibiotics as being prescribed in a clinic following a positive test for strep throat or some other bacterial infection, that is just one example of their use. One element of this paper that I found particularly insightful was how easily overlooked are the myriad uses of antibiotics in situations such as surgical procedures or following chemo- / radiation therapy.

 British health economists … recently calculated the costs of antibiotic resistance. To examine how it would affect surgery, they picked hip replacements, a common procedure in once-athletic Baby Boomers. They estimated that without antibiotics, one out of every six recipients of new hip joints would die.

Let me know what you think.

 
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Posted by on November 24, 2013 in Uncategorized

 

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Who isn’t fascinated by Ötzi?

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                       Otzi, the iceman

Radiolab posted a story about one of the most complete, ancient humans ever found. Most interesting is that we have no idea of who this man is. Ancient Pharaohs buried in tombs with slaves and riches have indications of who they were surrounding them. Ötzi was just a man hiking through the mountains who was killed and left with all (?) his belongings where he was for more than 5000 years.

Was he a trader?

A thief?

A hunted man?

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We know very little of the human circumstances that led this man into the mountains to his death by arrow and stone. We only have the forensic evidence he left. He was about 45 years old, he had wounds on this hands, an arrowhead in his shoulder bone, Pollen from both valley and mountain trees (layer as mountain,valley,mountain) in his intestines and la large meal of bread and goat meat in his belly. Genetically, he was lactose intolerant. He is related to people from Sardinia and Corsica and was infected with lyme disease, dental caries and whipworms.

As always, Radiolab gives us a taste of something interesting and leaves us hungry to fill in the gaps. Otzi has been known for twenty+ years now, which has allowed for fairly complete analysis of the body. Find more about him through the wiki site here or the museum in Tyrol devoted entirely to this find here.

 

 
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Posted by on November 23, 2013 in Uncategorized

 

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Why is this the image the public has of biotech?

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I don’t recall ever seeing these plants growing in the fields I pass on my way to work

The biotech revolution can easily be traced even before the publication of Watson and Crick’s landmark Nature paper describing the structure of DNA with clear tracings to Avery, McCarty and MacLeod; Hershey and Chase; Frederick Griffith and others. However, it has become a simple shorthand to start the journey with these two working in the Cavendish Laboratories in Cambridge, England. Their remarkable tale is somewhat like the silicon valley stories of massive industries sprouting up from the garages of Jobs and Wozniak, Gates or Hewlett and Packard. Almost without a detectable ember, a sudden fire erupts changing the landscape of the world.

DNA is a double helix composed of anti-parallel strands of chemically simple nucleic acids joined by millions of low energy hydrogen bonds – two between Adenine (A) and Thymine (T), three between Cytosine (C) and Guanine (G).

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Way to lock in a second paper

With this last sentence before their acknowledgements, they make a very reasonable and supremely important speculation about the mechanism of replication indicating that the race was far from over. Rather than being the finish line, this paper was only the beginning of a wealth of information to be gleaned about the mechanisms by which DNA is actually used to carry information and direct the construction of RNAs and Proteins that translate this information into action.

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Using EcoRI to move DNA sequences from one place to another ( or one organism to another)

Twenty years later work by Paul Berg, Herbert W. Boyer, and Stanley N. Cohen, to actually manipulate DNA, moving genes from one organism’s genome to another’s, marked another giant step. Their work with the Endonuclease (enzyme that cuts DNA internally), EcoRI, provided the first major tool for the biotech industry. This enzyme allowed researchers to cut DNA at a very specific place (at the sequence, GAATTC) and in a very specific way (leaving overhanging ends that could later be re-annealled with other DNA fragments cut by the same enzyme).

The advent of this technology accelerated research greatly as labs could now isolate and control for the actions of single genes and therefore greatly refine their ability to craft clean experiments to study the effects of these genes.

Today there are dozens of these enzymes (New England Biolabs (NEB) sells 276 different enzymes), known as restriction enzymes, that can be used to specifically cut and paste DNA with precision.  Below is a map of a common plasmid (a small piece of circular DNA that bacteria can easily take up and replicate). Each possible cut site is labelled with the enzyme that can cleave the DNA at that location. Shown are only the enzymes that NEB sells.

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A restriction map of the plasmid, pBR322

The only thing lacking was a method for specifically amplifying single genes from an organism’s DNA. This could be done, but the process was laborious and time consuming. Enter Kary Mullis (you might recognize the name from the OJ simpson trial in the 1990s if you are over a certain age). He was a biochemist and computer programmer working for Cetus Corporation when he had an epiphany while driving down the road, stopped and quickly mapped out an idea to amplify DNA using temperature cycling and a special enzyme cocktail that would later earn him a Nobel Prize.

The combination of his biotech background and the ability to think in the loops of a programmer enabled him to see the method illustrated below, which he called a Polymerase Chain Reaction (PCR). This used small DNA ‘primers’ that could be synthesized in high numbers in the laboratory, to specifically bracket an expanse of DNA. Cycling the temperature of the reaction stood in for the enzymatic zipping and unzipping of DNA that permitted these primers to bind to their target sequences. Then adding a polymerase enzyme and free nucleotides, provided all that was required to do in vitro DNA replication that was repeated several times (typically 20-40x) to exponentially amplify only the specific target sequence of DNA so that it could be isolated on a gel and manipulated.

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PCR amplification of a target gene

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Gel electrophoresis – separation of DNA by size. Here DNA ‘ladders’ are run on lanes 1 and 6 to indicate the size of the DNA fragments, lane 5 is a negative control and lanes 2-4 are PCR amplifications of a specific gene.

DNA fragments run on an agarose gel can be easily isolated (by cutting them free from the gel and chemically purifying them) and used in any of a number of downstream processes such as cutting them and pasting them into another organism’s genome (or more commonly, into another plasmid where they can be moved from organism to organism.)

Applications of this technology include the ‘cloning’ of human insulin from human DNA and moving it into a organism like yeast or bacteria, where these genes can be turned into protein for human use.

This allows for the high-yeild production of these specifically human proteins in a laboratory setting, rather than the old way of bleeding pigs and isolating porcine insulin for use in humans.

Of course, Recombinant DNA technology is like any other technology. A knife can be used to slice bread or as a weapon against another human being. However, it does seem awfully unfair to jump from medicinal uses to ‘The little shop of horrors’ in one leap while condemning everyone who has anything to do with the work along the way.

 
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Posted by on November 20, 2013 in Uncategorized

 

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