Microscopes and Mutants
Episode 2 of Cracking The Code: The Continuing Saga Of Genetics

Summary of the Video (with stopping and discussion points)
Activity Ideas
Connections with History
Song Lyrics
Timeline
Further Reading
Websites

Summary of the Video

Microscopes and Mutants is also introduced by the series theme song (as are all the other episodes). We then pick up the story of genetics where episode one left off - Gregor Mendel’s realization, after many thousand cross-breeding experiments with pea plants, that hereditary traits are determined by pairs of factors, that we now call genes. We then switch to another line of research - cell microscopy - that led to a similar destination and which took place in 19th century Germany. We are introduced to an animated German scientist, complete with monocle, top hat and beard. As we see, he is somewhat clumsy with his monocle, a recurring comic theme.

First came the microscopic discovery, in the 1830s and 40s, that plants and animals are composed of cells - the basic unit of all living things - and that within the cell is a central structure, which was termed the nucleus.

Then came the Rudolph Virchow’s cell theory of life, “all cells derive from pre-existing cells”, which we see him spelling out. That was followed in the 1870s by the discovery of chromosomes, thread-like shapes in the nucleus. It was also noticed that the threads split and move apart just before the cells divide into two during mitosis, which is how nucleated cells multiply, creating new tissue and allowing an organism to grow. Then using striking micro-photography footage and images, we are guided through the various phases of mitosis. Key elements like the centromere and the mitotic spindle are clearly identified. Returning to our animated German scientist, we learn that scientists also noticed that the various chromosomes come in pairs and that each species has its own constant number of chromosomes. But what was still a mystery was sexual reproduction - how the chromosomes of two parents combine together to create the very first cell. It could not be a simple combination of ordinary cells, as that would double the number of chromosomes with each new generation.

We now turn our attention to the germ cells - egg and sperm - and their collections of chromosomes. The first obvious difference is that gem cells are haploid (they have only one set of chromosomes) while somatic or non-germ cells are diploid (they have two sets of chromosomes). Another observation, made while studying sea urchins whose egg and sperm cells conveniently meet in the outside sea water, was that during fertilization the nucleus of a single sperm cell fuses with the nucleus of an egg cell, thereby restoring the original number of chromosomes. This two step process solved the problem of how a constant number of chromosomes is maintained over the generations. And it strengthened the case that the chromosomes are indeed the carriers of heredity.

First stopping point (6:27 - male and female dissolve into a single cell) This would be a good point to review Virchow’s cell theory; the various phases of mitosis; how germ cells differ from somatic cells; how a constant number of chromosomes is maintained during reproduction in spite of the fusing together of two sets of chromosomes; and the evidence so far that the chromosomes are the carriers of heredity. The ‘Chromosome Theory of Heredity’ will be more fully explained in the sections that follow.

We now turn our attention to meiosis, the process of germ cell production, which is the first step in sexual reproduction. It is itself a two step process, at the end of which a single diploid mother cell is transformed into four haploid germ cells. This is illustrated through a combination of microscopic footage and creative animation. To begin with we see how pairs of double-copy chromosomes line up side by side along the midline, rather than end to end as in mitosis. This is when the two chromosomes swap pieces of DNA, which is brought to life by striking animation of a pair of double-copy chromosomes dancing the ‘genetic tango’. It is this process of genetic reshuffling that makes each individual unique and we examine it in more detail later on. After this, the parent cell divides into two daughter cells, each of which have one set of double-copy chromosomes. This is contrasted with the daughter cells of mitosis, which have two sets of single copy chromosomes. In the second stage of meiosis, the two daughter cells, undergo another division, this time with their single set of double-copy chromosomes lined up end to end. These are pulled apart and four new cells are formed, each containing a single set of single-copy chromosomes. These are the completed germ cells. We then see that meiosis occurs only within specialized reproductive organs. Mitosis, on the other hand, takes place in all other tissues.

This is followed by an amusing Moxy Früvous song, in period costume, that summarizes meiosis and mitosis.

Second stopping point (10:36). This would be a good point at which to review the two stages of meiosis and also to discuss the two ways in which meiosis leads to a reshuffling of DNA and hence to uniquely different germ cells. One form of reshuffling was suggested by Mendel’s First and Second Laws (as covered in episode 1). Mendel’s concept of ‘segregation’ (his first law) corresponds to the first part of meiosis, when the chromosome pairs in the parent cell separate randomly into two daughter cells. Since the chromosomes pairs segregate independently of each other (his second law), the number of germ cell permutations increases exponentially with the number of chromosome pairs. For example, humans have 23 pairs of chromosomes, so the number of germ cell permutations based on random segregation = 223 or 8 million.

A second and even greater source of variation is the ‘genetic tango’ that occurs prior to segregation, when the chromosome pairs line up side by side and swap bits of DNA through ‘cross-overs’. There resulting permutations are endless in number and insure that each of us, except for identical twins, is genetically unique. Another source of genetic variation that can be introduced here is mutation, change within a small bit of DNA, usually prior to meiosis. It is the ultimate source of all variation.

The German scientists who discovered meiosis and mitosis were unaware of Mendel’s discovery that the units of heredity come in pairs, which segregate or split apart into two germ cells. And Mendel was as ignorant of chromosomes as the microscopists were of his laws of heredity. Through humorous animation, we see how the stage was now set for a momentous collision of ideas. When it finally happened, the brand new science of genetics was born. The humorous animation continues as we see how three different scientists simultaneously rediscovered Mendel’s work, 16 years after his death. Each probably hoped to reproduce it and then claim it for himself, until they each caught the other in the act. As a result Mendel finally got the credit he deserved, albeit posthumously.

His theory of segregation corresponded nicely with what was seen during early meiosis. Since chromosome pairs act like Mendel’s factors, it seemed only logical that they must carry them. This was called the ‘chromosome theory of inheritance’. It quickly gained acceptance and for the first time Mendel’s factors were referred to as ‘genes’.

Third stopping point (13:22) This would be opportunity to discuss how two different lines of research - in this case genetic analysis and microscopy - when combined together can lead to knowledge that neither one can achieve on its own. Existing theories can be confirmed or debunked and new ones suggested by previously unseen correlations. This is a good example of scientific collaboration. The opposite side of the coin is scientific competition and the temptation to claim credit for a discovery that belongs to someone else, an example of which is also found in this section - the rediscovery in 1900 of Mendel’s work by three different scientists, each of whom apparently hoped to claim it as his own.

The next step was to look for differences among the various chromosomes. In 1906 two unusual chromosomes were noticed in insects. The larger of the two was termed ‘X’ and the smaller one ‘Y’. Nettie Stevens and Edmund Wilson noticed that females always have two copies of the X chromosome in their nuclei while males always have a single X and a single Y in theirs. They had made the first ever correlation between an inherited trait and a particular chromosome.

We are then introduced to zoologist Thomas Hunt Morgan and his student colleagues. From about 1910 to 1930, they performed a series of ingenious cross breeding experiments, which allowed them to map out the genes on a chromosome. Using a combination of historic photographs and current shots from the room they worked in, we are introduced to their new experimental partner - the tiny fruitfly or drosophila - and its advantages over Mendel’s pea plants.

But unlike pea plants, fruit flies didn’t come in different varieties, a distinct disadvantage. Morgan and students finally noticed a male fly with white eyes, instead of the usual red. Using creative animation that distinguishes male from female through flamboyant headgear, we are introduced to the new pattern of recessive inheritance they discovered when they cross bred this mutant with a normal fruit fly. This was due to the location of this mutant recessive gene on the X or female chromosome.

The concept is further elaborated through the famous case of Queen Victoria and the hemophilia gene which she passed on to some of her offspring. Again using humorous animation, we see how this gene segregated out to three of her nine children, two daughter and a son. And why the two daughters remained carriers only, while the son, Leopold, ended up with the disease. This pattern of inheritance is called X-linked recessive. Through dynastic marriages, Victoria’s X-linked hemophilia gene eventually found its way into many of the royal families of Europe.

Fourth stopping point (19:34) This is an opportunity to review the X and Y chromosomes and the somewhat tricky concept of X-linked recessive genes, which at first glance do not follow Mendel’s Laws. It should be emphasized that this new pattern of inheritance is due to the unique status of the two sex chromosomes. They are different, yet in the male (XY) they are paired with each other before segregation; when they recombine after fertilization, the two possible outcomes, XX and XY, not only determine gender, they also determine whether an X-linked recessive gene is expressed or not. It can only be expressed in the male, where it exists in isolation. In the female, the expression of the other normal gene overrides it. Once all this is taken into account, Mendel’s Laws still hold true.

Next comes a long and somewhat demanding section that explains how Morgan and his students used cross breeding experiments and linkage analysis to map genes onto chromosomes. To make it easier to follow, it is broken down into its constituent concepts.

The first is ‘linkage’ - how genes on the same chromosome tend to travel together down the generations.

The next is the breakdown of this linkage due to the ‘cross-overs’ that take place in early meiosis, when pairs of chromosomes, one from each parent, come together to do the genetic tango. We revisit the animation of this elegant chromosome dance which shows how their limbs overlap and touch, this time highlighting how DNA gets swapped between the cross-over points, thereby breaking the linkage between two genes on either side of a cross-over point.

Next comes the correlation which is at the heart of linkage analysis and gene mapping - as the distance between two genes on the same chromosome increases, so does the likelihood that their linkage will be broken through cross-overs. This is visualized in an easy to grasp way with sliding genes. As they slide apart, more cross-over points are revealed, thereby increasing the odds of a cross-over. Conversely as they slide back together, fewer such points are revealed, thereby decreasing the odds.

Next comes an explanation, again using humorous animation, of how Morgan and his students put these concepts together to construct the first gene map of a chromosome (the identity of which they didn’t yet know). And then how they used the discovery of giant chromosomes within the saliva-producing glands of young fruit flies to visually tie each gene map to its corresponding chromosome.

In 1933 Morgan became the first geneticist to win a Nobel Prize.

This is followed by a song, in fruit fly costumes, that summarizes this entire section.

We are the fruit flies that Morgan kept in jars.
He won the Nobel Prize but we’re the real stars.
Check out the chromosomes in our saliva glands.
They’re awfully hunky and they have such gorgeous bands.

Oh he’d be nowhere without our quick birth rate
Or the way we strut our stuff when we mutate.
Then the color of our eyes becomes distinct.
That’s how we showed him that a trait can be X-linked.

We know we’re just insects, we can’t match their intellects,
But we’re superior to them at sex.
We’re fruit flies, not bar flies, not gad flies, please realize
We’re the ones that helped them get so wise.

Bizzzzzz, bizzzzzzzz
Our brains are buzzing, they never take a nap.
We gave them full instructions for the first gene map.
Just follow what goes on when genes get recombined.
Then you will see how chromosomes have been designed.

During meiosis, it’s sexual high jinks,
Crossing over, trading parts across the links.
Genes that were once, your mom or dad’s alone
Now join together in a single chromosome.

We know we’re just insects, we can’t match their intellects,
But we’re superior to them at sex.
We’re fruit flies, not bar flies, not gad flies, please realize
We’re the ones that helped them get so wise.

Fifth stopping point (26:17) The above is a challenging section, which may need to be repeated and reinforced by further explanation of the concepts of: gene linkage, cross-overs, the correlation between the cross-over frequency and the distance between two genes, and how the distances between genes A and B, B and C, and A and C can be used to map these three genes, relative to each other, on the same chromosome.

The next section deals with the eugenics movement, which forms the darkest chapter in the history of genetics. It was inspired, at the turn of the 20th century, by the rediscovery of Mendel’s Laws and Morgan’s achievements with fruit fly genes. Eugenicists held that all human traits are determined by genes, including complex behavioral ones like intelligence. And that just as crops and animals can be improved through controlled breeding, so too can humans. Over archival footage and photos, along with an interview with Jan Witkowski, a historian of genetics at the Cold Spring Harbor Lab on Long Island (which back then the site of the Eugenics Records Office), we learn about the history of this movement; the scientific fallacy on which it was based; how it provided a pseudo-scientific pretext for anti-immigrant prejudices; how it led to the mass sterilization of ‘defectives’ in US institutions; and how it was adopted by the Nazis, who invented the new horror of eugenic mass murder, the first step down the road to the Holocaust, the ultimate genetic cleansing. That also killed the eugenics movement, which was forever stained by this history

Activity Themes and Suggestions

1) Differences between mitosis and meiosis In both meiosis and mitosis cells divide and both processes consist of various subphases - prophase, metaphase, anaphase, telophase, cytokinesis - which they share in common. But there are key differences between the behavior of chromosomes during the subphases of meiosis and mitosis. The most important difference occurs during prophase (prophase 1 in meiosis). Figure out what that is and how it leads to subsequent differences in chromosome behavior during meiosis and mitosis. It would be helpful to first review the subphases of both processes in a textbook. There are also many web sites that do so: http://iknow.net/cell_div_education.html http://www.pbs.org/wgbh/nova/baby/divi_flash.html This learning can be reinforced by replaying the sections showing actual meiosis and mitosis with the sound turned down and asking students to do their own narration, pointing out the various subphases.
2) When mitosis or meiosis go wrong When mitosis or meiosis go wrong in humans, serious health problems can result. In the case of meiosis, things can go wrong when the chromosome pairs don’t split apart and a single germ cell ends up with both copies of a chromosome. After fertilization, the zygote will have three copies, rather than the normal two, a condition known as trisomy. The best known of these genetic conditions is Down’s Syndrome or Mongolism. Find out which chromosome is involved in this trisomy and what the resulting inborn defects are, both physical and mental. In the case of mitosis, the problem is usually one of too much or too little when it comes to the frequency and number of cell divisions. A case of ‘too little’ mitosis is a rare but fascinating condition called progeria which causes premature aging. Find out more about this disease and how it is related to mitosis. Cancer is a case of mitosis gone wild - too much mitosis. Find out more about the connection between mitosis and cancer.
3) New technology leads to new science Advances in technology preceeding advances in science is a common theme in the history of genetics and of science in general. What let to these new discoveries about chromosomes and cell duplication were new advances in the technology of microscopes and tissue staining. Find out about the development in the 1820’s of the achromatic lense and why it was such an improvement over prior microscope lenses. Also find out about the 17 year old whiz kid from England, William Perkin, and his invention in the 1850s of analine dye, which stained chromosomes and made them more visible. What new technology, if any, did Gregor Mendel take advantage of? (none really, other than the technique of cross-breeding plants, which is something plant breeders had been doing for some time)
4) Credit where credit isn’t due This episode tells the story of how in 1900 three different scientists independently claimed they had discovered the laws of genetics before co-incidentally finding Mendel’s long lost paper. A more likely explanation is that they had discovered Mendel’s paper first, which they thought no one else knew about, then caught each other trying to steal credit for his discoveries, This is an example of scientific competition leading to unethical behavior. Find out about the controversy over who first discovered the AIDS virus (American scientist Robert Gallo or French scientist Luc Montagnier) and decide whether it involved similar unethical behavior. Debate the proposition that competition among scientists is more harmful than helpful.
5) X-linked royalty The section on Queen Victoria’s X-linked hemophilia gene mentions that it was inherited by two of Victoria’s daughters, Alice and Beatrice, and one of her sons, Leopold. What are the odds that Alice and Beatrice would pass this gene on when they gave birth to daughters? When they gave birth to sons? And similarly when Leopold’s wife gave birth to both daughters and sons? Find out what actually happened. Who did Alice, Beatrice and Leopold marry? How many children did they have? Did any of them have hemophilia? Construct a family tree, with Victoria at the top, using your own symbols for males, female and hemophiliacs. Find out what happened in the next generation (Victoria’s grandchildren). Add their descendants to your family tree, then work backwards to figure out which of Victoria’s granddaughters must have been carriers. (The full family tree and a fuller version of this story can be found at: http://www.sciencecases.org/hemo/hemo.asp
6) Genetic testing Hemophilia is an example of a disease gene that can be tested for long before the actual disease reveals itself, even before birth. There are now many such genetic tests, with more to come. But is genetic testing always a good idea? Come up with a list of pros and cons for genetic testing. (Think of when this information would not be and when it might actually be harmful.)
7) Morgan’s students Some of Thomas Hunt Morgan’s students became famous scientists in their own right, such as Alfred Sturtevant, Calvin Bridges (who had a scandalous personal life) and H.J. Muller (who had a scandalous political life and also won a Nobel Prize). Find out about how they contributed to Morgan’s discoveries and about their later lives and achievements.
8) Converting a likelihood into a distance Go back and review the section that begins after the fourth stopping point (19:34), to better understand how the frequency of cross-overs (during meiosis) between two genes on the same chromosome can be used to locate those genes on that chromosome - a process known as linkage analysis. It makes use of the fact that during meiosis the odds of a cross-over occurring between the two genes (thereby allowing them to break their linkage and segregate apart into different germ cells) is proportional to the distance between them. The distance between genes is measured in centimorgans, in honor of Thomas Hunt Morgan. It is the distance between two genes such that a chance of a cross-over point occurring between them is 1 in 100. (That works out to about 1 million base pairs.) Mathematics was crucial to doing linkage analysis and gene maps. It was equally crucial to Mendel in working out the Laws Of Genetics. Can you think of reasons why it took so long to apply maths to genetics?
9) Colour blindness By the time Morgan realized that the rare trait in fruit flies of having white eyes was the result of an X-linked recessive gene, it was already known that another eye-related trait is passed along in humans in similar fashion. Find out what that trait is (colour-blindness) and how common it is. Draw up a family tree to show how this X-linked recessive gene might be transmitted from a colour-blind father to his children and grandchildren.

Connections with History

1) Victoria’s most famous descendent with hemophilia was probably Alexai, the Tsarevich of Russia. Find out who he was; how his disease influenced Russian history through the bizarre figure of ‘Mad Monk’ Rasputin; and what Alexai’s fate turned out to be.
2) Reel Life vs Real Life. In the 2001 film ‘Kate and Leopold’, the character Leopold is a duke who time travels from Victorian England to modern day New York. Some speculate that he was based on Leopold, Queen Victoria’s hemophiliac son, who also had the title Duke of Albany. Watch the movie, research the historical Leopold and find out what the two Leopolds have or don’t have in common.
3) Thomas Hunt Morgan was the nephew of John Hunt Morgan, who was a Confederate general and cavalry officer in the American Civil War. Find out about the famous raid he led (Morgan’s Raid) he led in 1863 deep into enemy territory.

Song Lyrics

Opening song

The script that’s written in our genes
Directs us from behind the scenes.
The words within it shape life’s destiny.

Hidden in your DNA
Is your genetic dossier.
It tells your future and your history

How traits get passed from parents to a child
Is something that has kept us so beguiled.

CRACKING THE CODE
GENETIC FUTURES WILL BE FORETOLD

CRACKING THE CODE
GENETIC POWER ABOUT TO EXPLODE

CRACKING THE CODE
GENETIC MYSTERIES TO UNFOLD

CRACKING THE CODE
GENETIC SECRETS WILL BE TOLD
CRACKING THE CODE

Mendel song

If it's the secrets of life that you seek, then
Through a microscope you must peek.

Mendel did wonders just using his eye, but
To really see, you must magnify.
You can't help but notice we're nothing but cells,
But where in the cell, does heredity dwell?

The nucleus, that's where it hides.
You don't see much, until it divides,
Then chromosomes enter new phases,
Split into two. And that is the basis, of
Sexual transmission which always engrosses
Our feverish minds, but it's only meiosis
Reducing the chromosomes fifty percent,
So when egg and sperm meet at that blessed event,
Their chromosomes form one full set
Just two of each kind, that’s the best bet.

And that new cell begins to grow,
Multiplies into an embryo.
The explanation of this growth is
It's due to a process we know as mitosis.

And that's what our microscopes helped us determine,
In Germany, where all the germ cells are German.

Closing song

Now we’re reading from life’s page
How did we get to this new stage,
To solving what was once life’s mystery.

Would you like to know from whence you’ve sprung.
Would you like to stay forever young.
Would you like to shape your own heredity.

We’re learning how to pull upon the strings
To rewrite the script from which life itself springs.)

CRACKING THE CODE
GENETIC FUTURES WILL BE FORETOLD
CRACKING THE CODE
GENETIC POWER ABOUT TO EXPLODE
CRACKING THE CODE
GENETIC MYSTERIES TO UNFOLD
CRACKING THE CODE
GENETIC SECRETS WILL BE TOLD
CRACKING THE CODE

Timeline

1665 - Robert Hooke coins the word ‘cell’ for the pores he saw microscopically in thin slices of cork
1674 - Van Leewenhoek observes the first living cell through a microscope, an algae. He also studied sperm and bacteria in dental plaque (his donors were two old men who never brushed their teeth)
1827 - von Baaer identifies the mammalian ovary (in a rabbit)
1833 - Robert Brown first describes the cell nucleus
1838-9 - Scheider and Schwann theorize that cells are the basic unit of life
1855 - analine dye discovered by 17 year old William Perkin, in England
1858 - Virchow develops his ‘cell theory of life’ - all cells derive from other cells
1875 - Hertwig observes fertilization in the sea urchin, on the French Riviera
1877 - Herman Fol first sees sperm penetrate egg, in starfish
1878 - Boveri discovers mitosis
1879-82 - Flemming discovers chromatin in the nucleus (using Perkin’s dye) and describes and names mitosis. Also that number of chromosomes is constant for each type of cell.
1883-87 - Weisman theorized that chromosomes are the carriers of heredity and male and female contribute equally. Also that germ cells have only half the number. Also that only the chromosomes in germ-producing cells are inherited, which argued against acquired inheritance since these cells seem to be protected from the environment. Theorist as opposed to experimementalist
1883 - Edouard van Beneden observes chromosome reduction in germ cells and restoration with fertilization. Also that different species have different number of chromosomes
1899 - First International Congress of Genetics in London
1900 - Mendel’s work rediscovered
1902 - Walter Sutton develops the chromosomal theory of heredity
1903 - Wilhelm Johannsen coins the word ‘gene’ to replace of Mendel’s ‘factor’
1905 - Edmund WIlson and Nellie Stevens show that X and Y chromosomes determine gender, the first proof of the chromosomal theory of heredity
1910 - Morgan and students discover white-eyed fruit flies and the first X linked recessive gene
1910 - Eugenics Records Office established at Cold Spring Harbor Lab
1913 - Alfred Sturtevant does the first gene map
1927 - US Supreme Court in Buck vs Bell approves forced sterilization
1931 - Thomas Hunt Morgan wins a Nobel prize, the first for a geneticist

Further Reading

1) ‘The Search For The Gene’, Bruce Wallace, Cornell U. Press, 1992
2) ‘A History Of Genetics’, Alfred H. Sturtevant, Cold Spring Harbor Lab Press, 2001
3) Morgan’s classic paper on X-linked inheritance can be found at:
http://www.esp.org/foundations/genetics/classical/thm-10a.pdf

Websites

1) animation of meiosis and mitosis - http://www.pbs.org/wgbh/nova/baby/divi_flash.html
2) http://www.bscs.org/search/index.html?ae=%DF&op=or&q=mitosis&x=11&y=6
3) http://learn.genetics.utah.edu/
4) http://www.pbs.org/wgbh/nova/baby/divi_flash.html - mitosis and meiosis
5) http://www.cellsalive.com/mitosis.htm - mitosis
6) http://www.accessexcellence.org/RC/VL/GG/mitosis2.php - mitosis
7) http://www.accessexcellence.org/RC/VL/GG/mitosis.php - mitosis
8) http://www.cellsalive.com/meiosis.htm - meiosis
9) http://www.accessexcellence.org/RC/VL/GG/meiosis.php - meiosis
10) http://www.accessexcellence.org/RC/VL/GG/comparison.php - comparison of mitosis and meiosis
11) www.biologyinmotion.com/cell_division
12) http://www.biologycorner.com/worksheets/mitosis.html
13) http://biologycorner.com/worksheets/meiosis_internet.html
14) http://www.eugenicsarchive.org
15) http://www.sciencecases.org/hemo/hemo.asp
16) http://www.geneticstv.org/microscopes_and_mutants/Microscopes%20and%20Mutants.pdf
17) http://www.esp.org/timeline/ - good time line

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