A really challenging puzzle – even with hints

I’ve been watching cryptography videos again on Khan Academy. In doing so, I created this puzzle. But don’t worry about it. It’s really hard, even with the hints I provide.

 

A Pointer

For my Microbiology students….

“I feel kinda sick”

As we finish up the year dividing out time between Immunology and Epidemiology, you may find it useful or just interesting to take a look at the online Epidemiology course offered at Coursera. It is a six-part course taught by Lorraine Alexander and Karin Yeatts of the University of North Carolina, Chapel Hill.

As all Coursera classes, this is 100% free unless you would like to receive a signed certificate of completion.

Enjoy.

 

Bell Ringers

Today, my wife and I toured a school that we are considering for our (present) fourth grader to move into when he starts sixth grade. It was a great little school with a motivated, engaged staff from whom I stole an idea or two that I think I can apply to my own teaching and am eager to start in with.

The first was the idea of starting every class with ‘Bell Ringers’, short worksheets that joggle students’ memories with concepts and simple questions that review prior work and provide a glimpse into future study. I’m not sure exactly how he operates these assignments, i.e. cooperative work vs single-person exercises and whether they are actually graded for a score or not. Regardless, I think they represent a fun way to get into the proper state of mind at the beginning of each class.

An article about these kind of exercises can be found at the Edutopia website.

In the same article, I found another activity that is used to open classes that I may consider using to finish each day. That idea, roundtable review, has students compile a list of idea-statements discussed in that class. I was thinking that this might be a good way to collaboratively compile a list of study notes. Maybe the best, or best-stated, idea can receive extra credit (??).

Both of these techniques echo ideas that I have been trying to come up with a way to actualize for some time. Perhaps this is just the right nudge I need to get started.

 

Blue Man Group – Kentucky Style

One of the more interesting cases of oddball genetics can be found by the banks of Kentucky’s Troublesome Creek. Some of the families these exhibit a hereditary condition known as methemoglobinemia which makes their skin appear a deep blue. E. M. Scott reported cases of this condition in his 1960 article in the Journal of Clinical Investigation (vol. 39, 1960).Scott found that “In normal people hemoglobin is converted to methemoglobin at a very slow rate. If this conversion continued, all the body’s hemoglobin would eventually be rendered useless. Normally diaphorase converts methemoglobin back to hemoglobin.” However, in people lacking the enzyme, diaphorase, hemoglobin is converted into methemoglobin and cannot be converted back resulting in a general blue coloration.

How blue? This blue.    —>

The condition is extraordinarily rare, and typically is seen only in inbred families. Given the pedigree below, suggest a pattern of inheritance that this condition may be exhibiting.

One thing you may notice from the beginning is that Zachariah Fugate is married to, and has children by his mother’s sister (that’s the odd looking relationship outlined in the top two rows). This consanguineous relationship is further illustrated by the double line between Zachariah and his (un-named) wife.

Once you’ve taken a stab at determining the inheritance of this trait, take a look at the excellent write-up of this condition here.

 

Microbiology Quiz Prep

Considering what you know about micro-organisms, germ theory, and experimental methods to address the following:

A new pathogen has recently been reported as spreading through the American Midwest. Currently, the pathogen is known only as MidAmerica1 (MA1) and thought to be a retrovirus. You work in a lab studying this disease and hope to make a vaccine.

MA1 infects both humans and mice (which makes it especially easy to do lab experiments with).

What experiment can be done to determine whether MA1 is a virus or not? How would you distinguish between a virus, a bacteria, and a toxin?

How ho each of the following treatments work? And which treatments might be effective in treating patients?

1. Amoxicillin

2. Augmentin

3. reverse transcriptase inhibitor

4. Tetracyclin

 

Looking Glass Genetics : Gene Mapping

The Mad Hatter and March Hair setting up a breeding experiment in a teapot

In addition to Genetic Counseling for the cards, your lab has been investigating the genetics of the Dormouse.

Dormice have either the ability to Speak (S) – or are Mute(s).

Additionally, they are either Cruel or Kind.

You wish to map the distance between the Speech and Disposition genes and determine whether Cruelty or Kindness is dominant. (Here, not a metaphysical question)

You begin by obtaining true-breeding animals:

1. A Speaking , Kind Male
2. A Mute, Cruel Female

(oh, the cries of misogyny!)

Once bred, this coupling gives rise to a litter of six offspring. All six can speak and are unfailingly kind.

These offspring are then bred to true-breeding homozygous recessive mates. The results of these matings are:

      #                     Phenotype

35                   Speaking, Kind

15                   Speaking, Cruel

15                   Mute, Kind

35                   Mute, Cruel

1. What can you determine from these results?

In similar experiments, Cruel, Longhair and Kind,Shorthair animals were examined. Both parentals were true breeding and the F1 litter consistend entirely of Kind, Longhair animals. These F1 were then crossed with homoztgous recessives for both traits, resulting in:

    #                     Phenotype

20                   Kind, Longhair

80                   Kind, Shorthair

80                   Cruel, Longhair

20                   Cruel, Shorthair

What do these data add to your understanding of Dormouse genetics? Can you map the three genes to one Chromosome? What experiment do you want to do next?

 

The first hand : Mendel in Wonderland

In wonderland, much depends upon the suit and rank of a card. In the time of Alice, the Hearts held power, but since then, the Queen of Hearts has been imprisoned and the Kind of Spades now rules the land.

Families now strive to have children of high suits in order to give them the best chance at a good life.

Suit values are as follows:

Clubs < Diamonds < Hearts < Spades

Conveniently, the inheritance of the suits follows the same order. That is Spades are dominant over all suits, Hearts are dominant over Diamonds and Clubs, and Diamonds are dominant over Clubs.

S^C < S^D < S^H < S^S

Two cards come into your clinic to get genetic counseling. They want to know what chance they have of having a Hearts or Spades baby.

Mom is the Three of Hearts

Dad is the Five of Diamonds

They already have three children: a Two of Hearts, a Seven of Clubs, and a Jack of Clubs.

From the information provided above, what do you know?

Is it possible that they can have a Hearts Baby?

 

Virus, Vaccine and Passive Antibody Therapy

The immune system is a many-layered construction that protects the body through barrier defences, additional non-specific responses including phagocytosis and chemokines, an antibody-mediated humoral response capable of neutralizing viral particles, and a cellular response for eliminating infected cells.

Ebola: Disease and Response

Ebola is a viral disease first identified during a first appeared in 1976 in two simultaneous outbreaks, one in Nzara, Sudan, and the other in Yambuku, Democratic Republic of Congo.  It is reasonable to suspect that Ebola has infected humans prior to this time without being identified specifically. This is a reasonable assertion because, like the first, all subsequent outbreaks have occurred in remote areas of Western African countries that are largely isolated. Although infamous for its lethality, this remoteness has proved self-limiting in terms spread.

The current epidemic has defied these rules resulting in escape from the remote areas of West African villages to larger population centers, and for the first time ever, even resulting in at least one case presenting in the United States. (citation)

In general, although viral infections are not treatable by classical antibiotics, vaccines against these types of organisms have been largely successful. Although it is impossible to know exactly why a specific vaccine works, it is reasonable to assume that a humoral response (i.e. mediated by antibodies) is involved in most cases as antibody titer correlates well with protection.

I the case of Ebola, there is data regarding the type of immune responses mounted by patients who have survived the disease compared to those who have not. Baize et al report that “early and increasing levels of IgG, directed mainly against the nucleoprotein and the 40-kDa viral protein, were followed by clearance of circulating viral antigen and activation of cytotoxic T cells” in survivors of disease. While “fatal infection was characterized by impaired humoral responses, with absent specific IgG and barely detectable IgM.” Again, this supports the idea that an effective humoral response is key to protection.

More evidence of the centrality of the humoral response comes from data published by Villinger, et al (citation) showing that “IL-6 levels are unusually low among fatal cases.” They suggest that this points to a deficiency of the endothelial cells that produce this cytokine leading to failure to protect. An alternative explanation may be that macrophages, which are key targets of ebola infection – and are producers of IL-6, are also failing to respond appropriately due to their involvement as targets. This leads to an obvious defect in immune response as IL-6 supports the growth of B cells and is antagonistic to regulatory responses (i.e. regulatory T cells).

If antibodies are so important to response, what are the targets of these antibodies and what issues are there related to this response?

Ebola Virus:

Ebola has only one known surface protein found on virions and infected cells. It is presumed that this protein, a ‘sugar-coated’ glycoprotein (GP), is what enables virions to adhere to target cells, a vital first step in the infection of host cells by animal viruses. As neutralizing immunity against viruses is presumed to be a result of the opsinization of viral particles by antibody, the Ebola GP is the obvious target of these antibodies. However, there are still a number of epitopes (regions of the protein to which immune reactions develop) on the GP protein to which antibodies bind. And, furthermore, two versions of GP are made, one in the viral envelope (membrane) and one that is secreted from infected cells. Together, this means that there are a lot of different spots for antibodies to bind, and some spots may be better for protective immunity, while others have no protective effect at all.

Vaccines against ebola are currently being developed with the hope of bringing these to affected areas to either prevent – or at least control- outbreaks at their source. The benefits of developing an effective vaccine include actively inducing life-long immunity.

A second method of fighting disease is to treat with previously generated antibodies in a way that the virus is neutralized, but life-long protection is not induced. One way of accomplishing this treatment is by harvesting serum from patients who were infected, but survived the disease. This has obvious limitations logistically and there is insufficient data on these treatments to know whether they were actually helpful in treating patients. Another way to transfer this sort of ‘passive’ immunity is by making large amounts of a single antibody in cell culture. These ‘monoclonal’ antibodies are highly standardized and can be produced in very large quantities.

A number of monoclonal antibodies targeting different epitopes on the Ebola GP have been developed and show protective effects when administered after viral exposure (i.e. therapeutically). One example of this kind of therapy is ZMapp  from Mapp biopharmaceutical. In studies with animals, they found that “a combination of monoclonal antibodies (ZMapp), optimized from two previous antibody cocktails, is able to rescue 100% of rhesus macaques when treatment is initiated up to 5 days post-challenge.”

Treatment of Ebola patients with Convalescent Serum

I’ve written before in this space about one of the challenges that antibody treatment against ebola. Because ebola infects macrophages as one of its targets, and because one of the jobs of macrophages is to clear opsonized (antibody-coated) particles, ebola appears to have co-opted this function as a mechanism for penetrating and infecting cells. This characteristic is termed Antibody-Dependent Enhancement (ADE) of infection and has been shown to increase the infectivity of the embryonic kidney cell line, HEK-293, in vitro (Takeda et al 2003). Reportedly, the mechanism for this enhancement is via the complement protein, C1q, and receptors on the host cells.

Together, these data beg the question of whether antibody treatments, such as ZMapp, or vaccines leading to humoral responses will be helpful or harmful in the treatment and protection of patients.

“On 11 August, a group of experts convened by WHO reached consensus that the use of experimental medicines and vaccines under the exceptional circumstances of the Ebola epidemic is ethically acceptable.” So, we may find out the answers to these questions much sooner than we would otherwise expect.

 

Blood and Genetics

Blood type is a fun and easy way to get to know genetics and learn some practical applications. In the simplest of ways, the three basic blood types are A, B and O.

A good place to brush up on blood type genetics is wikipedia, which has an excellent article on the topic.

Once you’ve reviewed this material (if you need to), then go to nobelprize.org to play a game about blood transfusions (all based on simple blood type genetics).

While you’re on the site, read a little about Alfred Nobel and why it was so important to him to have a lasting positive legacy.