Tuesday, July 31, 2007

More Déjà Vu...Autism Cured in Mice!

A group of scientists led by Susumu Tonegawa at MIT (Where have I heard that name before?) have demonstrated the first successful treatment for Fragile X Syndrome (FXS), a cause of mental retardation and autism. In mice genetically engineered as a model for FXS, they used genetic techniques to inhibit an enzyme called p21-activated kinase (PAK). Inhibiting PAK resulted in structural changes in the nerve cells as well as improvement of behavioral abnormalities.

This is not to say that we will be able to cure autism by genetic engineering, but there are drugs that inhibit PAK, and they might be useful for treating some kinds of autism.

Let me emphasize that FXS is only one cause of autism and mental retardation. The causes of the wide range of conditions along the autism spectrum remain unknown and have been the source of much controversy.

An interesting dialogue about the subject, including whether autism should even be “cured” at all, can be found here.

Here's the BBC story.

Here's the original paper.

Here's more than you would ever want to know about FXS.

Déjà vu in mice?

Neuroscientist Susumu Tonegawa at the Massachusetts Institute of Technology (MIT) has reported on a mechanism for déjà vu (French for “already seen”). We’ve all experienced it, that feeling that you’ve been somewhere, or seen something before, even though...

Wait a minute. I get a feeling I’ve already posted this piece.

I have.

But I also had a little bit of déjà vu when I first saw this article. I knew I’d seen that name before. It didn’t take me long to figure it out. Susumu Tonegawa won the Nobel Prize in 1987 for his work (in mice) on antibody diversity.

Tonegawa’s work had solved a problem that had perplexed scientists for years. Antibodies are proteins that attack invading germs (and other things) very specifically. An antibody can tell the difference between two very similar molecules. How can the body make antibodies that are so specific? If, as was thought at the time, each protein was coded by a different gene, it would require millions of genes just for making antibodies. There are only about 30,000 genes in the mouse.

The solution was elegant. Antibodies are made up of two kinds of proteins called heavy and light chains. Let’s just look at the heavy chain for now. Each heavy chain has a constant portion and a variable portion. It is the variable portion that binds to foreign substances. The gene for the heavy chain also has a constant portion, but the portion that encodes the variable portion is the part we’re interested in.

The variable portion can be divided into three parts, V, D, and J. There are hundreds of copies of the V part of the gene, each with a different sequence. There are 20 different D segments in humans (12 in the mouse) and 4 different J segments.

To make an antibody, you take one V segment, one D segment, and one J segment. That gives you tens of thousands of different combinations. The segments don’t always join up in the same way, adding more possibilities. Add to that different light chains with similarly arranged variable regions and there you have it—antibody diversity.

Déjà vu in mice?

Neuroscientist Susumu Tonegawa at the Massachusetts Institute of Technology (MIT) has reported on a mechanism for déjà vu (French for “already seen”). We’ve all experienced it, that feeling that you’ve been somewhere, or seen something before, even though you haven’t.

The basis for this feeling, according to Tonegawa, is that you are really experiencing something very similar to something you’ve experienced before, but your brain can’t tell the difference. The part of your brain that helps you distinguish between two very similar experiences is the dentate gyrus. Tonegawa bred some mice in which the dentate gyrus doesn’t function very well and these mice were less able to distinguish between two similar situations than control mice.

As we age, the dentate gyrus becomes less functional, which explains why déjà vu happens more frequently as we get older.

Clyde Keeler and Apollo Smintheus

Clyde Keeler went to Asia Minor to collect mice and search for new mutations. He claims that he was captured and tried for espionage in Turkey. Apparently officials found it hard to believe Harvard University would send someone so far just to catch mice.

He also had the chance to visit the temple on Tenedos:

“I wondered about the tiny Island of Tenedos at the mouth of the Dardanelles where stood the temple of Apollo God of Mice (Apollo Smintheus) since long before the Trojan War. Aristotle and other ancient writers told of the white mice raised under Apollo's altar. I went to Tenedos in 1930 and learned that in 1929 an albino house mouse was living in a garden shed a stone's throw from the site of the ancient temple of Apollo. Barring possible mutation, that could mean as much as 3,000 years of population inbreeding and with three generations a year the number of generations is staggering.”1

This cult started around 1400 B.C. and continued until at least A.D.1453. In comparison, modern strains of laboratory mice have been inbred for about 100 years. I wonder if any descendants of the sacred mice of Apollo Smintheus are still wandering about Tenedos. Now that would be an interesting genome to sequence!

To whet your appetite for more, here’s a juicy tidbit from the world of laboratory mice: Super-sized mice

Keeler, Clyde, “How it began” In: Morse, H.C., III, (Ed.) (1978)
Origins of Inbred Mice
. Academic Press, New York. http://www.informatics.jax.org/morsebook/

Apollo Smintheus—The Mouse God

There is a temple on the island of Tenedos dedicated to Apollo Smintheus, the Mouse God. According to Clyde Keeler, the cult of Apollo Smintheus thrived for 3,000 years. It all began when soldiers from Crete invaded Asia Minor and were victorious because mice had gnawed through the leather straps of their enemies’ shields.

Living in the temple were strange creatures—white mice. They scampered unmolested throughout the temple and were used to predict the future. According to Pliny “By the learning of soothsayers, observed it is, that if there be a store of white ones bred it is a good signe and presageth prosperitie.” (Quoted in Keeler, C.E. (1931). The Laboratory Mouse. Its Origins, Heredity and Culture. Harvard University Press, Cambridge.)

To finish up today's post, here are a couple of recent studies using mice:

Making a smarter mouse

Immunization against diabetes

Baldness cured in mice!

Well, not exactly, but scientists at the University of Pennsylvania School of Medicine have shown that mice with skin wounds can regrow hair. Something about the healing process caused the cells in the healing wound to “open an embryonic window,” and do things that can normally only be done in an embryo, like making hair follicles. Stem cells were recruited to the area and formed new follicles, just as they are formed in the embryo.

Although this might eventually lead to a new cure for baldness (which would certainly please some), it also could lead to more medically important developments, like improved wound healing.

What is most intriguing, at least to me, is that this is the first time anyone has demonstrated actual tissue regeneration in mammals. Some animals, like salamanders, can regenerate an entire limb or a tail, but the only kind of regeneration shown to occur in mammals (up to now) requires some fragment of the original tissue.

Clyde Keeler, the man who named this blog

Keeler introduces his 1931 book as follows:

“Small rodents will always find a place in the laboratory of the zöology teacher, the biological investigator, the medical researcher, and the fancier. Each man has different problems in mind: behavior, physiology, disease, and beauty among others...”

I’ll give him the benefit of the doubt on the “Each man” thing, since this was 1931, but there were actually women involved in mouse research even in the dark ages of the twentieth century.

“...Literature upon the house mouse, its origin, history, distribution, development, the nature of its variations, the hereditary transmission of its varietal characters, and methods of rearing it suitable to the needs of laboratories, has not been assembled so far as I am aware...To collect such valuable information as this concerning the house mouse and to present it in a usable form is the task of this book.”

I’m not sure how valuable Keeler’s recipe for mouse food is today (240 parts oatmeal, 30 parts powdered skim milk, 8 parts cod-liver oil, 1 part salt), but I find his collection of mouse lore from ancient civilizations fascinating.

Keeler, C.E. (1931). The Laboratory Mouse. Its Origins, Heredity and Culture. Harvard University Press, Cambridge.

Welcome to The Sminthophile

The word sminthophile is derived from the Greek word sminthos, meaning mouse. Clyde Keeler used the term in his speech at an awards ceremony on February 14, 1978. The ceremony celebrated inbred laboratory mice and honored the scientists who developed them and demonstrated their enormous scientific potential.1

Clyde Keeler was one of those pioneers of mouse research. He also wrote, in 1931, the definitive history of the relationship between mice and humans.2 His book describes waltzing mice in Japan, medical uses for mice and mouse products in medieval Europe, and the cult of Apollo Smintheus.

Stay tuned for more about the past, present, and future of mice.

1 Morse, H.C., III, (Ed.) (1978) Origins of Inbred Mice. Academic Press, New York. http://www.informatics.jax.org/morsebook/

2Keeler, C.E. (1931). The Laboratory Mouse. Its Origins, Heredity and Culture. Harvard University Press, Cambridge.