Wednesday, July 24, 2013

Animal Patents, huh? - Knockout (KO) mice

Copyrights © Françoise Herrmann                                                                                                                                                      

Readers beware! The following post is not for the faint of heart. Even if  KO mice are not pitted to compete in any Rodent Boxing Championships, they are genetically engineered.

 Knock-out (KO) mice come in many different varieties depending on the gene that has been knocked out of their phenotypes. The loss of a gene’s function (when it is targeted or trapped with an artificial-DNA replacement sequence) enables scientists to study the role of the knocked-out gene relative to various diseases and/or to develop and test various drug therapies. And since mice share many genes with humans, it is assumed that much information inferred in knock-out engineering is applicable to humans.

Knock-out mice are usually named after the knocked-out gene. For example, p53 mice have the p53 gene knocked out which normally suppresses cell division and the growth of tumors.  Humans born with p53 mutations suffer from L9-Fraumeni Syndrome where they tend to develop various types of cancers at an early age.

A search at the EPO (European Patent Office) of the terms “Knockout mice”  in patent titles and abstracts yields 230 different patents. So, indeed, there are quite a few varieties of knocked out mice pushing the frontiers of drug discovery. For example, among the more recent KO  mice patents, there are the following:  


  These CISD2-knockout mice have a  phenotype with mitochondrial breakdown and dysfunction. They are model mice for the Wolfman Syndrome 2 (WFS2) disease, characterized by premature aging.



 Here, the mice finally produced present serious heart conditions, enabling to screen drugs and to study the genesis of heart pathology.



These mice are engineered to exhibit abnormal muscular function due to the disruption of the function of the nuclear receptor interaction protein (NRIP) gene. Abnormal muscular function is observed in the diseases of muscular dystrophy.  This particular patent claims the engineering of such transgenic NRIP-knockout mice and all of the steps involved in the method for producing mice with a disrupted homozygous NRIP gene displaying abnormal muscular function.  This patent thus effectively lays claim on the invention/identification/production of the gene responsible for muscular dystrophies.  

Setting aside for the moment those issues of animals rights previously hinted at,  the limitations arising in equating the animal model with an undifferentiated and asexual human model,  the ethics of justification, and the ownership/claims laid on genetic material, let’s take a peek at the production process of genetically engineered mice.  There are millions of knockout mice bred and used worldwide.

Fifteen percent of the knockout genes are lethal (NIH-NHGRI), which means that 15% of the mice bred do not reach adulthood. Among other dismissed details, the NIH-NHGRI points out that the study of very early development limits the kinds of inferences that can be drawn, even in mice alone.  

Once a DNA sequence replicating the researched gene targets or traps the original sequence, knocking out its function, in a stem cell nucleus, and the cells are cultured and injected into the embryos of a pregnant mouse, the production of a knockout mouse is still a several-generation process.  The first generation yields some chimeric mice with mixed gene function . The chimeric mice are then crossbred with normal mice, whose offspring will finally either inherit or not inherit the researched gene in a homozygous manner (that is completely, in every tissue).  

The consensus of the scientific community, despite all the known limitations connected to inferences across species, inferences across age groups, the issues of animal rights, the ethics of  breeding practices and the ownership of genetic material,  is that this is an invaluable process:

Despite these drawbacks, knockout mice offer one of the most powerful means now available for studying gene function in a living animal. Such studies will accelerate efforts to translate newfound knowledge of the human and mouse genomes into better strategies for diagnosing, treating and preventing human disease.” (NIH - NHGRI)

Indeed, the production and use of KO mice is one of the hottest areas of biomedical research.

If you are speechless at this point, or feel you may have swept too many rodents under the rug, then you will need to turn to the voices of dissent….



- - The NIH - (National Institute of Health) National Human Genome Research Institute (NHGRI)  
- Knockout Mice Fact Sheet
- – What is a knockout mouse?
- What are Knockout mice used for?
- What are the drawbacks of knockout mice?
- How are knockout mice made?




Monday, July 22, 2013

Death of the father of the mouse (Douglas Engelbart 1925 – 2013)

Copyright © Françoise Herrmann

Not so very long ago in the land of informatics, computers were commanded to do their computations by people conversant in  the language of the computer’s operating system… already a step removed from the computer’s assembly language… The computer screen was black and commands were input either in amber or green using DOS or UNIX syntax… The idea of a user-friendly graphics interface, covering up all the linear command-based prompts -  came later. And so did a device able to command the computer from the outside of the machine - called “a mouse”. The inventor of the mouse, Douglas Engelbart, just died, on July 2, 2013.  

The mouse was called “a mouse” from the get go! It was made of wood, had wheels (respectively corresponding to X and Y coordinates) and a long cable…that looked like…  a tail!... It was invented in the 60s at SRI – the Stanford Research Institute-, patented in the 70s, and commercialized in the 80s by Steve Jobs, who put it all together with the developments of  graphic interfaces, in a single stroke of genius, called the Macintosh --the machine that still later would become known as the “fishbowl”!...

Douglas Engelbart’s mouse patent (US 3,541 541) titled “X-Y POSITION INDICATOR FOR A DISPLAY SYSTEM” was granted on Nov 17,  1970, and assigned to SRI.  It was filed on June 21, 1967. This is means that by the time it was commercialized in the 80s, the patent had expired.  To date there are more than 2 billion mice that have been sold worldwide!... And of course, that’s probably enough since Steve Jobs took a second stride with the capacitive technology of touch screens in Iphones, now replacing the mouse and mouse pad…   

Here is the abstract of Engelbart’s brilliant X-Y coordinated mouse patent, and a drawing of the work station of the 70s…

 Abstract US 3541541
An X-Y position indicator control for movement by the hand over any surface to move a cursor over the display on a cathode ray tube, the indicator control generating signals indicating its position to cause a cursor to be displayed on the tube at the corresponding position. The indicator control mechanism contains X and Y position wheels mounted perpendicular to each other,  which rotate according to the X and Y movements of the mechanism, and which operate rheostats to send signals along a wire to a computer which controls the CRT display. 

I suspect that my granddaughter will giggle when I tell her of the little mice that  used to turn pages, pick colors and draw rainbows… And I wonder what she will say…