Tuesday, August 13, 2013

Glowing Bunnies in the News: Why Make a Transgenic Rabbit?

As I've been reading a few of the articles that have reported on the recently produced "glow in the dark" rabbits (If you haven't heard or read about this, you can catch up here, here, here, or here), I've noticed that some of the comments are pretty harsh. A lot of people seem to think this is just some kind of a weird science experiment conducted by a bunch of "mad scientists." This couldn't be further from the truth.

Scientists from Hawaii and Turkey collaborated to develop the technology to take rabbit embryos and transfer a gene from jelly fish into them. This gene makes a protein called green fluorescent protein, or GFP, which glows when it absorbs a certain wavelength of light. The embryos were put back into their mother, and the animals that this gene was sucessfully added to now glows because their cells produce this fluorescent protein. On the surface, it is kind of a cool experiment from a "weird science" standpoint, but the anger comes from the perceived cost of such a "useless experiment." People seem to be wondering why these scientists (or whoever was funding them) didn't spend this money, time, and effort on something more useful. Well, the perception of high cost of these studies is almost certainly correct. The perception that this is useless is just wrong. Let's talk a little bit about why we might need these glowing bunnies after the jump.



This story has gotten a lot of press in the past few days, and I think that some of the vitriolic comments are partly due to the ignorance of the readers as well as bad reporting by the press. Too many of the reports that I've watched focus stupidly on how pet stores are going to want to stock up on these or how easy it will be to hunt glowing rabbits. In the press, it has been treated as a curiosity rather than as an important biomedical milestone. I also feel that the researchers should be marketing their discovery much better, as the interviews I've seen online appear to be focused on the new techniques they are developing to make these rabbits rather than why they are developing them.
Scientists in general, though, are often rather poor marketers. Scientists are used to writing academic journal articles directed at other scientists who often already know the implications of what they are reading; in these types of publications, the details of how things were done are very important. They aren't used to explaining things clearly to people who don't understand the jargon of their specialized field, and thus in these situations they often focus too much on the details of what they did rather than why they did it.

Why is the development of these GFP-expressing glowing bunnies important? Let's talk about that. The goal of these scientists is not just to make glowing bunnies. That would be ludicrous, but that's not the only thing that is going on here. What these scientists are doing is using GFP as a marker to study their ability to genetically manipuate the rabbits; that is, they are using GFP to test their ability to introduce a foreign gene into a rabbit.

Scientists have already used GFP to test their ability to introduce genes into bacteria and yeast as well as mice, pigs, cats, and other animals. Glowing versions of all of these animals exist now. We call such animals (in which a gene or piece of gene has been transferred into them) transgenic animals, though the term has now expanded to cover animals in which genes have been deleted (also called "knocked-out") or mutated. This is an important technique, mostly used in mice, that we use to study all kinds of human diseases, and it has been very successful.

Why start doing this in rabbits, though? What is the point? Actually, the first transgenic rabbit was created in 1985, and there are transgenic rabbit models varous cardiovascular diseases like atherosclerosis and long QT syndrome, retinal degernation, HIV infection and AIDS, and HPV infection. These scientists are working on improving our ability to make transgenic rabbit models. Using GFP, they can easily track the animals that have received the transferred gene (usually called the transgene). One reason that they want to do this, which was heavily described in the media, is that scientists could use this technology to eventually produce proteins or other chemicals in the rabbits milk to more cost effectively generate certain biologic therapeutics like insulin. Another reason, which I haven't seen discussed very much, goes back to the Krogh Principle that we discussed in a previous blog post. Basically certain animals are good for studying certain diseases.

Let's use the example of sinusitis. Chronic sinusitis affects millions of Americans and accounts for about 1 in 5 antibiotic prescriptions in adults. Its is a complex disease, but it is characterized by chronic bacterial, viral, or fungal infection of the upper airway (nose and sinuses), and creates both an enormous impact on quality of life as well as an enormous aggregate healthcare cost of around 5-6 billion dollars annually. That makes it an important disease to study. The first animal model for disease that a scientist will usually think about is the mouse. However, mice don't have sinuses, and their upper airways are much different than yours. You can't study sinusitis in the mouse. You can study sinusitis in a rabbit, and many labs use rabbits to do exactly that. Our ability to manipulate genes in rabbits and/or to introduce them into rabbits could be very important for studying the mechanisms of a disease like sinusitis.

Let's say that we discover a gene that causes people to be susceptible to sinus infections. We could test that and possibly learn how to treat the disease if we could put that gene in rabbits and study them. If you can create a better animal model to study even one human disease like sinusitis, you could get a huge return on the research dollars invested into the generation of the technology to develop the animal model.

Here's another example: Let's switch diseases from sinusitis to cystic fibrosis and switch animals from rabbits to pigs. Cystic fibrosis (also known as CF) is one of the most common lethal genetic diseases in the US. The major cause of death in CF patients is due to lung failure due to damage brought on by recurrent infections and inflammation. The cells lining the lungs of patients with CF can't efficiently clear and erradicate bacteria that they breathe in the same way that the lungs of a normal person can. While there are many promising new drugs in the pipeline for CF from companies like Pfizer and Vertex, right now the only "cure" for CF is a lung transplant. I'm using the word cure in quotes because lung transplants are diffucult to get and trick to do. After waiting up to 6 years for the transplant (if you can get one), you have about a 50% chance of surviving 5 years post-op. While that's not an accetable outcome, that's the best that's available right now to patients with severe CF.

The median lifespan of CF patients in 2009 was 37 years. While that's very young, it actually is dramatically increased over what it was 50 years before that. CF patients in the 1950’s frequently died before they could attend grade school. Now, they can expect to graduate college and go far beyond that. This is due to a miraculous combination of science and medicine, from the identification and characterization of the gene that causes CF up to the development of better treatments for the symptoms.There has been a steady progression in the improvement of the lives of those with CF, and everything points to even more improvement ahead. There are new drugs in the pipeline that may become available soon, and researchers are constantly searching for new drugs that could treat and possibly cure the disease. However, one major hurdle has always hurt CF research.

It has been known since 1990 that CF is caused by mutations (or abnormal changes) in the gene that carries the information your body uses to make a protein known by the intimidating name of the Cystic Fibrosis Transmembrane Conductance Regulator, or “CFTR” for short. CFTR is important for salt and water secretion in your lung. Without going too far into the details, your lung is lined by fluid and mucus that is critical for protecting you against all of the pathogens (bacterial, viruses, fungal spores, etc.) that you inhale everyday. Abnormal CFTR function causes abnormalities and thickening of the lung’s fluid/mucus lining, which leads to stagnant mucus in the lung and infection. Cells from your immune system rush in to try to kill the bacteria, resulting in inflammation. This leads to more mucus secretion (your lungs natural way to flush out the bacteria), which can lead to mucus plugging of the airways. The viscious circle creates a great environment for bacteria to grow and leads to irreparable lung damage.

One of the biggest problems to understanding how this occurs was that researchers didn’t have an animal model in which to study how CF lung disease develops. Whether you love or hate animal research, the simple fact is that having an animal model to test therapeutics is a major benefit if one wants to find treatments or cures for a disease, and animal research has saved countless human lives. Unfortunately, when researchers artificially made the same human disease-causing CFTR mutations in mice, the mice never developed any lung disease. This is likely at least partly due to differences in the types of cells that line the mouse and human lungs, but that’s not important for our discussion here.

A few years back, scientists at the University of Iowa thought that because pig lungs are remarkably similar to human lungs, pigs with CFTR mutations might develop lung disease like people. The generation of these pigs (originally published in the Sept. 2008 issue of the journal Science) was itself a massive undertaking. Making a transgenic pig was hard; it still is, but making the work leading to making the CF pigs vastly improved the technology. Trying to make a CF pig was also a gamble. It cost a lot of money and no one knew if these pigs would develop lung disease and be useful at all for CF research.

The researchers developed and studied pigs that were missing the CFTR gene (CFTR "knockouts") as well as pigs with CFTR harboring the most common mutation that causes the disease in humans. The Iowa scientists found that the CF piglets, while initially disease free at birth just like humans, do indeed develop lung disease, and it looks remarkably like human CF. Not only that, but watching the disease progress in these pigs has already given them insights into how CF lung disease starts and the relationship between infection and inflammation in the lung. And it is helping them test some of the drugs currently in development that may dramatically revolutionize how CF is treated.

The development of the CF pig was a huge milestone in our understanding of the mechanisms of CF disease, which in turn will likely lead to better treatments and, hopefully a cure someday. It's a big reason for CF patients and their families to remain optimistic about the future.

There very likely will be one or more human diesase that benefits from the development of these transgenic GFP rabbits. Don't think of them just as-glow-in-the-dark bunnies, a curiousity that some kooky scientists wasted money developing to satify their own sadistic or otherwise weird whims. There's a method behind this seeming madness, and that method is to eventually be able to better study human diseases.

Text © 2013, TheMadScienceBlog

--
Lisa: “I’m going to become a vegetarian”
Homer: “Does that mean you’re not going to eat any pork?”
Lisa: “Yes”
Homer: “Bacon?”
Lisa: “Yes Dad”
Homer: “Ham?”
Lisa: “Dad all those meats come from the same animal”
Homer: (sarcastically) “Yeah, right, Lisa. A wonderful, magical animal!”
The Simpsons.
--

Sources and Further Reading
  • Algner et al. "Transgenic Pigs as Models for Translational Biomedical Research." Journal of Molecular Medicine. 88:653-664.
  • Bosze et al. "The Transgenic Rabbit as Model for Human Diseases and as a Source of Biologically Active Recombinant Proteins." Transgenic Research. 2003. 12:541-553.
  • Christensen, N.D., and Peng, X. "Rabbit Genetics and Transgenic Models." Chapter 7 in The Laboratory Rabbit, Hamster, Guinea Pig, and Other Rodents. Elsevier, 2012.
  • Fan, et al. "Transgenic Rabbit Models for Biomedical Research: Current Status, Basic Methods and Future Perspectives." Pathology International. 1999. 49:583-594.
  • Fan, J., and Watanabe, T. "Transgenic rabbits as therapeutic protein bioreactorrs and human disease models." Pharmacology and Therapeutics. 2003. 99:261-282.
  • Hammer, et al. "Production of Transgenic Rabbits, Sheep, and Pigs by Microinjection." Nature. 315:680-683.
  • Houdebine, L.M. "Use of Transgenic Animals to Improve Human Health and Animal Production." Reproduction in Domestic Animals. 2005. 40:269-281.
  • Houdebine, L.M. "Production of Pharmaceutical Proteins by Transgenic Animals." Comparative Immunology, Microbiology, and Infectious Diseases. 2009. 32:107-121.
  • Luo, et al. "Genetically Modified Pigs for Biomedical Research." Journal of Interited Metabolic Disorders. 2012. 35:695-713.
  • Rogers, et al. "Disruption of the CFTR Gene Produces a Model of Cystic Fibrosis in Newborn Pigs." Science. 2008. 321:1837-1841.
  • Stoltz, et al. “Cystic Fibrosis Pigs Develop Lung Disease and Exhibit Defective Bacterial Eradication at Birth." Science Translational Medicine. 2010. 2:29ra31.

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