A boa constrictor with IBD, "mad snake disease".

Have you ever seen a sick boa constrictor? All of a sudden they start shedding, develop head tremors and secondary infections, twisting up into knots and wasting away. These poor animals may have acquired a fatal infectious disease called inclusion body disease (IBD). The disease can rapidly progress to the nervous system, with behavioral abnormalities such as disorientation, corkscrewing of the head and neck, holding the head in unnatural positions, or rolling onto the back. Affected snakes either die quickly or starve slowly over several years. The disease was first observed in captive snakes in zoos in the mid 1970s but the cause of the disease remained elusive. Unfortunately no treatment exists; snakes diagnosed with IBD are euthanized to stop transmission to other animals.

IBD is named after large eosinophilic inclusions (or “junk” in the form of huge protein aggregates) in the cytoplasms of nearly every cell in almost all tissues, possibly caused by replication of an unknown retrovirus. However it was unclear how the virus was transmitted.

Now the riddle has been solved and IBD treatments might be possible soon. And even more than that, by investigating the origin of IBD, the Joseph L. DeRisi lab at the University of California, San Francisco, identified a virus that shares characteristics with two known virus families that can cause fatal hemorrhagic fevers in humans!

It is well-established that some of the most medically important human diseases have origins in viruses from animal populations, or have animal reservoirs. Examples include HIV-1 and -2, influenza viruses, West Nile virus, severe acute respiratory virus (SARS), coronavirus, henipaviruses, rabies viruses, hantavirus, filoviruses, and arenaviruses. Therefore animal viruses and their hosts are excellent models for studying host-pathogen interactions and vaccine development.

To computationally identify the virus the researchers used high-throughput sequencing methods to search for candidate causes of IBD. Retroviruses are RNA viruses; each snake cell already contains 95% snake RNA needed for cell viability, plus the virus RNA. But how to separate the snake RNA from the virus RNA? The scientists simply compared sequences from the infected snake to sequences from a healthy snake to figure out what was foreign and therefore might belong to the virus. The problem was that the boa constrictor genome had not yet been sequenced. DeRisi organized the “Assemblathon 2” contest, in which teams competed to develop a computer program to assemble genetic sequences in a previously unknown animal genome, preferentially the boa constrictor genome.

The result of the RNA comparison shocked the scientists.

The foreign RNA sequences that were not present in the boa constrictor genome had several similarities to arenavirus genes. These similarities revealed the cause of the illness to be a completely new set of two arenaviruses. These viruses looked like distant relatives of other arenaviruses but had protein coats that were more similar to those of Ebola viruses. While nasty arenaviruses are common in rodents and cause infections in other mammals, we were unaware that they could infect reptiles. Like arenaviruses, Ebola viruses can cause fatal hemorrhagic fever or encephalitis when transmitted to humans. Neither of those viruses had ever been known to infect reptiles, and although it had been postulated that they shared a common ancestor, no link had ever been discovered.

The next step was genome assembly (building a complete genome out of raw data) using open access bioinformatics software, and then comparison with the RNA data. They found that the sequences from the snake virus belonged to four genes—one of which was most similar to genes found in filoviruses.

Turning back to the sick snakes, the scientists found the newly identified virus in six of eight snakes with IBD, and were able to isolate the virus.

Now the team had to find a way to grow the virus so that it could be studied further. They generated Boa constrictor cell lines to perform in vitro virus culture. When the virus was introduced into healthy boa constrictor cells, the virus replicated and the cells became clogged with giant protein aggregates like those in snakes with IBD. Antibodies aimed against the virus showed that these clumps were indeed derived from arenavirus protein, further strengthening the association of this new virus and the deadly disease. A final proof of this hypothesis will be a “challenge study,” where researchers intentionally infect boa constrictors and other captive snakes with the virus in order to induce and study IBD.

IBD is a very important disease of captive snakes. In solving this longstanding veterinary mystery and enabling the first steps towards treatment, vaccines, and perhaps even eradication of this disease, these scientists also discovered an unexpected new branch of virus biology: the viruses they found appear to be a combination of arenavirus and filovirus, neither of which had been known to infect reptiles. Their existence in reptiles raises an array of important questions about host range, evolution, basic biology and emergence of new diseases associated with this poorly understood branch of viral phylogeny.

—————

Further information:

The article, “Identification, characterization, and in vitro culture of highly divergent arenaviruses from boa constrictors and annulated tree boas: a candidate etiological agent for snake inclusion body disease (IBD)” by Mark D. Stenglein, Chris Sanders, Amy L. Kistler, J. Graham Ruby, Jessica Y. Franco, Drury R. Reavill, Freeland Dunker, and Joseph L. DeRisi is published in the open access journal mBio.

Press release video:

This week in virology podcast:

http://www.twiv.tv/2012/08/19/twiv-196-an-arena-for-snakes/

Vincent Racaniello´s virology blog:

http://www.virology.ws/

I recently blogged about harnessing the power of bioinformatics for cancer research. An interested reader, Linda Zabriske, commented that the blogosphere (and government organizations such as the Bureau of Labor Statistics) has been gradually filling with talk about cancer research and its role in our future. Linda’s tool, the Online Graduate Programs, collates some of these articles and ideas and she’s co-written this month’s post with me, reflecting on Online Graduate Education in Biotechnology.

In past decades, the field of biological science and engineering were considered separate and distinct. Biology dealt with the complexities and wonders of humans, animals and plants, while the engineering (and technology) revolved around mechanics, electronics, and other systems for developing new devices. Recently, however, scientists are creating ways to allow these schools of thought to interact with one another in new and exciting ways through biotechnology.

These breakthroughs have generated a slew of breakthroughs in health, medicine, technology, ecology, computing, telecommunications, the list goes on, with new fields constantly emerging. Case in point: bioinformatics, which was the topic of another DNALC blog post recently. In response, there are several new virtual masters degree programs.

What is Biotechnology?
As part of my role as Evaluation Manager at the DNALC, I’m currently asking biotechnology teachers at community college across America to help me define the term ‘biotechnology.’ (The teachers are participating in an NSF-funded training program, Genomic Approaches to Biosciences). According to the Biotechnology Institute, a nonprofit group that promotes biotechnology education and initiatives, biotechnology is “the use of living organisms by humans.” While most observers associate biotechnology with scientists in white lab coats, its origins stem back to ancient times. Farmers would employ biotechnology techniques to crossbreed plants to withstand adverse weather conditions or to produce more food (see, for example, the chapter on domestication of corn in Weed to Wonder, available as a website, iPad app, or PDF). Livestock owners would selectively breed their animals to provide more meat, carry more weight or run faster in a race.
Importance of Biotechnology
Biotechnology is applying the familiar scientific disciplines of biology and biochemistry, along with the fields of physics, engineering, and computer science, to produce new developments that carry extraordinary potential for the future of mankind. Advances in genetic engineering, nanotechnology, and microbiology have expanded human understanding of some of the most basic and vital processes of life.

Applications of Biotechnology
While many of these research efforts involve medical applications, biotechnology is not limited strictly to prolonging and improving the human body. Agricultural applications, such as genetic engineering of plants and animals (e.g for biofortification), can do the work of several generations of crossbreeding in a much shorter time frame. Other efforts involve the development of biofuels, including biodiesel for use in automobiles, which can reduce the worldwide dependency on fossil fuels and other pollutants.

Careers in Biotechnology
With so many different applications for biotechnology, the opportunities for new careers have been growing at a staggering pace. The DNALC teacher training program mentioned above specifically aims to train graduates for careers in biotechnology, partnering with Bio-Link, the Next Generation National Advanced Technological Education (ATE) Center of Excellence for Biotechnology and Life Sciences. Some students will use their biotechnology degrees in cutting-edge laboratories around the world, while others apply their knowledge as physicians, public health officials, and policy makers. Students also explore the legal, ethical and business applications of biotechnology to understand and resolve the inherent conflicts in
these fields, and become informed citizens.

Degrees in Biotechnology

Two of the top-flight medical schools in the US are endeavoring to give students the online education they need to pursue a career in biotechnology. Harvard University’s Graduate Program in Biotechnology allows students to pursue advanced degrees online. Fields of study include Life Sciences, Management Principles, Bioengineering/Nanotechnology, and Bioinformatics, which is the application of computer technology to solving biotechnology issues. For nearly a century, Johns Hopkins University in Baltimore, Maryland, has been one of the leading medical schools in the country. Today, the school offers students four online degree programs in biotechnology. The programs cover topics ranging from entrepreneurship and federal regulations of the biotechnology industry, to the development of complex computer programs that analyze data from biotechnology experiments.

Just as communications technologies brought in thousands of new jobs in previous decades, biotechnology is revolutionizing the workplace in the 21^st century. As the wave of advancing technology carries this field to new levels, the access to online classes in biotechnology has never been better.

And who knows, maybe one of the new grads may someone harness the power of bioinformatics to find a new treatment for cancer! Watch this space…

The NIH Biomedical Information Science and Technology Initiative defines bioinformatics as:

“Research, development, or application of computational tools and approaches for expanding the use of biological, medical, behavioral or health data, including those to acquire, store, organize, archive, analyze, or visualize such data.”

Still confused? Don’t fret, most people are when they hear that definition. I usually like to tell people:

“Bioinformatics combines the latest technology with biological research.”

Over the past decade or so, and even prior, computers have become an integral part of every industry. Biological research is no different. Computer technology has dramatically accelerated the rate at which scientists are able to acquire and analyze biological data. The vast amount of data that is produced more rapidly each day has introduced new challenges to the field, involving storing, organizing and archiving this data. The sharp increase in volume of data has also brought about the need for faster and better analysis and visualization tools. Each area of bioinformatics, from acquiring to storing to analyzing the data, has challenges of its own, and it is not uncommon for advancements in one area to drive advancements in another.

To gain a better understanding of the diversity of bioinformatics, let’s invent a hypothetical yet interesting problem that we want to tackle using bioinformatics:

Let’s assume we have a species of bacteria that is part of the normal millions of ‘good’ bacteria living on and inside healthy human beings; we’ll call this Bacteria X.0. One day Bacteria X started making people very ill. What happened to Bacteria X.0 to make it become the harmful Bacteria X.1? Let’s see how we could answer this question using bioinformatics, along the way gaining insight into the wonderful world of bioinformatics.

Using traditional molecular biology techniques, we isolate Bacteria X and extract its DNA. Then we “sequence” this DNA. Cue the first link in the bioinformatics chain: acquiring data! Acquiring data is the process of generating useable data from a biological sample. In our case, deriving and determining the DNA sequence of the Bacteria X genome.

The next link in the chain is storing this sequence data. While bacterial genomes are typically small, other genomes, such as those of human beings, can produce terabytes (1000 gigabytes) of data.

Now we analyze this sequence data. There are people who specialize in developing computational tools to analyze and visualize data, versus people who actually analyze the information. A typical analysis for our sample case might be to first graphically visualize and compare the genome of the original, harmless Bacteria X.0 with the genome of the new, harmful Bacteria X.1. A scientist might observe a segment of DNA in Bacteria X.1 which is not present in the original Bacteria X.0. This new region of DNA may be responsible for the harmful effects, so the next analysis steps might be to drill down deeper into this region and see what genes lie there, what the function of those genes are, where they may have come from, etc.

[Remember: all assumptions made and conclusions drawn in this example are hypothetical and for illustrative purposes only.]

In this example, we encountered at least 4 different specialized areas within the field of bioinformatics:

1)      Acquiring of data (working with machines and equipment, sequencing DNA)
2)      Storing data (typically working with databases)
3)      Developing tools to analyze and visualize data (programming)
4)      Analyzing data (statistics, analysis)

Typically, individuals will specialize in one particular area rather than working simultaneously across all these fields. That, combined with all the different applications of bioinformatics, means you could ask 100 different “bioinformaticians” what they do and get 100 very different answers!

Bioinformatics techniques are now employed in every area of biology and research, some of which include cancer research, crop yield optimization studies, medical genomics, ecology and evolution. The emerging field of DNA barcoding combines laboratory and bioinformatics techniques to catalogue all living species as well as identify new species. Since DNA is the blueprint of life, bioinformatics can be applied to any research involving living organisms (or organisms which once lived, see Otzi the Iceman).

One thing to remember: the four areas described above are not as simple as I’ve portrayed them to be. For example:

• When sequencing a sample, you might be interested in sequencing RNA as opposed to DNA.
• Before analyzing sequence data, the quality of this data must be validated. Sometimes large chunks of sequences need to be ‘put together’ (e.g., ‘genome assembly’). Both these areas (quality analysis and genome assembly) are highly sought after areas of specialization.
• In addition to sequencing, data analysis can also generate vast amounts of new data.

The field of bioinformatics is ever changing and rapidly evolving. Techniques that were new 2–3 years ago might be outdated today; vice-versa, techniques that were unpractical 2–3 years ago might be invaluable today, thanks to advances in computational processing capabilities, for instance.

So, whether you’re interested in plants, animals, bacteria, fungi, virology, genetics, developing databases, writing code, statistics, engineering, computer hardware, or web technologies, there may be a spot waiting for you in the field of bioinformatics.

Hope to see you on the inside!