University of Missouri

You shall not pass: the basic science of blocking HIV

 

Marc Johnson, associate professor of molecular microbiology and immunology at the Bond Life Sciences Center, studies viruses such as HIV. | photo by Jennifer Lu, Bond LSC

Marc Johnson, associate professor of molecular microbiology and immunology at the Bond Life Sciences Center, studies viruses such as HIV. | photo by Jennifer Lu, Bond LSC

Nineteen colorful foam flowers decorate the walls of Marc Johnson’s office, a memento from his lab members when they “redecorated” while he was out of town.

Each flower is labeled in bold Sharpie with the names of viruses and viral proteins that his lab studies—MLV, RSV, Gag, Pol, to name a few.

One flower stands out, marked in capital letters: H-I-V.

Johnson, an associate professor of molecular microbiology and immunology, is one of four researchers at Bond LSC who studies HIV, the virus that leads to AIDS. His research focuses on understanding how HIV assembles copies of itself with help from the cells it infects.

Like most viruses, HIV hijacks cellular functions for its own purposes.

“It has this tiny itty bitty little genome and yet it can infect 30 million people,” Johnson said. “It doesn’t do it by itself.”

To understand how viruses reprogram the proteins in our bodies to work against us, he said, you have to understand the cells they infect. If cells were a chamber, then viruses are the keyhole.

For example, cells use a protein called TSG101 to dispose of unwanted surface macromolecules by bending a patch of cellular membrane around the macromolecule until it is surrounded inside a membrane bubble. The process, like trapping a bug inside a sheet of tissue paper, is called budding.

The cell sweeps all the pinched-off bubbles into a larger receptacle, or multivesicular body. These bodies, Johnson said, act as the cell’s garbage collection system. To dispose of the trash, the compartments become acidic enough to disintegrate everything inside or fuse with the cell membrane so that the trash gets dumped outside the cell.

It’s like in the second Star Wars movie, “The Empire Strikes Back,” Johnson said. “They just drop all their garbage before they go into hyperspace, and that’s how the Millennium Falcon got out.”

HIV uses the same housekeeping mechanism to break out of infected cells and infect more cells, but it remains unclear which other host proteins HIV commandeers.

“It’s all part of the puzzle,” Johnson said.

THE GAME CHANGER

On his desk, Johnson keeps a white legal pad with a list of 16 projects written in blue ink.

Marc Johnson observes cells modified with CRISPR under the microscope. | photo by Jennifer Lu, Bond LSC

Marc Johnson observes cells modified with CRISPR under the microscope. | photo by Jennifer Lu, Bond LSC

“Things make it off the list or they’ll get added,” Johnson said. “Or they’ll spend years on the back burner. I have a lot of projects.”

One of the biggest projects involves using CRISPR/Cas9 — a precision gene-editing tool — to identify genes that make a cell resistant to viral infections.

“It’s a game changer. It really is,” Johnson said. “It’s so cool.”

The technology uses a missile-like strand of guide RNA to target specific sites in the genome for deletion. Before CRISPR, scientists had to suppress gene expression using methods that were neither permanent nor absolute.

But because CRISPR manipulates the genome itself, Johnson said, there’s less doubt about what is happening.

Using the CRISPR library, the Johnson lab can scan the effects of 20,000 unique gene deletions in a population of cells. When these cells, each of which contains a different deleted gene, are exposed to HIV, not all of them die. Those that survive can cue researchers in to which genes might be important for blocking HIV infection.

And if another researcher has doubts that a gene is truly knocked out, Johnson said, you can tell them, “I’ll just send you the cell line. You try it and see for yourself.”

A DAY IN THE LIFE

The Johnson lab is a tight-knit group that consists of a lab manager, two grad students, a postdoc and four undergrads.

Dan Cyburt — a third year grad student — studies molecules that interact with proteins that keep HIV from infecting the cell, such as TRIM5α. TRIM5α, a restriction factor, blocks replication of the viral genome.

Graduate student Yuleum Song prepares cells for viral infection in the BL-2 hood. | Image by Jennifer Lu, Bond LSC

Graduate student Yuleum Song prepares cells for viral infection in the BL-2 hood. | Image by Jennifer Lu, Bond LSC

Fourth year grad student Yuleum Song focuses on how the viral envelope protein, Env, is packaged into viruses before they break free from cells. While Env isn’t necessary for viral assembly and release, she said, it’s critical for the infection of new cells.

Undergrads work in a tag team, picking up where the other left off, to generate a collection of new viral clones.

And lab manager Terri Lyddon keeps day-to-day experiments on task.

Lyddon, who has been with the Johnson lab for ten years, spends much of her day working with cells inside the biosafety level 2 hood. The area is specifically designated for work with moderately hazardous biological agents such as the measles virus, Samonella bacteria, and a less potent version of HIV.

Normally, HIV contains instructions in its genome for making accessory proteins that help the virus replicate, but the HIV strains used in the Johnson lab lack the genes for some of these proteins. That means the handicapped viruses can infect exactly one round of cells and spread no further.

Lyddon also ensures quality control for the lab by making sure students’ work is reproducible.

As a pet project, Johnson also independently confirms new findings reported in academic journals about HIV. Sometimes, Johnson says, the phenotypes that get published are not wrong, but they tend to represent the best outcomes, which might only exist in very specific scenarios.

“They’re only right by the last light of Durin’s day,” Johnson said, making a Lord of the Rings reference to a phenomenon in The Hobbit that reveals the secret entrance to a dwarven kingdom only once a year.

Because scientists base their work on the research of other scientists, he said, it’s always important to check.

A RECONSIDERED POSITION

According to the World Health Organization, 37 million people worldwide in 2014 have HIV or AIDS. The virus infects approximately two million new individuals every year. Breakthroughs in treatment have turned the autoimmune disease from a highly feared death sentence into a chronic and manageable condition.

For the longest time, HIV researchers scrambled to find better therapies against HIV why trying to develop a vaccine that could prevent AIDS.

But in the past five years, Johnson says he’s noticed a shift: researchers are gaining confidence in the possibility of finding a cure, something he once thought was impossible.

“Now it’s been demonstrated that it’s possible to cure a person,” Johnson said, referring to the Berlin patient. “So it’s only going to get easier.”

However, Johnson pointed out, most people would never undergo the kind of high-risk treatment that Timothy Ray Brown, the Berlin patient, received. Brown underwent a bone marrow transplant to treat his leukemia, and his new bone marrow, which came from an HIV-resistant donor, cured him of AIDS.

A “full blown cure” will be hard to attain, but Johnson believes there may be ways for HIV patients to live their lives without having to constantly take medication.

As an example, he points to certain “elite controllers” who are HIV positive but never progress further to show symptoms of AIDS. If scientists can figure out what’s different about their immune systems, Johnson said, then researchers could train the immune response in AIDS patients to resist HIV or keep it in check.

That’s a project for the immunologists. As a basic scientist, Johnson says he adds to the knowledge of how HIV works.

“I am not thinking about a therapy,” Johnson said, “but I’m also acutely aware that some of the best solutions come from basic science. “

Even though scientists haven’t discovered all the mechanisms behind cellular and viral function yet, Johnson said, the rules do exist.

“The sculpture is already there in the stone,” he said.

Johnson’s job is to chip away at the marble until the rules are found.

Putting down roots

Plant scientist Ruthie Angelovici joins the Bond Life Sciences Center

By Jennifer Lu | MU Bond Life Sciences Center

Ruthie Angelovici

Ruthie Angelovici

Ruthie Angelovici clearly remembers her big eureka moment in science thus far. It didn’t happen in a laboratory. It wasn’t even her experiment.

At the time, Angelovici was in college studying marine biology. She had spent a year going on diving trips to figure out whether two visibly different corals were polymorphs of the same species, or two separate species.

A simple DNA test told her the answer in one afternoon.

“That’s the day I decided that there was a lot to be discovered, just in the lab,” Angelovici said. She switched majors and hasn’t looked back.

Better Nutrition in Crops

Angelovici studies the molecular biology of plants.

As a newly minted assistant professor in biological sciences at the Bond Life Sciences Center, her goal is to increase the nutritional quality of staple crops like corn, rice, and wheat.

Although these crops make up 70 percent of people’s diet across the world, Angelovici said, they aren’t very nourishing.

Corn, rice, and wheat are deficient in several key nutrients called essential amino acids. For example, if a person lived on wheat alone, they would have to eat anywhere from three to 17 pounds of the grain per day to reach the daily recommended amount for these nutrients.

Moreover, harsh growing conditions cause amino acids levels in plants to plummet—an increasingly grave problem as the earth’s climate gets warmer.

“If you think about the future, we’re going to face more droughts, more heat,” Angelovici said. “We need to figure out how we can maintain quality under those circumstances.”

Scientists have been trying to improve the nutritional quality of crops for years, whether through classical breeding or genetic engineering. The latter requires knowing which genes to alter.

Angelovici uses a technique called genome-wide association mapping. This allows her to link the natural variations within a particular trait — say, a special type of amino acids that are branched in structure — with the genes that affect this trait.

In previous studies, Angelovici chose Arabidopsis thaliana, which is popular among plant scientists for its simple genome and short life cycle, as her model plant.

She collected seeds from 313 varieties and burst them open, one seed type at a time, to release their contents. After separating the free amino acids from the rest of the seed pulp, she measured the branched amino acid levels — as a ratio to each other and to other amino acids — to build a nutritional profile that acts like a fingerprint for each plant.

Angelovici used this fingerprint to identify plants that shared similar traits. Then she scanned their DNA for any small genetic variations, or mutations, that plants had in common.

When she tallied up the frequency of each mutation in what is called a Manhattan plot, she found one particular variation that outstripped the others, standing out like a skyscraper over a city: a small section on chromosome 1 close to a gene called bcat2.

Angelovici then switched this gene off. When branched amino acid levels changed, it suggested that this trait was linked to the bcat2 gene.

However, Angelovici warned that often plants resist genetic tinkering. They lose viability, or cannot germinate seeds.

“We get yield penalty,” Angelovici says, “and the question is why?”

Metabolism, she explains, is like a network. “If you pull one way, something else is going to be affected.”

That’s where bioinformatics comes in handy. Angelovici uses an approach called network analysis to look at many pathways within the plant at once. This allows her to see the big picture, as well as the fine detail.

Moving to Missouri

Angelovici has being studying plant metabolism for ten years. Originally from Israel, she earned her PhD in 2009 under Gad Galili at the Weizmann Institute of Science in Rehovot, Israel. Then, she continued her research as a postdoctoral fellow at Michigan State University.

She prefers working with plants to animals because plants are relatively easy to manipulate and breed. Also, she loves animals and at one point wanted to be a veterinarian.

Angelovici says she was immediately drawn to the University of Missouri, and is looking forward to collaborating with researchers at Bond LSC.

“There is a great program here, great plant people here,” she said. “So, Mizzou is spot on.”

Although she has found an undergraduate and a post-doctoral researcher to help her so far, the benchtops in her laboratory remain uncluttered save for some equipment, like glassware and a few gel boxes. Three pristine white lab coats hang neatly from hooks on the wall.

But Angelovici is not fazed by the enormous task of getting her lab up and running.

“I just love doing this. It’s like climbing a mountain,” Angelovici said, about the research process. “You do it slowly and then you feel like you’re going up and you are achieving more and you can see more. It’s really fulfilling.”

As for that big eureka moment, Angelovici says she doesn’t put much stock in it.

Then she laughs. “But maybe I will experience one, and then I’ll change my mind.”

Five things you wanted to know about epigenetics (But were afraid to ask)

10960203_781430608590258_4910408420147962125_oWhat the heck is it, anyway?

Epigenetics involves changes in how your genes work.

In classical genetics, traits pass from generation to generation in DNA, the strands of genetic material that encode your genes. Scientists thought alterations to the DNA itself was the only way changes could pass on to subsequent generations.

So say you lost a thumb to a angry snapping turtle: Because your DNA hasn’t changed, your children won’t be born with smaller thumbs. Classic.

Things get way more complicated with epigenetics. It turns out that some inherited changes pass on even though they are not caused by direct changes to your DNA. When cells divide, epigenetic changes can show up in the new cells.

Getting nibbled on by an irate turtle isn’t likely to epigenetic changes, but other factors such as exposure to chemicals and an unhealthy diet, could cause generation-spanning epigenetic changes.

 

How does it work?

The main players in epigenetics are histones and methyl groups.

Imagine your genes are like pages in a really long book. Prior to the mid-1800s, books came with uncut edges, so in order to read the book, you’d have to slice apart the uncut pages. That’s sort of what a histone does to DNA: They are proteins that wrap DNA around themselves like thread on a spool. They keep the DNA organized and help regulate genes.

Methyl groups (variations on CH3) attach to the histones and tell them what to do. These molecules are like notes in a book’s margin that say, “These next few pages are boring, so don’t bother cutting them open.” As you read the book, you’ll save time and effort by skipping some sections even though those sections still exist. Or maybe the note will say, “This next section is awesome; you’ll want to read it twice.”

That’s epigenetics. Higher level cues that tell you whether or not to read a gene.

And when a scribe makes a copy of the book, they’ll not only copy all the words in the novel, but all the other stuff, too: the stuck-together pages and the margin notes.

 

What about my health?

Many areas of health — including cancer, autoimmune disease, mental illness and diabetes — connect with epigenetic change.

For example, scientists link epigenetic changes to neurons to depression, drug addiction and schizophrenia. And environmental toxins — such as some metals and pesticides — can cause multigenerational epigenetic effects, according to research. Once scientists and doctors decipher those processes work, they will be better equipped to treat the sick and be able to take preventative measures to help insure our health and the health of our kids.

 

Is it epigenetics or epigenomics?

Confusing, I know.

As we learned from the first question, epigenetics is “the study of heritable changes in gene function that do not involve changes in the DNA sequence,” according to my trusty Merriam-Webster.

Epigenomics is the study and analysis of such changes to many genes in a whole cell or organism. It’s comparable to the difference between genetics (dealing with particular pieces of DNA, usually a gene) and genomics (involving the whole genetic shebang).

 

Where can I learn more?

Start at this year’s Life Sciences and Society Program Symposium, “The Epigenetics Revolution: Nature, Nurture and What Lies Ahead,” on March 13-15, 2015. Speakers from all over the country will delve into the puzzles and possibilities of epigenetics.

For more background, Nature magazine also created this supplement on epigenetics.

“Mutant seeds” blossom in the pollen research field

  • A mutant arabidopsis model nearing pollination.

The thought of pollen dispersed throughout the air might trigger horrific memories of allergies, but the drifting dander is absolutely essential to all life.

Science has long linked this element of reproduction with environmental conditions, but the reasons why and how pollen functions were less understood. Now lingering questions about the nuanced control of plants are being answered.

“Pollen is a very important part of the reproductive process and if we understand how pollen develops and how environmental stresses impinge on this process, we might be able to prevent crop loss due to high temperature or drought stress etc.,” said Shuqun Zhang, a Bond Life Sciences Center investigator.

Zhang has developed a new line of seeds that helped him and his lab identify an influential signaling pathway that triggers a chain reaction associated with normal pollen formation and function.

This research could lead to improvement to a plant’s response to disastrous environmental variables like drought to optimize pollen production and increase the production of food crops.

 

Left: Pollen grains with MAPK3/4 genotypes are illuminated using a fluorescent microscope. RIGHT: Normally developed pollen grains shown by an electronic microscope scan. | Credit: Shuqun Zhang

Left: Pollen grains genotypes MAPK3 and MAPK6 are illuminated by red and yellow dye using a fluorescent microscope. RIGHT: Normally developed pollen grains shown by an electronic microscope scan. | Credit: Shuqun Zhang

Seeds of success

Mutant seeds are the key to this work.

Instead of glowing green in the soil like you might see in a science fiction movie, they are providing important insight on plant reproduction and stress tolerance.

Zhang developed these plants from a mutant strain of Arabidopsis, a model plant used in scientific research. Certain genes were “switched off”to pinpoint where important pollen functions were signaled.

Using this mutant plant and seed system, Zhang found that WRKY34and WRKY2, two proteins that turn on/off genes, are regulated by MPK3and MPK6signaling” enzymes. These enzymes basically transform proteins from a non-functional state to a functional state, turning on specific duties or functions. Zhang, a professor of biochemistry at MU, began tinkering with the MPK3 and MKP6 pathways more than twenty years ago during his post-doc at Rutgers University.

Zhang’s research shows the newly identified MPK3/MPK6-WRKY34/WRKY2 pathway is a key switch in the hierarchy of the signaling system in pollen formation.

The research showed that the plant’s defense/stress response and reproductive process are linked, and the influential proteins MPK3 and MPK6 were part of the bigger WRKY34/WRKY2control pathway, which is activated in early pollen production.

The system is so useful that researchers across the country won’t stop asking for the seeds, Zhang said.

“We have a lot of requests for seeds,” Zhang said. “This is a very nice system to study pollen formation and function.”

 

The cascade of control

The functions of MPK3/MPK6 in plants can be compared to a “mother board” switch. The pathway — MPK3 and MPK6 —are part of a hierarchy of response, turning functions on or off. In other words, it’s a switch that controls a lot of different things. Controlling WRKY34/WRKY2 is one of the many roles played by MPK3 and MPK6.

Shuqun Zhang, University of Missouri Bond Life Sciences investigator.

Shuqun Zhang, University of Missouri Bond Life Sciences investigator.

“Whatever is plugged into it is what comes on,” Zhang said. “We are actually very, very interested in the evolutionarily context, how this came to be.”

This signaling process is just one of many in plants. MPK3 and MPK6 are two out the 20 MPKs, or MAPKs (abbreviated from Mitogen-Activated Protein Kinases) in Arabidopsis. They control plant defense, stress tolerance, growth, and development including pollen formation and functions.

“We determined that this MAPK-WRKY signaling module functions at the early stage of pollen development,” Zhang said.

The “loss of function of this pathway reduces pollen viability, and the surviving pollen has poor germination and reduced pollen tube growth, all of which reduce the transmission rate of the mutant pollen,” according to the research.

Zhang and his lab worked with the MU Division of Biochemistry and Interdisciplinary Plant Group on the research, which published in PLoS Genetics in June of this year.

 

A world without pollen production and defense

Without pollen, plants would not reproduce — there aren’t any Single Bars in the plant world (that we know of) — and if plant generations don’t propagate, there would be no air or food for human life to sustain.

“The factors such as heat and drought stresses cause problems to the plant’s normal developmental process and that’s how pollen fails to develop,” Zhang said. “If we understand the process, and know how environmental factors impact negatively the process, we can then make plants that can handle environmental stress better.”

Zhang and his lab continue to research the complexities of these pathways. Next on the quest is to answer how MPK3/MPK6 are involved in pollen functions such as guiding the pollen tube growth towards ovule to complete the sexual reproduction process in plants.

“It is possible that MPK3 and MPK6 are activated quickly in response to the guidance signals,” he said. “There’s still a long way to go because very few players in this process have been identified, we try to understand the biological process how they work together.” This research is in collaboration with Dr. Bruce McClure, also professor of Division of Biochemistry.

Read more:

1. PLoS Genetics (May 2014): Phosphorylation of a WRKY Transcription Factor by MAPKs is Required for Pollen Development and Function in Arabidopsis — Funded by a Hughes Research Fellowship and grants from the National Science Foundation.

2. Plant Physiology (June 2014): Two Mitogen-Activated Protein Kinases, MPK3 and MPK6, are required for Funicular Guidance of Pollen Tubes in Arabidopsis — Funded by a National Science Foundation grant and a NSF Young Investigator Award.

 

The only thing you need to read about Ebola today: An expert Q&A

Jingwio Yu, a graduate studemt, does cell surface staining in Shan-Lu Liu's virology lab. The staining illuminates cell marker expressions in experiments that deduce how viruses spread once they are contracted. | Paige Blankenbuehler

Jingyou Yu, a graduate student, does cell surface staining in Shan-Lu Liu’s virology lab. The staining illuminates cell marker expressions in experiments that deduce how viruses spread once they are contracted. | Paige Blankenbuehler

News headlines seem to feverishly spread as if they were a pandemic of the brain.

Ebola hemorrhagic fever has been the most talked about disease of the year, appearing in thousands of headlines across the world since May. Through the noise of misinformation and sensationalism, fundamental information about the pandemic becomes harder to distinguish.

In an interview with Decoding Science on Tuesday, Shan-Lu Liu, MD, PhD, a Bond Life Sciences Center investigator who studies Ebola, weighed in on the latest news.

Liu, also an associate professor in the MU School of Medicine’s Department of Molecular Microbiology and Immunology, and his lab are particularly interested in the early behaviors of the virus in transmission and how it can navigate around the host immune response.

Shan-Lu Liu, Bond Life Sciences scientists and associate professor in the MU School of Medicine department of molecular microbiology and immunology.

Shan-Lu Liu, Bond Life Sciences scientists and associate professor in the MU School of Medicine department of molecular microbiology and immunology.

Q: Talk about the transmission. Ebola doesn’t spread through air, but how easily can it be transmitted through fluids?
A: It’s hard to say. It’s really not like: touch an infected person and you got it. I don’t see that could happen so easily. As an RNA virus, it’s not that stable outside of the body, unlike hepatitis B virus (HBV) where you need to boil the virus for 10 minutes and it becomes not infectious. Because Ebola is not that stable, that should not be the reason why it’s so efficient to transmit.
I think the transmission is one of the biggest things it’s, you know, I don’t think we have a complete  understanding. We do know that it spreads by contact through body fluids and many people don’t realize that the handling of the deceased — that’s very dangerous. Touching broken skin or mucous membranes like the nose and mouth is dangerous.

Q: Talk about the incubation period and how that relates to symptoms and spreading of the virus.
A: The incubation time is 2-21 days. At first, the person will have flu-like symptoms, so you know, that’s why it’s hard to notice in the early stages. Some doctors or nurses say ‘just give him antibiotics send him home.’ But in stage two, you get the hemorrhage and it gets serious. The mortality rate is high, from 50 to 90 percent.
I think the fatality is definitely related to the late stages of the disease, especially with the hemorrhaging fever. The early stages are almost unnoticeable but that’s the time transmission might spread easier through contact with an infected person’s fluid. Before symptoms, the virus doesn’t spread.

Q: The Centers for Disease Control and Prevention said the virus could infect 1.4 million people in West Africa. Is this a realistic expectation?
A: You know, it could happen. It’s a prediction again, right? But I think the agency and the scientific community need to look at this prediction very carefully. What could be done in terms to prevent this from happening? It’s alarming.

Q: Last week, an article seemed to contradict with the CDC estimate. The headline: Some good news about Ebola: It won’t spread nearly as fast as other epidemics. What do you make of that?
I don’t know, it’s hard for me to make a comment. Nobody knows. Things can always change. We didn’t expect to see a diagnosis in the United States — like this you know, this patient from Liberia was able to travel on a plane from virus country. Who can expect that? Anything can happen. There seem to have been some mishaps because he came from that area, right? Communication is more important now but it’s hard to predict because anything could happen.

Q: How has the Ebola virus behaved in previous outbreaks?
A: The first outbreak was in 1976 in Sudan and Congo — (Democratic Republic of Congo, known as Zaire at the time). It was from contaminated needles in a hospital and originally came from fruit bats — they are one of those animals that could transmit Ebola from animals to humans. The fruit bats transmitted the virus to primates, primates transmit to humans. It’s hard to notice in the early stages.
Editor’s note: The 1976 outbreak was the first occurrence of Ebola in humans. The outbreak affected one village, infecting 318 people that resulted in 280 deaths.

Q: Much of the media has reported a vaccine for ebola was delayed. How could this happen?
A: Drugs and vaccines are a little different. The Ebola vaccine was delayed, that’s for sure. That’s because, the vaccine on trial has to go through tedious steps to get approval and so thats why when this outbreak occurs the NIH (National Institutes of Health) decides to go ahead quickly. One of the things for ebola vaccine is um, the pharmaceutical companies and the industries are not interested in developing vaccines. Do you know why? It is not a big market. Only a hundred — or a thousand or more — people will be infected by ebola, unlike other vaccines like the HPV vaccination where 200 million people need it. The companies are not interested in developing it, because there’s no money in it.
A company needs to spend a lot of money to develop a vaccine, but they don’t see the market — the market can’t do it. But somebody needs to do it. Imagine if, if the virus spread like this, you know, unpredictable, it could be worse. In terms of therapy, the drugs and antibodies, we know they are really effective. And they are specific, so they can reach the market effectively.

Q: Will a drug be enough to prevent wide spreading of Ebola?
I  think the companies and governments are speeding up to make those available. To see this prediction (the CDC 1.4 million estimate), they have to be prepared. People have put increasing attention on antibodies because a vaccine is not in the near future. So what’s the approach? A “therapeutic vaccine.” The so-called therapeutic vaccine is an antibody so you engineer, you use you know, molecular engineering technique to generate those antibodies  and they can neutralize and block viral infection. It’s more realistic for Ebola and even for HIV. The HIV vaccine has failed so many times. So that’s why I think one of the new approaches is to use a new broad neutralizing antibody.

Q: Does Ebola stay in the body, like chicken pox?
A: Ebola do not cause latent infection. HIV can become latent and become chronic. So influenza virus, ebola viral infection and others normally do not lead to latency. I think for Ebola — for this type of infection — once you block the patient and clear the virus it should be good.

Q: Has the media done a good job in educating the public?
I think in terms of news coverage they are pretty careful. I looked at the news conference by the CDC director and by those doctors in Dallas, and when they make statements they are careful not to exaggerate and also give very cautious measurements. The news media need to be aware of the danger of the virus. In the meantime, you have to be aware of the possibility of being affected.
Again, I think it is a very important problem. It’s important to let the public know the situation. If you see people who have recently traveled from those West African countries, you have to be cautious — air travel is so common. But I think the media have generally done a good job.

Q: Has the government done a good job keeping the pandemic under control?
I don’t know what they do. The air travel is a problem. Intensified screening process, that should definitely be done. It’s very bad for people from the outbreak area, and I just hope that this community won’t be affected.
To control, they should be careful. A person with any sign of the disease — they need to be quickly monitored and treated.

Q: What’s the most important take-away message for the public?
A: I think it’s an important problem and we need to solve it urgently. I hope this outbreak will teach us a lesson in terms of how important emerging infectious viruses are as it comes and goes is to public health. Based on literature and reports, if people do not have obvious symptoms, they do not produce an infectious virus. The incubation time has a big range but again, we are still trying to understand the process better. Infection is a complex process. We need to better understand the viral transmission so I think for now, we need to be very cautious.

Liu and his lab do not work with the contagious Ebola virus on University of Missouri campus. All of the studies involve use of a recombinant or pseudotyped Ebola virus which is not infectious.

Viruses as Vehicles: Finding what drives

Graduate students Yuleam Song and Dan Salamango inoculate a bacteria culture in Johnson's lab. The inoculation takes a small portion of a virus and multiplies the sample, allowing researchers to custom-make viruses.

Graduate students Yuleam Song and Dan Salamango inoculate a bacteria culture in Johnson’s lab. The inoculation takes a small portion of a virus and multiplies the sample, allowing researchers to custom-make viruses.

By Madison Knapp | Bond Life Sciences Center summer intern

Modern science has found a way to turn viruses —tiny, dangerous weapons responsible for runny noses, crippling stomach pains and worldwide epidemics such as AIDS— into a tool.

Gene therapy centers on the idea that scientists can hijack viruses and use them as vehicles to deliver DNA to organs in the body that are missing important genes, but the understanding of virus behavior is far from exhaustive.

Marc Johnson, researcher at the Christopher S. Bond Life Sciences Center and associate professor of molecular microbiology and immunology in the MU School of Medicine, has been building an understanding of viral navigation mechanisms which allow a virus to recognize the kind of cell it can infect.

Johnson’s research specifically explores the intricacies of the viral navigation system and could improve future direction of gene therapy, he said.

 

Marc Johnson (left) with a post doctoral student that works in his lab. The lab does important research on the basic function and mechanisms of viral navigation and transport.

Marc Johnson (left) with Dan Salamango, a graduate student that works in his lab. The lab does important research on the basic function and mechanisms of viral navigation and transport.

Turning a virus into a tool

Conceptualized in the 1970s, gene therapy was developed to treat patients for a variety of diseases, including Parkinson’s, leukemia and hemophilia (a genetic condition that stops blood from clotting).

To treat disease using gene therapy, a customized virus is prepared. A virus can be thought of as a missile with a navigation system and two other basic subunits: A capsule that holds the ammunition and the ammunition itself.

The viral genetic material can be thought of as the missile’s ammunition. When a cell is infected, this genetic material is deployed and incorporated into the cell’s DNA. The host cell then becomes a factory producing parts of the virus. Those parts assemble inside the cell to make a new virus, which then leaves the cell to infect another.

The capsule is made of structural protein that contains the genetic material, and the navigation system is a protein that allows the virus to recognize the kind of cell it can infect.

 

Viral navigation

Gene therapy uses viruses to solve many problems by utilizing a virus’ ability to integrate itself into a host cell’s DNA; to do this successfully, researchers need to provide a compatible navigation component.

In the body, viruses speed around as if on a busy highway. Each virus has a navigation system telling it which cells to infect. But sometimes if a virus picks up the wrong type of navigation system, it doesn’t know where to go at all.

“What you can do is find a virus that infects the liver already, steal its navigation protein and use that to assemble the virus you want to deliver the gene the liver needs,” Johnson said. “You can basically take the guidance system off of one and stick it onto another to custom design your virus.”

But this doesn’t always work because of incompatibility among certain viruses, he said.

Johnson and his lab are working to understand what makes switching out navigation proteins possible and why some viruses’ navigation systems are incompatible with other viruses.

“I’m trying to understand what makes it compatible so that hopefully down the road we can intelligently make others compatible,” Johnson said.

 

The right map, the right destination

Johnson creates custom viruses by introducing the three viral components—structural protein, genetic material, and navigation protein—to a cell culture. The structural protein and genetic material match, but the navigation component is the wild card. It could either take to the other parts to produce an infectious virus, or it could be incompatible.

Johnson uses a special fluorescent microscope to identify which viruses assembled correctly and which didn’t.

A successful pairing is like making a match. If a navigation protein is programmed to target liver cells, it’s considered a successful pairing when the virus arrives at the liver cell target location.

The scope of gene therapy continues to widen. Improved mechanisms for gene therapy, and greater knowledge of how a navigation protein drives a virus could help more people benefit from the vehicles viruses can become.

Johnson uses several high-profile model retroviruses, including human immunodeficiency virus (HIV), which affects an estimated 35 million people worldwide each year, according to the World Health Organization.

Understanding nuances of HIV in comparison to other viruses allows Johnson to pick out which behaviors might be common to all retroviruses and others behaviors that might be specific to each virus.

Johnson said his more general approach makes it easier to understand more complex viral features.

“If there are multiple mechanisms at work, it gets a little trickier,” Johnson said. “My angle is more generic, which makes it easier to tease them apart.”

Supervising editor is Paige Blankenbuehler

Researchers flex new muscle in SMA drug development

By Paige Blankenbuehler

Lauren and Claire Gibbs share contagious laughter, ambition and a charismatic sarcasm.

Both are honor students at Shawnee Mission East High School in a Kansas City suburb.

They also share a neuromuscular disease called spinal muscular atrophy (SMA), designated as an “orphan disease” because it affects fewer than 200,000 people in the U.S.

However, the landscape for individuals with SMA is quickly changing with the development of new drugs.

More than 7 million people in the United States are carriers (approximately 1 in 40) of the so-called “rare” neurodegenerative disease, SMA.

 

Lauren,17 (left) and Claire, 16 (right), say their shared SMA diagnosis has strengthened their relationship and presented them with opportunities to travel and share their experiences. | Photo provided by the Gibbs family.

Lauren,17 (left) and Claire, 16 (right), say their shared SMA diagnosis has strengthened their relationship and presented them with opportunities to travel and share their experiences. | Photo provided by the Gibbs family.

SMA-sidebar

Faces of SMA

The success of therapeutics in lab experiments provides a new layer of hope for individuals and families living with the disease.

Lauren, now 17, fit the criteria for SMA Type III, while Claire, now 16, showed symptoms of a more severe manifestation of the disease, SMA Type II.

Lauren and Claire Gibbs were diagnosed on the same day.

Despite their numerous similarities, the biggest disparity between them is mobility.

Claire uses a power wheel chair while Lauren is able to use a manual chair. It’s not unusual to see Lauren being pulled along in her chair, playfully hanging onto the back of Claire’s motorized chair.

Lauren is participating in a clinical trial with ISIS-SMNRx a compound developed by Isis Pharmaceuticals, a leading company in the antisense drug discovery and development based in Carlsbad, Calif. Lauren feels that she has gained stamina and a greater ability to walk  — a feat that wasn’t routine just five years ago.

Prior to the trial, Lauren was able to walk only for short distances.

Time and Natalie Gibbs with their daughters Lauren, 17 (left) and Claire, 16 (right) in Washington D.C. The family have been visible advocates in the fight for a cure for spinal muscular atrophy. | Photo provided by the Gibbs family.

Tim and Natalie Gibbs with their daughters Lauren, 17 (left) and Claire, 16 (right) in Washington D.C. The Gibbs have been visible advocates in the fight for a cure for spinal muscular atrophy. | Photo provided by the Gibbs family.

 

Bringing New Hope

A new experimental drug developed by researchers at the Christopher S. Bond Life Sciences Center, is bringing hope to individuals with the orphan disease affecting one in 6,000 people.

Christian Lorson PhD, investigator in the Bond Life Sciences Center and Professor of Veterinary Pathobiology at the University of Missouri, has been researching SMA for seventeen years and has made a recent breakthrough with the development of a novel compound found to be highly efficacious in animal models of disease. In April, a patent was filed for Lorson’s compound for use in SMA.

Lorson’s therapeutic, an antisense oligonucleotide (a fancy name for a small molecule therapeutic that falls under the umbrella of gene therapy), repairs expression from the gene affected by the disease. The research was published May in in the Oxford University Press, Human Molecular Genetics.

The drug developed by Lorson’s lab is conceptually similar to ISIS-SMNRx already in clinical trial developed by Isis Pharmaceuticals and a team of investigators at Cold Spring Harbor Laboratory headed by Dr. Adrian Krainer.

Antisense drugs are not a new practice, but their wide-spread adoption seems to be on the cusp with recent success stories like the commercialization of an FDA-approved antisense compound produced by Isis in 2013 called Kynamro for the treatment of homozygous familial hypercholesterolemia, a high cholesterol disorder that is passed down through families.

 

Science behind success

The National Institutes of Health has listed SMA as the neurological disease closest to finding a cure. Discoveries made by the Lorson Lab have contributed significantly to current scientific understanding of the disease mechanisms and to the advances being made in finding an effective treatment for SMA.

These antisense therapies work because of the genetic makeup of SMA —the genetics are incredibly clear: a single, specific gene called Survival Motor Neuron 1  (SMN1) has been pinpointed as the cause of SMA.

SMA is a neurodegenerative disorder, meaning muscles become weaker over time due to sick or dying neurons.

These neurons become less functional because of low levels of the SMN.

Remarkably, the disease can be reversed in animal models of disease if the nearly identical duplicate gene, SMN2, can be “turned on” to compensate for low SMN levels.

Lorson’s antisense oligonucleotide therapeutic provides incredible specificity because it hones in on a specific genetic target sequence within SMN2 RNA and allows proper “editing” of the RNA encoding the SMN protein. The strategy is to “repress the repressor,” Lorson said.

The SMA-specific defect lies at the RNA step – the “cutting and splicing” of important RNA sequences does not happen efficiently in SMN2 RNAs because of a several “repressor” signals.

“The final chapter of the book — or the final exon — is omitted,” Lorson said. “But the exciting part is that the important chapter is still there – and can be tricked into being read correctly: if you know how.”

The new, antisense oligonucleotide seems to know how to get the job done.

The existence of such similar genes as SMN1 and SMN2 in humans creates a rare genetic landscape lending itself especially to a therapeutic development for SMA.

Humans are unique in this duplication — something Lorson calls a “genetic happenstance” that, on an evolutionary scale, may as well have happened yesterday.

Why humans have developed this redundant gene is unknown.

Thalia Sass, a University of Missouri biology major, genotypes samples in Christians Lorson's lab that conducts research on spinal spinal atrophy.

Thalia Sass, an MU biological sciences major, genotypes samples in the Lorson Lab where spinal muscular atrophy is researched.

 

Timing is everything

In addition to the developments of new SMA therapeutics, Lorson and his lab sought to answer an important biological question concerning the disease: When can a therapeutic be administered and still show some degree of efficacy?

Lorson’s research found that the earliest administration of a treatment provided the best outlook— extending the survival of laboratory mice by 500 to 700 percent, “a profound rescue,” according to his research published in April in the Oxford University Press, Human Molecular Genetics.

A near complete, 90 percent rescue was demonstrated in severe SMA mouse models. But even when the therapeutic was administered after the onset of SMA symptoms, there was still a significant impact on the severity of the disease.

“If you replace SMN early and get (a therapeutic) to cells that are important to the disease, you correct it,” Lorson said. “This provides hope that patients who have been diagnosed will still see some therapeutic benefit even if it is clear that the best results will likely come from early therapeutic administration.”

In Lorson’s study it’s definitive that the earlier a therapeutic can be administered, the better the outcome for individuals with SMA.

“This really points towards a strong push for neonatal screening,” Lorson said. “Infant screening would likely be incredibly beneficial for SMA and that’s something that the SMA community is really excited about.”

 

A breakthrough for families

On June 2, Lauren and Claire Gibbs attended a routine, annual rehab appointment with Dr. Robert Rinaldi, MD, division of pediatric rehabilitation medicine and attending physician at Children’s Mercy Hospital in Kansas City, Mo Dr. Rinaldi is not associated with the Isis clinical trial.

The appointment was like a reunion among close friends — Rinaldi began seeing Claire and Lauren Gibbs 16 years ago, the first year that he began working at the hospital and when the girls were one- and two-years-old, respectively.

The girls did all of the routine tests —measuring strength of grip and breathing, and assessing range of movement with the occupational and physical therapists.

A little later, Rinaldi sat with Natalie Gibbs, Lauren and Claire’s mother and a relentless advocate for advancement in SMA awareness.

Typically the muscles of individuals with SMA deteriorate over time, but together they inspected the definition of a new calf muscle on Lauren’s left leg.

For a young woman with Type III SMA — this means she can walk for short distances with little discomfort but still uses her wheel chair a majority of the time — Lauren’s new calf muscle is a remarkable achievement.

clinicaltrialinfoboxAs Lauren continues to participate in the ISIS antisense therapy clinical trial, her conditions continue to improve dramatically, even with the late administration of the therapy — in her case, 16 years after her diagnosis and onset of effects.

Lauren believes her ability and stamina for walking have increased significantly.

“Quite frankly my jaw almost hit the ground when she stood up — the change was that impressive to me,” Rinaldi said.

Rinaldi, also the co-director of the Nerve and Muscle Clinics at the hospital, had last seen Lauren two years ago. He said the Lauren he saw during a routine rehab appointment in June was like seeing a new person altogether.

“The way she stood up from the wheel chair — how quickly she did that with no support — her posture when she was standing up was more upright, her pelvis was in a much better position, her core was straighter,” Rinaldi said. “It struck me immediately how much better she looked.”

Lauren Gibbs is the first of Rinaldi’s patients to have participated in the ISIS clinical trial.

“It’s moving very fast in this field,” Rinaldi said. “I think the technology that’s evolving in research is opening up more avenues for investigation for us and there’s a big desire to find a cure for these types of diseases.”

The progress has rewarded the Gibbs family’s advocacy in SMA awareness and they’ve been able to set new goals they didn’t imagine were possible when the diagnoses for Lauren and Claire were made. Natalie Gibbs is a long-time member of Families of SMA and is currently on their Board of Directors.

The organization Families of SMA is currently providing funding to Lorson to advance this research area.

“We’re able to see first hand — and our physician who has been watching them for sixteen years has seen — that everything we’re doing in the clinical trials is really making a difference,” Natalie Gibbs said.

Over the course of their daughters’ lives, Natalie and her husband Tim Gibbs say a shift in momentum has accelerated the technology and research toward finding a cure for SMA.

“I am really impressed with the progress Lauren has made with the trial and how well Claire is doing overall,” Natalie Gibbs said. “Even though it’s a progressive and very devastating type of disease, I feel like we’re really conquering it.”

 

Link to publications:

Therapeutic window study:  http://www.ncbi.nlm.nih.gov/pubmed/24722206

University of Missouri ASO:  http://hmg.oxfordjournals.org/content/early/2014/04/29/hmg.ddu198.full.pdf+html

For more information on spinal muscular atrophy, visit FightSMA.org and fsma.org

 

Hearing danger: predator vibrations trigger plant chemical defenses

Experiments show chewing vibrations, but not wind or insect song, cause response

As the cabbage butterfly caterpillar takes one crescent-shaped bite at a time from the edge of a leaf, it doesn’t go unnoticed.

This tiny Arabidopsis mustard plant hears its predator loud and clear as chewing vibrations reverberate through leaves and stems, and it reacts with chemical defenses. Plants have long been known to detect sound, but why they have this ability has remained a mystery.

University of Missouri experiments mark the first time scientists have shown that a plant responds to an ecologically relevant sound in its environment.

“What is surprising and cool is that these plants only create defense responses to feeding vibrations and not to wind or other vibrations in the same frequency as the chewing caterpillar,” said Heidi Appel, an investigator at MU’s Bond Life Sciences Center and senior research scientist in the Division of Plant Sciences in the College of Agriculture, Food and Natural Resources.

Heidi Appel, investigator at MU’s Bond Life Sciences Center and senior research scientist in the Division of Plant Sciences in the College of Agriculture, Food and Natural Resources, and Rex Cocroft, a professor of Biological Sciences in MU’s College of Arts and Science, found that plants create chemical responses specifically to predator chewing vibrations.

Heidi Appel, investigator at MU’s Bond Life Sciences Center and senior research scientist in the Division of Plant Sciences in the College of Agriculture, Food and Natural Resources, and Rex Cocroft, a professor of Biological Sciences in MU’s College of Arts and Science, found that plants create chemical responses specifically to predator chewing vibrations.

Appel partnered with Rex Cocroft, an MU animal communication expert who studies how plant-feeding insects produce and detect vibrations traveling through their host plants.

“It is an ideal collaboration, that grew out of conversations between two people working in different fields that turned out to have an important area of overlap,” said Cocroft, a professor of Biological Sciences in MU’s College of Arts and Science. “At one point we began to wonder whether plants might be able to monitor the mechanical vibrations produced by their herbivores.”

While Appel focused on quantifying “how plants care and in what ways,” Cocroft worked to capture inaudible caterpillar chewing vibrations, analyze them and play them back to plants in experiments that mimic the acoustic signature of insect feeding, but without any other cues such as leaf damage.

Cocroft used specialized lasers to listen to and record what the plant hears.

“Most methods of detecting vibrations use a contact microphone, but that wasn’t possible with these tiny leaves because the weight of the sensor would change the signal completely,” said Cocroft.

This cabbage butterfly caterpillar munches on an Arabidopsis leaf adjacent to  a leaf where a piece of reflective tape bounces back a laser beam used to detect the vibrations created by its chewing. Roger Meissen/Bond LSC

This cabbage butterfly caterpillar munches on an Arabidopsis leaf adjacent to a leaf where a piece of reflective tape bounces back a laser beam used to detect the vibrations created by its chewing. Roger Meissen/Bond LSC

The laser beam reflects off a small piece of reflective tape on the leaf’s surface to measure its deflection, minimizing contact with the plant. The laser’s output can also be played back through an audio speaker, allowing human ears to hear the vibrations produced by the caterpillar.

Moved by the sound

Recording the sound is just the start.

You can’t put headphones on a leaf, so tiny piezoelectric actuators – essentially a tiny speaker that plays back vibrations instead of airborne sound – is required.

“It’s a delicate process to vibrate leaves the way a caterpillar does while feeding, because the leaf surface is only vibrated up and down by about 1/10,000 of an inch,” Cocroft said. “But we can attach an actuator to the leaf with wax and very precisely play back a segment of caterpillar feeding to recreate a typical 2-hour feeding session.”

Appel and Cocroft tested whether these chewing sounds could create more chemical defenses in the plants and whether these feeding recordings primed defenses when played before an actual caterpillar ate part of a leaf.

“We looked at glucosinolates that make mustards spicy and have anticancer properties and anthocyanins that give red wine its color and provide some of the health benefits to chocolate,” Appel said. “When the levels of these are higher, the insects walk away or just don’t start feeding.”

The researchers played 2 hours of silence to some Arabidopsis plants and 2 hours of caterpillar-chewing noises to others. They then chose three leaves around the plant, and allowed caterpillars to eat about a third of each leaf.  After giving the plants 24 to 48 hours to respond to the caterpillar attack, they harvested the leaves for chemical analysis.

When they found higher levels of glucosinolates in the plants that were exposed to chewing vibrations, they knew they were on the right track.

A similar second experiment went further, testing whether the plants would simply respond to any vibration, or whether their response was specific to chewing vibrations. In this case Appel analyzed anthocyanins, which again were elevated – but only when plants had been exposed to chewing vibrations but not to vibrations created by wind or the sounds of a non-harmful insect.

Past echoes and future promise

While the past is littered with suggestions that people talk to their plants, Appel and Cocroft hope their work is shifting the focus on plant acoustics towards a better understanding of why plants can detect and respond to vibrations.

“The field is somewhat haunted by its history of playing music to plants. That sort of stimulus is so divorced from the natural ecology of plants that it’s very difficult to interpret any plant responses,” Cocroft said. “We’re trying to think about the plant’s acoustical environment and what it might be listening for, then use those vibrational sounds to figure out what makes a difference.”

The National Science Foundation seems to agree with the merit of their endeavor, awarding a grant to extend this project.

The next step includes looking at how other types of plants respond to insect predator sounds and pinpointing precisely what features of the sounds trigger the change in plant defenses.

These questions aim to further basic research understanding of how plants know what’s going on to respond appropriately to their environment. This could one day lead to ways to create better plants.

“Once you understand these things you can mess around with it in plant breeding through conventional methods or biotech approaches to modify plants so they are more responsive in the ways you want to make them more resistant against pests,” Appel said. “That’s the practical application one day.”

This research was published online in the journal Oecologia July 1, 2014 and will appear in print in its August issue.

Nerve cell communication mechanisms uncovered, may lead to new therapeutic approaches for neurodegenerative diseases

 

Story by Madison Knapp/ Bond Life Sciences summer intern

Simple actions like walking, swallowing and breathing are the result of a complex communication system between cells. When we touch something hot, our nerve cells tell us to take our hand off the object.

This happens in a matter of milliseconds.

This hyperspeed of communication is instrumental in maintaining proper muscle function. Many degenerative diseases affecting millions of people worldwide result from reduced signaling speed or other cellular miscommunications within this intricate network.

Michael Garcia, investigator at the Christopher S. Bond Life Sciences Center and associate professor of biology at the University of Missouri, conducts basic research to answer fundamental questions of nerve cell mechanics.

“In order to fix something, you need to first understand how it works,” Garcia said.

Garcia’s research illuminates relationships between nerve cells to find factors affecting function.  His goal is to provide insight on fundamental cellular mechanisms that aren’t fully understood.

Garcia’s research has been funded partly by the National Science Foundation and National Institutes of Health.

Technological advancements have made it possible to better understand disease development in the human body to create more effective treatments. Alas, a scientist’s work is never finished— when the answer to one question is found, ten more crop up in its wake.

Garcia’s research, which appeared in several journals including Human Molecular Genetics andthe Journal of Neuroscience Research initially sought to shed light on the neuronal response to myelination, the development of an insulating border around a nerve cell, called a myelin sheath, which is critical in rapid communication between cells.

Eric Villalon, a graduate student in Michael Garcia's lab at the Bond Life Sciences Center, examines results. The Garcia Lab is answering news questions in cell mechanics. | PAIGE BLANKENBUEHLER

Eric Villalon, a graduate student in Michael Garcia’s lab at the Bond Life Sciences Center, examines results. The Garcia Lab is answering news questions in cell mechanics. | PAIGE BLANKENBUEHLER

How it works: Rebuilding cell theory

Garcia’s early research disproved a long-standing hypothesis concerning this cellular feature.

Mammals’ nervous systems are uniquely equipped with myelination, which has been shown to increase conduction velocity, or the speed at which nerve cells pass signals. Low velocity is often associated with neurodegenerative diseases, so research exploring why could later have application in therapeutic technology.

In addition to myelination, cell size makes a big difference in conduction velocity — the bigger the nerve cells, the faster they can pass and receive signals. Garcia’s findings disproved a hypothesis that related myelination to this phenomenon.

The hypothesis, published in a 1992 edition of Cell, claimed that myelination causes a cellular process called phosphorylation which then causes an increase in the axonal diameter (width of the communicating part of a nerve cell), leading to faster nerve cell communication. Garcia found that myelination did cause an increase in axonal diameter, and myelination was required for phosphorylation, but that the two results were independent of one another.

To narrow in on the processes affecting axonal diameter, Garcia identified the protein responsible for growth.

Garcia followed earlier work, showing that one subunit controls whether there is growth at all with myelination, by identifying the domain of this protein that determines how much growth.

After clarifying this part of the process, a question still remains: If not to control myelination, why does phosphorylation happen?

 

Looking forward

Jeffrey Dale, a recent PhD graduate from Garcia’s lab, said current research is in part geared toward finding a connection between phosphorylation and a process called remyelination.

Remyelination could be key to new therapeutic approaches. When a cell is damaged (as in neurodegenerative disease) the myelin sheath can be stripped away. Remyelination is the process a cell goes through to replace the myelin.

Imagine you have a new wooden toy boat, painted and smooth. If you take a knife and whittle away all the paint and then repaint it—even exactly how it was painted before—the boat is not going to be as shiny and smooth as it was before. This is how remyelination works (or rather, doesn’t).  When nerve cells are damaged, the myelin sheath is stripped away and even after the cell rebuilds it, the cell can’t conduct signals at the same speed it was able to before.

“If you can learn what controls myelination, maybe you can improve effectiveness of remyelination,” Dale said.

Garcia said it is possible that revealing the mechanics involved in phosphorylation could lead to better treatments. In context of neurodegenerative diseases, the question why don’t axons function properly might be wrapped up in Garcia’s question: In healthy cells, why do they?

Supervising editor: Paige Blankenbuehler

SoyKB: Leading the convergence of wet and dry science in the era of Big Data

Yaya Cui, an investigator in plant sciences at the Bond Life Sciences Center examines data on fast neuron soybean mutants that are represented on the SoyKB database.

Yaya Cui, an investigator in plant sciences at the Bond Life Sciences Center examines data on fast neuron soybean mutants that are represented on the SoyKB database.

The most puzzling scientific mysteries may be solved at the same machine you’re likely reading this sentence.

In the era of “Big Data” many significant scientific discoveries — the development of new drugs to fight diseases, strategies of agricultural breeding to solve world-hunger problems and figuring out why the world exists — are being made without ever stepping foot in a lab.

Developed by researchers at the Bond Life Sciences Center, SoyKB.org allows international researchers, scientists and farmers to chart the unknown territory of soybean genomics together — sometimes continents away from one another — through that data.

 

Digital solutions to real-world questions

As part of the Obama Administration’s $200 million “Big Data” Initiative, SoyKB (Soy Knowledge Base) was born.

The digital infrastructure changes the way researchers conduct their experiments dramatically, according to plant scientists like Gary Stacey, Bond LSC researcher, endowed professor of soybean biotechnology and professor of plant sciences and biochemistry.

“It’s very powerful,” Stacey said. “Humans can only look at so many lines in an excel spreadsheet — then it just kind of blurs. So we need these kinds of tools to be able to deal with this high-throughput data.”

The website, managed by Trupti Joshi, an assistant research professor in computer science at MU’s College of Engineering, enables researchers to develop important scientific questions and theories.

“There are people that during their entire career, don’t do any bench work or wet science, they just look at the data,” Stacey said.

The Gene Pathway Viewer available on SoyKB, shows different signaling pathways and points to the function of specific genes so that researchers can develop improvements for badly performing soybean lines.

“It’s much easier to grasp this whole data and narrow it down to basically what you want to focus on,” Joshi said.

A 3D-protein modeling tool lends itself especially to drug design. A pharmaceutical company could test the hypothesis and in some situations, the proposed drug turns out to yield the expected results — formulated solely by data analysis.

The Big Data initiative drives a blending of “wet science” — conducting experiments in the lab and gathering original data — and “dry science” — using computational methods.

Testament of the times?

“Oh, absolutely,” Joshi said.

 

Collaboration between the “wet” and “dry” sciences

Before SoyKB, data from numerous experiments would be gathered and disregarded, with only the desired results analyzed. The website makes it easy to dump all of the data gathered to then be repurposed by other researchers.

“With these kinds of databases now, all the data is put there so something that’s not valuable to me may be valuable to somebody else,” Stacey said,

Joshi said infrastructure like SoyKB is becoming more necessary in all realms of scientific discovery.

“(SoyKB) has turned out to be a very good public resource for the soybean community to cross reference that and check the details of their findings,” she said.

Computer science prevents researchers having to reinvent the wheel with their own digital platforms. SoyKB has a translational infrastructure with computational methods and tools that can be used for many disciplines like health sciences, animal sciences, physics and genetic research.

“I think there’s more and more need for these types of collaborations,” Joshi said. “It can be really difficult for biologists to handle the large scope of data by themselves and you really don’t want to spend time just dealing with files — You want to focus more on the biology, so these types of collaborations work really well.

It’s a win-win situation for everyone,” she said.

The success of SoyKB was perhaps catalyzed by Joshi. She adopted the website and the compilation of data in its infant stages as her PhD dissertation.

Joshi is unique because she has both a biology degree and a computer science background. Stacey said Joshi, who has “had a foot in each camp,” serves as an irreplaceable translator.

Most recently, the progress of SoyKB as part of the Big Data Initiative was presented at the International Conference on Bioinformatics and Biomedicine Dec. 2013 in Shanghai. The ongoing project is funded by NSF grants.