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Live long and prosper: healthy mitochondria, healthy motor neurons?

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Chris Lorson (front) and Mark Hannink (back) collaborate to study the role of mitochondria in motor neuron health, particularly in relation to spinal muscular atrophy, a neuromuscular disorder | photo by Jen Lu, Bond LSC

Chris Lorson, a professor of veterinary pathobiology, and Mark Hannink, a professor of biochemistry, want to find a new way to help motor neurons live a long and healthy life. Their question: what’s the relationship between motor neuron sruvival and a cellular component called mitochondria?

The two researchers at the Bond Life Sciences Center were awarded preliminary funding from the Bond LSC to pursue this question. Their findings could lead to new targets for therapies to treat a type of muscular dystrophy called spinal muscular atrophy, or SMA.

Spinal muscular atrophy, a genetic disease characterized by the death of motor neurons in the spinal cord, is caused by a mutation in the Survival Motor Neuron 1, or SMN1, gene. Patients with SMA develop muscle weakness and deterioration that spread inwards from the hands and feet, which progresses to interfere with mobility and breathing. The severity of symptoms and time of onset depend on how well a related gene is able to compensate for the lack of SMN1. As a result, treatment strategies usually focus on improving the activation of SMN1’s back-up gene.

Hannink and Lorson, however, are interested in a different pathway that is related to mitochondria dsyfunction.

Mitochondria are like the cell’s battery packs. Produced in the cell body, mitochondria migrate to the other end of the motor neuron to provide the energy to send electrochemical signals to recipient muscles and nerves. When mitochondria break down, the cell packs them into vacuoles that return to the cell body for recycling or removal.

“I saw a report that said that in SMA, there’s evidence for dysfunctional mitochondria in spinal motor neuron atrophy,” Hannink said. “My lab knows something about how mitochondria respond to stress.”

“There’s a lot of information out there that hints at it,” Lorson, an expert in SMA, said. “A number of the same responses you see in the stress pathway are also activated in neurodegeneration.”

To test their hypothesis, Hannink and Lorson plan to make motor neurons from pluripotent stem cells taken from people with and without SMA, and compare mitochondrial function and cell survival between the two groups. Then, they will test if a number of different genes that are known to be important for mitochondrial function will affect motor neuron health in both SMA and non-SMA derived cells.

“If you look at the tool chest of SMA therapeutics right now,” Lorson said, “you have a number of very obvious targets.”

Most approaches aim to boost the performance of the SMN or its back-up gene, but there are also options like neuroprotectants and skeletal muscle activators. Molecules that maintain healthy mitochondrial function could be another possibility.

“These are things that don’t worry about the state of the SMN gene and are targeting something in addition to, supplemental to or as an alternative to SMN,” Lorson said. “And that’s where this project would fall.”

This seed funding is one of seven awarded this year at the Bond Life Sciences Center. These awards, which range from $40,000 to $100,000 in funding, foster inter-laboratory collaboration and make possible the development of pilot projects.

Mizzou Epigenetics 2016

Five faculty speakers from five different universities, along with two trainees selected based on the merits of their poster abstracts, presented on current topics in epigenetics. The daylong symposium, titled Mizzou Epigenetics, took place on Wednesday, Nov. 9 at the Bond Life Sciences Center.

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Kenote speaker Dr. Jean-Pierre Issa talks about epigentic drift at the epigenetics symposium on Nov. 9th, 2016 | photo by Jen Lu, Bond LSC

Dr. Jean-Pierre Issa of Temple University, the keynote speaker, said he was a stickler for the definition of classical epigenetics: stable, long-term changes in gene expression. Textbook examples of epigenetics include X-inactivation, an irreversible process that happens at the beginning of gestation, and imprinting, where certain genes are not expressed based on their parental origins.

DNA methylation is one mechanism that cells use to control whether genes are activated. The presence of methyl tags—single carbons bonded to three hydrogen atoms—act like “off” switches when attached to a region of the gene called the promoter.

Enzymes that add or remove tags are normally busiest during the embryonic development. Cancer is the exception to the rule. According to Issa, cancer presents a “chaotic picture” where methyl tags get added to regions where they don’t belong, and removed from regions where they ought to be, resulting in epigenetic shift.

The greater the epigenetic shift, it seems, the greater the age of the cell. Regardless of whether you look at mice, monkeys or humans, Issa said, from a methylation perspective, “cancers look like very very very old cells.”

He also drew connections between epigenetic shift and other conditions related to aging. For example, specimens with chronic inflammation, infection or the introduction of a new microbiome to a germ-free body tended to show a higher than average amount of epigenetic shift as their cells age. Meanwhile, mice and monkeys who were exposed to calorie restriction tended to have lower amounts of epigenetic shift over time.

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Poster session from the epigenetics symposium held Nov. 9th, 2016 | photo by Jen Lu, Bond LSC

Other speakers who presented on epigenetics included:

  • Dr. Rick Pilsner, from the University of Massachusetts, on how paternal exposure to plasticizers affect sperm DNA methylation
  • Dr. Bob Schmitz, from the University of Georgia, on the identification of mechanisms behind spontaneous epigenetics variation
  • Dr. Zohreh Talebizadeh, from Children’s Mercy Hospital, on the genetics of autism
  • Dr. Andrew Yoo, from Washington University, on microRNA-mediated changes in chromatin during neuronal reprogramming of human fibroblasts

The event was sponsored by Mizzou Advantage, the School of Medicine, the College of Agriculture, Food & Natural Resources, the Bond Life Sciences Center and the Chancellor’s Distinguished Visitors Program.

 

 

 

 

 

 

 

 

Close encounters of the plant protein kind

Bond LSC researchers David Mendoza (left) and Scott Peck (right) are collaborating to develop a new method for studying plant signaling pathways as they happen inside the cell. | photo by Jennifer Lu, Bond LSC

Bond LSC researchers David Mendoza (left) and Scott Peck (right) are collaborating to develop a new method for studying protein signaling pathways inside plant cells. | photo by Jennifer Lu, Bond LSC

By Jennifer Lu | Bond LSC

Sometimes, timing is everything.

That was the case in what led to a new collaboration between the Mendoza and Peck laboratories. The two researchers were recently awarded $48,250 in seed money from the Bond Life Sciences Center to adapt a new technology to the study of signaling pathways in plant cells.

David Mendoza, a Bond LSC researcher and assistant professor of plant sciences who is interested in nutrient uptake in plants, got the idea for the project when he attended the Trace Elements in Biology and Medicine conference in June. There, he kept hearing about an enzyme called BioID used to identify protein interactions in mammalian cells.

“In plants, we have a hard time figuring out how proteins interact with each another to transfer information within the cell,” Mendoza said. BioID could be the key.

BioID works like a spy slipping a small tracker into the coat pocket of every person it encounters, but instead of a tracker, BioID transfers a unique molecular tag onto every protein that comes near. It’s a speedy process, no matter how brief the interaction between BioID and the incoming protein. But once the proteins are tagged, they can be rounded up and identified later, even if they’ve moved elsewhere in the cell.

Scientists can study which proteins interact with their protein of interest by linking BioID to their protein. This lets them track the signals being communicated to and through their protein without disrupting what’s happening inside the cell.

Although BioID has exclusively been used in animal systems, Mendoza talked to the scientist behind BioID to see if it could be used in plants.

Incidentally, BioID has been publicly available for several years but the enzyme was impracticable for plant experiments. It needed a lot of raw material on hand before it could start tagging proteins, much more material than what is normally found within plant cells.

However, research on a more suitable candidate called BioID2 was published just months before the conference. Unlike its predecessor, BioID2 required very little starting material to function in plants.

“Like a lot of things,” Mendoza said, “timing was key.”

When he approached Scott Peck, a colleague at the Bond LSC and professor of biochemistry specializing in plant proteomics, with the news, Peck saw immediate applications for BioID2.

With currently available methods, plant scientists have to look at protein interactions in artificial environments, such as in a test tube or in yeast systems. A real-time protein-tagging method would allow plant scientists to observe signaling pathways in their native environment–the cell–under a variety of conditions.

“It allows the contextual information within the plant to still be present,” Peck said.

For example, with BioID2 the Peck lab, which studies plant resistance to bacteria, could watch how incoming stimuli such as plant pathogens or stress from drought affect overall protein-to-protein interactions within plants, compare these protein interactions across different cell types, or even discover previously unknown protein interactions, he said.

“You know you have a good idea when the other person gets excited right away,” Mendoza said.

Peck also had a suitable model handy in which they could test BioID2 at work, but the two researchers first had to make sure plant cells could produce functional BioID2. Mission accomplished, the next step is to make plants produce BioID2 that is linked to their protein of interest.

“The nice part of this seed grant is it lets us get a jump on some new technology to develop here,” Peck said.

Using BioID2 in plants is an interesting and novel idea, Mendoza said. “For me, that’s enough to try.”

 

This seed funding is one of seven awarded this year at the Bond Life Sciences Center. These awards, which range from $40,000 to $100,000 in funding, foster inter-laboratory collaboration and make possible the development of pilot projects.

 

Expert Comment: How science made the “three-person” baby possible

Family silhouette

Stock image via iStock

By Jennifer Lu | Bond LSC
A new in-vitro fertilization technique that uses genetic material from three persons made the news last week following the announcement of the successful birth of a now five-month-old baby boy. The process allowed the mother, who had a rare mitochondrial disease known as Leigh Syndrome, to have a child without passing her faulty mitochondrial genes.  The nucleus from the mother’s egg was inserted into a prepared donor egg that had healthy mitochondria to make a cybrid, or cytoplasmic hybrid, egg that was then fertilized.

We asked Mark Hannink, Bond LSC scientist and professor of biochemistry, who studies oxidative stress in mitochondria, what this all means.

This is not the first “three-person” baby. Why is this technique new?

It’s another way of getting a healthy mitochondrial genome into the baby.

You have to bring together three parts: nuclear DNA from the mom, nuclear DNA from the dad, and mitochondrial DNA from the donor. The question is whether you bring together the mitochondrial DNA from the donor and the nuclear DNA from the mom first, and then add the DNA from the father.  The other way is making the diploid nucleus first (combining the mother and father’s DNA,) and then putting that into the donor.

Wait, so we have two types of DNA in our cells?

Way way early in evolution, a bacteria got together with a cell that had a nucleus, and they decided to cooperate. Over time, many of the genes that were originally in that bacteria’s genome moved to the nuclear genome. But some of them haven’t. The mitochondrial genome in humans has some 37 genes. But the mitochondria itself has about 1000 different proteins so those other proteins are encoded by the nuclear genome. Together, those proteins work together to form healthy mitochondria that, among other important jobs, provide energy for the cell.

What makes this procedure controversial?

Any time you manipulate the sperm and the egg, there is a chance that you will generate subtle alterations which result in defects in the child during development or after it’s born. Even in vitro fertilization, which has been shown to be effective and works, has a higher rate of diseases associated with it.

Now you’re doing a whole set of complicated manipulations before you get to IVF….You take out the existing nucleus from the donor. You put in the nuclear genome from the mother. And you hope that it all comes back together and then you do the IVF…. Any time you do a manipulation like that, you may cause subtle mistakes that you’re not aware of.

Then there’s the other concern. The mitochondrial proteins encoded by the nuclear genomes and the mitochondrial proteins encoded by the mitochondrial genomes  have to work together to form functional mitochondria that make energy, regulate signaling, regulate calcium, regulate nerve transmission and cell survival.

Your nuclear genes have been interacting with your mitochondrial genes throughout your entire natural lineage, so they’ve coevolved to work together. If, let’s say, there’s a minor mistake made in one of the nuclear genes that encodes a mitochondrial protein in your grandma, you might still get selected for a compensatory mutation in the mitochondrial genome that would still allow a functional mitochondria to be made….But the nuclear genome of one person may not be compatible with the mitochondrial genome of another person even though that mitochondrial genome is normal and works just fine in the context of that person’s nuclear genome. But there’s no way to know that in advance. So you may end up with a healthy baby, or you may end up with a baby in which the nuclear genome and the mitochondrial genome are not compatible.

Saturday Morning Science returns to Bond LSC

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This past weekend not only ushered in Mizzou’s first home game of the season, but the return of Saturday Morning Science. The weekly lecture series connects the Columbia community with MU scientists and their research, from bio-engineering to volcanology to anthropology and linguistics.

Elizabeth G. Loboa, dean of the College of Engineering, kicked off the semester with her talk on tissue engineering in the age of drug-resistant bacteria.

Tissue engineering is about turning cells into tissues and organs, for example, fat-derived stem cells into muscle, bone and cartilage. The tissues take shape on tiny scaffolds that are bio-compatible and biodegradable.

The Loboa lab does this, but they’ve added an extra layer to their research: Loboa’s scaffolds also act as pipelines that deliver wound-healing and anti-bacterial compounds to cells as they grow into tissue. The idea is to reduce infection, inflammation and scarring as the wound heals.

“We’re trying to kill these bacteria while helping these stem cells become the cells we want to create,” Loboa said, about her research at the University of North Carolina-Chapel Hill and North Carolina State University.

Using a process called electrospinning, Loboa’s group makes scaffolds shaped like porous fibers, sheaths, or hollow sheaths. Depending on their structure, these scaffolds act like faucet taps that control the rate and timing at which anti-bacterial compounds are released.

“I look at our fibers as delivery platforms,” Loboa said.

Saturday Morning Science takes place 10:30 a.m. Saturday at the Bond LSC’s Monsanto Auditorium. Coffee and bagels are available preceding the talks. This semester’s schedule is as follows:

9/17: Carolyn Orbann, Assistant Teaching Professor, Department of Health Sciences, “Historical Epidemics, Novel Techniques: Using Historical and Ethnographic Materials to Build Computer Simulation Models”

9/24: Michael Marlo: Associate Professor of English, “Documenting linguistic diversity: a view from the East African Great Lakes”

10/1: Steve Keller, Associate Professor of Chemistry, “The 20 Greatest Hits in Science…In an Hour”

10/8: Manuel Leal, Associate Professor of Biological Sciences, “Are Lizards Smarter Than Those Who Study them?”

10/15: Stephan Kanne: Executive Director and Associate Professor, Thompson Center for Autism & Neurodevelopmental Disorders, “What Do We Look For When We Diagnose Autism?”

10/29: Libby Cowgill, Assistant Professor Anthropology, “Fitness for the Ages: How to Lift Like a Neanderthal?”

11/5: Arianna Soldati, Ph.D. Candidate, Department of Geological Sciences, “Living in a Viscous World: A Volcanologist’s Perspective”

11/12: Frank Schmidt and Gavin Conant, Professor of Biochemistry (Schmidt); Associate Professor of Bioinformatics, Department of Animal Science (Conant), “Networks in Biology and Beyond”

12/3: Elizabeth King, Assistant Professor, Division of Biological Sciences, “What’s the Best Way to Divide up the Pie: The Price of Long Life”

One step closer from mice to men

Gene therapy treating the neurodegenerative disease, SMARD1, shows promising results in mice studies.

Shababi uses an instrument to measure grip strength in the forelimbs of mice. Healthy mice are able to cling to the rack with a stronger grip than SMARD1 mice. | photo by Jennifer Lu, Bond LSC .

Shababi uses an instrument to measure grip strength in the forelimbs of mice. Healthy mice are able to cling on with a stronger grip than SMARD1 mice. | photo by Jennifer Lu, Bond LSC

Monir Shababi was confident her experiments treating a rare genetic disease would yield positive results before she even ran them.

Scientists had success with a similar degenerative neuromuscular disease, so she had every expectation their strategy would work just as well in her mice.

Monir Shababi, assistant research professor in the Department of Veterinary Pathobiology, studies SMARD1 in mice. | photo courtesy of the Department of Veterinary Pathobiology

Monir Shababi, an assistant research professor in the Department of Veterinary Pathobiology, studies SMARD1 in mice. | photo courtesy of the Department of Veterinary Pathobiology

“I was expecting to get the same results,” said Shababi, an assistant research profession in Christian Lorson’s lab at the University of Missouri Bond Life Sciences Center. Shababi studies spinal muscular atrophy with respiratory disease type 1, or SMARD1.

The treatment worked, but not without a few surprises.

Her findings, published in Molecular Therapy, a journal by Nature Publishing Group, are one of the first to show how gene therapy can effectively reverse SMARD1 symptoms in mice.

In patients, SMARD1 is considered such a rare genetic disorder by the U.S. National Library of Medicine that no one knows how frequently the disease occurs. It’s only when babies develop the first symptom—trouble breathing–that pediatricians screen for SMARD1.

Shortly after diagnosis, muscle weakness appears in the hands and feet before spreading inwards to the rest of the body. The average life expectancy for a child diagnosed with SMARD1 is 13 months. There is currently no effective treatment.

Since the neuromuscular disease is caused by a recessive gene, SMARD1 comes as a shock to the parents, who are carriers but do not show signs of the illness, Shababi said. This genetic defect prevents cells from making a particular protein that scientists suspect is vital to replication and protein production.

The hereditary nature of the disease has a silver lining, though. Because SMARD1 is a caused by a single pair of faulty genes and not multiple ones, it is a prime candidate for gene therapy that could restore the missing protein and reverse the disease.

To do that, Shababi set up a dose-response study using a tiny virus to carry the genetic instructions for making the missing protein. She injected newborn mice with a low dose of the virus, a high dose, or a placebo with no virus at all.

Injecting at different doses allowed her to ask which dose worked better, Shababi said.

According to the previous research, a higher dose should have resulted in a more effective treatment.

“So I thought a higher dose was going to work better,” Shababi said.

Instead, the high dose had a toxic effect. Mice given more of the virus died sooner than untreated mice. Meanwhile, mice given a low dose of the gene therapy lived longest. They regained muscle function and strength in both the forearms and the hind limbs and became more active.

In fact, some of them survived long enough to mate and produce offspring.

Initially, Shababi housed her SMARD1 mice in the same cage as their mothers so that the moms could intervene if the sick pups become too feeble to feed themselves. When the male pups became well, their moms became pregnant.

“That was another surprise,” Shababi said. “That was when I knew I had to separate them.”

Shababi marks a pup, only a few days old, with permanent marker so she can identify each mouse in her study. | photo by Jennifer Lu, Bond LSC .

Shababi marks a pup, only a few days old, with permanent marker so each mouse in her study can be identified. | photo by Jennifer Lu, Bond LSC .

In another twist, Shababi discovered that the route of injection also mattered.

To get the treatment across the blood-brain barrier and to the spinal cord, Shababi used a special type of injection that passes through the skull and the ventricles of the brain, and into the spine.

This was no easy task.

The newborn mice were no larger than a gummy bear. To perform the delicate work, Shababi — who has written a chapter in a gene delivery textbook about this procedure — had to craft special needles with tips fine enough for this injection. She added food coloring to the injection solution so she could tell when it had reached its intended destination.

“After half an hour, you will see it in the spinal cord,” Shababi said. “The blue line in the spine: that’s how you can monitor the accuracy of the injection.”

Unfortunately, repeated injections in the mice caused hydrocephaly, or swelling in the brain.

“They get a dome-shaped head,” Shababi explained.

The swelling happened in all three treatment groups, but most frequently in the group that received a high dose of viral gene therapy. This reinforced the finding that while a low dose was beneficial, a high dose was even more harmful than no treatment at all. It’s unclear why.

Christian Lorson is a professor of veterinary pathobiology at the Bond LSC. His research focuses on spinal muscular atrophy and more recently, SMARD1. | photo by Hannah Baldwin, Bond LSC .

Christian Lorson is a professor of veterinary pathobiology at the Bond LSC. His research focuses on spinal muscular atrophy and more recently, SMARD1. | photo by Hannah Baldwin, Bond LSC .

The Lorson lab plans to continue studying SMARD1 and this treatment, in particular, how changing the delivery routes for gene therapy can improve outcomes in treating SMARD1.

“It’s not as simple as replacing the gene,” Lorson said. “It comes down to the delivery.”

Injections in the brains of mice are meant to mimic spinal cord injections in humans, but intravenous delivery could be another option. However, intravenous injections, which travel through the blood stream and to the entire body, might cause off-target effects that could interfere with the effectiveness of the treatment.

Once researchers better understand how to optimize dosing and delivery on the cellular and organismal level, the therapy can move closer to clinical trials, Lorson said.

Even though gene therapy for SMARD1 is still in its early stages, he said he was optimistic that developing treatments for rare genetic diseases is no longer the impossible task it seemed even ten years ago.

Spinal muscular atrophy (SMA) is a prime example of a recent success, Lorson pointed out. In the last six years, gene therapy for that disease has moved from the research lab to Phase I clinical trials.

“While it feels like a long time for any patient and their families,” Lorson reassured, “things are moving at a breakneck pace.”

 

The study, “Rescue of a Mouse Model of Spinal Muscular Atrophy With Respiratory Distress Type 1 by AAV9-IGHMBP2 Is Dose Dependent,” was published in Molecular Therapy, a journal published by Nature Publishing Group. This work was supported by a MU Research Board Grant (C.L.L.); MU College of Veterinary Medicine Faculty Research Grant (M.S.); the SMA Foundation (C.P.K.); National Institute of Health/National Institute of Neurological Disorders and Stroke grants; and the Missouri Spinal Cord Injury Research Program (M.L.G.).

Combating Climate Change: Q&A with Naomi Oreskes

Naomi Oreskes is a professor of the history of science at Harvard University and a geologist by training.

At a time when global warming was framed by the media as a debate, her 2004 paper in the journal Science showed that climate change was a settled fact among climate scientists.  Of the 928 papers she sampled in her literature search, not a single author denied the reality of climate change. Digging further, Oreskes explored in her book, Merchants of Doubt, co-authored with Eric Conway, the people, organizations, and motivations behind climate science misinformation. From cigarettes and acid rain to global warming and the ozone hole, Oreskes and Conway uncovered how industries such as Big Tobacco and Big Oil employed a core group of ideologically-motivated scientists to fabricate doubt and stymie government regulations.

Since the publication of Merchants of Doubt, Oreskes has been active in conversations about how we can move beyond debate and towards climate change intervention and action. She and Conway also wrote a sci-fi novel imaging a catastrophic future when society in the past (our present) failed to act on climate, The Collapse of Western Civilization.

Naomi Oreskes speaks on Saturday,3:30 pm as part of the LSSP Symposium, “Combatting Climate Change,” held at the Bond Life Sciences Center.

What has been the response of people who, through reading Merchants of Doubt or watching the documentary, have changed their minds about climate change?

Many people have written to me and Erik Conway to thank us for writing the book.  I’d say the most common response was that the book helped them to understand why there was so much opposition to accepting the scientific evidence.  I can’t say that I know for sure that thousands of people changed their minds after reading the book, but I do know that among those who did, the link to the tobacco industry was most compelling.  Our research showed that the opposition was not rooted in problems with or deficiencies in the science. 

You said in an interview with Mongabay, “In our society, knowledge resides in one place, and for the most part, power resides somewhere else.” How can we hold accountable oil and gas companies which have quietly known since the early 1980s that burning fossil fuels contributes to global warming, but used their power to impede actions that would combat climate change?

I’m not a lawyer, so I cannot answer the legal aspects of this question, but state attorneys around the country are now looking into that question.  As a citizen and a consumer, I can say this:  One way we can hold companies accountable by not investing in them,  and this is why I support the divestment movement. We can also boycott their products. In the current world, that is very difficult to do, but we can make a start. I installed an 8-watt solar PV system in my house, and we are now just about net-zero for electricity.

Is it possible to make up for 30 years of squandered time?

No of course not. Lost time is lost time. But knowing how much time has been lost, we should have a sense of urgency now, try not to lose any more. 

Which strategies are being proposed for immediate climate action? Are environmental scientists and economists in agreement over which courses of action make the most sense?

Yes I think so.  Nearly everyone who has studied the issue agrees that the most effective immediate action that is available to us is to put a price on carbon.  This will immediately make renewables and energy efficiency more economically attractive, and it will send a signal to investors that fossil fuels will no longer be given a free pass for their external costs. This means that future returns will be greater in the non-carbon based energy sector.  Anyone interested in this should read Nicolas Stern’s very informative book, Why are we Waiting?

How might the nomination of Merrick Garland to the Supreme Court and the results of the 2016 presidential elections affect the role that the US will play in combating climate change? Best case and worse case scenarios.

Best case: Republicans in Congress come to their senses, and listen to fellow Republicans like Bob Inglis, Hank Paulson, and George Schultz who have made the conservative case for putting a price on carbon.  They can do this pretty much any way they want— through  a tax, thru tradeable permits, or whatever.  it’s clear Democrats would support either, and we know from experience that either approach can work, so long as the price is real (i.e., not just symbolic.) Right now Alberta is talking about $20—that is probably a bit low. BC  is at $30 

Worst case: read The Collapse of Western Civilization.  You’ll find my answer there.

Of all the important issues out there, what motivates you to devote your time and energy to fighting climate change?

Oh that’s a good question.  I didn’t decide to work on climate change, I fell into it when Erik Conway and I tripped over the merchants of Doubt story.  Then, as I learned more and more about the issue, I came to appreciate scientists’ sense of urgency about it. 

 

Climate change to heat up discussion at annual LSSP symposium

By Jennifer Lu | MU Bond Life Sciences Center

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Thinkstock by Getty Images

Climate change is a pressing issue.

Just last week, the National Academies of Sciences, Engineering and Medicine published a report linking climate change to extreme weather conditions such as heat waves, droughts, and heavy snows and rains. Globally, 2015 was the warmest year on record, according to climate updates from the National Oceanic and Atmospheric Administration. And January kicked off this year by logging temperatures exceeding those of all previous Januaries on record, a disturbing trend that’s persisted for nine consecutive months to date.

Meanwhile, GOP candidates either do not believe in climate change or deny that it is caused by human activity, or have no strategies to combat climate change. And Democratic hopefuls Hillary Clinton and Bernie Saunders split on how to transition to renewable energy and reduce our carbon footprint.

How do we make sense of this?

The 12th annual Life Sciences & Society Program symposium — with events from March 17 to 19 — will tackle one of the most pressing issues facing the world today. Titled “Combating Climate Change,” speakers will address topics such as using technology to help curb global warming, how rising temperatures and more extreme weather will impact human health, the role of government in taking action to combat man-made climate change, and how to effectively communicate climate change.

Marcia McNutt–editor-in-chief of the leading journal, Science, and a geophysicist by training—will talk about the “promise and peril” of climate interventions such as carbon dioxide removal (CDR) and albedo modification, a process that involves spraying particles into the atmosphere to reflect more sunlight back into space to cool the earth.

There has been “significant advancement” in technologies such as carbon capture and storage, McNutt wrote by email, but these technologies have not moved beyond the research stages for economic reasons.

She pointed out that most climate interventions act slowly and take time to implement.

Albedo modification is the exception, McNutt said, but while quite a bit of work has been done to model its effects, the risks are high.

Few scientists believe we know enough about albedo modification to seriously consider it, she said.

“There is no silver bullet that is a magical antidote to climate change,” McNutt said.

The full line-up of speakers for this year’s symposium includes:

  • Andrew Revkin, environmental journalist and author, who proposed the term “anthrocene” to describe “a geological age of our own making” in his 1992 book, Global Warming: Understanding the Forecast. (Paul Crutzen, an atmospheric chemist who won a Nobel prize for studying ozone layer depletion , popularized the more familiar term, ”Anthropocene,” in 2000.)
  • Marcia McNutt, editor-in-chief of Science
  • Wes Jackson, founder and president of The Land Institute, a non-profit organization dedicated to sustainable agriculture
  • Marshall Shepherd, professor of geography and director of the atmospheric science program at the University of Georgia
  • George Luber, an epidemiologist at the Center for Disease Control and the associate director for climate change in the division of environmental hazards and health effects
  • Naomi Oreskes, professor of the history of science at Harvard University. Her book co-written with Erik M. Conway, Merchants of Doubt, showed how rich and powerful industries retained a core group of scientists who used their expertise to create doubt and protect industry interests

To see the schedule of this week’s events and register for the symposium, visit the MU LSSP website.

Rodents of unusual appetites

How food cravings and eating affects the brain
By Jennifer Lu | MU Bond Life Sciences Center

When it comes to cookie dough, we’re not the only ones who can’t control our cravings. Kyle Parker’s rats couldn’t resist, either, thanks to a tweak in their brain chemistry.

Parker studies the neuroscience of food-based rewards.

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Matthew Will, associate professor of psychological sciences at the Bond Life Sciences Center, studies the neuroscience of behaviors such as over-eating and addiction | photo by Jennifer Lu, Bond LSC

“It’s like when I eat dessert after I’ve eaten an entire meal,” said Parker, a former grad student from the lab of Bond LSC’s Matthew Will. “I know that I’m not hungry, but this stuff is so good so I’m going to eat it. We’re looking at what neural circuitry is involved in driving that behavior.”

Behavior scientists view non-homeostatic eating — that’s noshing when you’re not hungry — as a two-step process.

“I always think of the neon sign for Krispy Kreme donuts.” Will said, by way of example.

“The logo and the aroma of warm glazed donuts are the environmental cues that kick-start the craving, or appetitive, phase that gets you into the store. The consummatory phase is when you “have that donut in your hand and you eat it.”

Parker activated a “hotspot” in the brains of rats called the nucleus accumbens, which processes and reinforces messages related to reward and pleasure.

He then fed the rats a tasty diet similar to cookie dough, full of fat and sugar, to exaggerate their feeding behaviors. Rats with activated nucleus accumbens ate twice as much as usual.

But when he simultaneously inactivated another part of the brain called the basolateral amygdala, the rats stopped binge eating. They consumed a normal amount, but kept returning to their baskets in search for more food.

“It looked like they still craved it,” Will said. “I mean, why would a rat keep going back for food but not eat? We thought we found something interesting. We interrupted a circuit that’s specific to the feeding part — the actual eating — but not the craving. We’ve left that craving intact.”

To find out what was happening in the brain during cravings, Parker set up a spin-off experiment. Like before, he switched on the region of the brain associated with reward and pleasure and then inactivated the basolateral amygdala in one group of rats but not the other.

This time, however, he restricted the amount of the tasty, high-fat diet rats had access to so that both groups ate the same amount.

This way, both groups of rats outwardly displayed the same feeding behaviors. They ate similar portions and kept searching for more food.

But inside the brain, Parker saw clear differences. Rats with activated nucleus accumbens showed increased dopamine production in the brain, which is associated with reward, motivation and drug addiction. Whether the basolateral amygdala was on or off had no effect on dopamine levels.

However, in a region of the brain called the hypothalamus, Parker saw elevated levels of orexin-A, a molecule associated with appetite, only when the basolateral amygdala was activated.

“We showed that what could be blocking the consumption behavior is this block of the orexin behavior,” Parker said.

The results reinforced the idea that dopamine is involved in the approach — or the craving phase — and orexin-A in the consumption, Will said.

Their next steps are to see whether this dissociation in neural activity between cravings and consumption exists for other types of diets.

Will also plans to manipulate dopamine and orexin-A signaling in rats to see whether they have direct effects on feeding.

“Right now, we know these behaviors are just associated with these neural circuits, but not if they’re causal.”

 

Behavioral Neuroscience published the study, “Neural Activation Patterns Underlying Basolateral Amygdala Influence on Intra-Accumbens Opioid-Driven Consummatory Versus Appetitive High-Fat Feeding Behaviors in the Rat,” in the December 2015 issue. A grant from the National Institute of Drug Abuse supported this research.

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.