Monday, December 15, 2014

Penn researchers identify novel therapeutic target for kidney cancer

Kidney cancer, also known as renal cancer, is one of the ten most common cancers in both men and women. The American Cancer Society’s most recent estimates state that of the predicted 63,920 new cases of kidney cancer this year, roughly 20% of  patients will die from the disease. By far, the most common type of kidney cancer is renal cell carcinoma (RCC). The majority of RCCs are clear cell RCCs (ccRCCs), a subtype characterized by metabolic alterations, specifically increased carbohydrate and fat storage. More than 90% of ccRCCs have been found to have mutations in the von Hippel-Lindau (VHL) tumor suppressor gene; however, kidney specific VHL deletion in mice does not induce tumorigenesis or cause metabolic changes similar to those seen in ccRCC tumors. So what additional factors are needed for ccRCC tumor formation and progression? A recent study by Penn researchers published in the journal Nature identified the rate-limiting gluconeogenesis enzyme fructose-1,6-bisphosphatase (FBP1) as a key regulator of ccRCC progression.

To better understand ccRCC progression, the study’s first author, Bo Li, a post-doctoral researcher in the lab of Dr. Celeste Simon, performed metabolic profiling on human ccRCC tumors while also analyzing ccRCC metabolic gene expression profiles. Compared to the adjacent normal kidney tissue, ccRCC tumors had increased amounts of metabolites involved in sugar metabolism and significantly lower expression of carbohydrate storage genes, including FBP1. Further investigation revealed FBP1 expression was reduced in almost all tumor samples tested (>600) and reduced FBP1 expression strongly correlated with advanced tumor stage and poor patient survival. Thus, understanding the role of FBP1 in ccRCCs could significantly impact the treatment of this disease.

How do reduced levels of FBP1 promote ccRCC tumor progression? The authors found that FBP1 depletion in ccRCC cells stimulates growth and relieves inhibition of sugar breakdown (glycolysis), which provides energy for the growing cancer cells. In addition, VHL mutations associated with ccRCCs prevent the degradation of a transcription factor that responds to decreases in oxygen, known as hypoxia-inducible factor α (HIFα), thus stabilizing it. Stabilized HIFα does not cause FBP1 depletion, but its activity is tightly regulated by FBP1. This study emphasized the importance of the interaction between HIFα and FBP1, particularly when glucose and oxygen levels are low, for the formation and progression of the ccRCC.

Why is this work so important? Little is known about how changes in cell metabolism contribute to the formation and progression of ccRCC tumors. As stated by Li, “elucidating how FBP1 impacts the altered metabolic and genetic programs of ccRCC improves our knowledge of the molecular details accompanying ccRCC progression, and identifies novel therapeutic targets for this common malignancy.” Future work may focus on identifying how FBP1 is suppressed and whether reversing FBP1 suppression could improve patient outcomes. 

-Renske Erion

Wednesday, November 19, 2014

Purdue professor Dr. Sanders responds to commentary about his Ebola interview with Fox News

Last month I analyzed the media coverage of Ebola in a post where I dissected an interview between Fox News reporters and Dr. David Sanders. I was recently contacted by Dr. Sanders, who wished to clarify a few issues that I raised in my article. The purpose of my post was to demonstrate how the media sometimes covers scientific issues in ways that exaggerate and oversimplify concepts, which can potentially mislead non-scientist citizens.

I stated that the way Dr. Sanders described his research sounded a little misleading. I intended to convey how I thought an average non-scientist listener might interpret the dialogue. However, Dr. Sanders points out that he was careful with his wording to avoid possible confusion. He explained, “as you have pointed out, one says one thing, and the media (and the Internet) render it as something else.  I would just like to point out that I carefully stated that Ebola can ENTER human lung from the airway side; I never said infect.  I also try to avoid the use of the term ‘airborne’ because of the confusion about its meaning.”

Also, he had several good scientific points about the validity of using pseudotyped viruses and the comparison to other viruses when considering the potential for a change in Ebola transmission.

“Pseudotyped viruses are used widely for studying viral entry, and I know of no examples where the conclusions on the cell biology of the entry of pseudotyped viruses have been contradicted by studies of entry of the intact virus despite such comparisons having been published numerous times.” 

“When we discovered that there was maternal-child transmission of HIV was that a new mode of transmission or merely a discovery of a previously unknown mode of transmission? How was Hepatitis C transmitted between humans before injections and blood transfusions? I don't know either. How is Ebola virus transmitted between fruit bats or from fruit bats to humans? Perhaps modes of transmission differ in their efficiency. The HIV comparison with Ebola ("HIV hasn't become airborne") is fallacious given the cell biology of entry for the two viruses.  The receptors for HIV (the CD4 attachment factor and the chemokine receptor) are present on blood cells and not on lung tissue.  The receptors for Ebola are present on a diverse set of cells including lung cells. In addition, Influenza A switches in real time from a gastrointestinal virus in birds to a respiratory virus in mammals--not that many mutations required.”

Additionally, he wisely pointed out that “precedent may be a valid argument in medical practice or the law, but it is not valid in science.” In fact, science seeks to uncover things that were previously unknown, and thus were without precedent.

I appreciate Dr. Sander’s response to my article. I think that rational and in-depth discussions about science need to happen more frequently in the media. Short, simplified stories with shock-factor headlines only detract from the important conversations that are necessary to find practical solutions to challenges like Ebola.

-Mike Allegrezza

Monday, November 10, 2014

Penn researchers identify neurons that link circadian rhythms with behavioral outcomes.

Our bodies evolved to alternate rhythmically through sleep and wake periods with the 24-hr cycle of the day. These “circadian rhythms” are controlled by specific neurons in the brain that act as molecular clocks. The experience of jet lag when we change time zones is the out-of-sync period before the brain’s internal clock re-aligns with the external environment.

How does this molecular clock work in the brain? Decades of research have uncovered that environmental signals, such as light, are integrated into a circadian clock by specific neurons in the brain. However, little is understood about how these circadian clock cells drive biological effects such as sleep, locomotion, and metabolism. A study by Penn researchers published earlier this year in Cell has discovered critical neural circuits linking the circadian clock neurons to behavioral outputs.

The researchers used the fruit fly Drosophila as a model organism because like humans, they also have circadian rhythms, yet they are very easy to manipulate genetically and many powerful tools exist to study the 150 circadian clock neurons in their brains. The study found that a crucial part of the circadian output network exists in the pars intercerebralis (PI), the functional equivalent of the human hypothalamus.

“Flies are normally active during the day and quiescent at night, but when I activate or ablate subsets of PI neurons, they distribute their activity randomly across the day,” describes the study’s first author, Daniel Cavanaugh, PhD, a post-doc working in the lab of Amita Sehgal, PhD. Importantly, the research showed that modulating the PI neurons lead to behavioral changes without affecting the molecular oscillations in central circadian clock neurons, indicating that the PI neurons link signals from the circadian clock neurons to behavioral outputs.

The study also showed that the PI neurons are anatomically connected to core clock neurons using a technique involving the fluorescent protein GFP. Cavanaugh explains, “The GFP molecule is split into two components, which are expressed in two different neuronal [cell] populations. If those populations come into close synaptic contact with one another, the split GFP components are able to reach across the synaptic space to reconstitute a fluorescent GFP molecule, which can be visualized with fluorescence microscopy.”

Additionally, their experiments showed that a peptide called DH44, a homolog to the mammalian corticotropin-releasing hormone, is expressed in PI neurons and important for maintaining circadian-driven behavioral rhythms.

While these new data are interesting for understanding general mechanisms of biology, they also have implications for human health and disease.

“People exposed to chronic circadian misalignment, such as occurs during shift work, show increased rates of heart disease, diabetes, obesity, cancer, and gastrointestinal disorders,” says Cavanaugh. “In order to understand the connection between circadian disruption and these diseases, we have to understand how the circadian system works to control the physiological outputs that underlie these disease processes.”

-Mike Allegrezza

Friday, October 17, 2014

Fox News demonstrates both good and bad ways to cover Ebola

Some news outlets, including Fox, have been wildly spreading fears about Ebola. As an example of both good and bad ways that the media covers science, let’s take a look at a recent clip from Fox News in which they interview Dr. David Sanders about the possibility of Ebola virus mutating to become airborne-transmissible (right now it is only spread by direct contact!)

Their story is titled "Purdue professor says Ebola 'primed' to go airborne.Here is a link to the video.

I’ll start off with the good things:

1) Dr. Sanders did a good job explaining that Ebola is not airborne right now, but there is a "non-zero" probability that Ebola might mutate to infect the lungs and become air transmissible. And this probability increases as more people are infected.
2) The newscasters did a good job of accurately recapping what he was explaining without blowing it out of proportion.

Now for some bad things:

1) Quite obviously, the scare-you-into-clicking-on-it title. First of all, it's completely misleading for the sole purpose of grabbing attention (it got me!). Second of all, it's completely false. I watched it three times and Dr. Sanders never said "primed." So it is blatantly incorrect.
2) They did not include coverage of other scientists that claim the fears of airborne transmission are over-hyped because there are no instances of that ever happening naturally for a virus that infects humans. HIV and hepatitis are both good examples that have infected millions without changing their route of transmission.
3) The way Dr. Sanders describes his published research is a little misleading in the context of this story. It sounds like he describes the research demonstrated Ebola virus can infect the lungs. In fact, the actual study showed that if you take some of the proteins from the surface of Ebola and code them into a completely different virus (in this case a feline lentivirus, similar to HIV), you can infect human airway epithelial cells grown in cell culture. So this research did not use the full Ebola virus, and did not demonstrate this infection in a live animal model. Link to study here:

Some of these negative aspects might be a consequence of the brevity of this story. However, in an information-dense world, people get the news in short snippets, so the media needs to be careful not to compromise accuracy.

Interestingly, on the same network, Shep Smith reported on Ebola with commendable accuracy. He communicated the facts clearly and concisely while criticizing “hysterical” reporting as “irresponsible.” 

I hope future reports from Fox News and the rest of the media follow his tone.

*Update Nov 19, 2014: A follow up to this post detailing a thoughtful response from Dr. Sanders can be found here.

-Mike Allegrezza

Friday, October 3, 2014

At the interface of science and society - a career fostering public interest in science at The Franklin Institute.

Credit: The Franklin Institute
Everybody loves science museums. Their fun and interactive way of presenting science reconnects you with your childhood self, when you were curious, when you wondered, and when you were so amazed that you could only manage to say, “Wow!” But what is it like to work at a science museum?

On Wednesday, we hosted Jayatri Das, PhD, to describe her career engaging the public with science as the Chief Bioscientist at The Franklin Institute. As you would expect, her transition from the lab into the museum was cultivated by a strong interest in outreach and teaching. After receiving her PhD from Princeton, she gained experience as a Christine Mirzayan Science and Technology Policy Fellow developing programs for the Marian Koshland Science Museum in Washington, DC. Following a short post-doctoral appointment, she landed a position with The Franklin Institute, an opportunity that she partly ascribes to fortuitous timing, as PhD level positions at museums are rare.

In her job she embraces a new paradigm for how science should interact with society. The goal is no longer public understanding of science. Rather, she urges we should strive for public engagement with science. “We want to communicate to our visitors that they are part of the conversation on how we use science and technology,” she says.

Science and technology do not exist in a void. Jayatri describes that:

1) Values shape technology
2) Technology affects social relationships
3) Technologies work because they are part of systems.

As an example, consider nanotechnology. This field has opened new possibilities to create quantum computing, high-tech military clothing, flexible inexpensive solar panels, clean energy, simple water filters, and new cancer treatments; even invisibility cloaks and elevators into space have been envisioned. But which of these technologies are developed will depend on the values of those funding the research and the circumstances driving market demand for them. Priorities would be different for a wealthy businesswoman in Japan, a US-trained Iraqi solider, a European who lost a spouse to cancer, and a cotton farmer in India.

As she points out, “Investments [in R&D] are being made by people with values different than most of the world’s population.” Therefore, it is important to challenge people to think globally.

Why are science museums a great place for these conversations? First, they provide trusted and stimulating information. Second, they are a place where people can reflect on science, technology, and the world. And third, they are a place for conversation because many visitors attend in groups.

Part of her job involves designing the many ways that The Franklin Institute engages the public with science, which in addition to interactive exhibits includes public programs, digital media, and partnerships with schools and communities. For instance, she recently led a public discussion about concussions in sports. The all-ages audience was presented with the neuroscience of head trauma and testimony from former Eagles’ linebacker Jeremiah Trotter, and then they discussed what age kids should be allowed to play tackle football.

Because science and technology are so integrated into our lives now, conversations like these are crucial. In order for breakthroughs to be beneficial for society, they have to interact with public attitudes and values. This communication between science and society occurs naturally at science museums, so they offer fulfilling positions for people like Jayatri who are motivated to connect the frontiers of science with casual visitors. 

Interested in volunteering? You can find information here

-Mike Allegrezza