Good vibrations for male contraceptive

 Some might call it a kind of Holy Grail for reproductive science: the development of a long-term, inexpensive, completely reversible and nonhormonal male contraceptive, one that’s  suitable for use in developing to first world countries.

 And that is exactly the long-term goal that two UNC scientists have set out to accomplish. How? By using ultrasound from therapeutic instruments commonly found in sports medicine or physical therapy clinics. And their quest is well underway, with very promising results. 

James Tsuruta, PhD, assistant professor in the Laboratories for Reproductive Biology  in UNC’s Department of Pediatrics and Paul Dayton, PhD, associate professor and director of graduate studies in the Department of Biomedical Engineering successfully depleted testicular sperm in laboratory rats using therapeutic ultrasound. 

 And just this month, the pair received a $100,000 Grand Challenges Exploration grant from the Bill & Melinda Gates Foundation.  The project, aimed at further fine-tuning this technique for maximum effect and safety, could provide men with six months of reliable, low cost, non-hormonal contraception from a single round of treatment. 

Tom Hughes in our news office tells us that Tsuruta and Dayton’s project is one of 78 grants announced by the Gates Foundation in the fourth funding round of Grand Challenges Explorations, an initiative to help scientists around the world explore bold and largely unproven ways to improve health in developing countries.  The grants were provided to scientists in 18 countries on six continents.

The testis is composed of many tubes called “seminiferous tubules.”  In the accompanying image here, the seminiferous tubule on the left is from a testis that was not treated with ultrasound while the tubule on the right is from a testis that was treated with ultrasound. 

The tubule from the control testis has many darkly stained germ cell nuclei.  Most germ cell nuclei are round; the long, thin nuclei closest to the center of the tubule belong to germ cells called spermatids and they will soon be released as testicular sperm.  In contrast, the ultrasound-treated tubule is completely lacking testicular sperm and has lost almost all immature germ cells, decreasing its overall diameter while greatly increasing the amount of “empty” space in the center of the tubule.

“Once the testis has stopped producing sperm and all “sperm reserves” have been depleted, it is impossible to be fertile,” Tsuruta says. “Our Grand Challenges Exploration project will determine the appropriate ultrasound treatment to temporarily interrupt the supply of testicular sperm yet allow the testis to regenerate itself from the germ cells remaining after treatment.”

May the good vibes continue….

Les Lang

Leave a comment

Filed under Uncategorized

Palladin, the travels continue

Our second Hard Science blogpost “Have Palladin, Will Travel,” on January 19, 2009, introduced the work of UNC cell and molecular physiologist Carol Otey and the protein she discovered a decade or so ago that plays an important role in cell motility, adhesion and structure.

Study first author Silvia Goicoechea, PhD and, on the right, Carol Otey, PhD in the Otey Lab at UNC

Also mentioned was Otey’s most recent work in which  palladin was found mutated in an inherited form of pancreas cancer and was also produced in large amounts — “upregulated” — in a number of sporadic pancreas tumors.

Now it appears that the protein with the fancy name may prove to be a molecular marker of pancreatic cancer , one that might help spot the disease at its earliest stages, when it can be treated more successfully with surgery.

In a finding published April 26, 2010, in the online journal PLoS One, the researcher and her colleagues  showed that a specific form of a protein called palladin is produced in large amounts in the “tumor nest,” the cells that surround a pancreatic tumor. 

The blue cells in the middle, surrounding the “space” in the center of a pancreatic duct, are the tumor cells, and the brown cells around them are the tumor-associated fibroblasts (stained for palladin).

Measuring the levels of this form of palladin in patient samples could provide an improved way to screen for the deadly cancer, possibly catching it earlier than ever before, said senior study author Carol Otey, Ph.D., associate professor of cell and molecular physiology at UNC.

“The problem with pancreas cancer is it is almost never caught at an early stage,” said Otey. “By the time a person develops suspicious symptoms, the disease has typically progressed too far. But if you can diagnose it early, it can be treated very effectively with surgery.” 

Otey and her colleagues decided to see if the upregulation of palladin in the tumor nest could provide a useful diagnostic tool for identifying the disease at earlier stages. They knew that the single palladin gene message can actually be cut and pasted together in a manner that produces at least seven different palladin protein products. Turns out only a couple of these forms of palladin – called isoforms – appear in pancreatic tissue. 

The researchers found that the longer of these two isoforms was upregulated in the cells surrounding the tumor — called tumor-associated fibroblasts — when compared to normal pancreas. Their findings were consistent, regardless of whether they were looking in cultured cell lines, patient samples, or tumors from a mouse model. 

Otey thinks that the upregulation of this form of palladin in tumor-associated fibroblasts could help them become contractile and stiff — more like muscle than connective tissue — in order to generate channels through neighboring tissue so the cancer can metastasize and spread.  

“The interactions between these tumor-associated fibroblasts and tumor cells are really important and are probably what is causing pancreas cancer to be so deadly,invasive and resistant to current therapies,” said Otey.

And that is why raising public awareness and enhancing our abilities to diagnose the disease early is so critical, says Hong Jin Kim, associate professor of surgery at UNC, who along with Otey is senior author of the study.

“It appears that the upregulation of palladin in the tumor-associated fibroblasts is an early event in the neoplastic process,” said Kim. “We may be able to take advantage of these findings, since pathologic confirmation of pancreatic adenocarcinoma in the preoperative setting is often difficult, requiring an invasive procedure directed by endoscopic ultrasound.  If we can enhance the diagnostic efficiency of these studies by staining for palladin, it would be clinically helpful for interventional gastroenterologists and pathologists.”

For palladin, the travels continue….

Leave a comment

Filed under Uncategorized

Chemo drug awakens virus in cancer cells

Viruses and cancers interact in ways that were previously unknown  to science.  A new study led by UNC researchers shows that a common cancer drug can activate a viral infection that, paradoxically, can help anti-viral medications eradicate virus-associated cancer.  

The cooperative study, conducted by a team of UNC School of Medicine scientists and the UNC Project in Malawi, demonstrated for the first time in humans that a common drug used to treat Burkitt lymphoma can activate infection by the Epstein-Barr virus (EBV), a virus which typically lies latent inside the tumor cells of affected patients.

The finding paves the way for a future study using both a cancer drug and an antiviral agent to eradicate both the active virus infection and the tumor.  The study is reported in the April 1 issue of the journal Clinical Cancer Research.

Margaret L. Gulley, MD, professor of pathology and laboratory medicine, said,  “What we have learned from this work is a potential means of capitalizing on presence of viral genomes within tumor cells to alter those tumor cells in a way that makes them more susceptible to treatment. Our findings have implications for other EBV- related malignancies that, overall, are among the most common cancers worldwide.” Gulley is a member of UNC Lineberger Comprehensive Cancer Center. 

Weihua Tang, MD, PhD, the study's first author and research fellow with Margaret L. Gulley, MD

 EBV infects more than 90 percent of the world’s population and is associated with diseases ranging from infectious mononucleosis to lymphomas, gastric cancer and cancer of the nose and throat. 

Burkitt lymphoma, which is associated with EBV, is rare in most parts of the world, but is endemic in sub-Saharan Africa. Burkitt lymphoma is an aggressive, fast-growing type of non-Hodgkin lymphoma that often occurs in children. The disease may affect the jaw, bowel, lymph nodes, or other organs. 

The study demonstrated that initiating treatment with the anti-cancer drug  cyclophosphamide in children with Burkitt lymphoma simultaneously triggered an active EBV infection. The increased replication of EBV in cancer tissue makes these cells more susceptible to the antiviral drugs that kill cells containing replicating virus. Antiviral agents such as ganciclovir and valacyclovir are already in routine clinical use for treating active viral infections. 

Researchers enrolled 21 patients with a confirmed diagnosis of EBV-related Burkitt lymphoma. The patients ranged in age from 5-15 and were under treatment with cyclophosphamide for their cancer.  Through laboratory analysis of biopsy samples, researchers found that cyclophosphamide seems to induce the phase of viral infection most susceptible to antiviral therapy. 

Gulley points out that cyclophosphamide “is fairly efficacious, but it and even more expensive chemotherapeutic agents may be hard to come by in developing nations.”

Moreover, she says clinical trial data are needed to determine if chemotherapy and antiviral therapy synergize in managing Burkitt lymphoma.  

 “Our work provides scientific data to justify moving forward with a clinical trial.  Generic versions of several pertinent antiviral agents are available and are relatively inexpensive.”

Plans for such a trial are already underway under the leadership of Carol Shores, MD, PhD, associate professor of surgery in UNC’s Otolaryngology/Head and Neck Surgery Department and senior author of the study.  Shores says she is currently working to get approval for a Phase I/II clinical trial of the antiviral drug valacyclovir with cyclophosphamide in Malawi. “Valacyclovir recently went off patent, and a relatively generic form is available.  It is an oral drug approved in the US for children as young 3 years of age.

Leave a comment

Filed under Uncategorized

Sweet call on gene patents

Clinton Colmenares in our news office wrote this …

 Jim Evans is a self-proclaimed science geek whose intellect and wit move at warp speed. He rides a bike to work and wears neck ties fashioned with DNA patterns. In our popular Santa video he proclaimed that the jolly old elf is “clearly a mutant.” 

He’s also an expert in gene patenting and genetics policy. He led a program to educate federal judges about the intricacies of genetics and genetic policy. He chaired a Federal task force, part of the Secretary of Health and Human Services Advisory Committee on Genetics, Health and Society that recently made formal recommendations to the HHS secretary regarding the role of gene patents in medical diagnostics.  

James P. Evans, MD, PhD

When news broke that United States District Court Judge Robert Sweet ruled on March 29 that seven patents related to the BRCA 1 and BRCA 2 genes were invalid — genes cannot be patented, basically — we contacted Jim. So did reporters from The New York Times, the Wall Street Journal and the CBS Evening News (they decided not to run a story). 

Jim had the last quote in The Times:  

James P. Evans, a professor of genetics at the University of North Carolina, said that would not necessarily be the case. There is thriving competition in areas like testing for mutations that cause cystic fibrosis or Huntington’s disease, even though no company has exclusivity.  

“It’s quite demonstrable that in the diagnostic area, one does not need gene patents in order to see robust development of these tests,” he said.  The ruling “came as a surprise to everybody. It’s really quite unusual for plaintiffs to get a summary judgment.”

In the WSJ he said:  

“If this decision is upheld, it in the end is a win for patients and providers,” said Dr. Evans, also a medical geneticist at the University of North Carolina, Chapel Hill. 

Here are some of the comments he shared with me yesterday: 

“I think that the judge showed an impressive understanding of genetics and some of the nuances involved. I agree with him.  

“The essence of DNA is that it is an embodiment of biological information. As such it is distinct from other chemical compounds in nature. It is this informational content that makes it special and the act of isolating it therefore is less relevant to patent considerations than for other biological molecules. A gene still does the same thing (i.e. confer information) in the test tube as it does in the cell. Thus, Judge Sweet correctly noted that a gene is qualitatively different from other biological molecules such as adrenaline, which can be patented when isolated.  

“It’s a very important case, but its immediate impact shouldn’t be overestimated. It will be appealed to the Court of Appeals for the Federal Circuit, the court to which all patent cases are appealed. Then it will almost certainly be appealed to the Supreme Court, though who knows if they will agree to hear it. 

“There will be arguments about whether this ruling will be good for patients; I would say yes. The broad area of diagnostic testing is unduly hampered by gene patents and they are not necessary for the development of diagnostic genetic tests. This ruling, if upheld, will open the field of genetic diagnostics in time for the benefits of robust analytic techniques like whole genome sequencing to be applied for patient benefit.  

“While one can argue that the patent incentive may serve a more useful purpose in the realm of therapeutics, most useful therapeutic patents are considerably “downstream” of the genes themselves so I doubt that one will see any significant deleterious effect of such a ruling on therapeutics either. In broad terms I think this is a win for both patients and their providers. 

“The issue of gene patenting has been controversial since the United States Patent and Trademark Office first granted them. Such controversy and furor have arisen in part because people tend to perceive genes as different from other biological entities.  

“They are something we all share and they encode information that is unique to each of us as individuals. Thus it is difficult at one basic level to defend the patenting of genes. The idea that we would be prevented from having considerable latitude in analyzing our own genes is something that strikes people as a bit absurd on the face of it.”

Leave a comment

Filed under Uncategorized

Movies, microscopes, metastasis & melanoma

Contributed by Dianne Shaw, UNC Lineberger Comprehensive Cancer Center

Jim Bear’s movies won’t win Oscars, but they may save lives. He makes movies of moving cells, movements that can help or harm the body.

Bear studies cell migration.

“Cell migration is something that’s with us from birth to death. It’s a process that happens during development when we are in the womb. It happens in our immune system when we get an infection and our white blood cells have to migrate to that site of infection. It happens inside of our brains, when neurons make connections with other neurons leading to thoughts and feelings and the things that make us ‘us.’ But it goes wrong in cancer.”


Members of the Bear Lab
Front row: Sarah Creed, Sreeja Asokan, Emma Wu, Heather Aloor
Back row: Jim Bear, Stephen Jones, Brent Hehl, Matt Kuty, Dave Roadcap

Cancer cell movement is how tumors spread or metastasize. Bear’s lab and his colleagues at UNC Lineberger are now studying the migratory process of metastasis in the lab and have learned that as in human melanomas, metastasis targets the same places- the lungs and the brain.

Bear has a personal interest in melanoma. His father died of the disease when Jim was in graduate school, and his death motivates Jim: “I want to do something about this disease to make it so that other people don’t have to go through this.”

A Howard Hughes Medical Institute Early Career Scientist Award winner, Bear is probing the steps of cell motility- how cells move- with a goal of using that knowledge to derail cancer metastasis. He conducts research on a family of proteins called coronins.

“We think these proteins have been with us for nearly a billion years on planet earth. To me, something that’s that old is doing something interesting, even if we don’t understand it. That was one of the bases on which I founded my lab.”

Coronins regulate cell migration both at the leading edge of the movement and at the point of disassembling the cell as it unattaches and moves.

Watch videos

  • In this video interview Dr. Bear talks about how he got interested in becoming a scientist and a builder of microscopes to capture cell movement. Watch now
  • In this video presentation, Dr. Bear discusses cell movement and the proteins actin and coronin. Watch now
  • This set of videos provides a tutorial on the four steps of cell movement, with cell movies narrated by Dr. Bear.

Learn more about Dr. Bear’s Howard Hughes Medical Institute Early Career Scientist Award: http://www.hhmi.org/research/ecs/bearj_bio.html and
http://www.hhmi.org/research/ecs/bearj.html

Leave a comment

Filed under Uncategorized

What would Mendel say?

We’ve come a long way since Gregor Mendel published his “Experiments on plant hybrids” in 1866.

Okay, so he didn’t discover genes, but Mendel did use the terms  “dominant” and “recessive” to describe the appearance of a character (like the color purple), which in today’s parlance is roughly the  equivalent of gene expression. In any event, the full significance of his work wasn’t fully realized until the 1930s.

Gregor Johann Mendel

So here we are, twenty years into the genomic revolution, flush with the knowledge that mutations  play a role in more than 2,000 mendelian diseases.   And scientists are just now realizing that it’s more of the rare and less of the common variants that explain inherited risk for most common diseases.

So,  why not use whole genome sequencing to identify people with a specific inherited predisposition? Cost is becoming less of a factor. Today a person’s entire genome can be decoded with great accuracy for about $50,000. And a recent report in Science notes that costs should plummet within a few years to about $4,400.

The UNC Cancer Genetics clinic has been active for 15 years and counsels patients and their families for hereditary predisposition to cancer in an effort to assess risk, make recommendations for medical management and identify other at-risk relatives for purposes of prevention.

Dr. Jim  Evans, Bryson professor of genetics and medicine, tells me the clinic has identified approximately 100 families whose history and pedigree information strongly suggest a Mendelian predisposition to cancer, but for whom available clinical genetic testing for known genes has come up empty. 

This implies that other genes may be out there, as yet undiscovered, which, when mutated, confer a high risk of cancer. “Identifying such genes would be a great boon to patients but also promises to shed considerable light on the underpinnings of cancer and its causation,” Evans says. 

The Whole Genome Analysis of High Risk Cancer Families, is being conducted by Evans along with genetic counselor Kristy Lee, MS, CGC; Jonathan Berg, MD, PhD, assistant professor of genetics; and Patrick F. Sullivan, MD, professor of genetics.

“This is an important and wonderful example of the way in which next-generation sequencing will make tremendous contributions to our understanding of disease. Whole Genome Sequencing (WGS) has now become affordable and is being applied to a host of human diseases,” Evans says.

“The most challenging aspect of WGS, however, will be the interpretation of the avalanche of information that is generated. It represents the first medical test for which everyone is guaranteed to have an abnormal result (because we are all mutants!). Thus, there are formidable challenges to using this information for patient benefit.”

Evans says he has no doubt that in the long run the information obtained will benefit patients. But he cautions we also shouldn’t be unrealistic about deriving immediate benefits for them. “Remember that we have known the molecular underpinnings of sickle cell disease for over half a century and yet the information has still not revolutionized treatment of that condition. ”

“Applying science to the health of the individual often moves in a frustratingly slow and incremental manner. But in the end, it is the only way forward,” says Evans.

Were he with us today, I’d like to think a smiling Mendel would agree.

Les Lang

Leave a comment

Filed under Uncategorized

Playing metabolism tag

Welcome to …(drumroll here)…  Acetyl Tag, the new game that goes beyond the cellular nucleus to the cytoplasm, to a place where few would guess finding — let alone imagine — masses of acetylated metabolic enzymes.     

“We have discovered an entirely new layer of control of metabolism,” says Yue Xiong, Ph.D., professor of biochemistry and biophysics and a member of the UNC Lineberger Comprehensive Cancer Center.

Xiong points out that almost all previous studies on acetylation have focused on proteins in the nucleus, where acetyl tags on proteins regulate how tightly the DNA’s genetic code is packaged.  It’s known that protein acetylation plays a key role in gene expression.

But  Xiong along with study co-leader Kun-Liang Guan, professor of pharmacology at the University of California, San Diego, wanted to determine if acetylation also plays a role in the other half of the cell, the cytoplasm.

After separating the nucleus and the cytoplasm of human primary liver cells, the study team used mass spectroscopy to take a chemical census of the cytoplasm’s contents .

And to their surprise, they identified approximately a thousand new proteins that are acetylated, greatly expanding the previously recognized repertoire of fewer than one hundred.  Nearly every metabolic enzyme was acetylated, presumably because their starting material was liver, an organ rich in metabolic activity.

In addition, the researchers discovered that blocking acetylation chemically or genetically affected these metabolic enzymes in a number of different ways, either by stimulating its activity, inhibiting it, or degrading the protein itself. They suspect that acetylation is important for coordinating not only the players within a metabolic pathway but also between different pathways.

 The next step is to take their finding in normal cells and see how it can inform their study of tumor cells. The researchers are in the process of looking at each metabolic enzyme, one-by-one, to see which one displays the most disparate acetylation patterns between normal and cancer cells. They will then try to use the very same proteins that tack on or pull off those acetyl groups – called acetylases or deacetylases, respectively — to modify acetylation and thwart cancer development.

“If we can identify which enzyme or enzymes are responsible for the difference in metabolism between normal and tumor cells, then we may have  have new targets for the treating cancer patients,” says Xiong.

The study appears in the February 19 issue of  Science.

Les Lang

Leave a comment

Filed under Uncategorized