Whether it’s powering through the cytoplasm leaving a trail of polymerized actin, activating an arsenal of virulence factors through changes in RNA structure, or storing the code for RNA transcripts on the wrong side of DNA, Listeria makes up its own rules for survival.


The-Scientist.com, January 12, 2010, by Pascale Cossart  —  After several years at the Pasteur Institute working on protein structure and DNA-protein interactions, I had the chance in the mid-1980s to change projects and start studying bacterial pathogens. With my colleague Brigitte Gicquel, I identified two models to work on: the bacterium that causes tuberculosis, a disease that infects about 9 million people per year, or Listeria, a bacterium that causes disease in some 2,500 people in the United States annually, with only about 500 deaths per year. I chose Listeria.

To me, it seemed a perfect model organism. Unlike Mycobacterium tuberculosis, Listeria appeared easy to manipulate genetically, it grew fast, and had an interesting life cycle. At the time, many studies were carried out on extracellular pathogens and it seemed valuable to investigate intracellular bacterial pathogens. As knowledge accumulated, I marveled at how, once Listeria enters a cell, it appears to don a cape made of the host cell’s actin proteins and seemingly flies around the cytoplasm like a miniature supervillain. Then, rather than erupting from its host cell’s membrane into the extracellular space like many other bacteria, it bursts through the plasma membranes directly into the neighboring cell. By this method it can disseminate to its target organs, the brain and the placenta-the places in mammals that are usually protected from bacterial invasion. In addition, by avoiding the extracellular space, Listeria at least partly stays under the radar of the immune system.

By 1989, Lewis Tilney and Dan Portnoy discovered the cause of Listeria‘s jet-powered movement in the cell. It wasn’t due to its flagellum. The whiplike organelle is a major propellant used in the environment before Listeria enters the body via infected food, but is shed once the bacterium enters a host’s warm gut. By comparing the rate of actin polymerization in the host cell against the bacteria’s distance traveled, researchers surmised that Listeria was charging through the cell by rapidly building a stepladder of actin proteins underneath it, rung by rung.

Following these discoveries, there was a race to find the gene that enabled Listeria to polymerize actin. But it wasn’t the problem I was focusing on. My lab was working to identify the genes responsible for the bacterium’s virulence. I had created a panel of Listeria mutants, and with my colleague Edith Gouin, I was screening for clones lacking the enzyme phospholipase. I suspected the enzyme was involved in virulence by helping the bacterium lyse the membranes it crosses. Upon finding such a mutant, it became rapidly clear that the bacterium was dramatically attenuated in other ways. When my postdoc Christine Kocks infected cells with this mutant, it was unable to grow an actin tail and shuttle around the cytoplasm. Without the aim of participating in the race, it looked as though we had won! Indeed, the gene mutation mapped to the gene responsible for the actin-based motility. It was part of an operon that also contained the phospholipase gene, explaining why both genes were affected by the mutation. We named the new gene ActA,1 for Actin gene A, because I assumed that such an interesting and unique process would require the activity of multiple genes that we would find later. Remarkably, there is still only one gene controlling this bacterium’s unique property.

Listeria appears to don a cape made of the host cell’s actin and fly around like a mini supervillain.

By chasing answers to the questions that struck my curiosity, I’ve let Listeria lead me into new fields of biology, such as, in recent years, noncoding RNA and RNA-mediated regulation. Like making use of the host cell’s actin to power its movement within the cell, this unusual bacterium has developed very clever methods for utilizing nontranslated RNA transcripts.

Bacteria exploit every possible component of their host cell’s defenses for their own profit. They hide within cells, hijack receptors, and interfere with regulatory pathways. Listeria is especially adaptable, being as happy to grow in the fridge or in soil at 4°C as it is in a human body at 37°C. In its host, it quickly adapts to an oxygen-deprived environment and becomes a pathogen. It is this transition between saprophytic-living on decaying vegetation-and pathogenic-the ability to cause disease-that became increasingly interesting to me.

Since 1986 we had been studying virulence using molecular biology, biochemistry, and infection of tissue cultured cells. We had also used mice that we infected intravenously, but the model was quite artificial, as Listeria doesn’t naturally infect mice. (Its tropism is limited to humans and farm animals such as cows and sheep.) We discovered that the human version of the receptor E-cadherin, an adhesion molecule used to maintain the junctions between epithelial cells, was involved in bacterial entry. It acted as a receptor for the Listeria protein called internalin A (InlA), forcing those host cells that produce E-cadherin to engulf the bacterium. While E-cadherin is expressed by most animals, just one amino acid sequence variation between human and mouse E-cadherin is enough to ensure that mice are resistant to oral Listeria infection.


Listeria’s bag of tricks
Once inside the gut, Listeria expresses internalin, an adhesion molecule that attaches to the host’s E-cadherin 1. The bacterium becomes engulfed by the host membrane 2. Escaping the vesicle, Listeria replicates 3, with each new bacterium becoming surrounded by an actin cloud 4. The Listeria then shuttles through the cell by forming a comet of actin filaments, eventually punching through the membrane of a neighboring cell 5. in which it is engulfed and repeats steps 3 through 5.



To get around this issue, together with my colleagues Marc Lecuit and Charles Babinet, I created a relevant animal model by expressing the human E-cadherin in a mouse intestine.2 This was the first-ever use of humanized mice to study a bacterial disease, and it has proven to be a powerful method. We can infect the mouse orally to mimic the human path of infection, and have been using it to study how the bacterium crosses the intestinal barrier. We recently improved our model by creating a mouse that expresses human E-cadherin in place of mouse E-cadherin, and have used it to investigate how Listeria crosses the placental barrier.

As we identified more of Listeria‘s virulence factors, we noticed that they were only expressed at 37°C-body temperature. At room temperature, none of the virulence genes were expressed. We hypothesized that a switch, or transcription factor that regulates the major virulence genes, might be regulated by temperature.

We found that the switch was actually relying on the structure of the messenger RNA for PrfA.3 Below 37°C, the terminal sequence of the RNA folds on itself in a hairpin structure that makes the start sequence inaccessible to ribosome binding and translation. As the temperature is increased, the RNA unfurls and is translated into the transcription factor protein PrfA that turns on the set of virulence genes (see graphic below). Together with my postdoc Jörgen Johansson, I called the RNA element in the beginning of the transcript an RNA thermosensor.3

By then, around 2002, small RNAs were emerging as important regulators of genes in both eukaryotes and prokaryotes. But our RNA thermosensor certainly wasn’t behaving like most small RNAs. It was more in line with what had been described as riboswitches-elements within messenger RNAs that form a hairpin loop, inhibiting translation. Until our discovery, all riboswitches were thought to be released by small molecules rather than by temperature.

What other tricks did Listeria have up its sleeve to ensure its survival inside a human host?

The more papers I read on the subject, the more I was intrigued by the power of RNA. By 2005, researchers had been publishing on the role of small RNAs in animals and plants, but there hadn’t been much published on small RNA in bacteria. My lab undertook a project to investigate Listeria‘s noncoding RNA by analyzing the bacterium’s transcripts when it was in stationary phase (without food), when it was in growth phase, and when present in the blood in its pathogenic phase. We sought to understand which sequences were involved in regulating the bacterium’s behavior at the major turning points in its life cycle and to understand how it undergoes its switch from a harmless bacterium to a pathogenic one.


A thermosensor for virulence
The gene prfA acts as a master switch for Listeria’s virulence genes. At low temperatures, when the bacterium lives on decaying vegetation, the start sequence of the PrfA mRNA transcript is locked in a hairpin structure. When the temperature increases to 37°C, body temperature, the hairpin buckles outwards, releasing the start sequence that a ribosome can bind to and then initiate the translation of the gene.



We characterized the transcripts using a tiling microarray, a DNA chip that maps all the transcripts produced by a bacterium, on both strands of the DNA. Because we had sequenced and then annotated the complete genome of Listeria several years earlier, we could map each operon of the genome and carefully identify the beginning and end of their sequences.

Our scan revealed at least 50 small RNAs that could be involved in gene regulation, two of which were virulence factors.4 While we and others had already reported some 20 small RNAs regulating Listeria genes-which our screen also captured-none had been found to control virulence.

The study of Listeria has been a gold mine for me and others in the field. Many questions we asked led to the discovery of important concepts and mechanisms.

What was most surprising was that there were several long RNA transcripts on the opposite side of strands that encoded for genes. If you have a protein-coding gene on one strand of DNA, you never look to the opposite strand. Now, we had identified these long antisense transcripts, although we didn’t quite know what most of them did. One of these antisense threads comprised a long 5′ non-coding region as well as a region encoding a transcriptional regulator of the flagellin gene.5 This discovery added a level of complexity to the already complex regulation of Listeria’s flagella.

Together with Johansson, now a group leader at Umeä University, I showed that riboswitches can act on upstream genes. Moreover, when a riboswitch is produced as a small transcript, instead of being degraded, it can act on the opposite strand of DNA in distant genes. Indeed, we were able to show that two riboswitch elements, SreA and SreB, can act also on the PrfA transcript by binding to the very start of its message. The SreA and SreB short transcripts form when S-adenosyl is in excess in the bacterium, in nutrient-rich conditions. These transcripts bind pfrA, impairing its translation. Together, these results show that prfA-and Listeria virulence in general-are heavily controlled by a series of sophisticated environmental cues, including temperature and nutrient availability.

The study of Listeria has been a gold mine for me and others in the field. Many questions we asked led to the discovery of important concepts and mechanisms. More than using clever tricks for getting into cells and spreading intracellularly, Listeria also modifies its metabolism by turning on genes that allow it to survive in the host. For example it can absorb its host’s sugars. In addition, it escapes the innate immune system by deacetylating its peptidoglycan-a component of the bacterial cell wall that normally triggers inflammation. It also takes over histone modifications and reprograms the infected host cell. Recently we even discovered proteins Listeria sends to the host nucleus to reprogram the cell. And there is now evidence that Listeria manipulates ubiquitin-like pathways to increase infection.

Listeria is a bacterium that has developed amazingly creative mechanisms for survival in diverse environments. I have never regretted my choice to study this microscopic miscreant.

Pascale Cossart is a professor at the Pasteur Institute and an HHMI international research scholar.

Would you postpone a patient’s death to reduce the family’s estate taxes?


Medscape.com, January 12, 2010, by Leslie Kane  —  ‘Death elasticity,’ in which a doctor can hasten or postpone a patient’s death, has heated up as an issue due to the one-year reprieve of the US estate tax.

 A Chicago internist told me he struggled with this ethical dilemma just recently. In late December 2009, his 80-year-old woman patient in the hospital was comatose and nonresponsive, a result of the progression of terminal metastatic cancer. The patient was not brain dead nor was she in pain, and death was fairly imminent.

Some doctors have been asked, “Please don’t let Dad (or Mom) die on Christmas.” In those cases, the family wants Christmas to remain a joyous day, not an anniversary of a family member’s death.

This doctor heard a different request: The patient, a widow, would be leaving the family an estate of about $5 million, which included proceeds from a $1 million life insurance policy.

Starting Jan. 1, 2010, the US estate tax was repealed for one year, and will reappear on Jan. 1, 2011. If the doctor could use heroic measures to keep Mom alive from late December 2009 through Jan. 1, 2010, the family would save hundreds of thousands of dollars on the payment of estate taxes. The patient’s three grown children were all in moderate financial shape (prior to receiving the estate), but the 55-year-old son (and head of his own family) had recently lost his job.

“In 2009, $3.5 million of an estate was exempt from taxation, and any amount over that–in this case, $1.5 million–would have been subject to a maximum 45% marginal tax bracket,” says Robert A. Bernstein, Esq, LLC, estate planning attorney in Morristown, NJ, and New York City. “By waiting until Jan. 1, 2010, the family would not have to pay the tax, which would have been in the range of $660,000.”

The internist had cared for the patient and her late husband for years and tried his best to figure out what she might have chosen to do. The patient left no written direction telling what would want in this type of situation; and had not expressed a preference to anyone. 

                               Key Decision Factors

Some factors include:

The moral right or wrong of keeping alive a nonresponsive near-death patient for the family’s financial benefit;

The societal-responsibility factor regarding spending another $40k to $80k of the peoples’ money (Medicare) in order for the family to pocket more money. Medicare already has financial troubles.

What was the doctor’s responsibility as a physician?

Says Gregory A. Hood, MD, internist with Drs. Borders and Associates, PSC, in Lexington, KY, and Governor-Elect of the American College of Physicians, Kentucky chapter, “The physician’s top responsibility, trite as it may sound, is that he do no harm. The first question is whether keeping this unresponsive but not brain dead woman alive another week does harm to her. It also seems this is a different question than a patient in a persistent vegetative state, as this is a comatose but near time terminal patient.”

Spoiler alert: This doctor decided to use heroic measures to keep the patient alive until the new decade. He based his decision partly on his longstanding relationship with the widow and her late husband, and his knowledge of the relationships the parents had with their children. However, although the doctor chose a course of action, he was not entirely comfortable with his decision.

Do you agree with his decision? What would you have done in the same situation?

Important update on the repealed estate tax:

It’s possible that the one-year reprieve of the estate tax might not last the year, says Robert Bernstein, Esq.

“Most tax attorneys feel Congress will not sit idly and allow there to be no US estate taxes until 2011, with the economy being what it is and with the government need for revenue,” says Bernstein. “There are bills pending which could be passed in 2010 which would address this.

“The US estate tax is the easiest tax to impose,” says Bernstein. “It affects a much smaller population than does the income tax, and it affects the wealthier people.

“Also, it doesn’t affect the deceased husband and wife; it affects their children. A lot of people think that if the kids inherit a little less, and if the government gets more money, that’s not a bad thing.”

If Congress does pass a bill reinstating the estate tax for 2010, they could potentially make it retroactive to Jan. 1, in which case the doctor kept the patient alive for no reason. However, typically, tax bills are not retroactive.

“Right now, since Jan. 1, 2010, there’s no US estate tax. As of Jan. 1, 2011, the estate tax will go back into effect with a maximum marginal tax bracket of 50% and the exemption will be $1 million, not the $3.5 million of 2009,” says Bernstein.

Medscape.com, January 12, 2010, by Daniel J. DeNoon – How do common medications affect pregnancy? To the chagrin of women trying to decide whether they must forego helpful medicines during pregnancy, nobody really knows.

Now — at long last — the FDA and a consortium of HMOs have launched a huge set of studies to find out.

“These data will guide regulatory policy and influence medical practice,” FDA Commissioner Margaret Hamburg, MD, says in a news release.

Two out of three pregnant women in the U.S. take some kind of medicine during pregnancy. Yet very few drugs are tested in pregnant women.

What data now exists comes from two sources:

  • Pregnancy registries, mostly maintained by drug makers, that collect reports from pregnant women using various medications.  
  • Animal studies. However, drugs may be safer or more dangerous to humans than to the animals used in the studies.

Now comes the Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP). The program is a collaboration between the FDA, Kaiser Permanente, Vanderbilt University (using Tennessee Medicaid data), and a consortium of HMOs called the HMO Research Network Center for Education and Research in Therapeutics (managed by Harvard University).

The study will analyze health care data on about 1 million U.S. births from 2001 to 2007. The idea is to gather information on all medications prescribed for pregnant women and to look for health effects and birth outcomes.

“Results of these studies will provide valuable information for patients and physicians when making decisions about medication during pregnancy,” Gerald Dal Pan, MD, director of the Office of Surveillance and Epidemiology at the FDA’s Center for Drug Evaluation and Research, says in the news release.

Until the data become available, women and their doctors will have to make their own decisions on whether a drug provides enough of a benefit to pregnant women to override concerns about possible risk.

To help women make these decisions, the Department of Health and Human Services maintains a web site detailing what is and isn’t known about the use of medications during pregnancy.

The FDA maintains a list of pregnancy registries for pregnant women to report their medication experiences.

WebMD maintains a list of medications generally considered safe to take during pregnancy.

the proportion of abdominal to gluteofemoral  body fat, as measured, for example, by the waist-to-hip ratio is a stronger cardiovascular risk marker than BMI

Dailymail.co.uk/health, January 12, 2010  —  Fat around the backside and thighs reduces the effect of harmful proteins called cytokines which cause inflammation and illness.  A larger backside is less likely to develop heart disease and diabetes.

 The build up of lower body, or gluteofemoral, fat takes more time to generate and is harder to break down that upper body fat found around the stomach.

This upper body fat is designed to be quickly generated and then easily metabolised.  But the break down of these fat cells releases a lot of pro-inflammatory cytokines which have been linked to cardiovascular disease, insulin resistance and diabetes.  In comparison, far fewer of these cytokines are released when gluteofemoral fat (lower body) is broken down.  High levels of this type of fat have been associated with beneficial effects such as improved lipid profile and lower cholesterol.

This finding is reinforced by the beneficial effects being found more commonly in females than males due to the testosterone they produce suppressing fat storage around the thigh.

Reviewing previous research Dr Konstantinos Manolopoulos, of the University of Oxford, and colleagues say fat around the thighs and backside is far healthier than abdominal fat and could help to develop new approaches for maintaining lower body fat and reducing heart and metabolic problems.

Writing in the International Journal of Obesity, they say conditions characterized by lower body fat reduction, such as the glandular disorder Cushing’s syndrome, lead to serious metabolic problems and underline the value of this key storage area of the body.

Dr Manolopoulos said: ‘The fat around our thighs and hips is different to the fat we accumulate around our belly. There is “good” fat and “bad” fat – just like there is good and bad cholesterol.

‘The cells in lower body fat work differently from the cells in upper body fat.  Future uses of the study could include deliberately increasing gluteofemoral fat to abate cardiovascular and metabolic problems.   

The researchers said: ‘Body fat distribution is an important metabolic and cardiovascular risk factor, because the proportion of abdominal to gluteofemoral body fat correlates with obesity-associated diseases and mortality.

‘Population studies show that an increased gluteofemoral fat mass is independently associated with a protective lipid and glucose profile, as well as a decrease in cardiovascular and metabolic risk.

‘In day-to-day metabolism it appears to be more passive than the abdominal depot and it exerts its protective properties by long-term fatty acid storage.

‘This underlines gluteofemoral fat’s role as a determinant of health by the long-term entrapment of excess fatty acids, thus protecting from the adverse effects associated with ectopic fat deposition.

Obesity is defined as a body mass index (BMI) of 30 and an increased BMI has been associated with a high risk of heart disease and diabetes.

It has long been known that body fat distribution is also an important risk factor – the proportion of abdominal to gluteofemoral body fat, as measured, for example, by the waist-to-hip ratio is a stronger cardiovascular risk marker than BMI.

Added the researchers: ‘Body fat distribution is a major determinant of metabolic health and gluteofemoral adipose tissue exerts specific functional properties that are associated with an improved metabolic and cardiovascular risk profile.

‘The protective properties of gluteofemoral fat have been confirmed in large population studies.’


By Lyndsey Layton
Washington Post Staff Writer
Monday, January 4, 2010

Of the 84,000 chemicals in commercial use in the United States — from flame retardants in furniture to household cleaners — nearly 20 percent are secret, according to the Environmental Protection Agency, their names and physical properties guarded from consumers and virtually all public officials under a little-known federal provision.

The policy was designed 33 years ago to protect trade secrets in a highly competitive industry. But critics — including the Obama administration — say the secrecy has grown out of control, making it impossible for regulators to control potential dangers or for consumers to know which toxic substances they might be exposed to.

At a time of increasing public demand for more information about chemical exposure, pressure is building on lawmakers to make it more difficult for manufacturers to cloak their products in secrecy. Congress is set to rewrite chemical regulations this year for the first time in a generation.

Under the 1976 Toxic Substances Control Act, manufacturers must report to the federal government new chemicals they intend to market. But the law exempts from public disclosure any information that could harm their bottom line.

Government officials, scientists and environmental groups say that manufacturers have exploited weaknesses in the law to claim secrecy for an ever-increasing number of chemicals. In the past several years, 95 percent of the notices for new chemicals sent to the government requested some secrecy, according to the Government Accountability Office. About 700 chemicals are introduced annually.

Some companies have successfully argued that the federal government should not only keep the names of their chemicals secret but also hide from public view the identities and addresses of the manufacturers.

“Even acknowledging what chemical is used or what is made at what facility could convey important information to competitors, and they can start to put the pieces together,” said Mike Walls, vice president of the American Chemistry Council.

Although a number of the roughly 17,000 secret chemicals may be harmless, manufacturers have reported in mandatory notices to the government that many pose a “substantial risk” to public health or the environment. In March, for example, more than half of the 65 “substantial risk” reports filed with the Environmental Protection Agency involved secret chemicals.

“You have thousands of chemicals that potentially present risks to health and the environment,” said Richard Wiles, senior vice president of the Environmental Working Group, an advocacy organization that documented the extent of the secret chemicals through public-records requests from the EPA. “It’s impossible to run an effective regulatory program when so many of these chemicals are secret.”

Of the secret chemicals, 151 are made in quantities of more than 1 million tons a year and 10 are used specifically in children’s products, according to the EPA.

The identities of the chemicals are known to a handful of EPA employees who are legally barred from sharing that information with other federal officials, state health and environmental regulators, foreign governments, emergency responders and the public.

Last year, a Colorado nurse fell seriously ill after treating a worker involved at a chemical spill at a gas-drilling site. The man, who later recovered, appeared at a Durango hospital complaining of dizziness and nausea. His work boots were damp; he reeked of chemicals, the nurse said.

Two days later, the nurse, Cathy Behr, was fighting for her life. Her liver was failing and her lungs were filling with fluid. Behr said her doctors diagnosed chemical poisoning and called the manufacturer, Weatherford International, to find out what she might have been exposed to.

Weatherford provided safety information, including hazards, for the chemical, known as ZetaFlow. But because ZetaFlow has confidential status, the information did not include all of its ingredients.

Mark Stanley, group vice president for Weatherford’s pumping and chemical services, said in a statement that the company made public all the information legally required.

“It is always in our company’s best interest to provide information to the best of our ability,” he said.

Behr said the full ingredient list should be released. “I’d really like to know what went wrong,” said Behr, 57, who recovered but said she still has respiratory problems. “As citizens in a democracy, we ought to know what’s happening around us.”

The White House and environmental groups want Congress to force manufacturers to prove that a substance should be kept confidential. They also want federal officials to be able to share confidential information with state regulators and health officials, who carry out much of the EPA’s work across the country.

Walls, of the American Chemistry Council, says manufacturers agree that federal officials should be able to share information with state regulators. Industry is also willing to discuss shifting the burden of proof for secrecy claims to the chemical makers, he said. The EPA must allow a claim unless it can prove within 90 days that disclosure would not harm business.

Meanwhile, the Obama administration is trying to reduce secrecy.

A week after he arrived at the agency in July, Steve Owens, assistant administrator for the EPA’s Office of Prevention, Pesticides and Toxic Substances, ended confidentiality protection for 530 chemicals. In those cases, manufacturers had claimed secrecy for chemicals they had promoted by name on their Web sites or detailed in trade journals.

“People who were submitting information to the EPA saw that you can claim that virtually anything is confidential and get away with it,” Owens said.

The handful of EPA officials privy to the identity of the chemicals do not have other information that could help them assess the risk, said Lynn Goldman, a former EPA official and a pediatrician and epidemiologist at the Johns Hopkins Bloomberg School of Public Health.

“Maybe they don’t know there’s been a water quality problem in New Jersey where the plant is located, or that the workers in the plant have had health problems,” she said. “It just makes sense that the more people who are looking at it, they’re better able to put one and one together and recognize problems.”

Independent researchers, who often provide data to policymakers and regulators, also have been unable to study the secret chemicals.

Duke University chemist Heather Stapleton, who researches flame retardants, tried for months to identify a substance she had found in dust samples taken from homes in Boston.

Then, while attending a scientific conference, she happened to see the structure of a chemical she recognized as her mystery compound.

The substance is a chemical in “Firemaster 550,” a product made by Chemtura Corp. for use in furniture and other products as a substitute for a flame retardant the company had quit making in 2004 because of health concerns.

Stapleton found that Firemaster 550 contains an ingredient similar in structure to a chemical — Di(2-ethylhexyl) phthalate, or DEHP — that Congress banned last year from children’s products because it has been linked to reproductive problems and other health effects.

Chemtura, which claimed confidentiality for Firemaster 550, supplied the EPA with standard toxicity studies. The EPA has asked for additional data, which it is studying.

“My concern is we’re using chemicals and we have no idea what the long-term effects might be or whether or not they’re harmful,” said Susan Klosterhaus, an environmental scientist at the San Francisco Estuary Institute who has published a journal article on the substance with Stapleton.

Chemtura officials said in a written statement that even though Firemaster 550 contains an ingredient structurally similar to DEHP does not mean it poses similar health risks.

They said the company strongly supports keeping sensitive business information out of public view. “This is essential for ensuring the long-term competitiveness of U.S. industry,” the officials said in the statement.

Staff researcher Madonna Lebling contributed to this report.


Dr. Alexander Eaton, director of Retina Health Center, right, checks Edward Sweeney’s vision during his exam at Retina Health Center in Fort Myers. Sweeney had lost his vision in one eye two years ago. (Lindsay Terry/news-press.com)


Fort Myers macular degeneration treatment an eye-opener

Injections, medication improve sight of man with wet age-related macular degeneration


GoogleNews.com, News-press.com, January 12, 2010, by Francesca Donlan  — 

It’s all pretty clear to Edward Sweeney, a 69-year-old computer programmer from Buckingham.

He was going blind and now, after 23 monthly treatments for macular degeneration at Retina Health Center, he can see.

Sweeney began losing vision in his left eye nearly two years ago and was diagnosed with wet age-related macular degeneration.

In wet AMD, new blood vessels grow beneath the retina and leak blood and fluid. This leakage causes disruption and dysfunction of the retina, creating blind spots in central vision. Wet AMD is the leading cause of blindness for people over the age of 65 in the U.S. and Europe.

“Working daily on the computer, my vision is critical to my job and lifestyle,” said Sweeney. “My vision loss came on very suddenly and everything was distorted and elongated. It was so bad that I had to wear a patch over my eye to see.”

Sweeney is in his second year of participating in an investigational study of VEGF Trap-eye for the treatment of wet macular degeneration. This investigational drug is being evaluated at Retina Health Center and other research centers around the world. Recent data is showing that patients are achieving improved vision with few repeat injections.

It’s a resounding success for Sweeney. Before the treatments, he had very little vision in his left eye and had no color perception. His right eye was a healthy 20-20 vision but could potentially be damaged by the left eye.

“It’s saving my eyesight,” he said.”I can see color now.”

Part of his treatment includes medication and an injection in his eye that doesn’t hurt, he said. And it’s all free because he is part of a study that includes 26 locals just like him.

His vision was almost legally blind, said Dr. Alexander Eaton, director of Retina Health Center in Fort Myers.

“Now his vision is good enough so he could get his driver’s license on only the right eye,” he said.

Eaton, who has been practicing ophthalmology in Lee and Collier counties for more than 13 years, is excited about the study because it requires less intervention.

“Realistically, with time he’ll be able to get medicine less frequently and maintain improvement,” Eaton said.

Eaton will be speaking about VEGF Trap-eye and other new treatments for wet macular degeneration at a public health seminar presented by Retina Health Center and the Foundation Fighting Blindness on Jan. 30. At the seminar, leading experts from throughout the country present latest research findings on wet and dry macular degeneration.

The study is expected to conclude next fall and the drug could potentially get approved by the FDA, he said.

Retina Health Center’s research arm, the Macular Degeneration Research Center, is continuously conducting studies to determine the effectiveness of investigational drugs and delivery methods that may prevent and treat macular degeneration. It’s a national test site for the evaluation of new treatments and delivery systems for retinal disorders.


For More Info………………

Southwest Florida Macular Degeneration Symposium

What: Retina Health Center and the Foundation Fighting Blindness will host this seventh annual event.

When: Jan. 30

Where: Two identical sessions will take place at 9 a.m. and 2 p.m. Jan. 30 at the Hyatt Regency Coconut Point Resort & Spa in Bonita Springs. Low-vision devices will be available. Both sessions will be identical.

Who: This year’s symposium features two keynote speakers, Dr. Brent Zanke, chairman and chief medical officer of ArcticDX Inc., and Edmund Mickunas, vice president of Advanced Cell Technologies, a biotechnology company that is developing stem cell technology for the treatments of macular degeneration.

A staff scientist at the Ottawa Health Research Institute, Zanke has extensive experience in the field of genetics, particularly as it relates to macular degeneration, which he will speak about at the symposium. In addition, Mickunas has extensive experience in gene therapy, and will discuss the latest stem cell research.

Also presenting will be Drs. Alexander Eaton and Hussein Wafapoor of Retina Health Center, along with Dr. Timothy Schoen of the Foundation Fighting Blindness. Eaton, director of Retina Health Center, will provide an overview of macular degeneration and an update on the prevention of vision loss from macular degeneration. Wafapoor will cover some of the ongoing studies at Retina Health Center that are helping patients on a local, national and international level.

Cost: Admission is free, but reservations are required. Call               800-455-0060         800-455-0060.

14th Annual Eye and Vision Research Symposia

Scientists from Harvard Medical School’s Schepens Eye Research Institute will visit Southwest Florida for the 14th Annual Eye and Vision Research Symposia, set for Friday and Saturday in Fort Myers and Naples.

Retina Consultants of Southwest Florida is hosting the event. Retina Consultants is currently involved in four VEGF-Trap studies, and VEGF-Trap will be addressed at the symposia, in addition to stem cells/regenerative therapy, a news release said.

In addition to highlighting the latest discoveries in the field of stem cell and gene therapy in treating eye diseases such as age-related macular degeneration, the symposia will also discuss some of the other clinical studies taking place at Retina Consultants.

The first session takes place from 9 to 11:30 a.m. Friday at Broadway Palm Dinner Theatre, 1380 Colonial Blvd., Fort Myers. The second session will take place from 9 to 11:30 a.m. Saturday at Hilton Naples, 5111 Tamiami Trail N., Naples.

The series is free, but registration is required. Call               866-258-8505         866-258-8505 to register.

Dr. Kameran Lashkari will be the keynote speaker. His research into stem cell and gene therapy has allowed him to discover a connection between systemic inflammation and the potential development of AMD. Lashkari uses biomarkers in a patient’s DNA to determine if a patient could develop the disease prior to any onset of symptoms, the release said.
Lashkari, along with his SERI colleagues, has also successfully regenerated adult stem cells that could be used to replace cells that are either damaged or dead because of eye diseases. With both of these approaches, SERI scientists are hoping they can take proactive steps to stop or slow the disease before it begins or help repair any damage that may be done in the future.

The specialists at Retina Consultants of Southwest Florida will also discuss the latest research taking place in Fort Myers for patients with AMD, diabetic retinopathy, and other eye diseases. In just the past few years, their research, in part, has resulted in numerous new treatments available for AMD, macular edema and retinal vein occlusion, according to the news release.

Learn more about Retina Consultants of Southwest Florida at eye.md.


GFP-tubulin spindle of a Ptk2 cell, before and after compression.

Courtesy of Sophie Dumont

The-Scientist.com, January 12, 2010, by Jef Akst  —  It was the last week of her summer of research at Woods Hole Marine Biological Laboratory on the coast of Massachusetts in 2007, and biophysicist Sophie Dumont decided to try one final experiment. With the state-of-the-art microscopes that had been loaned to the research station, Dumont started pressing on mammalian cells and watching what happened. She was hoping to see the effects of such mechanical distortion on the mitotic spindle, the apparatus responsible for divvying up the chromosomes during cell division. It was an important experiment, since mechanical forces may direct the length of the spindle, which varies greatly during development and between cell types, so understanding how the spindle responds to those forces could help illuminate that process. However, like so many of her attempts earlier that year, she succeeded only in killing the cells. Until, that is, the very last night.

It was already dark outside, but Dumont’s eyes were still glued to the microscope in front of her. She gently laid down a tiny pad of agarose gel atop the cells. Then, using a joystick not too dissimilar from an old video-game system, she navigated a hydraulics-controlled needle down to the surface of the agarose pad, then just a few microns farther, compressing the cells below. This time, to her relief, the cells didn’t die. Instead, as the cells flattened out, Dumont could see a healthy-and dramatically longer-mitotic spindle.

 “It took me maybe 5 or 10 minutes to realize it’s not just a random chance event-that it was a directed elongation,” Dumont recalls. What convinced her was the fact that she saw three cells in mitosis, all responding the same way. The spindle-a spidery collection of microfilaments that stretch from the chromosomes at the center of the cell to the poles at the edges during mitosis-grew in response to the pressure. “It was very lucky for me that on that particular day there were three” dividing cells in view, she says. “It’s hard enough to find one. If you’re really lucky, you get two.”

When Dumont excitedly showed the results to her advisor, cell biologist Timothy Mitchison of Harvard Medical School, who was also spending the summer at Woods Hole, he was pleased. “It was very clear something interesting was going on,” Mitchison says of the initial discovery. “The spindle elongated spectacularly.”

Dumont was eager to dig her heels in, but alas, she was out of time. The next day, she packed up and headed back to Boston, where she didn’t have the necessary equipment to continue the experiment. She spent the next few months setting up the lab and trying to recreate the exciting phenomenon she had witnessed back at Woods Hole. Finally, in December, she succeeded: She once again flattened dividing cells without killing them, and saw the spindle double in length (Current Biology 19, 1086-95, 2009).

“It wasn’t hit or miss,” says cell biologist and mitosis researcher Ted Salmon of UNC Chapel Hill, who shares lab space with Mitchison at Woods Hole during the summer months. “[Dumont] figured out a way to flatten the cells reliably and reproducibly and record the response”-something previous scientists had failed to do in mammalian cells.

Now that Dumont seemed to be able to lengthen spindles by simply pressing on the cells, the big question was how.

One thing she noticed in these initial experiments was the relative timing of everything: The spindle widened quickly upon compression, but lengthening took an average of 12 minutes-about four times as long as widening. This slower speed suggested that elongation was not merely a passive response to the lengthening of the cell itself, as previously thought. Indeed, further experiments revealed that compression switched off the microtubule disassembly process that occurs during microtubule renewal, causing the microtubules to lengthen.

“[The] identification of this mechanical regulation of spindle fiber was a really important contribution to the mitosis field,” Salmon says, “[but] I think this is just the start of things.” The next step, he says, is to learn about the nanometer-scale properties of the connections between chromosomes and spindles, “and the technology that she developed is going to provide the opportunity to do that.”