AIDS activists demonstrating in Pittsburgh, Pennsylvania

VIENNA GoogleNews.com, (Reuters), July 20, 2010, by Kate Kelland VIENNA – Many low-income urban areas across the United States have epidemics of HIV, with 2.1 percent of heterosexuals in poverty-stricken urban areas infected with the incurable AIDS virus, U.S. scientists said on Monday.

In a study of rates of HIV across the United States, researchers from the Centers for Disease Control and Prevention (CDC) found that poverty is the single most important factor linked to HIV infection among inner-city heterosexuals.

“In this country, HIV clearly strikes the economically disadvantaged in a devastating way,” said CDC HIV/AIDS expert Kevin Fenton, whose findings were presented at an international conference on AIDS in Vienna.

He said the research showed there was “a widespread HIV epidemic in America’s inner cities.”

More than 1.1 million people in the United States are infected with the human immunodeficiency virus that causes AIDS, according to the CDC, and there are around 56,000 new infections there every year.

Many studies have shown that blacks, gay and bisexual men and Hispanics are the most affected groups, and Fenton said this study found heterosexuals in the poorest city neighborhoods are also hit hard. The researchers found no differences in HIV prevalence by race or ethnicity in heterosexuals in poor areas.

The United Nations Joint Program on HIV/AIDS (UNAIDS) defines an HIV epidemic as one where prevalence in the general population is more than 1 percent.

The CDC analysis looked only at heterosexuals and did not include gay and bisexual men, sex workers, or injecting drugs users, who are often the highest risk groups.

It found that HIV rates were especially high among the poorest people. Those living below the poverty line were at greater risk for HIV than those living above it — with rates of 2.4 percent versus 1.2 percent — and prevalence for both groups was far higher than the national average of 0.45 percent.

“This analysis points to an urgent need to prioritize HIV prevention efforts in disadvantaged communities,” said Jonathan Mermin of the CDC’s HIV/AIDS prevention division.

U.S. President Barack Obama last week set out a new domestic AIDS policy which asked states and federal agencies to find ways to cut new infections by 25 percent, get more patients treated quickly and educate Americans about HIV.

But the plan did not include any new funding above the $19 billion the United States already spends a year on domestic HIV prevention, care and research.

VIENNAAn underground HIV epidemic in Eastern Europe and Central Asia is building at an alarming pace, fueled by drug use, risky sex and severe social stigma that stops people asking for help, the United Nations said.

GoogleNews.com, Reuters, July 20, 2010, by Kate Kelland, VIENNA  —  In a report published at an international conference on AIDS, the U.N. children’s fund UNICEF said health and social services in the region do little for young people at high risk of HIV, who are instead subject to judgment, recrimination and even prosecution if they seek treatment or information on HIV.

The incurable human immunodeficiency virus (HIV) that causes AIDS is now spreading faster in Eastern Europe and Central Asia than anywhere else in the world.

According to UNAIDS, the prevalence of HIV in the region has risen by 66 percent since 2001, bringing the number of people living there with HIV to 1.5 million in 2008. The rate of spread means that during the six-day Vienna AIDS conference, another 3,000 people in the region will become infected with HIV.

UNICEF said it had had reports of increases in HIV prevalence of up to 700 percent in five regions of Russia. In Ukraine HIV rates of 1.6 percent of the general population are the highest in Europe and experts say Central Asian countries are the new hot-spots of rapidly increasing HIV transmission.

Anthony Lake, UNICEF’s executive director, said efforts to contain this rapid spread were being thwarted by harsh political and social attitudes, particularly to the 3.7 million injecting drug users in the region who are at very high risk of HIV.

“Children and adolescents living on the margins of society need access to health and social welfare services, not a harsh dose of disapproval,” he said in commentary with the report. “We need to build an environment of trust and care, not one of judgment and exclusion.”

About 33.4 million people worldwide are infected with HIV. Since AIDS emerged in the 1980s, almost 60 million people have been infected with it and 25 million have died. Drug users can spread HIV by sharing needles with an infected person.

UNICEF said authorities in Eastern Europe and Central Asia needed to set up non-judgmental services to address the needs of marginalized people such as drug addicts and prostitutes.

Its report pointed to a few examples of success: In Russia, for example, more than 100 youth-friendly HIV service facilities have been established, it said, to provide sexual health services, information, counseling and psychological support.

And in Tajikistan a center set up to promote HIV prevention and treatment is breaking down barriers and reaching young women who sell sex. It quoted one client as saying:

“In the beginning, I did not believe that the medical check-up, the treatment and condoms would really be free of charge and anonymous. I thought it was another trap by the police. I agreed to go there with an outreach worker for the first time, but now I go there alone and encourage my friends to use the service as well.”

UNICEF said another recent U.N. study of six countries in the region showed that many adults living with HIV fear the social stigma of seeking treatment more than they fear the disease — a factor it said was “driving the epidemic further underground.”

AIDS Rally in Moscow – the Virus is Spreading into the Heterosexual Population

GoogleNews.com, July 20, 2010, by Guy FaulconbridgeMOSCOW (Reuters) MOSCOW – Russia‘s AIDS epidemic is worsening with as many as 1.3 million people infected with HIV as the virus spreads further into the heterosexual population, Russia’s top AIDS specialist said on Tuesday.

Russia has registered 402,000 people with HIV, of whom 17,000 have died, but the real figure is much higher, said Vadim Pokrovsky, head of Russia’s federal AIDS centre.

“Not only is the number of Russians infected with HIV rising but there is an increase in the rate at which the epidemic is spreading, so a rise in the number of newly infected,” Pokrovsky told reporters.

“We have an estimate of up to 1.2 million to 1.3 million infected with HIV,” he said, adding that the number of those registered as infected was rising by 8 to 10 percent a year.

The United Nations estimates 65 million people worldwide have been infected with HIV and that 25 million people have been killed by AIDS since it was first recognized in 1981.

AIDS, which stands for Acquired Immune Deficiency Syndrome, is caused by the human immunodeficiency virus (HIV).

Most of those infected with HIV are unaware they are carrying the virus, according to the UN.

“ONE IN TEN MALES”

Pokrovsky said HIV was high among Russia‘s intravenous drug users but that many of those newly infected were not needle users. And he warned that the virus was spreading fast into the heterosexual population.

Women made up 44 percent of 39,589 registered new infections last year, he said adding that in some cities one in ten Russian males were infected with HIV.

“Evidence of the strengthening heterosexual HIV infection is the increase in the number of women among those newly registered with HIV,” Pokrovsky said.

“On average for the country, one out of every fifty males is infected with HIV but in some cities it is one in ten,” he said.

Russia‘s northern city of St Petersburg was worst affected followed by Sverdlovsk region, greater Moscow, Samara region and Moscow, though Pokrovsky said figures for Moscow were probably much higher than the data indicated.

The United Nations said in a report published on Tuesday that HIV was higher in richer regions.

“HIV prevalence is in an inverse relationship to economic development: HIV is more widespread in ‘rich’ regions,” the UN said in a report about Russia‘s regions.

Pokrovsky said overall funding for fighting AIDS in Russia was rising but that just 200 million roubles ($7.75 million) would be spent on prevention in 2007 out of a total budget of 5.3 billion roubles ($205.4 million).

“The financing is sharply rising,” he said. “There is now a lot of money, but the spending is not done entirely properly.”

“A very small amount of that money…is directed to preventing the further spread of the epidemic; most of it is being used for treatment. That is good but you need prevention too,” he said.

The medical elite thought they knew what caused ulcers and stomach cancer. But they were wrong—and did not want to hear the answer that was right.

DiscoverMagazine.com; by Pamela Weintraub; photography by Ian Regnard

For years an obscure doctor hailing from Australia’s hardscrabble west coast watched in horror as ulcer patients fell so ill that many had their stomach removed or bled until they died. That physician, an internist named Barry Marshall, was tormented because he knew there was a simple treatment for ulcers, which at that time afflicted 10 percent of all adults. In 1981 Marshall began working with Robin Warren, the Royal Perth Hospital pathologist who, two years earlier, discovered the gut could be overrun by hardy, corkscrew-shaped bacteria called Helicobacter pylori. Biopsying ulcer patients and culturing the organisms in the lab, Marshall traced not just ulcers but also stomach cancer to this gut infection. The cure, he realized, was readily available: anti­biotics. But mainstream gastroenterologists were dismissive, holding on to the old idea that ulcers were caused by stress.

Unable to make his case in studies with lab mice (because H. pylori affects only primates) and prohibited from experimenting on people, Marshall grew desperate. Finally he ran an experiment on the only human patient he could ethically recruit: himself. He took some H. pylori from the gut of an ailing patient, stirred it into a broth, and drank it. As the days passed, he developed gastritis, the precursor to an ulcer: He started vomiting, his breath began to stink, and he felt sick and exhausted. Back in the lab, he biopsied his own gut, culturing H. pylori and proving unequivocally that bacteria were the underlying cause of ulcers.

Marshall recently sat down with DISCOVER senior editor Pam Weintraub in a Chicago hotel, wearing blue jeans and drinking bottled water without a trace of Helicobacter. The man The Star once called “the guinea-pig doctor” can now talk about his work with the humor and passion of an outsider who has been vindicated. For their work on H. pylori, Marshall and Warren shared a 2005 Nobel Prize. Today the standard of care for an ulcer is treatment with an antibiotic. And stomach cancer—once one of the most common forms of malignancy—is almost gone from the Western world.

Having rid much of the globe of two dread diseases, Marshall is now turning his old enemy into an ally. As a clinical professor of microbiology at the University of Western Australia, he is working on flu vaccines delivered by brews of weakened Helicobacter. And in an age when many doctors dismiss unexplained conditions as “all in the head,” Marshall’s story serves as both an inspiration and an antidote to hubris in the face of the unknown.

You grew up far from big-city life. What was it like?
I was born in Kalgoorlie, a gold mining town about 400 miles east of Perth. My father was a fitter and turner, fixing steam engines and trains. My mother was a nurse. All the miners owed a lot of money and drank a lot of beer, so Mom said, “We’ve got to get out of here before we go the way of everybody else.” In 1951 we headed for Rum Jungle, where a uranium boom was on, but halfway there we stopped in Kaniva, another boomtown, with a whaling station and high-paying jobs. Then my father started managing chicken factories in Perth. We never wanted for anything. It was like the TV show Happy Days.

What sparked your interest in science?
My mother had nursing books around. I had three brothers, and we always had electronics and gunpowder and explosions and welding. All I can say is that some things you get from your parents through osmosis. In high school I had Bs and Cs, not too many As, but I must have done well on that medical school test and I must have had some charisma in the interview, so I ended up in medicine. Being a general practitioner was all I aspired to. I was good with patients and very interested in why things happened. Eventually I developed a more mature approach: I realized that at least 50 percent of patients were undiagnosable.

You found yourself confronting unexplainable diseases?
In medical school it’s quite possible to get taught that you can diagnose everybody and treat everything. But then you get out in the real world and find that for most patients walking through your door, you have no idea what’s causing their symptoms. You could slice up that person into a trillion molecules and study every one and they’d all be completely normal. I was never satisfied with saying that by ruling out all these diseases, a person must have a fake disease, so I accepted the fact that lots of times I couldn’t reach a fundamental diagnosis, and I kept an open mind.

Is that how you came to rethink the cause of ulcers?
Before the 20th century, the ulcer was not a respectable disease. Doctors would say, “You’re under a lot of stress.” Nineteenth-century Europe and America had all these crazy health spas and quack treatments. By the 1880s doctors had developed surgery for ulcers, in which they cut off the bottom of the stomach and reconnected the intestine. We’re pretty certain now that by the start of the 20th century, 100 percent of mankind was infected with Helicobacter pylori, but you can go through your whole life and never have any symptoms.

What was the worst-case scenario for ulcer patients?
An ulcer with a hole in it, called a duodenal ulcer, is acutely painful due to stomach acid. When you eat a meal, the food washes the acid away temporarily. When the meal is digested, the acid comes back and covers the raw base of the ulcer, causing pain to start up again. These problems were so common that the Mayo Clinic was built on gastric surgery. After that surgery, half the people would feel better. But about 25 percent of these cured patients became so-called gastric cripples, lacking appetite and never regaining complete health.

With so much physical evidence of a real condition, why were ulcers routinely classified as psychosomatic?
Eventually doctors realized they could see the ulcers with X-ray machines, but, of course, those machines were in big cites like New York and London—so doctors in those cities started identifying ulcers in urban businessmen who probably smoked a lot of cigarettes and had a high-pressure lifestyle. Later, scientists induced ulcers in rats by putting them in straitjackets and dropping them in ice water. Then they found they could protect the rats from these stress-based ulcers by giving them antacids. They made the connection between ulcers, stress, and acid without any proper double-blind studies, but it fit in with what everybody thought.

How did you come to challenge this prevailing theory?
I was in the third year of my internal medicine training, in 1981, and I had to take on a project. Robin Warren, the hospital pathologist, said he had been seeing these bacteria on biopsies of ulcer and stomach cancer patients for two years, and they were all identical.

What was distinctive about these infections?
The microorganisms all had an S-shaped or helical form, and the infections coated the stomach. Warren had found them in about 20 patients who had been sent to him because doctors thought they might have cancer. Instead of cancer, he had found these bacteria. So he gave me the list and said, “Why don’t you look at their case records and see if they’ve got anything wrong with them.” It turned out that one of them, a woman in her forties, had been my patient. She had come in feeling nauseated, with chronic stomach pain. We put her through the usual tests, but nothing showed up. So of course she got sent to a psychiatrist, who put her on an antidepressant. When I saw her on the list, I thought, “This is pretty interesting.”

Then another patient turned up, an old Russian guy who had severe pains. Doctors gave him a diagnosis of angina, pain that occurs when blood to the heart can’t pass through a narrowed artery. It’s rare, but you can theoretically get that in your gut, too. There was no treatment for an 80-year-old man in those days, so we put him on tetracycline and sent him home. He goes off, and two weeks later he comes back. He’s got a spring in his step, he’s practically doing somersaults into the consulting room. He’s healed. Clearing out the infection had cured him. I had one more year to go, so I did the paperwork to set up a proper clinical trial with 100 patients to look for the bacteria causing the gut infection; that started in April of 1982.

But at first nothing was turning up, right?
Yes—not until patients 34 and 35, on Easter Tuesday, when I got this excited call from the microbiologist. So I go down there and he shows me two cultures, the grand slam, under the microscope. The lab techs had been throwing the cultures out after two days because with strep, on the first day we may see something, but by the second day it’s covered with contamination and you might as well throw it in the bin. That was the mentality of the lab: Anything that didn’t grow in two days didn’t exist. But Helicobacter is slow-growing, we discovered. After that we let the cultures grow longer and found we had 13 patients with duodenal ulcer, and all of them had the bacteria.

When did you realize H. pylori caused stomach cancer, too?
We observed that everybody who got stomach cancer developed it on a background of gastritis, an irritation or inflammation of the stomach lining. Whenever we found a person without Helicobacter, we couldn’t find gastritis, either. So as far as we knew, the only important cause of gastritis was Helicobacter. Therefore, it had to be the most important cause of stomach cancer as well.

How did you get the word out about your discovery?
I presented that work at the annual meeting of the Royal Australasian College of Physicians in Perth. That was my first experience of people being totally skeptical. To gastroenterologists, the concept of a germ causing ulcers was like saying that the Earth is flat. After that I realized my paper was going to have difficulty being accepted. You think, “It’s science; it’s got to be accepted.” But it’s not an absolute given. The idea was too weird.

Then you and Robin Warren wrote letters to The Lancet.
Robin’s letter described the bacteria and the fact that they were quite common in people. My letter described the history of these bacteria over the past 100 years. We both knew that we were standing at the edge of a fantastic discovery. At the bottom of my letter I said the bacteria were candidates for the cause of ulcers and stomach cancer.

That letter must have provoked an uproar.
It didn’t. In fact, our letters were so weird that they almost didn’t get published. By then I was working at a hospital in Fremantle, biopsying every patient who came through the door. I was getting all these patients and couldn’t keep tabs on them, so I tapped all the drug companies to request research funding for a computer. They all wrote back saying how difficult times were and they didn’t have any research money. But they were making a billion dollars a year for the antacid drug Zantac and another billion for Tagamet. You could make a patient feel better by removing the acid. Treated, most patients didn’t die from their ulcer and didn’t need surgery, so it was worth $100 a month per patient, a hell of a lot of money in those days. In America in the 1980s, 2 to 4 percent of the population had Tagamet tablets in their pocket. There was no incentive to find a cure.

But one drug company did provide useful information, right?
I got an interesting letter from a company that made an ulcer product called Denel, which contained bismuth—much like Pepto-Bismol in the United States. The company had shown that it healed ulcers just as quickly as Tagamet, even though the acid remained. The weird thing was that if they treated 100 patients with this drug, 30 of them never got their ulcer back, whereas if you stopped Tagamet, 100 percent would get their ulcer back in the next 12 months. So the company said: “This must heal ulcers better than just removing the acid. It must do something to the underlying problem, whatever that is.” They sent me their brochure with “before” and “after” photographs. On the “before” photograph they had Helicobacter in the picture, and in the “after” picture there was none. So I put their drug on Helicobacter and it killed them like you wouldn’t believe. They helped me present at an international microbiology conference in Brussels.

The microbiologists in Brussels loved it, and by March of 1983 I was incredibly confident. During that year Robin and I wrote the full paper. But everything was rejected. Whenever we presented our stuff to gastroenterologists, we got the same campaign of negativism. I had this discovery that could undermine a $3 billion industry, not just the drugs but the entire field of endoscopy. Every gastroenterologist was doing 20 or 30 patients a week who might have ulcers, and 25 percent of them would. Because it was a recurring disease that you could never cure, the patients kept coming back. And here I was handing it on a platter to the infectious-disease guys.

Didn’t infectious-disease researchers support you, at least?
They said: “This is important. This is great. We are going to be the new ulcer doctors.” There were lots of people doing the microbiology part. But those papers were diluted by the hundreds of papers on ulcers and acid. It used to drive me crazy.

To move forward you needed solid experimental proof. What obstacles did you encounter?
We had been trying to infect animals to see if they would develop ulcers. It all failed; we could not infect pigs or mice or rats. Until we could do these experiments, we would be open to criticism. So I had a plan to do the experiments in humans. It was desperate: I saw people who were almost dying from bleeding ulcers, and I knew all they needed was some antibiotics, but they weren’t my patients. So a patient would sit there bleeding away, taking the acid blockers, and the next morning the bed would be empty. I would ask, “Where did he go?” He’s in the surgical ward; he’s had his stomach removed.

What led up to your most famous and most dangerous experiment, testing your theory on yourself?
I had a patient with gastritis. I got the bacteria and cultured them, then worked out which antibiotics could kill his infection in the lab—in this case, bismuth plus metronidazole. I treated the patient and did an endoscopy to make sure his infection was gone. After that I swizzled the organisms around in a cloudy broth and drank it the next morning. My stomach gurgled, and after five days I started waking up in the morning saying, “Oh, I don’t feel good,” and I’d run in the bathroom and vomit. Once I got it off my stomach, I would be good enough to go to work, although I was feeling tired and not sleeping so well. After 10 days I had an endoscopy that showed the bacteria were everywhere. There was all this inflammation, and gastritis had developed. That’s when I told my wife.

How did she react?
I should have recorded it, but the meaning was that I had to stop the experiment and take some antibiotics. She was paranoid that she would catch it and the kids would catch it and chaos—we’d all have ulcers and cancer. So I said, “Just give me till the weekend,” and she said, “Fair enough.”

Your personal experience convinced you that Helicobacter infection starts in childhood. Can you explain?
At first I thought it must have been a silent infection, but after I had it, I said, “No, it’s actually an infection that causes vomiting.” And when do you catch such infections? When you’re toddling around, eating dirty things and playing with your dirty little brothers and sisters. The reason you didn’t remember catching Helicobacter is that you caught it before you could talk.

You published a synthesis of this work in The Medical Journal of Australia in 1985. Then did people change their thinking?
No, it sat there as a hypothesis for another 10 years. Some patients heard about it, but gastroenterologists still would not treat them with antibiotics. Instead, they would focus on the possible complications of antibiotics. By 1985 I could cure just about everybody, and patients were coming to me in secret—for instance, airline pilots who didn’t want to let anyone know that they had an ulcer.

So how did you finally convince the medical community?
I didn’t understand it at the time, but Procter & Gamble [the maker of Pepto-Bismol] was the largest client of Hill & Knowlton, the public relations company. After I came to work in the States, publicity would come out. Stories had titles like “Guinea-Pig Doctor Experiments on Self and Cures Ulcer,” and Reader’s Digest and the National Enquirer covered it. Our credibility might have dropped a bit, but interest in our work built. Whenever someone said, “Oh, Dr. Marshall, it’s not proven,” I’d say: “Well, there’s a lot at stake here. People are dying from peptic ulcers. We need to accelerate the process.” And ultimately, the NIH and FDA did that. They fast-tracked a lot of this knowledge into the United States and said to the journals: “We can’t wait for you guys to conduct these wonderful, perfect studies. We’re going to move forward and get the news out.” That happened quite quickly in the end. Between 1993 and 1996, the whole country changed color.

You have since devised tests for H. pylori. How do they work?
The first diagnostic test, done after a biopsy, detected Helicobacter that broke down urea to form ammonia. More recently I developed a breath test for Helicobacter based on the same principle. That test was bought by Kimberly-Clark, and they sell it all over the world. That one little discovery set me up for the rest of my career.

Is it possible to create a vaccine against Helicobacter?
After 20 years and a lot of hard work by companies spending millions, we have still been unable to make a vaccine. The reason is that once it’s in you, Helicobacter has control of your immune system. Once I realized this, I said, well, if it’s too difficult to make a vaccine against H. pylori, what about loading a vaccine against something else onto the Helicobacter and using it as a delivery system? So that is my vaccine project, and it is my life at the moment. I’m making a vaccine against influenza. We’ll find a strain of Helicobacter that doesn’t cause any symptoms. Then we’ll take the influenza surface protein and clone that into Helicobacter and figure out how to put it in a little yogurt-type product. You just take one sip and three days later the whole surface of your stomach is covered with the modified Helicobacter. Over a few weeks, your immune system starts reacting against it and also sees the influenza proteins stuck on the surface, so it starts creating antibodies against influenza as well.

How would this be better than current flu vaccines?
Right now it takes a year to make 50 million doses of flu vaccine, so you only get vaccinated against last year’s flu. Whereas we are building swine flu vaccine as we speak. We know the sequence of the swine flu virus. You can make the DNA. You can put it in Helicobacter—with a home brew kit, I can make 100,000 doses in my bathtub. Using the same method, a Helicobacter vaccine against malaria would be dirt cheap. You could make 100 million doses in the middle of Africa without a refrigerator. You could distribute it at the airport through something like a Coke machine.

Based on this experience, should we be taking a fresh look at other diseases that do not have well-understood causes?
Helicobacter made us realize that we can’t confidently rule out infectious causes for most diseases that are still unexplained. By the 1980s, infectious disease was considered a has-been specialty, and experts were saying everyone with an infectious disease could be cured by antibiotics. But what about when your kids were 2 years old? Every week they’d come home with a different virus. You didn’t know what the infections were. The kids had a fever for two days, they didn’t sleep, they were irritable, and then it was over. Well, you think it is over. It might be gone, but it has put a scar on their immune system. And when they grow up, they’ve developed colitis or Crohn’s disease or maybe eczema. There are hundreds of diseases like this, and no one knows the cause. It might be a germ, just one you can’t find.

How can we track down these mystery pathogens?
What we would like to do, hopefully with funding from NIH, is launch big, long-term programs. You would enter your baby into a trial the day he is born. We would have his genome decoded. We’d survey your microbiome [all the microorganisms in the body and their DNA] and maybe your husband’s microbiome, and all that would go in a database. Then we would come along and take a feces culture from your baby each month. And if ever he got a fever, we would swab his cheek and save that. We would do 10,000 kids like this. Then, in 20 years’ time, we would find that 30 of them developed colitis, and we would go back. If we could get all of that material out of the deep freeze and run it through the sequencing machine, we would find the answer. In the last 20 years, people have been so focused on linking disease with environmental factors like chemicals and pollution. But the environmental factor could be an infectious agent that you had in your body at some time in your life. Just because somebody ruled out an infectious cause in the 1980s or ’90s doesn’t mean this was correct. Technology has moved forward a long way.

Even now, though, isn’t it hard for new ideas to be heard when medical journals are gatekeepers of the status quo?
It’s true, but they have their ears pricked up now because every time a paper comes to them, they say: “Hang on a minute, I had better make sure that this is not a Barry Marshall paper. I don’t want to have my name on that rejection letter he shows in his lectures.” Now they might say, “It’s so off-the-wall….Is it true?” 

JULY 19, 2010

Cells, it turns out, remember where they came from. Four years ago, scientists made a breakthrough in stem cell research, when they discovered how to turn back the developmental clock on skin cells, muscle cells, and other “adult” cells so the cells would behave like embryonic stem cells. These induced pluripotent stem cells (iPS cells) were touted as an alternative to the ethically contentious embryonic stem cells.

Now, though, two groups of Howard Hughes Medical Institute researchers report that iPS cells retain a genetic memory of their tissue of origin. In a sense, the iPS cells “remember” that they came from skin, muscle, blood, and so on. This memory impedes the transformation of iPS cells into other types of cells, a prospect that has deep implications for researchers working with these kinds of cells, say HHMI investigator George Q. Daley and HHMI early career scientist Konrad Hochedlinger, who led the two research groups. The scientists worked independently but shared manuscripts and coordinated joint publications on July 19, 2010 in Nature (Daley) and Nature Biotechnology(Hochedlinger).

Creating iPS cells is an important research tool because the technique can be used to generate disease-specific stem cell lines that, like embryonic stem cells, can develop into many cell types.

“The backdrop to this research is that a lot of people have the impression that iPS cells are the equivalent of embryonic stem cells,” says Daley. “That has been used as an argument that we do not need to keep studying embryonic stem cells. But iPS cells often don’t function as well as embryonic cells, and our new research offers an explanation as to why that is the case.”

“But iPS [induced pluripotent stem cells] cells often don’t function as well as embryonic cells, and our new research offers an explanation as to why that is the case.”

– George Q. Daley

Daley and his colleague Kitai Kim stumbled onto the iPS memory phenomenon while trying to cure mice of the blood disease thalassemia. Thalassemias are caused by inadequate production of the globin protein, which helps transport oxygen in red blood cells. The disease can be caused by different mutations in globin genes that reduce the blood cells’ ability to carry oxygen. In investigating a possible treatment model for human disease, Daley’s group took skin cells from a sick mouse, turned those cells into iPS cells, repaired the defective gene that causes thalassemia, and then attempted to grow healthy blood cells from the iPS cells to implant back into the mice. But the iPS cells failed to make many blood cells.

Puzzled, the team then repeated the procedure, this time starting with blood cells instead of skin cells. These “blood-originated” iPS cells made many more blood cells than the iPS cells that had begun as skin cells. “This was such a fascinating observation we really wanted to understand it,” says Daley, who is director of the Stem Cell Transplantation Program at Children’s Hospital Boston.

Working with colleagues at Harvard Medical School and Johns Hopkins University, the team analyzed gene activity in iPS cells that had originated from different tissues. In particular, they scanned the genomes of the iPS cells for a chemical signature indicative of gene silencing. This chemical signature, called methylation, tells the cell to deactivate the expression of certain genes. New technology allowed the team to scan nearly all of the methylation sites across the entire genome of the iPS cells – in essence, surveying which genes were switched off. Hochedlinger’s team performed a similar analysis.

Both teams found that iPS cells that originated from different tissues displayed different gene activation and silencing patterns. In iPS cells that had originated as skin cells, for instance, genes required for blood cell formation were silenced. Likewise, iPS cells originating as blood cells had silenced the genes required to make bone cells. “The differences we found were significant enough that we could distinguish the iPS cells from different tissues,” says Hochedlinger, an associate professor of stem cell and regenerative biology at Harvard University.

Hochedlinger adds that researchers need to be aware of these differences when using iPS cells to study human diseases. For instance, if a researcher is studying neurons grown from iPS cells isolated from patients with Parkinson’s disease, those cells may behave differently depending on whether the iPS cells originated as skin cells, muscle cells, or brain cells. “Any subtle differences you see in your patient-derived iPS cells could in fact be the result of not only the disease abnormality, but also the memory retained in the iPS cells,” he says.

Daley says another implication is obvious: If a researcher wants to study, for example, a blood disease with iPS cells, it makes sense to begin with blood cells rather than skin cells, which have become the standard starting cell in iPS experiments because they are easy to retrieve.

However, both teams offer intriguing footnotes—methods for erasing the memory of iPS cells to make the cells more like embryonic stem cells. Daley’s group found that drugs that modify DNA methylation could reset iPS cells into a more embryonic state. In practice, that means those cells more easily formed all of the tissues of the body then iPS cells not treated with the drugs. Hochedlinger, in contrast, found that simply growing iPS cells in dishes for a long period – about three weeks – erased the memory of those cells’ origins. “The longer you passage the iPS cells, the closer you come to getting embryonic stem cells,” he says. “Reprogramming the cells seems to be a slow process.”

Both groups conducted their experiments in mouse cells, but they expect the results to hold in human iPS cells, too. Hochedlinger has begun confirming the results in human iPS cells.

George Q. Daley, M.D., Ph.D.

Like a movie with multiple plots spiraling around an intriguing lead character, George Daley’s scientific career centers on a major player in human biology—the cell that creates the entire array of blood cells.

The hematopoietic stem cell (HSC), which gives rise to the progenitors of all the differentiated, specialized blood cells, is at center stage in Daley’s laboratory. Research in his lab and others has shown that the HSCs can have both positive and negative influences on the course of some diseases.

In some of his earliest research, Daley showed that an oncogene known as Bcr-Abl, which spurs malignant growth of HSCs and overproliferation of white blood cells, is responsible for chronic myelogenous leukemia (CML). Bcr-Abl is created when two normal chromosomes inappropriately swap genetic material. The highly successful drug Gleevec (imatinib) can restore the normal ratios of blood cells by blocking Bcr-Abl‘s errant growth signals, but many patients become resistant to the drug when new mutations arise.

In more recent studies, Daley and his colleagues identified many of the changes that confer resistance to Gleevec. Now, his research group is devising methods to detect these mutations and is evaluating drugs that target them. Of special interest, Daley says, is a “mutation from hell” that makes relapses in CML patients very difficult to treat.

Although the master blood stem cell is at the heart of CML, the regenerative power of even more versatile stem cells underlies some of the most exciting prospects in biomedicine—correction of genetic disease and the potential to regenerate healthy tissue to repair damage in the brain, heart, pancreas, and other organs.

What Daley has learned about how Bcr-Abl sends blood stem cells down a cancerous path was crucial to understanding how normal HSCs are generated from the true master cells of the body—embryonic stem cells. “Back in 1990, when I was in David Baltimore’s laboratory at the Whitehead Institute, I began treating mouse embryonic stem cells with different kinds of serum and getting them to become blood cells in a Petri dish,” Daley recounts. “Even then I was thinking that if you could make the complete hematopoietic lineage, you would have a universal donor cell for bone marrow transplantation.”

Thus far, Daley and his colleagues have been able to make blood stem cells that will regenerate a new blood-forming system in mice—a step toward a universal marrow transplant source—but not without certain genetic manipulations. “We’re still missing some of the key elements of the differentiation program that would allow us to understand how embryonic stem cells produce HSCs,” he says.

While continuing to study these questions, Daley has always kept his eyes on the bigger goal of reprogramming adult tissue cells from an individual patient so they revert to an embryonic state. Once in this more primitive state, the adult cells can theoretically be coaxed into developing as healthy replacement tissues.

Daley and others are refining and testing several approaches to make reprogramming more efficient. One approach relies on a technique called nuclear transfer, in which the nucleus of an adult cell from a mouse with a genetic blood disease is placed into a hollowed-out human egg cell containing natural factors that reprogram the nucleus, creating a new embryo. Embryonic stem cells removed from the embryo are then grown in culture, where the genetic flaw is repaired. Researchers can then direct the cultured stem cells, by chemical and other means, to produce HSCs that can regenerate a healthy blood system in the mouse, curing the disorder. The Daley group has accomplished this with a genetic immune disease in mice, but so far the process is extremely inefficient.

Another powerful technique, parthenogenesis, does not require a donor nucleus. Eggs, or oocytes, are artificially stimulated to duplicate their chromosomes, resulting in an embryo for cell regeneration therapy that can be tailored to be immunologically compatible with any recipient. Daley ultimately envisions “banks” of master cells and tissues for matching to specific patients, but the transplantation work is currently in a basic modeling stage in animals, he says.

A third strategy under investigation in Daley’s lab involves nuclear transfer using animal instead of human oocytes to get around the shortage of human eggs.

In parallel with his research, Daley has been an articulate and authoritative voice in the public discussion of stem cell research and its future prospects. He is often invited to speak at public forums and has testified before Congress in support of fewer governmental restrictions on research with human embryonic stem cells. He was elected president of the International Society for Stem Cell Research (ISSCR) for 2007–2008 and headed the ISSCR committee that published international guidelines for the ethical and responsible conduct of research with stem cells.

Because of restrictions on federal funding of research on embryonic stem cells derived from cell lines not approved by the Bush administration, “we remain excessively constrained in the United States in the kinds of questions we can ask,” says Daley, who receives some private research support from the Harvard Stem Cell Institute and Children’s Hospital. “It is tremendously exciting that the HHMI funding will give me greater flexibility to do research on `nonpresidential’ cell lines and take it in a direction that won’t be as limited.”

Dr. Daley is also Samuel E. Lux IV Professor of Hematology and Director of the Stem Cell Transplantation Program at Children’s Hospital Boston and Professor of Biological Chemistry and Molecular Pharmacology and Pediatrics at Harvard Medical School.

RESEARCH ABSTRACT SUMMARY: Through his studies of hematopoietic stem cells, George Daley is working toward improving drug and transplantation therapies for patients with bone marrow disease

http://www.nature.com/nature/journal/vnfv/ncurrent/full/nature09342.html

Konrad Hochedlinger, Ph.D.

Looking back, Konrad Hochedlinger can’t believe he considered giving up when his Ph.D. project ran into trouble. He had joined Rudolf Jaenisch’s lab at the Massachusetts Institute of Technology in 2000, intent on creating a mouse from “scratch” by transferring DNA from mature mouse cells into egg cells stripped of their DNA—a scientific feat that no one had yet accomplished. After working for 18 months without success, Hochedlinger fought the urge to quit. He decided to scrap his original plans and begin trying new approaches

The goal was worthy of the effort because the experiments could help answer longstanding questions about the developmental potential of mature cells. But try as he might, Hochedlinger could not produce cloned mice by the simple act of transferring nuclei from adult immune system cells into mouse egg cells.

After many failed attempts, in 2002 he finally cloned a mouse derived entirely from the nucleus of a mature lymphocyte.”That was a big moment in my career. It led me to stay in science.”

Today at Massachusetts General Hospital, Hochedlinger continues to enhance development of genetically reprogrammed cells. He is developing safer and more efficient methods, with a long-term aim of generating custom-tailored cells for treating and understanding disease.

After receiving his Ph.D. from MIT in 2003, Hochedlinger was invited to stay on in Jaenisch’s lab to tackle another big problem. Two years earlier, President George W. Bush had announced that the U.S. government would fund research only with human embryonic stem cell lines created before August 9, 2001. Researchers could not apply for National Institutes of Health (NIH) grants, or any other federal funds, to support development of new human embryonic stem cells, nor could they use equipment funded by federal grants to work with newer stem cell lines. Jaenisch and others were working furiously to determine whether mature cells could somehow be coaxed into reverting to stem cells. With Hochedlinger’s help, Jaenisch’s group found that when an embryonic gene called Oct-4 is activated in adult tissues, it blocks their maturation and causes cancer. While these experiments did not yield stem cells from adult cells, they demonstrated that Oct-4 activation has a strong effect on the differentiation of adult cells, making it a likely candidate gene for attempts to convert mature cells directly into stem cells.

In 2006, a new finding energized the world of stem cell research. Japanese scientist Shinya Yamanaka converted skin cells into stem cells by using a nontraditional approach—employing viruses to insert four specific genes, including Oct-4, into the cell’s DNA. Hochedlinger, who was in the midst of setting up his own lab at Massachusetts General Hospital, quickly reproduced the results and showed that the reprogrammed cells, called induced pluripotent stem (iPS) cells, are functionally similar to embryonic stem cells. He also improved on Yamanaka’s technique by using a harmless adenovirus that disappears after its job is done. Yamanaka and others employed retroviruses to shuttle the genes into the mature somatic cells. Retroviruses, however, can integrate into the host genome and set the stage for the development of cancer.

Since then, Hochedlinger has been studying the mechanisms behind iPS cell development. “We know that sticking these four genes into an adult cell transforms the cell into an embryonic-like cell, but what’s actually going on inside the cell? What happens to the modification of DNA as you turn an adult cell into an embryonic cell? What genes are turned on and what genes are turned off? Does it matter whether the cell is a skin cell or a neural cell or a pancreas cell in terms of what it can do? How similar are reprogrammed cells to embryonic stem cells from an embryo? These are all questions that we are interested in addressing.”

The answers could have major medical implications, and Hochedlinger is exploring the possibilities with colleagues at MGH and elsewhere. Reprogrammed adult cells could reveal the genetic mechanisms behind common diseases and possibly lead to therapies in which a person’s cells could be converted to stem cells and used to grow replacement tissues.

Dr. Hochedlinger is also Assistant Professor in the Department for Stem Cell and Regenerative Biology at Harvard University and a member of the Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine and the Harvard Stem Cell Institute.
RESEARCH ABSTRACT SUMMARY:

Konrad Hochedlinger uses mouse as a model system to study cellular reprogramming of adult cells into pluripotent stem cells.

By Gabe Mirkin MD, July 20, 2010  —  To help you determine how many calories you use during various activities, scientists recommend a common measure called a MET, the amount of energy you use when you sleep. It comes out to about one kilo-calorie per kilogram of body weight, or one half a calorie per pound. For example, a 130-pound person burns 60 calories per hour during sleep. A 155-pounder uses 70 calories per hour.

When you ride a bicycle at 12 miles per hour, you are exercising at about ten METS or 10 times the amount of energy that you use during sleep. That’s the same as running a 10-minute mile, playing racquetball competitively, jumping rope at a moderate pace or playing in a soccer game. To show you how much you increase your metabolism during exercise, consider that 10 METS are equal to five times as much energy as you use when you wash dishes, shop, cook, iron or walk at a leisurely pace.

Through the state-funded project, low-income and unemployed adults take free classes and complete paid internships as medical assistants, pharmacy technicians and certified nursing assistants.

July 20, 2010|By Anna Gorman, Los Angeles Times

Hundreds of low-income and unemployed residents in Los Angeles County are receiving job training and placement at local hospitals, clinics and pharmacies in an ambitious effort that taps into the growing need for healthcare workers.

The Youth Policy Institute, a local nonprofit managing the program, opened its doors to applicants in March and has already enrolled about 400 trainees. There is room for 1,200 participants total.

FierceHealthcare.com, July 20, 2010, by Dan Bowman  —  Texas Tech University believes it has the solution to the nation’s continuing primary-care physician shortage problem [1]: a less costly three-year degree program with incentives. 

The Lubbock-based university’s medical school announced the Family Medicine Accelerated Track (FMAT) plan this week, which entails three years of school at a cost of $75,000, followed by three years of residency with a family practice, according to the Associated Press. A four-year degree at Texas Tech costs roughly $150,000. 

A $13,000 scholarship also will be given to each student who chooses to participate in the program to cover tuition and other fees for the first year. Michael Ragain, chair of Texas Tech’s Department of Family and Community Medicine, believes that through this program and others like it, the number of primary-care physicians in the U.S. could potentially double. By 2020, 39,000 more primary-care doctors will be needed [2] in the U.S., according to a 2006 study from the American Academy of Family Physicians. 

“Our program addresses debt on two levels, first by shortening the program from four to three years, and second, by providing scholarships to all qualifying students,” Ragain said. “Training primary-care physicians is a national issue that targets both rural and urban areas.” 

Simon Williams, the associate dean for the school’s health sciences center, said that students in the program would “participate in additional activities during the revised three-year curriculum” in order to fulfill the necessary requirements for a degree.

FierceHealthcare.com, July 20, 2010, by Sandra Yin  —  The Robert Wood Johnson Foundation released a report that looks at what state-level partnerships have done to expand America’s capacity to teach and graduate more nurses.

With baby boomer nurses poised to begin retiring in the next few years and the market for healthcare services growing fast as America ages, nurses are in high demand. Experts have projected that we could face a shortfall of at least 260,000 nurses by 2025. And that’s a conservative estimate, because it account for the increased demand for care due to the new healthcare legislation.

But nursing schools can’t produce enough nurses to meet demand.

There aren’t enough slots in each class, so they’re rejecting qualified applicants. In 2009, entry-level baccalaureate nursing programs rejected more than 42,000 qualified applicants, according to the American Association of Colleges of Nursing (AACN). That was up from 16,000 in 2003.

Major barriers to expanding admissions to BSN-RN programs include a shortage of faculty, clinical sites, and classroom space. Sixty-one percent of nursing schools cited lack of faculty as a barrier, according to the AACN.

In Michigan, half of the nursing faculty in many state schools are eligible to retire, according to the report. To help students speed their way to teaching positions, the governor established the Michigan Nursing Corps, with $7 million in appropriations (2008-2010), to train clinical and classroom faculty. Participants receive tuition and stipends in exchange for agreeing to teach in Michigan nursing programs. Michigan has added 277 new clinical instructors, and 150 new faculty-in-training (for MSNs or PhDs) since 2005.

Concern about a nursing shortage is especially acute in Texas, which faces a projected shortage of 70,000 nurses by 2019, up from 22,000 in 2009. Texas Workforce Shortage Coalition leaders noticed that the graduation rates of state nursing programs were all over the map, ranging from: 22 percent to 98 percent, according to the RWJF report. A resulting legislative proposal took a pay-for-performance approach to incentivizing nursing programs to produce a high percentage of graduates. It divided nursing programs into high grad producers (70 percent or more) and lower producers (below 70 per­cent). 

The proposal called for new and continuing funding. Most of money would be earmarked for high producers to expand enrollment. The lower producers would receive much less new money to improve graduation rates. Schools in both groups that failed to meet set target percentages would have to return state money.

The legislature ultimately appropriated $50 million in new and continuing capacity-building funds. High-producing schools will receive approximately $20.5 million over two years in new money. Lower producers will receive approximately $9.5 million.

The efforts to ramp up the number of nursing school graduates also included:

  • The creation of a statewide nursing corps to quickly educate faculty and students;
  • Multi-state partnerships among community colleges and baccalaureate programs to bridge the gaps between programs offering associates degrees and BSNs;
  • Alliances of nursing programs from institutions around the state to share curriculum, administrative resources, faculty, admissions standards, and reliance on web-based instruction and mobile simulators to maximize reach; and
  • A focused program of distance-learning and web-based simulation to overcome geographical challenges. 

http://www.rwjf.org/files/research/20100608cnf.pdf

read the Robert Wood Johnson Foundation’s Report

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