A confocal microscopic image of a neurosphere, a ball of human embryonic stem cells

“Oh, it’s breathtaking!”  Noseworthy said.

“This is really big!”

 

     
  Regenerative medicine summarized in four steps

1. Take a few cells from a human.

2. Keep the patient stabilized long enough for more cells to be grown.

3. Re-engineer the cells to turn them into adult pluripotent stem cells (the kind that can be triggered to change into any tissue, without the need for controversial embryonic stem cells).

4. Inject the cells into the damaged tissue of the person from whom they were taken. Or replace the patient’s damaged organ with a new, healthy one (grown from the person’s own cells).

 
     

 

By Jeff Hansel, May 4, 2010, The Post-Bulletin, Rochester MN — known for decades by the popular nickname “the Med City” — might soon get a new name: the City of Regenerative Medicine.

Mayo Clinic CEO Dr. John Noseworthy says regenerative medicine — the science of growing tissue to replace damaged human organs — has been named a top priority for Mayo.

“Regenerative medicine, it would be fair to say, has been identified as a research priority” Noseworthy told the Post-Bulletin editorial board last week.

On the same path is a small startup company called ReGen Theranostics, which recently got Rochester City Council approval to lease space in the Minnesota Biobusiness Center. That company plans to produce cell lines for use by researchers.

ReGen is seeking a license agreement to use cell-growth technology developed at Mayo, but Mayo’s ambitions go beyond ReGen.

Noseworthy said one Mayo physician researcher, Dr. Timothy Nelson, was studying to become a heart surgeon “and he says, wait a minute. We’re going to be able to grow heart cells. We’re going to be able to regrow the heart!”

Nelson and colleagues figured out how to re-engineer simple skin cells so they could be grown, over the course of about four or five months, into substantial enough numbers that they could be injected into the patient’s heart. Once there, the newly formed “pluripotent stem cells” (stem cells derived from the patient’s own skin that take a few months to grow) can heal the heart.

Pluripotent stem cells can be triggered to develop into any type of human tissue. They eliminate the need to use controversial embryonic stem cells.

Mayo is also moving forward with its own regenerative medicine team. It’s seeking research faculty in areas related to stem cell biology, according to a posting in the online Cell Career Network. It lists developmental biology, tissue bioengineering, islet cell regeneration for diabetes, cartilage biology, neuroregeneration, and heart repair among the sought-after specialties or expected future research areas.

“We’re actually currently looking to identify the leader of the regenerative-medicine team,” Noseworthy said.

Regenerative medicine, he said, has been identified among the top four “major institutional directions” for the clinic.

The possibility to individualize medicine in a way that would allow someone to be treated using the patient’s own cells has profound potential.

“Oh, it’s breathtaking,” Noseworthy said. “This is really big.”

A fluorescent microscopic image of hundreds of human embryonic stem cells in various stages of development

 

 


 

Regenerative Engineering – Constructing Body Parts

 

Mouse study suggests Wnt protein might help humans with fractures, too

GoogleNews.com, May 4, 2010, by Amanda Gardner — Stanford researchers have found a way to significantly speed up the healing of broken bones in mice, a feat which, if replicated in humans, could mean people with fractures would be free of their casts a lot sooner.

“This has huge implications,” said Dr. Victor Khabie, co-director of the Orthopedic and Spine Institute at Northern Westchester Hospital in Mt. Kisco, N.Y. “Broken bones is a big problem, and this is just the tip of the iceberg.”

The technique could help in fusing bones as well, and many other surgeries that rely on bone growth and bone healing to succeed, he added.

“A lot of the surgeries we do rely on bone growth and bone healing, and a lot of the failures of surgery have to do with the fact that the bone never heals or the fusion never [takes],” Khabie explained.

And this might have applications beyond bones.

“It isn’t limited to bone injuries,” said Dr. Jill Helms, senior author of the study published in the April 28 issue of Science Translational Medicine. “There’s a lot of interest in the role that [the protein used in these experiments] plays in tissue repair and tissue regeneration.”

That also includes blood, neural and cardiac cells, added Helms, who is a professor of surgery and of plastic and reconstructive surgery at Stanford University School of Medicine.

The research borrowed a chapter from the lives of animals that can regenerate on their own, such as zebrafish and flat worms.

Scientists already knew that this capability was partly due to a class of proteins called Wnt proteins.

Although mammals don’t have the same innate ability to regenerate, the researchers speculated that, with a little help from Wnt proteins, maybe they could.

The researchers actually conducted two experiments, both testing the idea that tissues might heal faster if the Wnt signal was ramped up.

The first used a genetic approach, involving mice that had been genetically engineered to respond better to a Wnt signal, then administering purified Wnt via fat particles known as liposomes.

The second strategy involved raising levels of the Wnt protein in normal mice. Both groups of mice had sustained bone injuries.

“Both experiments showed us the same thing, that when Wnt signals were prolonged in an injury site then healing was much more robust,” Helms reported. “When we delivered this form of the protein in a little lipid [fat] particle to an injury site, we accelerated the healing quite dramatically.”

In fact, within the first three days, those mice had 3.5 times more new bone than the mice in the other groups, according to background information about the study.

Helms and her colleagues believe Wnt causes bone stem cells to divide more and turn into bone-forming cells much sooner.

J. Edward Puzas, a professor of orthopedics and senior associate dean for basic research at the University of Rochester Medical Center, added that the idea might also benefit people who sustain potentially life-threatening fractures as a result of osteoporosis.

In separate ongoing studies, Puzas is finding that the osteoporosis drug Forteo is also useful in healing bones.

The Stanford group is now expanding its work to speed tissue regeneration after skin wounds, heart attacks and stroke.

More information

The American Academy of Orthopaedic Surgeons has more on bone fractures.

At a magnification of 13172x, this scanning electron micrograph (SEM) depicted a number of Gram-positive Mycobacterium tuberculosis bacteria. As an obligate aerobic organism M. tuberculosis can only survive in an environment containing oxygen.

 

Medscape.com, May 4, 2010, by Howard Bell — Low vitamin D levels are associated with a 5-fold increased risk for tuberculosis (TB) disease progression in previously healthy household contacts of patients with TB, according to the results of a 4-year cohort follow-up study in Pakistan, reported in the May issue of Emerging Infectious Diseases.

“Deficiency of vitamin D (25-hydroxycholecalciferol) has long been implicated in activation of [TB],” write Najeeha Talat from Aga Khan University in Karachi, Pakistan, and colleagues. However, disease progression in healthy patients has not been previously studied.

During 2001 to 2004, the researchers studied 109 healthy people in close contact with 20 different patients with TB and found that those with low vitamin D levels, especially women, were 5 times more likely to contract TB.

Cohort participants were in “household contact” with patients recently diagnosed with sputum-positive pulmonary TB. The researchers collected blood samples at baseline and at 6, 12, and 24 months’ follow-up. Stanford University in California analyzed vitamin D levels in the plasma samples.

Total circulating serum 25 [OH] vitamin D was measured using enzyme-linked immunosorbent assay, duplicated and reported in nanograms per milliliter.

The researchers classified vitamin D levels as low, middle, or high. Median level for the cohort participants was 9.1 ng/mL. Median level for the disease-free household contacts was 9.6 ng/mL, 7.9 ng/mL for the TB index case-patients, 4.6 ng/mL for 2 coprevalent TB case-patients who were receiving antituberculous treatment at recruitment, and 5.1 ng/mL in 6 household contacts with a history of TB treatment.

Vitamin D levels of the disease-free study participants were significantly higher than in participants with a history of TB diagnosis at baseline (P = .02). “When we stratified the cohort by vitamin D level,” the researchers write, “79% were deficient (<20 ng/mL), 14% were insufficient (20-30 ng/mL), and 7% were sufficient (>30 ng/mL). Median vitamin D levels were significantly lower in the 74 female patients than in the 54 male patients [p=0.0004].”

Progressing to Active TB

Talat and colleagues next analyzed risk for progression to active TB in relation to vitamin D levels. One hundred household contacts were disease-free at baseline; 8 (8%) progressed to active disease during the 4-year follow-up, with the following breakdown (P = .002, log rank):

  • 7 (23%) of 30 patients with vitamin D levels in the lowest tertile (<7 ng/mL)
  • 1 (3%) of 32 patients with vitamin D levels in the middle tertile (7 – 13 ng/mL)
  • none in the highest tertile (>13 ng/mL)

“TB progression was significantly associated with relatively lower plasma vitamin D levels,” the authors write. “Our findings also suggest that vitamin D deficiency may explain the higher susceptibility of women to disease progression in our cohort.” In a separate study, researchers at Aga Khan University in Karachi reported a high prevalence of vitamin D deficiency in ambulatory women patients.

Limitations of this study include the small cohort size and lack of information about diet, body mass index, and exposure to sunlight. However, the study results are supported by a meta-analysis of 7 case-control studies of different ethnic populations that showed 70% of healthy control patients had higher vitamin D levels than did untreated patients with TB.

As the authors explain, vitamin D supplementation during TB treatment remains controversial, with mixed results from clinical trials to date of vitamin D for pulmonary TB. “Our findings,” conclude Talat and colleagues, “indicate that further studies should be conducted regarding use of vitamin D as a supplement for persons undergoing treatment for TB and those with latent TB infection.”

The study was supported by funding from the National Commission on Biotechnology, the Higher Education Commission, the International Research Support Initiative Program of the Higher Education Commission Government of Pakistan, and the Bill and Melinda Gates Foundation.

Emerg Infect Dis. 2010;16:853-855. 

By GARDINER HARRIS

The New York Times, May 4, 2010

The birth control pill has been called the most important scientific advance of the 20th century, and no wonder. Fifty years after its approval by the Food and Drug Administration, it is still one of the leading methods of contraception, in the United States and around the world.

Much has been written about how it revolutionized sexual and social relationships, allowing women to defer pregnancy, enter the work force and make life choices their mothers could not — or, if you prefer, spawning promiscuity and undermining the foundations of marriage.

But the pill also led to profound changes in the F.D.A. itself — a revolution in what Dr. Margaret Hamburg, the current food and drug commissioner, calls regulatory science. Many of the steps that underlie modern drug approvals — extensive clinical trials, routine referrals to panels of outside experts, continuing assessments of a medicine’s safety, and direct communications between the F.D.A. and patients — were pioneered to deal with evolving concerns about the pill’s safety.

In regulatory terms, the pill brought about a kind of reformation: just as Martin Luther insisted that individual Christians could communicate directly with God without the mediation of priests, the pill eventually led the F.D.A. to communicate directly with patients without going through doctors.

That change, fiercely resisted by some physician groups, is now firmly entrenched; the F.D.A. now routinely requires that many medicines carry significant and sometimes complex warnings that patients are expected to read and understand.

But the pill was the first.

“The F.D.A. had been battling with the American Medical Association for years about who would talk to patients,” said Daniel P. Carpenter, a professor of government at Harvard. “And with the pill, the F.D.A. clearly established the upper hand.”

The pill’s role in the maturing of the F.D.A. has often been overlooked because shortly after the agency’s approval of the contraceptive, news of the horrific effects of thalidomide swept the world. That drug had been introduced in Europe as a sedative but was withdrawn in 1961 after it was linked with profound birth defects.

Although thalidomide was never approved in the United States, the horror surrounding its effects led Congress to toughen the drug approval process by requiring manufacturers to prove their medicines were both safe and effective.

It was a standard the F.D.A. had already been putting into effect, quietly if fitfully, in part because of the growing view that the safety of a medicine was inextricably linked with its efficacy.

Enovid, a pill combining the hormones estrogen and progestin, was already being prescribed for menstrual problems. But in approving it as a contraceptive, the agency’s reviewers required Searle to prove that it was effective in preventing pregnancy. (If it worked, the pill would spare women the risks of pregnancy and childbirth, which dwarfed any known risks from the drug.)

So the company undertook one of the most extensive clinical trial programs to date, said Suzanne Junod, an F.D.A. historian. The pill was formally tested in 897 women, mostly in Puerto Rico and Haiti.

The trials were relatively brief and did not answer fundamental questions about risks of cancer, heart disease and other chronic diseases. Uncertain about the long-term effects of hormonal contraceptives, the F.D.A. mandated that doctors limit prescriptions to two years.

The pill’s overwhelming popularity, however, soon rendered this limitation unenforceable. New versions were introduced, so women could simply switch brands — or find another doctor to prescribe the old one. And many doctors ignored the limit anyway.

Then in November 1961, a British physician reported in The Lancet that a young woman had developed a blood clot and died while taking the pill. Within months, two similar fatalities were reported in the United States, and by August 1962, the F.D.A. had received 26 reports of users’ suffering blood clots.

By the end of 1964, more than four million women had used Searle’s pill, and a blizzard of competitors had begun to blanket the market. With something so popular, the agency had no way of knowing if the problems experienced by users were related to the pill or would have happened anyway — the kind of mystery that has plagued drug regulators ever since.

So agency officials did two things for the first time that would eventually become routine. They asked a panel of outside experts to review the evidence on a continuing basis, and they and British regulators pressed for a large epidemiological investigation that would become a model for the future.

Even before the pill, the federal government had a long history of using advisory committees to assess specific subjects and issue reports. But in 1965, the F.D.A. established its first permanent advisory panel, the Obstetrics and Gynecology Advisory Committee, largely to track the safety of the pill. The agency now has 32 permanent advisory committees, one of them with 18 different panels. These committees provide crucial advice not only about whether to approve certain medicines and devices but also how to address safety concerns that arise after approval.

“What the pill does,” said Dr. Carpenter, of Harvard, “is show the F.D.A. that postmarketing surveillance is a tough problem.”

The challenge of communicating these risks to patients while still supporting the product’s continued use bedeviled top agency officials. Protests by women’s groups and hearings on Capitol Hill made clear that despite the agency’s attempts, many women said they took the pill without being fully informed of its risks.

Frustrated that some doctors were not communicating adequately with their patients, the F.D.A. created a handout in 1975 that doctors could use in counseling patients. Many doctors, incensed at what they saw as the agency’s intrusion into the doctor-patient relationship, either ignored the material or refused to give it out.

In 1978, faced with mounting complaints that women did not have the information they needed, the F.D.A. mandated that patients be given the handouts when they picked up their prescriptions at the drugstore.

“It was the first time that the agency had provided information directly to patients at the point of sale instead of relying on physicians,” said Dr. Junod, the historian.

More recently, the Ortho Evra birth control patch has become a telling example of the continuing challenges that the F.D.A. faces in regulating a global, multibillion-dollar industry on which the agency depends for crucial information about drug safety.

Johnson & Johnson developed the patch in hopes of exposing women to even lower doses of estrogen than they got with the pill. But the company’s own studies showed that the patch actually delivered far higher doses.

The finding was buried in a mathematical formula in a 435-page report filed with the F.D.A. The company said it acted responsibly, but after four years, the F.D.A. issued a warning about high estrogen doses, and sales plunged.

One last bit of lore about the pill: no one is even sure when to celebrate its birthday. Ten years ago, the agency honored the occasion on June 23, the date that the F.D.A. gave formal approval for Searle to market the product. This year, the agency is celebrating on May 9, which coincides with the period 50 years ago when it announced its intention to approve the pill when a few technical details were ironed out. That this happens to be Mother’s Day this year may have played a role in the decision.

But whatever the date, it represents the F.D.A.’s first steps into adulthood.

“The pill was a landmark in the field of drug regulation,” said Peter Barton Hutt, a former top agency lawyer. “This is the drug that started it all.”

A version of this article appeared in print on May 4, 2010, on page D1 of the New York Times edition.

The New York Times, May 4, 2010, by Jane E. Brody  –  Human growth hormone has acquired a bad reputation, thanks to athletes who have abused it in their quest for stardom. But for tens of thousands of children whose growth and development are stymied by a deficiency of growth hormone, daily injections of this biologically synthesized growth stimulant can put them on track toward normality.

I’m not talking about children with normal hormone levels whose genetic heritage will keep them well below the average height for American men and women (respectively, 5 feet 9 inches and just under 5 feet 4), although they, too, can sometimes benefit from an artificial boost from the hormone.

According to Dr. Judith L. Ross, a pediatric endocrinologist at Jefferson University Hospitals in Philadelphia, even hormonally normal children genetically destined to be short can gain one and a half to perhaps four inches in final height, depending on when treatment is begun. Thus, a boy who would otherwise top out at 5 feet 3 could conceivably reach 5 feet 7 through hormone therapy begun at an early age, well before puberty.

But the claims for human growth hormone have been considerably overstated, perhaps because it is such a profitable product, costing tens of thousands of dollars a year — only sometimes covered by insurance. “Many kids who are not actually growth-hormone-deficient will not respond to the treatment, so it is a very expensive crapshoot,” Dr. Philippa Gordon, a pediatrician in Brooklyn, told me in an e-mail message. “What is the psychological fallout when the parents have spent $30,000 a year and the child fails to grow? Also, the long-term side effects are not known.”

Who Can Benefit

Although treatment of hormonally normal children is still highly controversial, therapy is clearly indicated for those with a diagnosed deficiency in growth hormone, which has health benefits beyond height stimulation, according to a report by Dr. Ross and colleagues in the April issue of the journal Pediatrics.

At age 14, Cutler Dozier of Minneapolis was 4 feet 10 inches and weighed 76 pounds, smaller than the average 12-year-old and showing no signs of puberty. His mother, Phyllis Dozier, said she had long thought his size was because of his extremely premature birth. Then, she said in an interview, she learned that “while most preemies eventually catch up, Cutler was falling further and further behind.”

“He was growing only one-quarter to one-half inch a year,” she added, “whereas most children grow about two inches a year.”

Although Cutler’s pediatrician was surprisingly unconcerned, Mrs. Dozier wisely insisted on a referral to a pediatric endocrinologist, who found that Cutler had a serious growth hormone deficiency. He strongly recommended treatment (80 percent of the cost was covered by insurance, leaving the family with a $535 monthly co-payment) and in just one year of daily hormone injections, Cutler grew four and a half inches. His mother said, “At 15, although he was still small for his age, he was finally on the chart for a 15-year-old.”

She added: “Not only did he get taller, his appetite really picked up and his hands grew bigger. He reached 5 feet 4 inches at age 16 but had not yet completed puberty, so the endocrinologist recommended he continue treatment. We left the decision up to Cutler, who decided to continue injecting the hormone for four more years.”

Now 22 and fully grown, Cutler weighs 140 pounds and stands a confident 5 feet 9 inches.

Dr. Ross says that other children who can benefit from growth hormone therapy are those who were born small for their gestational age and who fail to catch up by age 2 or so; girls born with a chromosomal abnormality called Turner syndrome; and children with genetic disorders called SHOX deficiency and Noonan syndrome.

The Pediatrics authors wrote that “short children who were born small for gestational age have relatively large hands and feet and relatively broad shoulders and pelvis.” But six years of hormone therapy can help to normalize their body proportions.

Other conditions still under study for possible benefits from growth hormone therapy include Prader-Willi syndrome, which can result in extreme obesity; cystic fibrosis; and juvenile arthritis that is treated with steroids. In each of these disorders, the researchers reported, growth hormone therapy may improve body composition.

Children who are deficient in growth hormone tend to accumulate body fat, especially around the abdomen, and develop more fragile bones and abnormally low muscle mass. Treating them with the hormone reverses these effects, and results in increased bone density and improved muscle mass in the arms, legs and trunk.

Still, the levels can remain below normal even after six years of treatment. Two studies have shown that further improvement in body composition can result if growth hormone therapy is continued for several years after a child reaches adult height.

The authors reported that discontinuing growth hormone therapy in adolescence would limit the child’s ability to attain “peak bone mass.” They suggested that “growth hormone should be administered in adequate doses and for an adequate length of time to help achieve a bone mineral density within normal range.”

Another potential benefit of continuing treatment throughout adolescence is the effect of growth hormone on a child’s later risk of developing heart disease. In addition to the increase in total body fat and abdominal fat associated with the hormone deficiency, blood levels of low-density-lipoprotein cholesterol (LDL, the so-called bad cholesterol) and triglycerides tend to be abnormally high. Because there is evidence that abnormal lipid levels in early adulthood raise the risk of cardiovascular disease in middle age or later, the Pediatrics authors suggest continuing hormone therapy throughout adolescence.

Are There Risks?

As Dr. Gordon noted, the long-term effects of growth hormone therapy are not known, particularly for children whose hormone levels are normal to begin with. There has been some concern that IGF-1, a protein produced by the liver that mediates the action of growth hormone, may raise the risk of developing cancer. When the hormone is administered, IGF-1 levels rise.

Dr. Ross said that “we monitor the levels of IGF-1 in children treated with growth hormone and adjust the dose so that IGF-1 stays within normal range.” Thus far, she said, there has been no evidence of an increased risk of cancer recurrence in children with leukemia who were treated with growth hormone, although there has been a slight increase in recurrence in children with brain tumors.