Researchers at Columbia University use a bioreactor, left, to house and help cultivate material, right, that evolves into a bone.
The New York Times, March 29, 2010, by Anne Eisenberg – IF a lover breaks your heart, tissue engineers can’t fix it. But if sticks and stones break your bones, scientists may be able to grow custom-size replacements.
Gordana Vunjak-Novakovic, a professor of biomedical engineering at Columbia University, has solved one of many problems on the way to successful bone implants: how to grow new bones in the anatomical shape of the original.
Dr. Vunjak-Novakovic and her research team have created and nourished two small bones from scratch in their laboratory. The new bones, part of a joint at the back of the jaw, were created with human stem cells. The shape is based on digital images of undamaged bones.
Tissue-engineered bones have many implications, according to a leading figure in the field, Dr. Charles A. Vacanti, director of the laboratories for tissue engineering and regenerative medicine at the Brigham and Women’s Hospital in Boston. He has no connection to the Columbia work. “If your imaging equipment has sufficient high resolution, you can construct virtually any intricate shape you want — for example, the middle ear bone, creating an exact duplicate,” he said. “It’s a splendid example of tissue engineering at its best.”
Engineered bones are being tested in animals and in a few people, and may be common in operating rooms within a decade, said Rosemarie Hunziker, a program officer at the National Institute of Biomedical Imaging and Bioengineering, which sponsors research in the field, including that at Columbia.
“It’s a field that is attracting much interest from venture capitalists,” said Robert Langer, a professor at M.I.T. Dr. Langer has more than 750 patents issued or pending in tissue engineering and drug delivery systems, and is an adviser to many companies that have started businesses based on his work.
Scott Hollister, a professor at the University of Michigan, Ann Arbor, is a co-founder of Tissue Regeneration Systems, a company that is commercializing technology his group is developing for skeletal reconstruction in the face, spine and extremities.
Dr. Vunjak-Novakovic, who has filed a patent application through Columbia, said that her lab’s work had attracted considerable interest from investors, but that it was too soon to talk about commercial applications. “We are starting studies with large animals that will establish safety and feasibility before commercialization, “she said.
Dr. Vunjak-Novakovic, Dr. Warren L. Grayson and other members of the team used digital images of the joint to guide a machine that carved a three-dimensional replica, called a scaffold, from cleansed bone material. The team turned the bare scaffold into living tissue by putting it into a chamber molded to its exact shape, and adding human cells, typically isolated from bone marrow or liposuctioned fat. A steady source of oxygen, growth hormones, sugar and other nutrients was piped into the chamber, or bioreactor, so the bone would flourish.
“The cells grow rapidly,” Dr. Vunjak-Novakovic said. “They don’t know whether they are in the body or in a culture. They only sense the signals.”
Traditional bone grafts are typically harvested from other parts of the body, often a traumatic step, or made of materials like titanium that aren’t always compatible with host bones or cause inflammation, said Dr. Francis Y. Lee, a professor of clinical orthopedic surgery at Columbia’s College of Physicians and Surgeons. Dr. Lee also has no connection to Dr. Vunjak-Novakovic’s work.
“If we have an anatomically matching scaffold that can host bone cells,” Dr. Lee said, “this will provide a new way of reconstructing bone and cartilage defects.”
The design of the bioreactor is ingenious, said Dr. Vacanti of Boston, because it allows sources of nourishment and other fluids to permeate the pores of the scaffold as new bone grows within the pores. Often, cells make tissue mainly on the outside of a scaffold, while cells inside tend to die. But Dr. Vunjak-Novakovic’s bioreactor permits close observation and control of additives by the research team. “They can direct the flow and monitor the effect on the development of tissue,” Dr. Vacanti said.
PROFESSOR Hollister at Michigan is also working on creating bones of a jaw joint. But instead of using a bioreactor to grow them, he plans to use the human body as the incubator. The scaffold for the new bone, designed from a CT scan and printed directly using a laser system, is filled with cells from bone marrow or fat that are taken from the patient to prevent immune-system reactions. “Then we will let the patient’s body naturally heal and reconstruct the tissue as the implant is resorbed by the body,” he said.
Many of the components to generate good bones are in place, said David L. Kaplan, professor and chairman of the department of biomedical engineering at Tufts University. “The technology is here,” he said, “to control the size, shape and functional features of human tissue in the lab.”
The complex problems of keeping tissue alive and integrated when implanted in the body are also well on their way to being solved, Dr. Hunziker said. “We are starting to put the pieces of the puzzle together in various combinations to generate good bone,” she said, “and it’s all going to come together in a reasonable amount of time.”
ScienceDaily (Mar. 29, 2010) — Scientists at Oxford University have led a study that shows how simple diagnostic tests to identify which patients will respond to which cancer drugs can be developed, potentially ushering in a new era of personalized cancer medicine.
The Oxford researchers, with colleagues at the MD Anderson Cancer Center at the University of Texas, Houston, confirm their approach works in results published in the journal PNAS. They show that a specific protein can be used as a ‘biomarker’ to identify which patients with a rare type of non-Hodgkin lymphoma would benefit from a new class of cancer drug. ‘This is the first report of a biomarker that predicts how a patient’s cancer will respond to a cancer drug,’ says Professor Nick La Thangue of Oxford University, who led the research. ‘The presence or absence of the biomarker can now be used as a diagnostic test to identify which patients will benefit from this drug.
‘It’s one of the first examples of being able to personalize cancer medicine and tailor treatment for the individual patient,’ he adds.
Biomarkers also have implications for reducing the cost burden of introducing new cancer drugs on the NHS, as only the subset of patients that would see a benefit would receive the treatment.
‘New cancer drugs would be more likely to gain approval from the National Institute for Health and Clinical Excellence where biomarkers exist to identify the appropriate patient group,’ believes Professor La Thangue, as their analyses of how well the treatment works in relation to how much it costs the NHS would improve.
Cancer drug discovery and development has changed significantly with greater understanding of what goes wrong in biological processes within cancer cells. New drugs target a variety of these cellular processes, but they will often only be effective in a subset of patients according to the profile of their particular cancer.
For example, trastuzumab (Herceptin) is an effective drug against breast cancer but only among those patients with cancers that express the protein which the drug targets. Patients without that protein see no benefit from the drug.
A biomarker is something that can be measured to predict whether a particular cancer will respond to treatment with a particular drug. Simple diagnostic tests based on the level of biomarker present can then flag up patients that will respond to that drug.
Biomarkers can also be used to identify appropriate patient groups for clinical trials. This would improve the ability of the trial to determine a drug’s clinical benefits and increase the likelihood that new and effective drugs make it into clinics. Currently the failure rate for new drugs in development is estimated to be 80%.
The Oxford and Texas team focused on a new class of cancer drug called HDAC inhibitors because they stop the action of the protein histone deacetylase. SAHA (Vorinostat or Zolinza) was the first drug of this class to gain regulatory approval, and can be used in the treatment of a rare type of non-Hodgkin lymphoma known as cutaneous T-cell lymphoma, or CTCL.
The researchers used a whole-genome screen to identify those genes active in CTCL cells that govern whether the cancer cells respond to the drug SAHA or not. The screen works by silencing each gene in turn to assess its effect on how well the drug works. HR23B was found to determine the CTCL cells’ sensitivity to SAHA.
The scientists now report that HR23B works as a biomarker in a clinically relevant setting. The presence of HR23B in biopsies from patients with CTCL predicted who would respond to the treatment 71.7% of the time.
With this first demonstration of a predictive biomarker for a cancer drug, the approach using a whole-genome screen can be done again and again to find biomarkers for different cancers and different drugs. The hope is that the identification of new biomarkers can become routine.
The Oxford group has a patent on the whole-genome screen for identifying biomarkers and is looking at options for commercializing a biomarker kit using HR23B as a companion diagnostic test to go with the drug SAHA.
‘This new work validates our approach for identifying biomarkers,’ says Professor La Thangue. ‘It should be possible to find biomarkers for every drug on the market and every drug in development and truly personalize cancer medicine.
‘You can imagine in the future a biopsy will be taken of a patient’s tumor and screened for the presence of a hundred different biomarkers. They’ll then be given a cocktail of drugs that is tailored for the profile of their particular cancer,’ he adds.
March 29, 2010, by Gabe Mirkin MD – Researchers at Columbia University Medical Center used magnetic resonance imaging to show that even small rises in blood sugar levels can reduce blood flow to the dentate gyrus, the part of the brain that controls memory (Annals of Neurology, December 2008). This may give us the explanation for memory loss that occurs with aging and why exercise helps to prevent memory loss.
The brain gets more than 98 percent of its energy from a steady supply of sugar circulating in the bloodstream. When blood flow is reduced, the brain is deprived of its source of energy and oxygen, causing injury to brain cells.
When you eat, sugar goes from your intestines into your bloodstream. The rise in blood sugar calls out insulin that drives sugar from your bloodstream into cells, keeping blood sugar levels steady. However, with aging, the body starts to lose its fine ability to control blood sugar, and blood sugar levels can rise too high. However, you are protected when you exercise because contracting muscles draw sugar so rapidly from the bloodstream that your blood sugar level doesn’t rise very high and your pancreas doesn’t need to release very much insulin. This rapid withdrawal of sugar from the bloodstream by exercising muscles is dramatic during exercise and can last up to eighteen hours after you finish exercising.
Hundreds of other studies show that 1) exercise slows loss of memory with aging, 2) diabetes markedly increases risk for dementia, 3) diabetes damages the dentate gyrus, 4) exercise helps to prevent the rise in blood sugar after eating and the associated age-related loss of mental function, 5) regular exercisers suffer far less from age-related memory decline, 6) obesity markedly increases risk of age-related loss of mental function, and 7) exercise helps to prevent and treat obesity. This new study should encourage you to exercise to save your mind.
Read more by Gabe Mirkin MD………………
Gabe Mirkin, M.D. – A study from Brown University Medical School showed that Alzheimer’s disease may be another form of diabetes, and all the recommendations for avoiding diabetes may also protect your memory (Journal of Alzheimer’s Disease, November 2005).
Like the pancreas, the brain produces insulin. Professor Suzanne M. de la Monte showed that brain levels of insulin and insulin receptors fall during the early stages of Alzheimer’s and continue to drop progressively as the disease progresses. Other features of Alzheimer’s, such as cell death and tangles in the brain, could be caused by abnormalities in insulin functions.
Furthermore, lack of insulin lowers brain levels of the neurotransmitter acetylcholine, which is seen regularly in Alzheimer’s disease. This would explain why every factor known to increase risk for heart attacks also increases risk for Alzheimer’s disease. Even though these studies are preliminary, it is a good idea to reduce susceptibility to developing diabetes by markedly reducing your intake of sugar and flour; increasing your intake of fruits, vegetable, whole grains, beans, and nuts; avoiding weight gain and exercising regularly.
Read more by Gabe Mirkin MD…………….
By Gabe Mirkin MD – Recent research shows that a regular exercise program can help to prevent some of the loss of memory that comes with aging. A part of your brain called the hippocampus is the control station for memories that you store in other parts of the brain. Another brain structure called the prefrontal cortex is the central station that assembles data from other parts of your brain when you want to recall something from your past. Aging causes the brain to shrink and you lose synapses that transmit messages from one nerve to another.
Exercise causes the brain to produce a substance called Brain Derived Neurotropic Factor (BNDF) that strengthens old synapses and causes new one to grow (Proceedings of the National Academy of Sciences, May 2007). Researchers used MRIs of their human subjects to show that an exercise program of an hour a day, four days a week for three months caused new neurons to grow in the hippocampus. Several previous studies showed that exercise enlarges the hippocampus in rats and doubles or even triples the rate of the formation of new nerves. However, one way that rats differ from humans is that most of them like to run and need no encouragement to spend several hours a day on a treadmill.
There is also emerging evidence that physical activity may be protective against neurological disorders, including Alzheimer’s and other forms of dementia, Parkinson’s disease, strokes and spinal cord injuries. If you are not a regular exerciser, check with your doctor and get started.
Read more by Gabe Mirkin MD…………….
Gabe Mirkin, M.D. – You can tell if you are at high risk for diabetes if you store fat primarily in your belly. Pinch your belly; if you can pinch an inch, you are at increased risk and should get a blood test called HBA1C. Having high blood levels of triglycerides and low levels of the good HDL cholesterol that helps prevent heart attacks also increases your risk for diabetes.
When you eat sugar or flour, your blood sugar rises too high. This causes your pancreas to release insulin that converts sugar to triglycerides, which are poured into your bloodstream. Then the good HDL cholesterol tries to remove triglycerides by carrying them back into the liver, so having high blood levels of triglycerides and low blood levels of the good HDL cholesterol are both individual risk factors for diabetes.
High blood levels of insulin constrict arteries to raise blood pressure, so many people who have high blood pressure are also prediabetic. High insulin levels also constrict the arteries leading to your heart to cause heart attacks directly. People with insulin resistance have an increase in small, dense, low-density lipoprotein (LDL) cholesterol, which is more likely to cause heart attacks than the large, buoyant regular LDL cholesterol. High levels of insulin also cause clotting to increase your risk for heart attacks.
A study from Sweden showed that many people discover that they are diabetic only after they have had a heart attack. Researchers recorded blood sugar levels in men who had had heart attacks and then did sugar tolerance tests at discharge and three months later. They found that 40 percent had impaired sugar tolerance tests three months later. This suggests that 40 percent of people who have heart attacks are diabetic, even though they may not know it. The authors recommend that all people with heart attacks be tested for diabetes (1).
You can help to prevent diabetes and heart attacks by avoiding sugar and flour, exercising and eating lots of vegetables.
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Quantum information, the UK’s very own Nasa, the Templeton prize controversy and a rainforest at London Zoo
Growth at Target Health
Target Health is pleased to announce that as a small business, we are contributing to the overall recovery of the US economy. If every small business followed our path, the recession would be over. Over the past 6 months, we have added five jobs and we are still hiring. Three of the positions were in Clinical Research where we have added 2 project managers and one Sr. CRA. With the layoffs in Big Pharma, we were able to get very experienced people from Wyeth, Merck and a device company. We also hired a top web programmer who will strengthen our software development group, as well as a data manager. Target Health is a privately held business with no investors and no debt. In today’s economy, this conservative business approach allows us to optimize our client services and at the same time provide stability to our dedicated staff.
For more information about Target Health and our software tools for paperless clinical trials, please contact Warren Pearlson (212-681-2100 ext 104) or Ms. Joyce Hays. Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health website at: www.targethealth.com
Kidney Disease Hides in People with Undiagnosed Diabetes
Millions of Americans may have chronic kidney disease (CKD) and not know it, according to a study appearing in an upcoming issue of the Clinical Journal of the American Society Nephrology (CJASN). “Our research indicates that much of the CKD burden in the US is in persons with prediabetes and undiagnosed 1) ___, who are not being screened for CKD,“ said Laura C. Plantinga, ScM (University of California, San Francisco). The researchers believe that broader 2) ___ may be needed to detect patients with these two relatively silent yet harmful diseases. The study analyzed a nationally representative sample of about 8,200 Americans from the National Health and Nutrition Examination Survey. Standard laboratory tests were used to assess the rate of CKD, focusing on people with undiagnosed diabetes or prediabetes (sometimes called 3) ___ diabetes). Based on laboratory tests, 42% of subjects with undiagnosed diabetes had CKD – similar to the 40% rate in those with diagnosed diabetes. Only a small percentage of participants were aware of the 4) ___ of CKD. In addition, CKD was present in nearly 18% of subjects with prediabetes. Among participants without diabetes or prediabetes, the rate of CKD was about 11%. According to the authors, there may be a substantial number of individuals in the US – up to 13 million – who have undiagnosed diabetes or prediabetes and who already have 5) ___ of kidney damage and/or reduced kidney function. Such patients would be at high risk for worsening kidney disease and diabetes, and for the poor outcomes associated with both conditions – including 6) ___ disease and death. Diabetes is the most important risk factor for kidney disease, but the new results suggest that harmful effects on the kidneys may be occurring even before diabetes is diagnosed. Persons at 7) ___ for diabetes and their health care providers should be aware that earlier screening for both diabetes and kidney disease may be warranted. Earlier screening would allow for appropriate, timely medical care to prevent further progression and poor outcomes. Although the study shows an association, it cannot determine whether the development of CKD followed the development of diabetes, or whether CKD was actually caused by diabetes.
ANSWERS: 1) diabetes; 2) screening; 3) “borderline” 4) diagnosis; 5) signs; 6) cardiovascular; 7) risk
Hans Adolf Krebs – 1900-1981
Sir Hans Adolf Krebs was a German Jewish born British physician and biochemist. Krebs is best known for his identification of two important metabolic cycles: the urea cycle and the citric acid cycle. The latter, the key sequence of metabolic chemical reactions that produces energy in cells, is also known as the Krebs cycle and earned him a Nobel Prize in 1953. Krebs was born in Hildesheim, Germany, to Georg Krebs, an ear, nose, and throat surgeon, and Alma Davidson . He went to school in Hildesheim and studied medicine at the University of Goettingen and at the University of Freiburg from 1918-1923. He earned his Ph.D. at the University of Hamburg in 1925. He then studied chemistry in Berlin for one year, where he later became an assistant of Otto Warburg at the Kaiser Wilhelm Institute for Biology until 1930. Krebs joined the German army in 1932, and was appointed to the 13th mechanized infantry division in spite of his Jewish faith. Krebs returned to clinical medicine at the municipal hospital of Altona and then at the medical clinic of the University of Freiburg, where he conducted research and discovered the urea cycle. Because he was Jewish, Krebs was barred from practicing medicine in Germany and he emigrated to England in 1933. There he was invited to Cambridge, where he worked in the biochemistry department under Sir Frederick Gowland Hopkins (1861-1947). Krebs became professor of biochemistry at the University of Sheffield in 1945. Krebs’s area of interest was intermediary metabolism. He identified the urea cycle in 1932, and the citric acid cycle in 1937 at the University of Sheffield. He moved to Oxford as Professor of Biochemistry in 1954 and after his retirement continued work at the Radcliffe Infirmary, Oxford until his death. In 1953 he received the Nobel Prize in Physiology for his discovery of the citric acid cycle and was knighted in 1958. In short, the Krebs cycle constitutes the discovery of the major source of energy in all living organisms. Within the Krebs cycle, energy in the form of ATP is usually derived from the breakdown of glucose, although fats and proteins can also be utilized as energy sources. Since glucose can pass through cell membranes, it transports energy from one part of the body to another. The Krebs cycle affects all types of life and is, as such, the metabolic pathway within the cells. This pathway chemically converts carbohydrates, fats, and proteins into carbon dioxide, and converts water into serviceable energy. The Krebs cycle is involved in the second of three major stages every living cell must undergo in order to produce energy, which it needs in order to survive. The enzymes that cause each step of the process to occur are all located in the cell’s “power plant.“ In animals, this is the mitochondria; in plants, it is the chloroplasts; and in microorganisms, it can be found in the cell membrane. The Krebs cycle is also known as the citric acid cycle, because citric acid is the very first product generated by this sequence of chemical conversions.