Medical News – Health News

Diabetes Raises Risk For Post-Surgical Mortality In Cancer Patients

Undergoing surgical cancer treatment holds greater risk for people who also have diabetes than it does for people who just have cancer, according to a study being published this month in Diabetes Care.

The study, conducted by researchers at Johns Hopkins University, found that people who have both diabetes and cancer are 50 percent more likely to die following surgery than people who don’t have diabetes.

“We already know that diabetes appears to increase the risk for some cancers,” said Dr. Hsin-Chieh Yeh, one of the lead researchers in the study. “This study shows that having pre-existing diabetes also increases the chance of postoperative mortality in newly diagnosed cancer patients. Although we don’t yet know the specific mechanism in cancer patients, diabetes has been shown to increase the risk of infection and cardiovascular and renal complications after surgery in the general population.”

The study, a meta-analysis, showed postoperative mortality was higher across a range of cancer surgeries and types of cancer, particularly in cancers of the colon and esophagus. The researchers concluded that further research was called for into whether improvements in perioperative diabetes care could reduce the excess risk in mortality.

“Care of diabetes before, during and after surgery is very important,” Dr. Yeh said. “It should be part of the preoperative discussion.”

Diabetes Care, published by the American Diabetes Association, is the leading peer-reviewed journal of clinical research into one of the nation’s leading causes of death by disease. Diabetes also is a leading cause of heart disease and stroke, as well as the leading cause of adult blindness, kidney failure, and non-traumatic amputations.

Self-Powered Nanosensors

By combining a new generation of piezoelectric nanogenerators with two types of nanowire sensors, researchers have created what are believed to be the first self-powered nanometer-scale sensing devices that draw power from the conversion of mechanical energy. The new devices can measure the pH of liquids or detect the presence of ultraviolet light using electrical current produced from mechanical energy in the environment.

Based on arrays containing as many as 20,000 zinc oxide nanowires in each nanogenerator, the devices can produce up to 1.2 volts of output voltage, and are fabricated with a chemical process designed to facilitate low-cost manufacture on flexible substrates. Tests done with nearly one thousand nanogenerators – which have no mechanical moving parts – showed that they can be operated over time without loss of generating capacity.

Details of the improved nanogenerator and self-powered nanosensors were scheduled to be reported March 28 in the journal Nature Nanotechnology. The research was supported by the National Science Foundation, the Defense Advanced Research Projects Agency, and the U.S. Department of Energy.

“We have demonstrated a robust way to harvest energy and use it for powering nanometer-scale sensors,” said Zhong Lin Wang, a Regents professor in the School of Materials Science and Engineering at the Georgia Institute of Technology. “We now have a technology roadmap for scaling these nanogenerators up to make truly practical applications.”

For the past five years, Wang’s research team has been developing nanoscale generators that use the piezoelectric effect – which produces electrical charges when wires made from zinc oxide are subjected to strain. The strain can be produced by simply flexing the wires, and current from many wires can be constructively combined to power small devices. The research effort has recently focused on increasing the amount of current and voltage generated and on making the devices more robust.

In the paper, Wang and collaborators report on a new configuration for the nanowires that embeds both ends of the tiny structures in a polymer substrate. The wires can then generate current as they are compressed in a flexible nanogenerator enclosure, eliminating the contact with a metallic electrode that was required in earlier devices. Because the generators are completely enclosed, they can be used in a variety of environments.

“We can now grow the wires chemically on substrates that are foldable and flexible and the processing can now be done at substrate temperatures of less than 100 degrees Celsius – about the temperature of coffee,” explained Wang. “That will allow lower cost fabrication and growth on just about any substrate.”

The nanogenerators are produced using a multi-step process that includes fabrication of electrodes that provide both Ohmic and Shottky contacts for the nanowires. The arrays can be grown both vertically and laterally. To maximize current and voltage, the growth and assembly requires alignment of crystalline growth, as well as the synchronization of charging and discharging cycles.

Production of vertical nanogenerators begins with growing zinc oxide nanowires on a gold-coated surface using a wet chemical method. A layer of polymethyl-methacrylate is then spun-coated onto the nanowires, covering them from top to bottom. Oxygen plasma etching is then performed, leaving clean tips on which a piece of silicon wafer coated with platinum is placed. The coated silicon provides a Shottky barrier, which is essential for maintaining electrical current flow.

The alternating current output of the nanogenerators depends on the amount of strain applied. “At a strain rate of less than two percent per second, we can produce output voltage of 1.2 volts,” said Wang. “The power output is matched with the external load.”

Lateral nanogenerators integrating 700 rows of zinc oxide nanowires produced a peak voltage of 1.26 volts at a strain of 0.19 percent. In a separate nanogenerator, vertical integration of three layers of zinc oxide nanowire arrays produced a peak power density of 2.7 milliwatts per cubic centimeter.

Wang’s team has so far produced two tiny sensors that are based on zinc oxide nanowires and powered by the nanogenerators. By measuring the amplitude of voltage changes across the device when exposed to different liquids, the pH sensor can measure the acidity of liquids. An ultraviolet nanosensor depends on similar voltage changes to detect when it is struck by ultraviolet light.

In addition to Wang, the team authoring the paper included Sheng Xu, Yong Qin, Chen Xu, Yaguang Wei, and Rusen Wang, all from Georgia Tech’s School of Materials Science and Engineering.

The new generator and nanoscale sensors open new possibilities for very small sensing devices that can operate without batteries, powered by mechanical energy harvested from the environment. Energy sources could include the motion of tides, sonic waves, mechanical vibration, the flapping of a flag in the wind, pressure from shoes of a hiker or the movement of clothing.

“Building devices that are small isn’t sufficient,” Wang noted. “We must also be able to power them in a sustainable way that allows them to be mobile. Using our new nanogenerator, we can put these devices into the environment where they can work independently and sustainably without requiring a battery.”

Compulsive Eating That Leads To Obesity Has Similar Biology To Drug Addiction

US researchers working with rats have shown for the first time that the compulsion to overeat that leads to obesity has the same biological mechanism as seen in addiction to drugs like cocaine and heroin abuse: it affects the brain’s pleasure circuitry in a similar way.

You can read about the study, conducted by Scripps Research Associate Professor Paul J Kenny and graduate student Paul M Johnson from The Scripps Research Institute in Jupiter, Florida, in the 28 March advanced online issue of Nature Neuroscience.

According to a press statement from The Scripps Research Institute on Sunday, the study appears to confirm what many obesity patients have been saying for years: like drug addiction, binging on junk food is very hard to stop.

Kenny and Johnson show that as pleasure centers in the brain become less responsive, rats quickly develop compulsive overeating habits, eating increasing amounts of high-calorie, high-fat foods until they become obese.

This is the same progressively deteriorating chemical balance in reward brain circuits seen in rats that overconsume cocaine or heroin that is thought to lie behind the development of compulsive drug use.

Kenny told the press that the study confirms that junk food can become “addictive”. It explains what happens in the brains of the animals when they can easily get hold of high-calorie, high-fat food, he said.

“It presents the most thorough and compelling evidence that drug addiction and obesity are based on the same underlying neurobiological mechanisms,” added Kenny, explaining that:

“In the study, the animals completely lost control over their eating behavior, the primary hallmark of addiction.”

One of the tests of addictive behaviour is to train lab animals to anticipate an electric shock. At first the animals receive the mild shocks at the same time as a light coming on, eventually they learn to anticipate the shock when they see the light and they avoid doing the thing that then triggers the shock.

In this case, the rats that had become “addicted” to junk food ignored the light and continued to binge, highlighting how motivated they were, said Kenny.

For the junk food they used in the study, Kenny and Johnson bought foods people love to eat: cheesecake, bacon, sausage, Ding-Dongs (a flat-shaped chocolate cake popular in the US).

“The stuff that you enjoy, but you really shouldn’t eat too often,” Kenny said, as reported by Reuters.

They also bought healthy foods and put the rats into three groups: (1) a balanced healthy diet group, (2) a healthy diet group with access to high-calorie “junk” food for one hour a day, and (3) a group that was fed healthy food but also had unlimited access to the high-calorie “junk” food.

Kenny said the third group quickly showed a preference for the junk food, ate it all day long and quickly became obese.

“They always went for the worst types of food,” said Kenny.

“As a result, they took in twice the calories as the control rats,” he added, explaining that when they removed the junk food and tried to feed them a healthy diet, “the salad bar option”, they just refused to eat.

“The change in their diet preference was so great that they basically starved themselves for two weeks after they were cut off from junk food,” said Kenny.

“It was the animals that showed the “crash” in brain reward circuitries that had the most profound shift in food preference to the palatable, unhealthy diet. These same rats were also those that kept on eating even when they anticipated being shocked,” he added.

What happens in addiction is “lethally simple”, said Kenny, “the body adapts remarkably well to change — and that’s the problem”.

“When the animal overstimulates its brain pleasure centers with highly palatable food, the systems adapt by decreasing their activity. However, now the animal requires constant stimulation from palatable food to avoid entering a persistent state of negative reward,” he explained.

After this first stage, where they showed the obese rats had developed clear addiction-like food seeking behavior, Kenny and Johnson then examined the underlying biological mechanisms that might explain the change.

They were particularly interested in the dopamine D2 receptor in the brain, a receptor that is already known to play a role in vulnerability to drug addiction and obesity. The receptor responds to dopamine, a chemical that the brain releases in response to pleasurable experiences like food, drugs and sex.

For example, in cocaine abuse, the drug blocks the retrieval of dopamine, causing it to flood the brain and overstimulate the receptors. Eventually this leads to physical changes in the brain and how it responds to the drug.

Kenny and Johnson have shown this to be the same in addiction to junk food.

Kenny said their findings confirm what they and many others had long suspected:

“Overconsumption of highly pleasurable food triggers addiction-like neuroadaptive responses in brain reward circuitries, driving the development of compulsive eating.” he said.

They also found that the levels of the D2 dopamine receptors were significantly lower in the brains of the obese animals, similar to what has been reported in human drug addicts.

And when they used a specialized virus to knock down the receptor (“lentivirus-mediated knockdown”) the addiction-like eating accelerated dramatically.

The addiction-like eating started almost as soon as they knocked down the receptors, said Kenny.

“The very next day after we provided access to the palatable food, their brains changed into a state that was consistent with an animal that had been overeating for several weeks,” he added.

Kenny and Johnson concluded that:

“These data demonstrate that overconsumption of palatable food triggers addiction-like neuroadaptive responses in brain reward circuits and drives the development of compulsive eating. Common hedonic mechanisms may therefore underlie obesity and drug addiction.”

Grants from the Bank of America Fellowship, The Margaret Q. Landenberger Research Foundation and the National Institutes of Health paid for the study.

“Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats.”
Paul M Johnson and Paul J Kenny.
Nature Neuroscience, Published online 28 March 2010.
DOI:10.1038/nn.2519

AARP CEO A. Barry Rand released this statement following today’s passage of the Health Care and Education Affordability Reconciliation Act of 2010 by the House of Representatives:

“We applaud the House for passing this critical legislation to make our health care system work for more Americans. Both chambers have now passed a bill that will make health care more affordable for American families, strictly limit insurance companies from denying affordable coverage because of age or medical history, and protect and strengthen the benefits promised to people in Medicare.

“But the job is not finished.

“The Senate must act-and act quickly. The changes to the Senate bill passed by the House today are crucial to all older Americans and their families. Most importantly, this final package closes the dreaded gap in Medicare drug coverage known as the ‘doughnut hole.’ For too long, seniors in Medicare have struggled with the rising cost of prescription drugs. The Senate must seize this opportunity to ensure that no one in Medicare is ever again forced to split pills in half, or go without the medicines they need.

“We will not stop fighting to ensure that our members and all older Americans have the affordable health care they need. We look forward to working with the Senate in the coming days to finish this truly historic task.”

In response to the U.S. House vote to pass the U.S. Senate health insurance reform bill, Twila Brase, RN, PHN, president of Citizens’ Council on Health Care, releases the following statement:

“President Obama, Speaker Pelosi, and Senator Reid hope the public will go away in defeat. No such thing will occur. This is not the end of the battle over health care. This is just the end of the beginning. The American people will not stand by while President Obama tries to destroy America and its foundation of freedom.”

For an as yet unknown reason, cancer radiotherapy can increase the risk of cardiovascular disease later in life, a problem that is growing as more and more people survive their cancer diagnosis. New research from Karolinska Institutet now suggests that sustained inflammation induced by post-radiotherapy changes in the gene expression in the arteries could be the cause.

Epidemiological studies have shown that a course of radiotherapy increases the risk of cardiovascular disease in the same part of the body; for example, myocardial infarction after left-side breast cancer treatment, or stroke after the treatment of head and neck or brain tumours. Scientists know very little, however, about the biological causes of these serious side-effects, which often do not appear until many years following treatment.

“Studies have been hampered by the fact that the disease process is so slow,” says Martin Halle, researcher at Karolinska Institutet. “Cell studies and animal studies are best suited to the more immediate effects, and studies on human subjects have been ruled out for ethical reasons.”

By studying autografts that have been carried out after cancer, Martin Halle and colleagues have now for the first time managed to study the long-term effects of radiotherapy on human blood vessels. This type of autograft involves the transplantation of skin, muscle or bone tissue from one part of a patient’s body to reconstruct defects that arise after the removal of a tumour in another, often irradiated, part. By harvesting biopsies from previously irradiated branches of the carotid arteries and non-irradiated arteries from grafts, the researchers have been able to compare the difference in global gene expression between irradiated and non-irradiated arteries from the same patient at the same time.

They found that the irradiated arteries showed signs of chronic inflammation and an increase in activity of Nuclear Factor- kappaB (NF-kappaB), a transcription factor known for playing a key part in the development of atherosclerosis. The greater inflammatory gene expression was visible for several years after irradiation, and might, the researchers believe, explain why cancer patients can suffer cardiovascular disease many years after radiotherapy.

“Hopefully, these findings will one day help medicine to mitigate the side effects by administering radiotherapy in combination with an anti-inflammatory treatment,” says Dr Halle. The importance of the results is underscored by the publication of an explanatory commentary in the journal’s editorial.

“Sustained Inflammation Due to NF-Kappa B Activation in Irradiated Human Arteries”
Halle M, Gabrielsen A, Paulsson-Berne G, Gahm C, Agardh HE, Farnebo F, Tornvall P
Journal of the American College of Cardiology, 23 March 2010; 55:1227-1236, doi:10.1016/j.jacc.2009.10.047

A team of US and German scientists has found that we differ from each more because of the way our genes are regulated, such as which are switched on and which are switched off, than because of the differences among the genes themselves: furthermore there appears to be as much variation among humans as between humans and chimpanzees when it comes to gene regulation.

Researchers from the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, and Yale and Stanford Universities in the USA wrote about their findings in a paper that was published online in Science on 18 March.

After the human genome was sequenced and published nearly ten years ago, scientists have been searching for the genes that make individual humans unique.

The process is now so technologically advanced that scientists can obtain the genome of several people in a fraction of the time and cost it took for the first human genome, and we are now beginning to understand a lot more about how genes work.

But as we get to know more about how genes and DNA works, we realize that perhaps the picture is more complex than we imagined.

The team on this study, led by Jan Korbel at EMBL and Michael Snyder initially at Yale and now in Stanford, wrote that it is becoming increasingly apparent that:

“Differences in gene expression may play a major role in speciation and phenotypic diversity.”

So they decided to investigate genome-wide differences in a key component of gene expression called transcription factor (TF) binding.

While each of us inherits genes from our biological parents, those genes are effectively “switched off” in our DNA until they are transcribed into mRNA, the process that switches them on and thereby allows them to express control over the production of proteins.

However, the transcription of genes from DNA to mRNA is itself regulated by TF proteins, and a key part of how they work is they have special DNA-binding domains (DBDs) that attach to areas of DNA that lie next to the genes they are transcribing.

In a very crude sense it is like a TF protein has to “dock” next to the gene before it can start transcribing it. These “docking” area sections of DNA are not like genes: they don’t hold instructions for coding proteins, but they can vary from person to person and in this way influence whether genes are switched on or off.

As Korbel explained to the media:

“We developed a new approach which enabled us to identify cases where a protein’s ability to turn a gene on or off can be affected by interactions with another protein anchored to a nearby area of the genome.”

“With it, we can begin to understand where such interactions happen, without having to study every single regulatory protein out there,” said Korbel.

The team found that up to a quarter of all human genes are regulated differently in different people: this is more than the genetic variation among genes themselves.

Thus even if different people have exactly the same copy of a gene, for instance ORMDL3, thought to influence the development of asthma in children, the way their cells regulate the gene can vary among them.

They discovered that many of the differences are due to how TF proteins behave because of DNA sequencing differences in the “docking” areas between the genes: some of the differences comprising only a single-letter change in the DNA code.

They also found variations they could not explain, and proposed these might be used by TF proteins acting together in some way.

Finally, they compared the information they obtained on humans with that of a chimpanzee, and found that gene regulation seems to vary almost as much among humans as it does between humans and chimpanzees.

They concluded that:

“Our results indicate that many differences in individuals and species occur at the level of TF binding and provide insight into the genetic events responsible for these differences.”

Snyder said these discoveries may change the way we think about ourselves and diseases:

“As well as looking for disease genes, we could start looking at how genes are regulated, and how individual variations in gene regulation could affect patients’ reactions.”

“Variation in Transcription Factor Binding Among Humans.”
Kasowski M, Grubert F, Heffelfinger C, Hariharan M, Asabere A, Waszak SM, Habegger L, Rozowsky J, Shi M, Urban AE, Hong MY, Karczewski KJ, Huber W, Weissman SM, Gerstein MB, Korbel JO, Snyder M.
Science, 18 March 2010 (Epub ahead of print).
DOI: 10.1126/science.1183621

Scientists from a leading European medical university suggest that the sustained inflammation in the arteries brought on by changes in gene expression as a result of cancer radiotherapy could be the reason why so many people who survive their cancer diagnosis go on to develop cardiovascular disease later in life.

You can read about the study by the team from Sweden’s Karolinska Institutet online in the 23 March issue of the Journal of the American College of Cardiology.

Previous studies have found that cancer radiotherapy increases the risk of cardiovascular disease in the same part of the body. For instance, having radiotherapy to treat breast cancer in the left breast increases the risk of heart attack, and having radiotherapy to treat head and neck tumors increases the risk of a stroke.

However, we know very little about the underlying biology of these serious radiotherapy side-effects, which in most cases don’t develop until many years later.

Dr Martin Halle, a researcher in the Department of Medicine, Center for Molecular Medicine at the Karolinska Institutet in Stockholm, told the press that it has been difficult to do research in this area because the disease takes so long to develop:

“Cell studies and animal studies are best suited to the more immediate effects, and studies on human subjects have been ruled out for ethical reasons,” he explained.

However, the researchers found a way to examine the long-term effects of radiotherapy on human blood vessels by studying autografts: where skin, muscle or bone has been transplanted from one part of the body to another in order to reconstruct defects left after a tumor is removed.

Radiotherapy often follows tumor removal (before the graft takes place), so offers the opportunity to recover tissue at the irradiated site from arteries that are in situ before radiotherapy and also from tissue transplanted there afterwards.

Thus Halle and colleagues were able to compare the differences in global gene expression in biopsies taken from the previously irradiated branches of the carotid arteries with biopsies of non-irradiated arteries from grafts from the same patient at the same time.

They found that the arteries that had been exposed to radiotherapy showed signs of chronic inflammation and increased activity of a transcription factor (a protein important for gene expression) that is central to the development of atherosclerosis. The transcription factor is called Nuclear Factor-kappaB (NF-kappaB).

The increased activity in inflammatory gene expression was present several years after the radiotherapy treatment, leading the researchers to suspect that this is why the cardiovascular disease only develops a long time after treatment.

Halle said they hoped these findings will help develop ways to reduce the long term risk of radiotherapy: perhaps by combining it with anti-inflammatory treatment.

“Sustained Inflammation Due to NF-Kappa B Activation in Irradiated Human Arteries.”
Halle M, Gabrielsen A, Paulsson-Berne G, Gahm C, Agardh HE, Farnebo F, Tornvall P.
Journal of the American College of Cardiology, 23 March 2010; 55:1227-1236.
DOI:10.1016/j.jacc.2009.10.047

A study of over 80,000 American live kidney donors found they were likely to live just as long as people who have two healthy kidneys and that the procedure carries very little medical risk.

You can read about the landmark study by lead author and transplant surgeon Dr Dorry L Segev, from the Johns Hopkins University School of Medicine, Baltimore, Maryland, and colleagues, online in the 10 March issue of JAMA, Journal of the American Medical Association.

The researchers said the findings confirm what many doctors have believed for a long time, as Segev, who is also associate professor of surgery at the Johns Hopkins University School of Medicine, told the media:

“Donating a kidney is safe. Live donors start healthy and it’s the highest priority of the surgeon and the entire transplant community to make sure they stay healthy,” he said, adding that these findings show “we have succeeded”.

“While there are never any guarantees with surgery, donating a kidney is safer than undergoing almost any other operation,” said Segev.

There is a profound shortage of transplant organs in the US, where thousands of patients die every year waiting for a new kidney. There is an increasing reliance on live donors such as family members, friends, and even altruistic donors. Live donor transplants also tend to survive longer than those from cadavers.

For the study, Segev and colleagues examined records in a national registry of over 80,000 live kidney donors registered between the beginning of April 1994 to end of March 2009. It is thought to be the first study to use national data: previously published studies of live donors have used data from individual transplant centers.

The researchers found that over that period of 15 years:
There were 25 deaths among 80,347 donors in the first 90 days after undergoing donation surgery.

This translated to a risk of surgery mortality of 3.1 per 10,000 cases.

This risk was found to be slightly higher (but still very small) in some subgroups where there is typically a higher risk from surgery already, ie men (5.1 deaths per 10,000 cases) and African-Americans (7.6 deaths per 10,000 cases).

The risk remained low even as the number of live donor kidney transplants nearly doubled in the US from just over 3,000 in 1994 to nearly 6,000 in 2008.
Segev said these figures show that the risk of dying from kidney donation (3.1 per 10,000) is about one sixth of the risk of dying from having one’s gallbladder removed (18 per 10,000).

And if you compare it to the risk of dying from having a kidney removed because of cancer or another medical reason, the contrast is even greater: for the latter the risk is about 260 per 10,000 cases, nearly 100 times the risk of dying from donating a kidney.

The researchers also compared the data from the kidney donors to a matched cohort of over 9,000 people taken from the third National Health and Nutrition Examination Survey (NHANES III), after excluding any persons who would not qualify for kidney donation.

The authors wrote that this comparison showed that:

“Long term risk of death was no higher for live donors than for age- and comorbidity-matched NHANES III participants for all patients and also stratified by age, sex, and race.”

Segev said the study shows that:

“Whatever happens when people donate kidneys, on average, it doesn’t affect the rest of their lives.”

“That never been shown before in a study of this size and scope,” he added.

The authors also pointed out that over the 15 years of the study much has changed in the live donor kidney transplant procedure: it has moved from being a mostly open-abdomen to a minimally invasive laparoscopic operation that leaves tiny scars and has shorter recovery time.

“Perioperative Mortality and Long-term Survival Following Live Kidney Donation.”
Dorry L. Segev; Abimereki D. Muzaale; Brian S. Caffo; Shruti H. Mehta; Andrew L. Singer; Sarah E. Taranto; Maureen A. McBride; Robert A. Montgomery
JAMA, Published online 10 March 2010; Vol. 303, No. 10, pp 959 – 966.

Heralding what they hope is a new era of personalized genomic medicine, experts in the US have identified the gene behind a patient’s inherited neurological disorder, in this case a form of Charcot-Marie-Tooth disease, by sequencing his complete genome.

Details of the quest are published online in the 10 March issue of the New England Journal of Medicine. Among the authors is the patient, Dr James Lupski, vice chair of molecular and human genetics at Baylor College of Medicine (BCM) in Houston, Texas, and Dr Richard Gibbs, director of the Human Genome Sequencing Center at BCM, where the sequencing was performed.

Charcot-Marie-Tooth (CMT) disease (which gets its name from the three people who first identified it in 1886: Jean-Martin Charcot and Pierre Marie in Paris, France, and Howard Henry Tooth in Cambridge, England) is a not uncommon inherited neurological disorder that affects the nerves in a person’s limbs, hands and feet (the peripheral nerves).

According to the National Institute of Neurological Disorders and Stroke, CMT, which is also known as hereditary motor and sensory neuropathy (HMSN) or peroneal muscular atrophy, affects around 1 in 2,500 in the US.

Lupski told the press that he has known for 40 years that he has a “genetically-recessive disease”.

He and his colleagues have been working on tracking down the genetic causes of CMT for decades. In 1991 they published results of a study where they identified the first duplication on a chromosome that gave rise to CMT. Since then 40 other genetic mutations and changes have been identified as leading to CMT, but none of these explained the form of CMT that affects Lupski and some of his siblings.

The quest came to an end earlier this year when the team at BCM’s Human Genome Sequencing Center sequenced his entire genome and concluded that in his case the culprit is a gene called SH3TC2. Lupski has inherited two mutant forms of the gene, one from each parent.

“I have the disease and I have two mutant genes,” said Lupski.

Neither of Lupski’s parents had the disease, but four of their children inherited both mutant copies of the gene and inherited the disease.

The BCM researchers are excited because this is the first time they have tried to identify a disease gene by sequencing a patient’s entire genome.

“It demonstrates that the technology is robust enough,” said Lupski, “We can start to use this technology to interpret the clinical information in the context of the sequence – of the hand of cards you have been dealt. Isn’t that the goal or dream of personalized genomic medicine?”

The researchers also discovered that a person who carries only one of the recessive mutations is susceptible to carpal tunnel syndrome, a painful progressive condition caused by compression of a key nerve in the wrist and that usually affects people who perform repetitive motions.

Lupski said it makes you wonder how often it occurs that carrying only one gene for a recessive disease leaves a person susceptible for complex traits.

“Will we be able to look at some alleles (gene copies) like this to see what you might be susceptible to?”

Lupski’s is not the first genome to be sequenced, but so far there have been less than 10 reported cases, most of them intellectual exercises. In fact in 2007, Gibbs was one of the scientists who presented 1953 Nobel Laureate James Watson, co-discoverer of the DNA double helix and developer of the Human Genome Project, his full genome in a ceremony at BCM.

Lupski said decoding a genome is not an easy task and “one is struck with awe at the inability to interpret a lot of what we see”.

“Currently, we only know the function of 5 percent to 10 percent of the approximately 25,000 genes in our genome that it takes to make a human being. I think at least what this paper tells us is that the data are robust enough that we can start to use it to interpret clinical information in the context of the genome sequence,” he added.

To find a specific disease-causing mutation of a gene, the scientist must not only understand its sequence, but also the different ways it can change (the nucleotide switches, deleted or duplicated genetic material). And added to this is another layer of complexity: mutations in different genes can result in similar diseases.

For the study, Gibbs and colleagues used a “whole genome shotgun” approach, where they took Lupski’s genome, broke it up into small fragments called “snips” (short for SNPs, single-nucleotide polymorphisms) and then cloned them. They then isolated and sequenced the clones and used a computer algorithm to reassemble the genome.

They identified all the function variants in genes that were likely to be linked to CMT.

In one allele (member of the gene pair) for SH3TC2, they found what they called a “nonsense” mutation that results in a premature stop to a protein-building instruction. This mutation has been seen before in CMT patients of particular ethnic groups. They also identified what they descirbed as a “missense” mutation in the other allele that results in the production of the wrong amino acid (so the associated protein can’t do its job properly inside cells).

The first mutation was found in one parent and two siblings who did not have CMT, and the other was found in the other parent and one grandparent, who also did not have the disease. Only siblings who inherited both genes had this particular form of CMT, including Lupski.

There are other ways of sequencing genomes which can for example look for particular variations, but in this case, because of the potential of different kinds of changes in different genes, some inherited recessively and some dominantly, the “whole shotgun” approach was thought to be a better option.

The authors wrote that experts struggling to understand diseases with these kind of genetic properties should also consider trying this approach:

“Clinical and genetics experts struggling with poorly understood high-penetrance genetic diseases must now seriously consider this approach for illuminating the molecular etiology of these cases, and ultimately providing better patient management for families living with such diseases,” they wrote.

Lupski said the study heralds a new era of clinical sequencing whereby a patient will one day be able to have his or her genome analysed in order to determine the best treatment for even quite common disorders.

“If you have hypertension, can we use your genome to figure out a better treatment for you? It will take a lot of time. We don’t know what 90 percent of the genes in the genome do,” said Lupski, explaining that his own genome contains 3.5 million differences to the reference genome that was sequenced in the Human Genome Project:

“I expect that to hold true for others. Everyone is truly unique,” said Lupski.

The study was funded by the National Human Genome Research Institute and the National Institute of Neurological Disorders and Stroke.

“Whole-Genome Sequencing in a Patient with Charcot-Marie-Tooth Neuropathy.”
Lupski, James R., Reid, Jeffrey G., Gonzaga-Jauregui, Claudia, Rio Deiros, David, Chen, David C.Y., Nazareth, Lynne, Bainbridge, Matthew, Dinh, Huyen, Jing, Chyn, Wheeler, David A., McGuire, Amy L., Zhang, Feng, Stankiewicz, Pawel, Halperin, John J., Yang, Chengyong, Gehman, Curtis, Guo, Danwei, Irikat, Rola K., Tom, Warren, Fantin, Nick J., Muzny, Donna M., Gibbs, Richard A.
N Engl J Med, Published online 10 March 2010.
DOI: 10.1056/NEJMoa0908094