Day: 05/02/2017

Gene-editing technology has successfully targeted cancer’s “command centre”

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The CRISPR gene-editing tool has already shown a lot of potential for helping doctors treat the most stubborn diseases, and now scientists have used it to target the “command centre” of cancerous tumours, stopping their growth and boosting survival rates in mice.

In this new study, CRISPR was aimed directly at fusion genes – formed when two genes combine to form a hybrid, resulting in abnormal proteins which often cause cancer or help it to grow.

 

These fusion genes also have a unique DNA fingerprint, which researchers from the University of Pittsburgh were able to use to hunt down and modify them. Specially engineered viruses were then applied to replace the fusion genes with cancer-killing ones.

“This is the first time that gene-editing has been used to specifically target cancer fusion genes,” says lead researcher Jian-Hua Luo. ” It is really exciting because it lays the groundwork for what could become a totally new approach to treating cancer.”

CRISPR lets scientists effectively cut and paste the DNA in cells to fix problems or make improvements, and it has already been used to boost immune cells in the fight against certain types of cancers.

In this case, the researchers went for one of the causes of growth, demonstrating a new way to tackle the disease.

A type of fusion gene called MAN2A1-FER was targeted – previously identified by the same team as being present in certain types of aggressive cancer in the prostate, liver, lungs, and ovaries.

“Other types of cancer treatments target the foot soldiers of the army,” explains Luo. “Our approach is to target the command centre, so there is no chance for the enemy’s soldiers to regroup in the battlefield for a comeback.”

 Once modified, the CRISPR-edited, cancer-killing genes were injected into mice carrying human prostate and liver cancer cells. The tumours reduced in size by up to 30 percent, no secondary growths were noted, and all the mice survived until the end of the eight-week test.

In contrast, in a control group of mice that didn’t receive the treatment, the cancer tumours increased nearly 40-fold in size, metastasis or cancer spread was common, and all the animals died before the study ended.

Even better, because fusion genes only occur in cancerous cells, healthy cells are left alone.

This could give the new technique a big advantage over chemotherapy, which has numerous unwanted side effects on healthy parts of the body.

Tackling the fusion genes didn’t kill off the cancer altogether, but there is hope a refined process could make that a possibility for the future.

More research is also needed to see if this can work as well in humans as it does in mice, but as these were human cancers xenografted to mice, the work so far is much more promising than a traditional mouse study.

“[T]he genome approach described here should in principle be applicable to most human cancers carrying fusion genes,” the researchers conclude. paper.

Source:Nature Biotechnology.

Tensions flare as scientists go public with plan to build synthetic human DNA.

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One of the greatest ethical debates in science – manipulating the fundamental building blocks of life – is set to heat up once more.

According to scientists behind an ambitious and controversial plan to write the human genome from the ground up, synthesising DNA and incorporating it into mammalian and even human cells could be as little as four to five years away.

 

Nearly 200 leading researchers in genetics and bioengineering are expected to attend a meeting in New York City next week, to discuss the next stages of what is now called the Genome Project-write (GP-write) plan: a US$100 million venture to research, engineer, and test living systems of model organisms, including the human genome.

Framed as a follow-up to the pioneering Human Genome Project (HGP) – which culminated in 2003 after 13 years of research that mapped the human genetic code – this project is billed as the logical next step, where scientists will learn how to cost-effectively synthesise plant, animal, and eventually human DNA.

“HGP allowed us to read the genome, but we still don’t completely understand it,” GP-write coordinator Nancy J. Kelley told Alex Ossola at CNBC.

While those involved are eager to portray the project as an open, international collaboration designed to further our understandings of genome science, GP-write provoked considerable controversy after its first large meet-up a year ago was conducted virtually in secret, with a select group of invite-only experts holding talks behind closed doors.

“Given that human genome synthesis is a technology that can completely redefine the core of what now joins all of humanity together as a species, we argue that discussions of making such capacities real … should not take place without open and advance consideration of whether it is morally right to proceed,” medical ethicist Laurie Zoloth from Northwestern University and synthetic biologist Drew Endy of Stanford University wrote at the time for Cosmos Magazine.

Since then, the researchers behind the initiative have been more candid, announcing details of the project in a paper in Science, as well as releasing a white paper outlining GP-write’s timeline and goals.

One of GP-write’s lead scientists – geneticist and biochemist Jef Boeke from NYU Langone Medical Centre – says the approach has always been to consult the scientific community at large, to help frame and steer the research as it develops.

“I think articulation of our plan not to start right off synthesising a full human genome tomorrow was helpful. We have a four- to five-year period where there can be plenty of time for debate about the wisdom of that, whether resources should be put in that direction or in another,” he told CNBC.

“Whenever it’s human, everyone has an opinion and wants their voice to be heard. We want to hear what people have to say.”

But while that conversation is taking place, the science is developing regardless.

In March, Boeke shared details on a related project he’s involved with, where he oversees hundreds of scientists who are working together to synthesise an artificial yeast genome, which is expected to be complete by the end of 2017.

There might be a large gap between successfully synthesising yeast DNA and creating artificial human DNA from scratch. But the overall goal is to figure out how to synthesise comparatively simple genetic codes (such as microbial and plant DNA), before moving on to the ultimate prize.

“If you do that, you gain a much deeper understanding of how a complicated apparatus goes,” says Boeke. “Really, a synthetic genome is an engine for learning new information.”

Under its new organisational structure, GP-write is the parent project, which encompasses the core area of Human Genome Project-write (HGP-write), focussed on synthesising human genomes in whole or in part.

In addition to synthesising plant, animal, and human DNA, the primary goal of the project is to lower the cost of engineering genomes.

At present, it’s estimated to cost about 10 US cents to synthesise every base pair of nucleobase molecules that make up our DNA – and given humans have about 3 billion of these pairs, that makes for some pretty prohibitively expensive synthesis.

The plan is to reduce this cost by more than 1,000-fold within 10 years.

If that happens, the lower expense involved in synthesising DNA could unlock all kinds of new potential medical treatments – targeting illnesses such as cancer and genetic diseases, helping the body to accept organ transplants, and learning more about immunity to viruses.

Of course, before that can happen, GP-write’s organisers need to raise an estimated US$100 million in funding – which will be another of the drivers of next week’s get together.

It’s an incredibly exciting undertaking, although there’s bound to be more controversy as GP-write marches ahead.

Blood test to spot lung cancer relapse hailed as ‘new hope’

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Scientists screened their blood for circulating tumour DNA - bits of DNA that had "broken off" from a tumour
Scientists screened their blood for circulating tumour DNA – bits of DNA that had “broken off” from a tumour 

Scientists have developed a blood test which spots the relapse of lung cancer in patients, up to a year before the disease can be detected by CT scans and X-rays.

The groundbreaking TRACERx study, funded by Cancer Research UK, identified the cause of relapse of the disease and how it spreads, in a discovery that could lead to earlier treatment for patients.

By analysing tumours from 100 lung cancer patients, researchers at medical research centre Francis Crick Institute found that those containing a higher proportion of “unstable chromosomes” – those which cause genetic chaos and allow the tumour to evolve – were four times more likely to encounter a relapse or die within two years.

 Genetically diverse tumours are harder to treat as they are more likely to spread and become drug-resistant.

In a study using 96 of those 100 patients, scientists screened their blood for circulating tumour DNA – bits of DNA that had “broken off” from a tumour – in order to uncover defects present in the patient’s cancer.

They used this information to analyse blood samples from 24 patients who had undergone surgery, and were able to identify more than 90% of cancer cases likely to return, up to a year before other clinical methods, such as CT scans or an X-ray, could detect the illness.

Lung cancer is the leading cause of cancer death among men and women in the UK, causing more than 20% of cancer deaths, according to Cancer Research UK.

Scientists also compared levels of tumour DNA in patients’ blood before and after post-surgery chemotherapy in the study, which was published in science journal Nature.

 They found that the cancer returned when levels of tumour DNA in the blood were not reduced after the treatment, showing that the tumour had become partially resistant to the chemotherapy.

The findings could pave the way for the development of new drugs to target resistant parts of lung cancer tumours.

Dr Christopher Abbosh, lead author of the study, said: “In the future patients could be offered personalised treatments that target parts of the cancer responsible for relapse following surgery.

“Using circulating tumour DNA, we can identify patients to treat even if they have no clinical signs of disease, and also monitor how well therapies are working.

“This represents new hope for combating lung cancer relapse following surgery, which occurs in up to half of all patients.”

TRACERx is the first of its kind to trace the evolution of the cancer in real time, from diagnosis to its death.

Professor Karen Vousden, Cancer Research UK’s chief scientist, said: “These findings could also help us to identify how lung cancers respond to therapy, building a bigger picture of the disease and potentially pointing the way to developing new treatments and, crucially, saving more lives.”

Source:www.telegraph.co.uk

Cryogenically frozen brains will be ‘woken up’ and transplanted in donor bodies within three years, claims surgeon

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Dr Xiaoping Ren and Professor Sergio Canavero
Dr Xiaoping Ren and Professor Sergio Canavero, who believes a brain will be transplanted in the near future 

People who have had their brains cryogenically frozen could be ‘woken up’ within three years, a pioneering Italian surgeon has claimed.

Professor Sergio Canavero, Director of the Turin Advanced Neuromodulation Group, is aiming to carry out the first human head transplant within 10 months and then wants to begin trials on brain transplants.

If the procedures are successful, he believes that frozen brains could be thawed and inserted into a donor body.

 Hundreds of people who are dying or paralysed have had their bodies or brains cryogenically preserved in the hope that medical science will be able to bring them back to life and cure their conditions.

Although many experts are sceptical that huge organs like the brain can be thawed without damage, Prof Canavero said he believes the first frozen head could soon be resurrected.

Prof Canavero was talking to the German magazine Ooom
Prof Canavero was talking to the German magazine Ooom

Speaking to the German magazine Ooom, he said he planned to awaken patients frozen by the Alcor Life Extension Foundation which is based in Arizona.

“We will try to bring the first of the company’s patients back to life, not in 100 years. As soon as the first human head transplant has taken place, i.e. no later than 2018, we will be able to attempt to reawaken the first frozen head,” said Prof Canavero.

“We are currently planning the world’s first brain transplant, and I consider it realistic that we will be ready in three years at the latest.

“A brain transplant has many advantages. First, there is barely any immune reaction,which means the problem of rejection does not exist.

 “The brain is, in a manner of speaking, a neutral organ. If you transplant a head with vessels, nerves, tendons and muscles, rejection can pose a massive problem. This is not the case with the brain.”
The head transplant gives us the first insight into whether there is an afterlife, a heaven, a hearafter.Professor Sergio Canavero

However Prof Canavero admitted that there could be physical and psychological problems which come with putting a brain in an entirely different body.

“What many be problematic, is that no aspect of your original external body remains the same. Your head is no longer there; your brain is transplanted into an entirely different skull.

“It creates a new situation that will certainly not be easy.”

However British scientists are skeptical about whether frozen organs as complex as the brain could ever be fully restored. When the High Court last year ruled that teenage girl could be cryogenically preserved,experts said the chances of revival were “infinitesimal”.

Clive Coen, Professor of Neuroscience at King’s College London, said: “The advocates of cryogenics are unable to cite any study in which a whole mammalian brain, let alone a whole mammalian body, has been resuscitated after storage in liquid nitrogen.

“Even if reviving that body were possible – it isn’t – all the complicated organs would have been wrecked from the start, and warming them up again would wreck them further.

“Irreversible damage is caused during the process of taking the mammalian brain into sub-zero temperatures. The wishful thinking engendered by cryogenics companies is irresponsible.”

Russian man set for world’s first head transplant

 Prof Canavero is working with a Chinese team of doctors led by Dr Xiaoping Ren, of Harbin Medical Centre who helped perform the first successful hand transplantation in the US. The technology to carry out the world’s first head transplant is expected to be in place by the end of the year, and then the team will then need to find a suitable donor body.
 Although Russian computer scientist Valery Spiridonov, who suffers spinal muscular atrophy, had volunteered to become the first head transplant patient, the team have since said the first trial is likely to be carried out on someone who is Chinese, because the chance of a Chinese donor body will be higher. Prof Canavero said a ‘high number’ of people had volunteered for the transplant.

Last year, the team announced they had successfully carried out a head transplant on a monkey, and released images from the procedure.

Last year scientists claimed to have carried out the first head transplant using a monkey 
Last year scientists claimed to have carried out the first head transplant using a monkey 

Prof Canavero said if the human head transplant works, it could have fundamental implications for human consciousness and even religion.

“In a few months we will sever a body from a head in an umprecedented medical procedure. In this phase, there is no life activity, not in the brain, not anywhere else in the body.

“If we bring this patient back to life we will receive the first real account of what actually happens after death. The head transplant gives us the first insight into whether there is an afterlife, a heaven, a hearafter.

“If we are able to prove that our brain does not create consciousness, religions will be swept away forever. They will no longer be necessary, as humans no longer need to be afraid of death.  We no longer need a Catholic Church, no Judaisim, and no Islam because religions in general will be obsolete.

“It will be a turning point in human history.”

Source:http://www.telegraph.co.uk

 

Generic Drugs: Questions and Answers

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What are generic drugs?

A generic drug is identical — or bioequivalent — to a brand name drug in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use. Although generic drugs are chemically identical to their branded counterparts, they are typically sold at substantial discounts from the branded price. According to the Congressional Budget Office, generic drugs save consumers an estimated $8 to $10 billion a year at retail pharmacies. Even more billions are saved when hospitals use generics.

Generic vs Brand: Same Quality and Performance

Is there a generic equivalent for my brand-name drug?

To find out if there is a generic equivalent for your brand-name drug, use Drugs@FDA, a catalog of FDA-approved drug products, as well as drug labeling.

You can also search for generic equivalents by using the “Electronic Orange Book.” Search by proprietary “brand” name,” then search again by using the active ingredient name. If other manufacturers are listed besides the “brand name” manufacturer when searching by the “active ingredient,” they are the generic product manufacturers.

Since there is a lag time after generic products are approved and they appear in the “Orange Book,” you should also consult the most recent monthly approvals for “First Generics“.

Are generic drugs as effective as brand-name drugs?

Yes. A generic drug is the same as a brand-name drug in dosage, safety, strength, quality, the way it works, the way it is taken and the way it should be used.

FDA requires generic drugs have the same high quality, strength, purity and stability as brand-name drugs.

Not every brand-name drug has a generic drug. When new drugs are first made they have drug patents. Most drug patents are protected for 20 years. The patent, which protects the company that made the drug first, doesn’t allow anyone else to make and sell the drug. When the patent expires, other drug companies can start selling a generic version of the drug. But, first, they must test the drug and the FDA must approve it.

Creating a drug costs lots of money. Since generic drug makers do not develop a drug from scratch, the costs to bring the drug to market are less; therefore, generic drugs are usually less expensive than brand-name drugs. But, generic drug makers must show that their product performs in the same way as the brand-name drug.

How are generic drugs approved?

Drug companies must submit an abbreviated new drug application (ANDA) for approval to market a generic product. The Drug Price Competition and Patent Term Restoration Act of 1984, more commonly known as the Hatch-Waxman Act, made ANDAs possible by creating a compromise in the drug industry. Generic drug companies gained greater access to the market for prescription drugs, and innovator companies gained restoration of patent life of their products lost during FDA’s approval process.

New drugs, like other new products, are developed under patent protection. The patent protects the investment in the drug’s development by giving the company the sole right to sell the drug while the patent is in effect. When patents or other periods of exclusivity expire, manufacturers can apply to the FDA to sell generic versions.

The ANDA process does not require the drug sponsor to repeat costly animal and clinical research on ingredients or dosage forms already approved for safety and effectiveness. This applies to drugs first marketed after 1962.

What standards do generic drugs have to meet?

Health professionals and consumers can be assured that FDA approved generic drugs have met the same rigid standards as the innovator drug. To gain FDA approval, a generic drug must:

  • contain the same active ingredients as the innovator drug(inactive ingredients may vary)
  • be identical in strength, dosage form, and route of administration
  • have the same use indications
  • be bioequivalent
  • meet the same batch requirements for identity, strength, purity, and quality
  • be manufactured under the same strict standards of FDA’s good manufacturing practice regulations required for innovator products.

Source:www.fda.gov

Ancestral Climates May Have Shaped Your Nose

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A study led by Penn State researchers looked at nose shape in people whose parents and ancestors came from four regions of the world.

Ask anyone what the nose does, and the reply will most likely be related to smell. We appreciate our noses because they help us experience flowers and fresh-baked cookies.

In fact, our honkers have another, more important function: They warm and humidify the air we breathe, helping prevent illness and damage in our airways and lungs. Because of this, scientists have long suspected that nose shape evolved partly in response to local climate conditions. In cold, dry climates, natural selection may have favored noses that were better at heating and moisturizing air.

A team led by scientists at Pennsylvania State University has found more evidence of the relationship between the noses we have now and the climates where our ancestors lived.

In a study published in PLOS Genetics on Thursday, the researchers found that nostril width differed significantly between populations from different regions around the world. Moreover, the higher the temperature and absolute humidity of the region, the wider the nostril, the researchers found, suggesting that climate very well may have played a part in shaping our sniffers

Physical traits that are in direct contact with the environment often undergo natural selection and evolve faster, said Arslan Zaidi, a postdoctoral scholar in genetics at Penn State and an author of the paper. “This is one of the reasons why we looked at nose shape.”

All in all, Dr. Zaidi and his colleagues measured seven nose traits, including the nose’s height, protrusion and nostril width, along with skin pigmentation and overall height in men and women whose parents were born in regions that corresponded with their genetic ancestry. They looked at four regions — West Africa, East Asia, Northern Europe and South Asia — with at least 40 participants in each group.

“We selected these to maximize the distance across populations,” Dr. Zaidi said, adding that his team wants to sample more groups in future research.

Between the groups in this study, only nostril width and skin pigmentation showed greater differences than would be expected because of chance accumulations of genetic mutations.

Over all, people whose parents and ancestors came from warm, humid climates tended to have wider nostrils, whereas those from cold, dry climates tended to have narrower ones. Correlations between nostril width and climate were strongest for Northern Europeans, the researchers found, suggesting that cold, dry climates in particular may have favored people with narrower nostrils.

These findings align with those of previous studies of the skull, which have shown that narrower internal nasal inlets tend to be more efficient at warming and humidifying air, said Katerina Harvati, director of the paleoanthropology department at the University of Tübingen in Germany, who was not involved in this study.

Dr. Zaidi and his colleagues also demonstrated that nose shape is a heritable trait. They did this by showing a relationship between shared genes and similarities in nose shape in large groups of unrelated people.

This is important because natural selection can act only on characteristics that can be passed from one generation to the next, said Todd Yokley, a biological anthropologist at the Metropolitan State University of Denver, who did not participate in the study.

The fact that nose shape is subject to natural selection and showed evidence of varying with climate paints a convincing picture that climate adaptation played some role in the evolution of nostril width, Dr. Zaidi said.

He added, however, that nostril width does not seem to correlate with climate as closely as skin pigmentation does. That may indicate that other factors are involved in what kinds of noses are passed down, he said, such as “cultural differences in what is considered an attractive nose or not.”

It’s also important to note that less than 15 percent of genetic variation in humans can be attributed to differences between people from different continents, Dr. Zaidi said.

In actuality, the genes that differ because of geographic origin, such as those affecting skin color, hair texture and nose shape, are the rare exception, rather than the rule.

“People are more similar than they are different. What this research does is offer people a view of why we’re different,” he said. “There’s an evolutionary history to it that, I think, kind of demystifies the concept of race.”

Studying how certain traits evolved as environmental adaptations that may no longer be relevant could also help us understand disease risk today, Dr. Zaidi said.

“We know there are variable risks of respiratory diseases across different populations in the U.S.,” he said. “Can we find an explanation for that in morphology?”

Source:nytimes.com

A Pungent Life: The Smells in My Head

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I am in my kitchen smelling dirt. Three new plants — a white kalanchoe and two red begonias — sit on a stand at my window. It is April, nearly a decade ago, and I have bought them because it is finally spring. I admire their small, dense flowers and green, waxy leaves.

But I hadn’t planned on their powerful, raw smell. Working around the house, I try to think about something else. When I go upstairs, the smell follows me, earthy, pushy, almost wet. I wonder how it is that I can smell three small houseplants on the floor below.

That afternoon, at the grocery, I can’t shake their dank odor. Could the smell somehow have gotten into my clothes? A day later, miles away at my doctor’s office in Manhattan, I am shocked that it smells there, too. But she has no potted plants.

I finally get it. This assertive smell, my uninvited companion for almost two days, is inside my head, not out. Mortified, I think I must smell. Talking to friends, I cover my mouth with my hand. I brush my teeth more often, swish mouthwash compulsively. But my husband says I smell fine — no bad breath. I finally call my doctor.

I discover that I suffer from phantosmia. “Osmia,” from the Greek osme, means “smell.” Coupled with “phanto” (like “phantom”), it refers to an illusory sense of smell. I smell a smell when no odorant is present.

Inevitably, medical tests followed. I had an M.R.I. of my brain (ruling out a tumor), then a CT scan of my sinuses (looking for infection), and finally, an EEG (olfactory hallucinations do occur in epilepsy). The results were negative, and two rounds of antibiotics (was there a hidden nasal or sinus infection?) constituted my only — and fruitless — treatment.

One day a year later I realized that the earthly smell was finally gone. But to my dismay a new smell immediately took over. My husband had burned a big pot of chili. Burned chili became my new default odor. At least it smelled better than dirt.

Then, about seven years ago, a trip to Provence erased the chili. Lavender wafted in the air, becoming my new smell du jour. Southern France’s lavender-infested landscape — dried bouquets, scented soaps and candles, even flavorings for food — trailed me back home. Some might think me lucky — lavender is hugely popular. But I hated this smell that had squirmed its way into my brain.

I tried in vain to fool my nose. Holding lemons under my nose didn’t kill the odor. Smearing pungent perfumes and lotions around my nose didn’t work either. A powerful odor like ammonia might trump the lavender for a moment, but that cure is worse than the disease.

Sometimes I can’t tell whether a smell is inside or outside my head. Walking my dog, I cried as I smelled manure, convinced it would lodge in my head. At home, I rejoiced that the stink was gone. The next day, the horrid smell reappeared at the same spot. This time I noticed the warning sign: gardeners had spread fertilizer. Only then did I know the smell was real.

Avoiding gruesome odors is my first line of defense. There’s a coffee shop nearby that I simply won’t enter. It’s jam-packed with wooden barrels of reeking coffee beans; locals complain they can smell the roasting blocks away. I send my husband to buy coffee while I wait in the car with the windows up.

I’ve tried the opposite tactic, going out of my way to imprint favorite perfumes, fresh flowers, that wonderful bakery smell. Alas, my phantosmia specializes in the disagreeable.

That is typically the case, I now know. Dr. Donald Leopold, chairman of the department of otolaryngology at the University of Nebraska Medical Center in Omaha, has studied smell disorders for 30 years. In phantosmia, Dr. Leopold says, both the upper nasal passages and the brain play a part, especially the brain, “where the actual smell perception is generated.”

Almost always the patient has lost some ability to smell. Dr. Leopold says that the brain, “which has a propensity to make smell,” overcompensates by offering up odors, usually disagreeable ones, that may have existed previously but were suppressed. It appears that certain “traffic cop” neurons, which had worked to exclude such odors, turn off.

Though Dr. Leopold assures me that “treatment is available,” I haven’t tried the nasal saline drops, antidepressants, antiseizure medicines or sedativesrecommended by one doctor or another. Mainly I try to think past the phantosmia, forcing my attention elsewhere. If that fails, I try to laugh at it, more absurd than awful. I win more of these skirmishes than one might expect.

I learn that this disorder is best kept private. Some friends squirm when they hear about it, as if I were crazy. For that matter, phantosmia is linked to certain psychiatric disorders (schizophrenia, depression, Alzheimer’s), but I don’t have them. I do wonder, though, what it means to hallucinate smell. Those neurological explanations aren’t entirely satisfying. There’s nothing plainer than the nose on my face, but nothing more mysterious, either.

Source:nytimes.com

Smell Turns Up in Unexpected Places

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A team of biologists has found that our skin is bristling with olfactory receptors.

Smell is one of the oldest human faculties, yet it was one of the last to be understood by scientists. It was not until the early 1990s that biologists first described the inner workings of olfactory receptors — the chemical sensors in our noses — in a discovery that won a Nobel Prize.

Since then, the plot has thickened. Over the last decade or so, scientists have discovered that odor receptors are not solely confined to the nose, but found throughout body — in the liver, the heart, the kidneys and even sperm — where they play a pivotal role in a host of physiological functions.

Now, a team of biologists at Ruhr University Bochum in Germany has found that our skin is bristling with olfactory receptors. “More than 15 of the olfactory receptors that exist in the nose are also found in human skin cells,” said the lead researcher, Dr. Hanns Hatt. Not only that, but exposing one of these receptors (colorfully named OR2AT4) to a synthetic sandalwood odor known as Sandalore sets off a cascade of molecular signals that appears to induce healing in injured tissue.

In a series of human tests, skin abrasions healed 30 percent faster in the presence of Sandalore, a finding the scientists think could lead to cosmetic products for aging skin and to new treatments to promote recovery after physical trauma.

The presence of scent receptors outside the nose may seem odd at first, but as Dr. Hatt and others have observed, odor receptors are among the most evolutionarily ancient chemical sensors in the body, capable of detecting a multitude of compounds, not solely those drifting through the air.

“If you think of olfactory receptors as specialized chemical detectors, instead of as receptors in your nose that detect smell, then it makes a lot of sense for them to be in other places,” said Jennifer Pluznick, an assistant professor of physiology at Johns Hopkins University who in 2009 found that olfactory receptors help control metabolic function and regulate blood pressure in the kidneys of mice.

Think of olfactory receptors as a lock-and-key system, with an odor molecule the key to the receptor’s lock. Only certain molecules fit with certain receptors. When the right molecule comes along and alights on the matching receptor, it sets in motion an elaborate choreography of biochemical reactions. Inside the nose, this culminates in a nerve signal being sent to brain, which we perceive as odor. But the same apparatus can fulfill other biological functions as well.

Dr. Hatt was one of the first scientists to study these functions in detail. In a study published in 2003, he and his colleagues reported that olfactory receptors found inside the testes function as a kind of chemical guidance system that enables sperm cells to find their way toward an unfertilized egg, giving new meaning to the notion of sexual chemistry.

He has since identified olfactory receptors in several other organs, including the liver, heart, lungs, colon and brain. In fact, genetic evidence suggests that nearly every organ in the body contains olfactory receptors.

“I’ve been arguing for the importance of these receptors for years,” said Dr. Hatt, who calls himself an ambassador of smell, and whose favorite aromas are basil, thyme and rosemary. “It was a hard fight.”But researchers have gradually awakened to the biological importance of these molecular sniffers and the promise they hold for the diagnosis and treatment of disease.

In 2009, for instance, Dr. Hatt and his team reported that exposing olfactory receptors in the human prostate to beta-ionone, a primary odor compound in violets and roses, appeared to inhibit the spread of prostate cancer cells by switching off errant genes.

The same year, Grace Pavlath, a biologist at Emory University, published a study on olfactory receptors in skeletal muscles. She found that bathing the receptors in Lyral, a synthetic fragrance redolent of lily of the valley, promoted the regeneration of muscle tissue. Blocking these receptors (by neutralizing the genes that code for them), on the other hand, was found to inhibit muscular regeneration, suggesting that odor receptors are a necessary component of the intricate biochemical signaling system that causes stem cells to morph into muscles cells and replace damaged tissue.

“This was totally unexpected,” Dr. Pavlath said. “When we were doing this, the idea that olfactory receptors were involved in tissue repair was not out there.” No doubt, few scientists ever imagined that a fragrance sold at perfume counters would possess any significant medical benefits.

But it may not be all that surprising. Olfactory receptors are the largest subset of G protein-coupled receptors, a family of proteins, found on the surface of cells, that allow the cells to sense what is going on around them. These receptors are a common target for drugs — 40 percent of all prescription drugs reach cells via GPCRs — and that augurs well for the potential of what might be called scent-based medicine.

But because of the complexity of the olfactory system, this potential may still be a long way off. Humans have about 350 different kinds of olfactory receptors, and that is on the low end for vertebrates. (Mice, and other animals that depend heavily on their sense of smell for finding food and evading predators, have more than 1,000.)

Despite recent advances, scientists have matched just a handful of these receptors to the specific chemical compounds they detect — an effort further complicated by the fact that many scent molecules may activate the same receptor and, conversely, multiple receptors often react to the same scent. Little is still known about what most of these receptors do — or, for that matter, how they ended up scattered throughout the body in the first place.

Nor is it even clear that olfactory receptors have their evolutionary origins in the nose. “They’re called olfactory receptors because we found them in the nose first,” said Yehuda Ben-Shahar, a biologist at Washington University in St. Louis who published a paper this year on olfactory receptors in the human lung, which he found act as a safety switch against poisonous compounds by causing the airways to constrict when we inhale noxious substances. “It’s an open question,” he said, “as to which evolved first.”

Source:nytimes.com

What Does Cancer Smell Like?

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On a lab bench in Philadelphia sits a tiny box lined with nearly invisible nanotubes and gold. A clear plastic pipe runs through it, and a thicket of pins, each sprouting a red or blue wire, protrudes from its end. As air from the pipe wafts over the nanotubes, electrical signals surge out of the box along the wire threads. The whole apparatus is situated near a vial of blood, “sniffing” the air above it through the pipe.

The box, an electronic nose, is a key part of a theory being explored by George Preti, an organic chemist at the Monell Chemical Senses Center, and an interdisciplinary team that includes physicists and veterinarians at the University of Pennsylvania. Preti is an expert on human odors, having studied them for more than 40 years. He has sniffed — both with machines and with his nose — breath, sweat and other secretions in search of answers about why we smell the way we do. This latest project seeks to answer a question others might have never thought to ask: Does ovarian cancer have a smell?

In modern cancer medicine, doctors tend to rely on advanced imaging techniques and the detection of lumps. The widely acknowledged problem with these methods, though, is that by the time doctors have reason to order a scan or feel something, it’s often too late. Ovarian cancer has usually spread to other organs by the time it’s detected. If it is caught early — which happens only 15 percent of the time, often by accident when doctors are looking for something else — 92 percent of patients live for at least five years. But when it’s caught late, that rate drops to 27 percent. Scent might be a way to get there sooner.

Discovering earlier and better markers for all kinds of cancer, especially in blood, is a priority, said Dr. J. Leonard Lichtenfeld, deputy chief medical officer of the American Cancer Society. Ovarian cancer already has a blood test that has turned out to be not as useful as hoped — giving out both false positives and negatives. A smell-based test would need to perform better.

Diseases can subtly alter people’s fragrance. In the normal course of metabolism, thousands of waste products are swept out in our breath, blood and urine, or simply released into the air above the skin. Metabolic disorders, like diabetes, interfere with the way the body breaks down nutrients and thus make that exhaust especially stinky. People with phenylketonuria (or PKU) tend to smell musty. A faulty or missing digestive enzyme makes people with trimethylaminuria (or TMAU) smell fishy. Untreated diabetics can smell like nail-polish remover: Unable to get energy from sugar, their bodies burn fat for fuel and release acetone as a by-product. (These scents don’t always smell bad; there exists a disorder known as “maple syrup urine disease.”) For Preti, originally from Brooklyn, this makes a subway ride unusually informative. “I often tell people I work with, ‘I bumped into the guy with isovaleric acidemia today.’ ”

Cancer cells, though they don’t alter human metabolism overall, can have altered metabolisms themselves. That means the substances they release could differ from those generated by healthy cells. This idea has been around for decades, but only very recently have biochemical and sensor technology advanced to the point where we can develop portable, hand-held sniffing machines.

Electronic noses have the potential to detect even very small amounts of molecules — but they need to be programmed to look for specific signs wafting up from patient samples. To do that, A.T. Charlie Johnson, a physicist and collaborator of Preti’s at Penn, has the electronic nose sniff blood samples from both sick and healthy patients. As the air passes through the tube, molecules from the samples alight on strands of sticky DNA attached to the carbon nanotubes, changing the electrical signals running out of the box. The team can look for patterns in the signals and use the difference — if there is one — between cancer samples and healthy samples to create an odor-based ovarian cancer test. (Preti is also attempting to identify the specific molecules present in ovarian cancer sufferers’ blood using a much larger machine called a gas chromatograph-mass spectrometer.)

A work in progress, the electronic nose is, for now, an example of how modern medicine can look for answers in unusual places. The impetus that finally pushed Preti and his team to seriously investigate the possibility of cancer detection by smell traces its roots to a dog. In 1989, a letter published in The Lancet reported that a woman had come into the doctor’s office to have a mole looked at. She hadn’t noticed it until her collie-Doberman mix began to sniff the spot intently — even through her pants — and tried to bite it off when she wore shorts. The mole turned out to be an early-stage malignant melanoma, inspiring researchers to test whether dogs, whose smell machinery is at least 10,000 times as sensitive as ours, can tell healthy samples from cancerous ones.

The results from the dog tests have been inconclusive, but to Preti, who has mulled the idea that hidden cancers could be detected from smell molecules since the 1970s, they suggested that there was a real possibility for a new diagnostic. “We think that they’re present very early in the carcinoma process,” Preti said of the scents. “The main question is: Can we be as sensitive as the dogs in picking these things up?”

Source:nytimes.com

For Bad Backs, It May Be Time to Rethink Biases About Chiropractors

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Spinal manipulation or physical therapy such as heat and stretches (above) seem as effective as traditional approaches to help lower back pain. 

About two of every three people will probably experience significant low back pain at some point. A physician like me might suggest any number of potential treatments and therapies. But one I never considered was a referral for spinal manipulation.

It appears I may have been mistaken. For initial treatment of lower back pain, it may be time for me (and other physicians) to rethink our biases.

Spinal manipulation — along with other less traditional therapies like heat, meditation and acupuncture — seems to be as effective as many other more medical therapies we prescribe, and as safe, if not safer.

Most back pain resolves over time, so interventions that focus on relief of symptoms and allow the body to heal are ideal. Many of these can be nonpharmacological in nature, like the work done by chiropractors or physical therapists.

Physicians are traditionally wary of spinal manipulation (applying pressure on bones and joints), in part because the practitioners are often not doctors and also because a few chiropractors have claimed they can address conditions that have little to do with the spine. Patients with back pain haven’t seemed as skeptical. A large survey of them from 2002 through 2008 found that more than 30 percent sought chiropractic care, significantly more than those who sought massage, acupuncture or homeopathy.

Researchers have been looking at the evidence supporting spinal manipulation for some time. Almost 35 years ago, a systematic review evaluated the available research, most of which was judged to be low in quality, and found that there might be some short-term benefits from the procedure. Two reviews from 2003 agreed for the most part, finding that spinal manipulation worked better than a “sham procedure”, or placebo, but no better or worse than other options.

Almost a decade later, a Cochrane review assessed the literature once more, and found 12 new trials had been conducted. This review was more damning. It found that spinal manipulation was no better than sham interventions.

But since then, data have accumulated, as more higher-quality studies have been performed. Recently, in The Journal of the American Medical Association, researchers looked for new studies since 2011, as well as those that had been performed before.

The evidence from 15 randomized controlled trials, which included more than 1,700 patients, showed that spinal manipulation caused an improvement in pain of about 10 points on a 100-point scale. The evidence from 12 randomized controlled trials — which overlapped, but not completely with the other trials — of almost 1,400 patients showed that spinal manipulation also resulted in improvements in function.

In February, in Annals of Internal Medicine, another systematic review of nonpharmacologic therapies generally agreed with the other recent trials. Based upon this review, and other evidence, the American College of Physicians released new clinical practice guidelines for the noninvasive treatment of subacute back pain. They recommended that patients should try heat, massage, acupuncture or spinal manipulation as first-line therapies.

The only things that might detract from the use of spinal manipulation in this situation would be its cost and potential harms.

Because they fear those potential harms, some physicians are hesitant to refer patients to chiropractors or physical therapists for care. But in all the studies summarized above, there were really no serious adverse events reported. It’s possible to find anecdotes of harm to the spinal cord from improper manipulations, but these are rare, and almost never involve the lower spine.

Some physicians are concerned about the cost of spinal manipulation, especially since most insurance carriers don’t cover it. Visiting a chiropractor costs more than taking many non-narcotic pain medications. But more invasive interventions can cost a lot of money. In addition, studies have shown that, in general, users of complementary and alternative medicine spend less over all for back pain than users of only traditional medicine.

Medication and surgery can also lead to harms. We shouldn’t forget that prescription pain medications, like opioids, can lead to huge costs, especially when they’re misused.

Some physicians are uncomfortable that we don’t have a clear picture of how spinal manipulation actually works to reduce pain. It’s also possible that some chiropractors do it “better” than others, and we can’t tell. This concern should be tempered by the fact that we don’t have a great understanding of why many other therapies work either. Some of the more traditional things we recommend don’t even work consistently.

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Still, there is no merit to many other claims about spinal manipulation — that it has been proved to work for things like infantile colic, painful periods, asthma, gastrointestinal problems, and more. For most conditions, the therapy lacks a good evidence base.

But given the natural course of back pain — that most of it goes away no matter what you do — the ideal approach is to treat the symptoms and let the body heal. Noninvasive therapies seem to do that well enough.

Source:www.nytimes.com