A Cause of Sporadic ALS

August 28, 2015 by

Aug. 14, 2015

By Medical Discovery News

A Cause of Sporadic ALS

When the groundbreaking theoretical physicist Stephen Hawking was diagnosed with amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s disease at 21, he was given two years to live. Now he is 73 years old. How has he managed to survive this invariably fatal disease for so long? We may not have all the answers when it comes to ALS, but one study has brought us closer to understanding its cause.

ALS is a devastating, progressive neurodegenerative disorder characterized by gradual degeneration and death of motor neurons responsible for controlling voluntary muscles, resulting in the loss of all voluntary movement including the face, arms, and legs. The disease becomes life-threatening when the muscles in the diaphragm and the chest wall fail and the patient requires a ventilator to breathe. Most people with ALS die from respiratory failure three to five years after the onset of symptoms. Only 10 percent survive 10 years or longer.

One tragic aspect of ALS is patients usually retain their awareness, intelligence, taste, sense of smell, hearing, and touch recognition, making them acutely aware of their deteriorating condition. ALS is one of the most common neuromuscular diseases, afflicting 12,000 people in the United States. Some 90-95 percent of all ALS cases are sporadic, so they have no family history. The remaining cases, called familial ALS, have a genetic component.

While its cause has long been sought after, recently scientists conducted the largest genetic sequencing study of ALS patients thus far. The genetic information of nearly 3,000 ALS patients and over 6,400 control subjects were sequenced, leading to the identification of a new gene associated with ALS. It took a study of this size to detect such a rare gene variant, as it is only mutated in about 2 percent of sporadic ALS cases.

The gene, TANK-Binding Kinase 1 (TBK1), is involved in a cell system that degrades and recycles waste. Scientists are trying to link mutations in the gene with the accumulation of protein aggregates that are killing motor neurons. TBK1 is also important to the immune response. Scientists have long thought inflammation in the brain plays a role in ALS. Since TBK1 tamps down inflammation, a mutation in the gene could interfere with that function.

Researchers are also studying a gene, OPTN, that interacts with TBK1. Together they regulate cell waste disposal and inflammation. Scientists are experimenting on mice engineered with mutations in both genes to determine how they contribute to ALS. These models will also be used to develop future therapies. However, genetic profiling of ALS patients will be necessary to determine which therapy is appropriate depending on the gene that is mutated.

Since ALS can be caused by dozens of gene mutations, the more we can identify, the better scientists can understand their influence on the pathways that lead to this disease.

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A Close-Up Look at Metastasis

June 12, 2015 by

By Medical Discovery News

May 29, 2015

A Close-Up Look at Metastasis

One of the things that make cancer cells so deadly is metastasis, their ability to dislodge from their original location and migrate to other tissues. Most people who die of cancer are victims of this process. Even if a tumor is removed surgically, doctors can’t be certain that some of the tumor cells haven’t already metastasized, hence the need for treatments such as chemotherapy to target those cells. Unsurprisingly, metastasis is a subject of intense research, and luckily scientists now have a new tool to help them understand how tumor cells move.

While most tumors have the ability to metastasize to many different tissues, they prefer to spread to certain ones, like those in the bones, liver, and lungs. Cancer begins to spread by invading nearby tissue, then through a process called intravasation, tumor cells enter a blood or lymphatic vessel, allowing them to circulate to other parts of the body.

When tumor cells stop moving in a tiny blood vessel called a capillary, the can move out of the blood vessel and into the tissue, which is called extravasation. They will proliferate in this new location and release signals to stimulate the production of new blood vessels to satisfy the oxygen and nutrient demands of the tumor, a process called angiogenesis. Not all cells of the tumor are equally capable of metastasizing, and depending on the new environment they may not be able to grow in their new locations. In general, cells in metastatic tumors acquire additional genetic mutations that make them better able to relocate to other sites in the body. In some cancers, the metastatic cells have evolved to be remarkably different from the original tumor cells, which may contribute to the failure of treatments, the identity of the original cancer, and the recurrence of cancer.

Engineers and scientists at Johns Hopkins University have reproduced the 3-D extracellular matrix (ECM) that surrounds human cells. They also created an artificial blood vessel that runs through the matrix to simulate the flow of blood or lymph. They then added breast cancer cells either individually or in clumps.

Using fluorescent microscopy, they studied how the tumor cells interacted with the model to investigate how tumor cells get into and out of vessels, a key step in metastasis. They found that the tumor cells first dissolved some of the ECM to form a tunnel. The cells moved back and forth within this tunnel, occasionally coming into contact with the vessel. Then the cancer cells attached to the vessel through a long process, finally sitting on the surface of the blood vessel. They appear to change shape and move along the outer surface of the blood vessel. After a few days, the cancer cells force their way between the outer cells of the vessel and are swept away by the fluid moving through it.

About 60-70 percent of cancer patients are already at the stage of metastasis by the time they have been diagnosed. This new device will allow scientists to gain a better understanding of the processes and molecular players in metastasis, which will hopefully lead to new interventions or therapies that could interrupt or prevent this process.

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Biological Fountain of Youth

April 25, 2015 by

March 27, 2015

By Medical Discovery News

The Biological Fountain of Youth

Over 500 years ago, Ponce de Leon landed in Florida as part of his search for the fountain of youth – magical waters that reverse aging, prevent illness, and grant immortality. He never found it, and neither has anyone else. While immortality is still impossible, we have come a long way in understanding the aging process.

We do not know the precise mechanism of aging, but there are some fundamental processes in our bodies that begin to change and this can drive aging. There are several theories of aging under intense scientific investigation.

A widely accepted theory of aging today is called evolutionary senescence, which mainly hinges on the concept of mutation accumulation. As we age, our cells accumulate mutations in our genetic material or DNA, which affects the ability of our cells to replicate and our tissues to regenerate. Also, some of our genes are designed to enhance reproduction early in life, but can cause problems later. Since genes can only be passed on during reproduction, which generally occurs earlier in life, genes that have negative effects later in life are not removed from the population – we are stuck with them! A good example is a gene called p53, which controls the fate of damaged cells by preventing their replication or directing them to die. This is important in preventing cancer in young people, but it may negatively impact our ability to replace aging cells in tissues as we grow older.

Another widely discussed theory centers on the maintenance of our genomes. As we get older, we accumulate damage to our DNA, which affects cellular function and our ability to renew tissues in the body. In a sense, this is a high mileage effect. Take for example the production of free radical molecules. These highly reactive molecules are normally produced in mitochondria, which use oxygen to produce cellular energy, a process that creates free radical molecules as a by-product. These free radical molecules lead to oxidative damage of DNA and other cellular components.

There is also evidence the neuroendocrine system (hormones that affect neurological function) influences aging. For example, a reduction in hormone levels can lead to a lengthening of life, at least in experimental animals. We are beginning to suspect that the insulin-related hormonal pathway may play a significant role in aging, at least in mice. Mutations that reduce the amount of this circulating hormone extend life.

A relatively new model of aging involves the replication of chromosomes as cells divide. When cells replicate, specialized structures at the ends of chromosomes called telomeres are shortened. Shortened telomeres are linked to decreased viability and increased cancer risk. Cells whose telomeres reach a critical length can no longer divide and are described as senescent.

We are expanding our understanding of how aging occurs. The search for a modern-day fountain of youth will require a great deal of dedicated work by biomedical scientists to safely improve and extend human life.

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More Bad News for Smokers

October 27, 2014 by

Oct. 24, 2014

By Medical Discovery News

Lung X-ray

Smoking isn’t the only thing that raises your risk of lung cancer. As it turns out, your DNA can have that effect too.

A scientific study scanned the genomes, the entire genetic code, of 11,000 people of European descent in an effort to identify if there was any correlation between gene sequences and a common form of lung cancer, non-small cell carcinoma. They discovered that variants of certain genes increase a person’s susceptibility to developing lung cancer, especially in smokers.

One of the three gene variants they identified, named BRCA2, can double a smoker’s chance for developing lung cancer. BRCA2 is a tumor suppressor gene. It encodes a protein involved in the repair of damaged DNA, which is critical to ensure the stability of cell’s genetic material. When cellular DNA is damaged, there are several ways for the body to detect and repair that damage. If the damage to DNA cannot be repaired, then the cell is programmed to die by a process called apoptosis in order to prevent the damage being passed on to its daughter cells.

Like other tumor suppressor genes, the BRCA2 protein helps to repair breaks in DNA. It also prevents damaged cells from growing and dividing too rapidly. Variants of BRCA2 associated with breast, ovarian, and now lung cancers produce proteins that do not repair DNA damage properly. This causes cells to accumulate additional mutations, which can lead to cells that grow and divide uncontrollably. Such mutations lead to an increased risk of developing cancer.

Scientists have discovered over 800 mutations of BRCA2 that cause disease, including breast, ovarian, lung, prostate, pancreatic, fallopian, and melanoma cancers. Most of the mutations result from the insertion or deletion of a few letters of genetic code into the part of the gene that code for a protein. This disrupts the production of the BRCA2 protein and results in a shortened and nonfunctional form of the BRCA2 protein.

Lung cancer is a leading killer of Americans. Nearly 160,000 Americans will die from lung cancer this year, representing 27 percent of all cancer deaths. Active smoking causes close to 90 percent of lung cancers.

The good news from this discovery is that since scientists first linked BRCA2 to an increased risk of breast cancer, new therapies have been developed. Current treatments for breast and ovarian cancers could be effective with BRCA2-associated lung cancers, such as PARP inhibition.  PARP1 is another protein involved in repairing DNA damage. When one of two strands of DNA are broken or nicked, PARP1 moves to the region and recruits other proteins to the site to repair the damage. Many chemotherapy agents kill cancer cells by inducing DNA damage in the tumor and inhibiting PARP1. This doesn’t allow cancer cells to repair damage and makes them more susceptible to chemotherapy and radiation therapy. Now that we know this gene is linked to lung cancer, such therapies may be more effective in treating lung cancer and saving lives.

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Bring on the Milk

June 22, 2014 by

June 20, 2014

By Medical Discovery News

Milk

Drinking milk might seem perfectly natural, but it’s actually anything but. Humans are the only species who retain the ability to digest milk after childhood, or at least some of us do. Up to half of adults worldwide don’t have the ability to break down lactose, the main sugar in milk, because their bodies stop producing the enzyme lactase after the age of five.

About 65-75 percent of the population has some degree of lactose intolerance, the most common cause for digestive issues with dairy. Lactase breaks down lactose into simpler forms of sugar that can be absorbed by the bloodstream. Without this enzyme, lactose is fermented by bacteria, causing symptoms like abdominal pain, bloating, flatulence, nausea, and diarrhea 30 minutes to two hours after eating. Populations that have long relied on unfermented milk have the lowest rate of lactose intolerance – only five percent among the Swiss.

Humans’ ability to drink milk actually began as a genetic mutation, like the superheroes of X-Men comics. According to the leading theory, 7,800 years ago humans began to move northward. Since the sun is not out as long in northern latitudes, they could not absorb enough vitamin D from sunlight and needed another source to thrive. Milk is high in vitamin D, which aids in calcium absorption. Humans adapted to this change in their diets and developed a variant of the lactase gene that allowed them to continue synthesizing the enzyme throughout their lifetimes. Since humans with the gene variant had the advantage of consuming more vitamin D, they were successful in passing that gene on to future generations.

But new research suggests that this theory is either wrong or other factors were involved. Scientists in northeastern Spain discovered well-preserved skeletons of people who lived 5,000 years ago. DNA testing revealed that none of these eight skeletons carried the genetic mutation for lactase production. Further testing also showed that these ancient humans are indeed related to modern Spaniards. Next, computer simulations determined that over 5,000 years, chance alone would not have allowed one-third their descendants to digest milk. Strong selection for this trait would have been necessary.

These scientists developed a theory that early farmers began eating fermented dairy products such as cheeses, which have lower levels of lactose. But when food was scarce, they ran out of fermented dairy products and began to consume unfermented milk as a food source. Then, those who acquired the mutated gene for lactose production would have thrived. Those without the mutation would have suffered from diarrhea, making their situation worse, perhaps even life-threatening if they were already starving.

While the need for vitamin D from milk may have been a factor in the spread of lactase persistence, these new findings show that other factors may have also been a part of the selection process that drove this mutation into the population. Now if we could only figure out a way to turn on lactase genes again during adulthood, everyone with lactose intolerance could enjoy a pain-free ice cream cone.

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When Two Parents Aren’t Enough

April 5, 2013 by

April 5, 2013

By Medical Discovery News

Ask expectant parents what kind of child they want, and one word almost always comes up: healthy. So, the possibility that a new baby may carry a genetic disorder can be understandably devastating. But a recent research from the Oregon Health Sciences Center may offer a unique approach to actually preventing certain types of genetic diseases – the three-parent child. 

When they invented this approach, researchers were thinking of the 4,000 children born each year with genetic defects in their mitochondrial DNA. These children consequentially develop one or more of 50 known mitochondrial diseases, many with devastating symptoms like stroke, epilepsy, dementia, blindness, deafness, and kidney or heart failure. Mitochondria are the power plants of the cell, producing the energy needed for a cell to function. Each mitochondrion has its own DNA independent and outside of a person’s DNA, which is housed in the cell’s nucleus. Diseases affecting mitochondria are difficult to treat, so this new way of actually preventing them is a welcome, while controversial, discovery.

First, eggs are obtained from the mother and a female donor. The nucleus from the egg of the natural mother is removed, separating her chromosomal genetic information from her mitochondria, which would have been passed on with the mutation to the child. This nucleus is then transferred to the donor egg, from which the nucleus and genetic information has been removed and discarded. The result is an egg with the nucleus and genes of the natural mother and the functioning mitochondria of the donor.

Then the egg is fertilized with the natural father’s sperm (which does not contribute any mitochondria to an egg), producing a fertilized egg with the DNA of the natural mother and father and the healthy mitochondrial DNA of the donor.  However, the contribution of the donor egg’s mitochondrial DNA is not much – the mitochondrial genome accounts for only 1 percent of the total DNA present in a human cell. So, the embryo will have genetic information from three people. The future child would share the genetic characteristics of the mother and father but have the mitochondrial genetic makeup of the egg donor.

In recent studies, scientists removed the nuclei and the DNA within from 65 human eggs and replaced them with donated nuclei. After fertilization, just under half of the eggs grew to a 100-cell stage called a blastocyst, the precursor to an embryo. This is the same rate seen for unaltered fertilized eggs. While the blastocysts were not implanted into wombs, they could have eventually developed into three-parent children. The change to their mitochondrial DNA could be permanent, and they could pass on the functional mitochondria to future generations. 

While this is huge progress for treating genetic disease, it also raises some significant ethical questions, such as whether the discovery could eventually be used to create “designer” babies, whose DNA has been manipulated to meet parents’ wishes. This technique holds great potential as an advance in genetic therapy, but its ensuing controversy means scientists should take steps to prevent abuses. 

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Susceptibility to Mesothelioma

June 24, 2012 by

By Medical Discovery News

May 26, 2012

Susceptibility to Mesothelioma

Today a simple blood test can tell whether someone carries the genetic mutation for breast, colon, and possibly even lung cancer. This is possible because years of research have allowed scientists to identify genes responsible for tumor development.

Among the most recent discoveries is the genetic mutation behind mesothelioma, an aggressive cancer that forms in the lining of the chest and abdomen. About 3,000 people die of mesothelioma every year, nearly half within one year of diagnosis.

The main cause of this cancer is asbestos, a fibrous material that gets inhaled into the lungs. The National Institutes of Health estimate 11 million people were exposed to asbestos between 1940 and 1978, but symptoms typically don’t show up for 25 to 50 years, so the number of mesothelioma cases won’t peak until about 2020.

Yet for years scientists have been puzzled as to why only a small fraction of people exposed to asbestos develops mesothelioma. Scientists at the NIH may have just discovered the reason. They’ve identified a gene that, if mutated, predisposes people to mesothelioma and melanoma of the eye.

The study focused on two American families with a high incidence of mesothelioma and other cancers. Every family member who developed mesothelioma or melanoma of the eye had mutations in a gene called BAP1. In another 26 mesothelioma patients with no family history of cancer, a quarter of them also had BAP1 mutations.

Some of these same patients developed additional cancers such as breast, ovarian, pancreatic or renal cancers. This suggests BAP1 gene mutations may contribute to multiple types of cancer. Since the gene is responsible for repairing DNA damage and suppressing tumor activity, a mutation of BAP1 explains why those who carry it face higher cancer risks.

While some genetic mutations are inherited, the vast majority are likely due to random mutations in healthy cells. However, for cancer to actually develop, different genes that cause cells to grow out of control and spread must also accumulate mutations.

These random mutations can occur from exposure to carcinogenic substances such as asbestos, but another fibrous mineral called erionite can also cause cancer. The federal government recently issued a health warning to workers in gravel pits or on road projects in 12 western states where erionite has been used. Early studies indicate erionite is much more potent than asbestos when inhaled.

Since new tools have made DNA sequencing cheaper and easier, more scientists are now studying and identifying an increasing number of genetic mutations associated with cancer. And as more genetic testing becomes available, people who learn of their predisposition for cancer can avoid being exposed to erionite, asbestos, UV light, cigarette smoke, and other DNA damaging mechanisms.

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