Biological Fountain of Youth

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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The Irresistible Rise of Genomic Medicine

Feb. 6, 2015

By Medical Discovery News


It’s only been 150 years since scientists discovered what we now call DNA. Today, it’s a household word, the basis for the field genomics, and an integral part to multitudes of scientific studies. It’s remarkable how relatively quickly our understanding of genes has progressed.

DNA was first thought to represent the genetic material of living organisms in the 1940s. Doctors Francis Crick and James Watson revealed the double helix structure of DNA in 1953, which is widely considered to be the first revolution in modern biology. In 1977, we first decoded the entire genome of a living organism, a tiny virus that infects bacteria called ФX174. This was the first time we understood all the DNA required to produce a life form. The term genomics was first coined in 1987 to describe the structure and functions of an organism’s entire genetic blueprint.  In 1995, we determined the genome of a free-living organism, a bacterium called Haemophilus influenza, for the first time. The genome of a eukaryotic organism, Baker’s yeast, was first completed in 1996. These early studies provided the novel approaches and advanced technologies that were later used to sequence the human genome, which consists of 3 billion base pairs. The human genome project, the second revolution in modern biology, began in 1990, and was completed in 2003. Since then, the genomes of more than 4,000 other organisms, including the ancient human species Neanderthal and the coffee plant, have been completely determined.

Genomics continues to be a part of the third revolution, convergence, which merges the rigors of computational science and engineering with modern biology. It cost $1 billion and took eight years to complete the sequence of the first human genome. Now, the cost of sequencing a human genome is a fraction of that at $2,000-$4,000 and takes a mere 1-3 days to complete. More than 2,500 human genomes have been sequenced from 26 distinct populations, and 100 million genetic variations have been discovered from these human samples so far. These variations are part of what make us each unique as people, but they can also reveal why we might be experiencing or have susceptibility to disease.

This is where genomic medicine comes in. Dr. Eric Green, the director of the National Human Genome Research Institute at the National Institutes of Health, says there are multiple studies with great promise in this emerging field. For example, cancer genomics has been used to determine the DNA sequence of tumor cells, which can help identify the type of cancer cells in a tumor and the cause of the cancer. That information can then be used to direct the type of treatment that would be the most effective for each individual, creating a personalized approach to medicine. A person’s DNA sequence may also disclose what pharmaceuticals will work most effectively.

The human genome project advanced our understanding of genetics and heredity. Much research is now focused on genomes and their relation to disease. More recently, scientists are using this newfound knowledge to further the science of medicine.

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More Bad News for Smokers

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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A One-Letter Blond

Oct. 10, 2014

By Medical Discovery News

Blond hair

Out of the 3 billion letters contained in the human genetic code, all it takes to be born a blond is a single change in a certain place from an A to a G. With the sheer complexity of the human genome, this new discovery shows how remarkably simple it is to be a natural blond. Especially when you consider the lengths people go to become one artificially.

This discovery actually came from research on the evolution of Sticklebacks, small fish that emerged from the oceans and colonized streams, rivers, and lakes at the end of the last Ice Age. Scientists at Stanford University have been studying how Sticklebacks have adapted to different habitats around the world, and particularly how different populations acquired their skin colors. They discovered that changes in a single gene determined the pigmentation of fish throughout the world. The gene responsible, the Kit ligand gene, is also in the human genome. Different versions of it have evolved around the world and are associated with differences in skin color.

The protein encoded in the Kit ligand gene aids in the development of pigment-producing cells, so its role in skin and hair color makes sense. However, the Kit ligand protein plays other important roles elsewhere in the body, such as developing stem cells into blood cells and producing sperm. Therefore, changes to this gene are not simple and could have detrimental consequences. This caused scientists to wonder how such an important gene could evolve while still preserving its essential roles. Both in fish and humans, the changes that lead to differences in pigmentation were not in the genetic region that encodes the Kit ligand protein, but rather at sites in the genome quite distant from here, where elements responsible for regulating that gene are located.

To find the regions that regulate the Kit ligand gene and therefore influence hair color, scientists cut out various regions at a time and linked them to a gene that produces a color when activated. Done in mice, only one of the regions activated in developing hair follicles. Comparing the DNA sequence of that region between brunettes and blonds, they then identified the single A to G change unique to blonds. This change reduced the amount of Kit ligand protein by 20 percent compared to brunettes. Even in mice, when scientists made this genetic alteration, their hair was lighter too. This means that changing a single letter only affects the utilization of the Kit ligand gene in one part of the body – the hair follicles. This region contributes to the diversity of hair color in humans while maintaining the same roles in other parts of the body. As it turns out, being blond is only skin deep.

This work further proves that large regions of our genetic information once thought of as “junk” DNA actually play critical roles. Subtle changes like this reveal how intricately genes are controlled and how even simple alterations are responsible for human diversity. This information can also help us understand how other gene variations may be associated with disease or resistance.

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The Human Genome Revisited

March 1, 2013

By Medical Discovery News

When scientists sequenced the human genome in 2000, it revolutionized biomedical research, much like the invention of the Internet forever changed communications. The project aimed to identify all the genes in the human genome.

At first, they estimated that humans had less than 100,000 genes, then improved methods lowered that to 35,000, and a new analysis suggests that humans have no more than 21,000 genes. When considering the complexity of a human being, that number does not seem very high.

However, even the highest of those estimates accounted for less than 20 percent of the DNA sequence in the human genome. The rest of sequence did not appear to encode genes that led to proteins and was therefore considered non-functional or “junk” DNA.

Now a recent study by more than 400 researchers at 32 institutions costing almost $300 million challenges that notion and suggests that more than 80 percent of the human genome is indeed utilized and therefore important in the overall biology of each person – so much for “junk” DNA. The Encyclopedia of DNA Elements (ENCODE) project concluded that 20,687 genes produce proteins and an additional 18,400 genes produce RNA involved in coordinating the activity of the genes that produce proteins. 

This extensive effort originally focused on the genomes of a small number of human cells but later expanded to include almost 150 different cells, including immune, embryonic, liver tissue, umbilical cord, and cancer cells. Specific genes produce proteins for different tissues at different stages of human growth, so using this wide array insured that the analysis included all active genomic regions and gave a broader view of the genome. 

The analysis also identified genome regions associated with specific human diseases, creating an opportunity for better understanding these diseases and treating them. In addition, the ENCODE project revealed just how different humans are from other mammals like monkeys, dogs, or dolphins. While previous estimates suggested that just 5 percent of the human genome is unique from other animals, ENCODE’s research doubled that estimate to almost 10 percent. Another revelation showed just how complex the control mechanisms of the human genome really are. They signal almost 20,000 genes at the exact time and location to allow a fetus to develop normally and instruct the specific workings of tissues, like in the kidneys, lungs, or brain.

So the action of genes is controlled by layer upon layer of interacting and intricate controls that make each person who they are. Homo sapiens are a species of biological wonder and will require many years of intense study to even begin to understand the mysteries of how genes are regulated to make a human being. 

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Personal Genome Sequencing – Not Worth It Yet

By Medical Discovery News

July 28, 2012

It took 10 years and over $3 billion to sequence the first human genome. Now, more than three dozen companies will soon offer personal genome sequencing for less than $1,000. So anyone can mail a tissue sample and get a USB drive with their DNA sequence in return. The problem is a person can’t do much with all that information just yet.

One of the great promises of this technology is that one day, doctors will routinely practice personalized medicine. Genome sequencing may eventually identify a person’s susceptibility to developing certain diseases, predict how a disease will progress, and how the person will respond to different types of treatments.

Certain genetic disorders are easily predictable based on the inheritance of simple genetic variances. For example, inheriting two hemoglobin genetic mutations can cause sickle cell disease. Other examples of genetic diseases easily identified by DNA sequencing include muscular dystrophy, chronic myelogenous leukemia, hemophilia, and Huntington’s disease, which are among an estimated 4,000 single gene disorders.

Genome sequencing will likely identify more of these relatively simple genetic disorders involving one or a few genes. However, the majority of diseases are going to be much more complex, and involve multiple genes with products that may interact or combine to influence disease development.

As a result, the potential of genome sequencing will be limited until scientists are able to further understand how diseases develop. For years scientists have studied identical twins to determine whether genes or the environment have a greater impact on disease development.  Surprisingly, twins with the same genomes, socioeconomic background, childhood environment, upbringing, and environmental exposures usually do not die of the same thing.

This shows that any set of risk predictors is not defined well enough to guarantee a person’s health destiny. In time, geneticists may be able to define these genetic risk factors, making them more reliable. But even when a genetic test clears someone of the risk for certain diseases, it is not a free pass because environment and lifestyle choices are critical factors.

It’s possible that as geneticists better understand the role of specific genes on human health, genome sequencing may be a valuable tool for guiding physicians on how to treat diseases. Since people respond differently to treatments and drugs, this information may help doctors personalize treatment plans so that they are safe and effective for each individual.

Even though genome sequencing is becoming affordable, there’s little a person can do with the information right now. Also, consider how insurance companies or potential employers could misuse such private information. Always ask about a company’s privacy policy before deciding to plunk down the money for a test.

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Spotlight on Genetic Research

Local geneticist featured on cover of Parade magazine

By Pamela Bond

Washington, D.C. Examiner

Nov. 9, 2009

Leonardo DiCaprio. Robert DeNiro. Nicole Kidman. Eric Hoffman. One of these is not like the others.

Dr. Hoffman, director of the Center for Genetic Medicine Research at Children’s National Medical Center, joined the ranks of countless actors, musicians and other celebrities on August thirtieth, 2009, when he appeared on the cover of Parade magazine. While he is not known as a household name, Hoffman is a bit of a rock star in the field of medicine. He has published over two hundred and fifty scientific articles, some of which are among the most cited in the world. He secures about nine million dollars each year to fund his research on different diseases.

While the media has not always accurately represented complicated scientific research, Hoffman decided to put aside his reservations and agree to be in the story as a way of publicizing his work to cure a debilitating disease.

The article? “Discoveries That Can Save Your Life,” which is a good way to describe Hoffman’s work. The geneticist, along with teams of researchers all over the world, is trying to find a treatment for muscular dystrophy.

“It’s a devastating disease,” Hoffman said. “Kids are normal until about four years of age and then gradually they lose all the muscles in their body so they can’t walk anymore by eleven and can’t breathe anymore by sixteen and they just die.”

Muscular dystrophy is a genetic disease, caused by a mutated gene, so people are born with it. It causes the muscles, which include not just the skeletal muscles such as those in arms and legs used for movement but muscles like the heart as well, to weaken and waste away.

Currently, Hoffman is working on a possible treatment project in London – the world’s first clinical gene therapy trial for muscular dystrophy. So far, research shows that the gene associated with the disease can be repaired using an enzyme, but researchers still have a lot of work to do before it can be tested on humans.

The article originated because Parade has a long-standing relationship with the Muscular Dystrophy Association, which hosts the famous telethon around Labor Day. Hoffman, however, was not thrilled when he was chosen to be the face of the cause.

“One thing which I think speaks to what you are trying to get at is part of the nature of people that mainly have their pictures on the cover of magazines, like actors, like you pointed out, is that that’s a good thing, right?” Hoffman said. “In other words, if you get your picture on the cover of something that’s considered a good thing. But from the scientist’s perspective, that’s not necessarily true. In fact, I was very hesitant.”

One reason he said he was cautious was because being photographed was not part of what he expected in his job as a geneticist. Another reason was because he was afraid of “overselling” the research he was doing. Hoffman had been a part of the team that worked on the Human Genome Project, which aimed to identify what trait each human gene represented. During that time, he saw that the media misrepresented a lot of the team’s work.

“They almost thought you could just sprinkle this gene on a person’s head and they’d jump out of their wheelchair,” Hoffman said. “Twenty years later that didn’t happen. So the false expectation created false hope in so many families as a consequence of those news reports and scientists.”

Finally, he works with a team of one hundred and twenty researchers at Children’s and other medical centers in different countries, and he didn’t want to seem like he was taking full credit for all their work.

“It’s the analogy of a soloist versus a chorus,” Hoffman said. “Me, I work as part of a chorus, which when we’re all unified and we’re all doing the same thing is a tremendous thing. That’s one of the things I like about it – it’s incredibly orchestrated.”

In the end, bringing awareness to the research at the center and the potential it has to save children’s lives satisfied his doubts.

“The end result of the article was to generate interest and public awareness in muscular dystrophy and its research progress, which is tremendous,” Hoffman said. “In the last few years, we’ve been actively involved in a treatment for the kids that are just dying. So that was the focus of the article, even though it only had a few sentences on that.”

Actually seeing his face on the cover, however, was a whole different story.

“My initial reaction, now that I think about it, was wondering how many people’s cup of coffee I ruined that morning,” Hoffman said, because he does not picture himself as glamorous as most celebrities who pose for magazine covers.

Relatives who had never met Hoffman told him at a family get-together that they had placed the magazine on their mantels in hopes of meeting him.

Hoffman’s interest in genetics began in high school, when he took a course on biology and human values, which looked at the intersection of science and societal values. The ethics of that subject attracted him to the field, he said.

Hoffman studied biology and music at Gettysburg College in Pennsylvania, then earned his doctorate in genetics from Johns Hopkins University. His post-doctoral work at Harvard University consisted of experimenting on fruit flies, changing their eye color or wings. But Hoffman wanted to work with human diseases. His goal now is to “fix these kids, to dramatically change their way of life.” He still carries his passion for science and society.

“To some respect I feel that my goal now is a people scientist, someone who tries to get people from very diverse backgrounds working together for a common goal,” Hoffman said. “I think that’s great. It’s the fundamental strength of humanity to take on these large, collaborative projects.”

Although the Parade article was short, he believes it accomplished what it was meant to.

“It’s so much of a balance of hope and hurt,” Hoffman said. “I think Parade achieved that so I was quite happy.”

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