Genetics For The Rest Of Us: August 2015

Thursday, August 27, 2015

Turmeric: An Indian Spice With Potential Medical Use

My wife and I were making Indian food last weekend, and turmeric is a major component of curry blends. The spice gives curry its distinctive yellow color, it smells delicious, and it tastes even better.

Turmeric (Curcuma longa) also has a storied history outside the kitchen. Both Ayurvedic (traditional Indian) and traditional Chinese medicine incorporate turmeric in many of their treatments¹. People still use turmeric for indigestion, eczema, and other maladies¹.

Labs investigating medicinal properties of turmeric focus on the molecule curcumin, one of many chemical compounds the plant naturally produces. Studies on curcumin began in earnest around 2000, and since then, the number of articles published on its possible applications in modern medicine skyrocketed.

Early results in cell-based and animal studies indicate curcumin may help reduce arthritic pain, combat inflammation, help prevent diabetes, and help prevent certain forms of cancer². These results are preliminary and haven’t been replicated in people in large-scale clinical trials, but they’re certainly promising.

How does curcumin work in such a wide range of diseases?

At first, it might seem like many of the diseases curcumin may help treat are completely unrelated, but they actually have much more in common than you might think. Arthritis, general inflammation, diabetes, and cancer all primarily affect adults and the elderly. It’s becoming increasingly clear the same metabolic pathways contribute to age-related diseases and perhaps aging itself.

The term “inflammaging” emerged around 2000 when scientists began to recognize the close relationship between inflammation and aging³. People with obesity are also at high risk for arthritis and a higher risk for developing cancer⁴, for example. These diseases all have strong connections to inflammation.

Curcumin may work by targeting pro-inflammatory proteins like TNF-α and NF-κB^5-6. Both of these proteins are transcription factors, or proteins responsible for turning on other genes in the cell. TNF-α helps turn on genes that produce cytokines that promote inflammation⁵. NF-κB also instructs the cell to produce cytokines and other proteins involved in blood vessel formation, a phenomenon that occurs in cancerous tumors⁶.

So, if curcumin seems to work, why isn’t it used in modern medicine now?

As it turns out, the body metabolizes curcumin so quickly that it’s difficult to keep enough of it in the body to work for any appreciable length of time⁵. Scientists are currently trying to improve upon the natural curcumin chemical structure to make it more resistant to breakdown in the body or develop different delivery strategies so it can act directly on target tissues⁵, but it will take years to make it to the clinic.

Based on the best estimate I can come up with⁷, people would need to around one tablespoon of turmeric a day to see a benefit. Most likely, people would need to eat more because the amount of curcumin in turmeric can vary quite a bit⁷.

I should stress, however, that turmeric is not a substitute for other medicine. If you have diabetes, you should take insulin. If you have cancer, for the love of God, get chemotherapy. It’s important to keep in mind I have a Ph.D., not an M.D. You should always talk to your doctor (i.e. not WebMD and certainly not Dr. Oz) to get the best medical advice.

On the other hand, it might not be a bad idea to incorporate more turmeric into your diet if you can. Indian food is tasty, after all.

References

Wednesday, August 19, 2015

When good cells go bad

The week my family moved from the Appalachian Mountains in Virginia to Atlanta, my great uncle lost his fight against lung cancer.

Like many people in Appalachia, Uncle Carl smoked. When his doctors found the tumor, he underwent the standard chemotherapy treatments and went into remission. A few months later, he went back into the clinic complaining of a pain in his shoulder, and a quick workup determined there was another tumor pressing against his spine. Two days before we moved, I said my farewell to him in hospice care after he was put into an induced coma to ease his pain. Around four hours later, he died.

I don’t know of anyone that doesn’t have a story similar to that one.

In a nutshell, cancer is a disease of uncontrolled cell growth. Most cells in the body don’t divide. With the exception of adult stem cells that serve as a reservoir for new cells to replace old or dead ones, a cell stops dividing once it turns into specific type of cell. For example, once a stem cell becomes a neuron, it stops dividing. Once a cell reaches that point, we refer to it as being post-mitotic. Cancer is what happens when post-mitotic cells start dividing uncontrollably to form tumors. Patients die when tumors interfere with normal body functions enough to kill them.

Cancer is a disease of uncontrolled cell growth. This video was created

by Cold Spring Harbor Laboratory and licensed under a Creative Common

Attribution Noncommercial-No Derivative Works 3.0 US license.

Cancer-related genes fall into two broad categories: tumor suppressors and oncogenes. Tumor suppressors keep cells from dividing or cause cells to kill themselves when they take too much damage. Oncogenes help cells survive or promote cell division. A careful balance between tumor suppressors and oncogenes allow cells to divide when needed but only under strict control.

For a cell to become cancerous, there have to be multiple failures in tumor suppressors and oncogenes. Carcinogens cause cancer by interfering with tumor suppressors and oncogenes, often by mutating them. If high levels of carcinogens bombard a cell for a long time, the number of mutations can overwhelm the redundant fail-safe systems. When that happens, you get cancer.

Cancer is hard to treat because it can take on many diverse forms. Treatments that work for one cancer might not work for others. Some cancers are particularly aggressive and progress rapidly while other cancers are slow to develop. Cancers can kill at high rates or can rarely do so.

On the other hand, many cancers have a lot in common. We’re hoping that if we discover what all cancers have in common, we’ll be able to cure it. Leading the charge is The Cancer Genome Atlas¹ (TCGA), a large group of scientists working together to sequence the genome from tumors isolated from thousands of patients to look for mutations shared by all cancers.

For example, mutations in the TP53 tumor suppressor gene appear to be common in many tumors^2-4. TP53 makes the p53 protein, which monitors the genome for mutations and signals the cell to either repair DNA damage or die so the cell doesn’t become cancerous². p53 is one of the principal tumor suppressor proteins in the cell, and TCGA estimates it’s mutated in half of all tumors^3-4.

In addition to the p53 tumor suppressor, tumors seem to have high rates of mutations in the PIK3CA oncogene. Affecting almost 20% of tumors across all cancer types, PIK3CA mutants signal the cell to divide uncontrollably³. Mutations in other oncogenes like PIK3CA are common in many cancers.

TP53 and PIK3CA are only two genes out of hundreds that may be commonly mutated in cancer. The problem with cancer is that even if we develop drugs that specifically target those proteins, the disease can evade those drugs by accumulating more mutations in different genes. Not all of the cells in a tumor carry the same mutations, and a handful of cells that survive one anti-cancer therapy could continue to divide to cause the tumor to grow back.

Cancer is the bane of developed nations. With the advent of both modern public health practices and antibiotics in the first half of the twentieth century, cancer replaced infectious disease as one of the biggest health threats. In 1971, President Nixon signed the National Cancer Act of 1971, effectively starting what the lay press calls the “War on Cancer⁵.”

Over 40 years later, progress against cancer has been…mixed.

We’ve undoubtedly made enormous advances in treating certain cancers, particularly childhood cancers. Other cancers, such as pancreatic cancer, have roughly the same prognosis they did several decades ago.

If we’ve learned anything from TCGA, it’s that cancers may be infinitely more complicated than we feared. Mutations common to one cancer may not occur in another^3-4. To win the War on Cancer, we need to accept the fact that it’s going to be a long fight. We just have to keep trying.

References

http://cancergenome.nih.gov/
http://cshperspectives.cshlp.org/content/2/1/a001008.long
http://www.nature.com/nature/journal/v502/n7471/full/nature12634.html
http://www.nature.com/ng/journal/v45/n10/full/ng.2762.html
http://legislative.cancer.gov/history/phsa/1971

Tuesday, August 11, 2015

Too many chromosomes

This question was submitted by my dad, who wanted to know what caused Down Syndrome.

At this point, I think it’s hard to deny we’re making great strides with Down Syndrome, both from a cultural and medical standpoint.

Just last week, the 2015 Special Olympic World Games wrapped up in Los Angeles after its arguably best year ever. Michelle Obama opened the games, and ESPN televised the ceremony¹. Special Olympics athletes, many with Down syndrome, set new world records².

From a medical standpoint, the gains for individuals with Down syndrome are also tremendous. A little over a hundred years ago, Down syndrome life expectancy was less than 10 years, but now people with Down Syndrome routinely live well past 50³.

Most of us are familiar with Down syndrome. Many, but by no means all, people with Down syndrome have a characteristic appearance and have challenged intellectual development⁴. Thanks to modern advances, Down syndrome patients live full, happy, productive lives.

But what exactly causes it?

Down syndrome is known as Trisomy 21 in medical and scientific circles because it’s caused by an extra copy of chromosome 21. The human genome is split into 23 chunks known as chromosomes, numbered 1-22; the 23^rd chromosome is the sex chromosome (i.e. X and Y chromosomes). A normal, healthy individual will have 46 total chromosomes in the average cell, one set of 23 chromosomes coming from the mother and the other set of 23 chromosomes coming from the father. People with Down syndrome have an extra copy of chromosome 21, giving them 47 chromosomes total.

That extra copy of chromosome 21 comes from an error occurring during a process known as meiosis, the process that makes oocytes (a.k.a. eggs) and sperm. Meiosis is different from normal cell division (mitosis) because instead of making two identical copies of a cell after dividing, the cell splits into two unique cells with half the number of chromosomes.

When oocytes and sperm fuse, they make a fertile cell with 46 chromosomes that develops into a fetus. This recombination of genetic information from generation to generation allows for the diversity we see in the human population and protects us from becoming vulnerable to genetic and infectious diseases.

Each oocyte or sperm is supposed to have only one copy of each chromosome, but the cell sometimes makes a mistake during meiosis. Sometimes an oocyte or sperm will get two (or no) copies of a particular chromosome, and we call this chromosomal nondisjunction. If an oocyte gets two copies of chromosome 21 instead of only one and it’s fertilized by a sperm, it will develop into a child with three copies of chromosome 21 (hence the name Trisomy 21), causing Down syndrome.

Getting the wrong number of chromosomes in a sex cell is much more common than many people think. A surprising number of pregnancies—1 in 5, at least—result in miscarriage, and medical researchers think that half of those miscarriages happen because of chromosomal nondisjunction⁵. Having the wrong number of chromosomes in an embryo is almost always fatal very early in pregnancy, and most of these miscarriages happen before the mother even knows she’s pregnant.

Animals are particularly sensitive to something called gene dosage, which means that we need two copies of each gene—no more and no less—in order to function normally. Many genetic diseases result from having only one functioning copy of a gene, or in the case of Down syndrome, from having three copies of all the genes found on chromosome 21. People with Down syndrome simply have too much of what they need from that chromosome in every cell.

Chromosome 21 is one of the only chromosomes we can survive with if we have an extra copy of it. Chromosomes are numbered based on their size; chromosome 1 is the largest chromosome and chromosome 22 is the smallest. Because chromosome 21 is so small compared to some of the larger chromosomes, the excessive genetic material from chromosome 21 isn’t fatal.

Trisomies with larger chromosomes produce diseases that are much more severe than Down syndrome. Patau syndrome (a.k.a. Trisomy 13), for example, causes severe nervous system and urogenital defects, and the few fetuses carried to full term perish only 4 months after being born⁵. Likewise, infants born with Edwards syndrome (a.k.a. Trisomy 18) have severe organ system defects and rarely survive past their first year⁵.

By comparison, Down syndrome is relatively mild. Although people with Down syndrome are likely to suffer hearing loss, vision problems, and leukemia^4,7, they can live long, full lives.

There is still much to learn about Down syndrome. That being said, people with Down syndrome now live over 40 years longer and have much happier lives than they did at the turn of the 20^th century. If we came that far last century, the next century should hold plenty of promise.

References

http://www.nytimes.com/aponline/2015/07/26/us/ap-us-special-olympics.html

http://www.npr.org/2015/08/03/428901750/after-9-days-special-olympics-world-games-come-to-a-close

http://www.who.int/genomics/public/geneticdiseases/en/index1.html

http://www.cdc.gov/ncbddd/birthdefects/downsyndrome.html

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991414/

http://www.ncbi.nlm.nih.gov/pubmed/19212162

http://www.ncbi.nlm.nih.gov/pubmed/8197171

Monday, August 3, 2015

Eye drops for cataracts

Medical researchers may have found a way to treat cataracts with eye drops instead of surgery, the long-sought Holy Grail for lens biologists.

When light enters the eye, a structure called the lens helps to focus it onto the light-sensitive retina in the back of the eye. In order to do this, the lens needs to be completely transparent. Put simply, a cataract is a lens that became opaque.

Unlike most other cells in the body that produce thousands of different types of proteins, cells in the lens produce only a few different types of proteins called crystallins. These crystallin proteins pack together in a specific way to form the lens’ transparent structure¹. A cataract forms when crystallins aggregate, or clump together, to make the lens opaque². Often, cataracts only appear in elderly patients.

In the US, it’s easy to dismiss cataracts as a relatively trivial problem because they’re so easy to treat here. Before cataracts significantly impair vision, patients can get a routine, relatively simple surgery performed to have them removed. In place of the original lens in the eye, surgeons implant an artificial lens, called an intraocular lens, or IOL³. After surgery, the problem is effectively fixed for the rest of their lives.

Cataract removal unfortunately isn’t an option for many patients in underdeveloped nations. According to the World Health Organization (WHO), cataracts account for ~48% of cases involving significant visual impairment⁴. Cataract patients in the underdeveloped parts of the world eventually lose their vision because IOL implant surgery isn’t widely available.

In addition to the elderly, cataracts can develop early in childhood or as the result of an injury to the eye. Childhood cataracts are known as congenital cataracts and are usually the result of some sort of genetic disease.

Unlike in adults, IOL implantation in children isn’t as straightforward because of complications surrounding the surgery in young patients. Early surgical intervention is critical to prevent problems with eye growth and visual cortex development in the brain, but the surgery itself also can cause problems in children. Even when a surgeon successfully removes a cataract in a child, there is a significant risk of amblyopia (lazy eye), glaucoma, severe inflammation, and retinal detachment (when the light-sensitive retina rips away from the back of the eye)³.

Because surgery isn’t a great option for children and is unavailable to many patients in poorer parts of the world, lens biologists have worked for decades towards a better treatment option. Eye drops, like the one proposed by a group of researchers recently, may be that better option. The researchers conducting the study stumbled upon the treatment when they were looking at some families with a history of congenital cataracts.

When they were looking at these families to try to gain some understanding about how cataracts form, they found these families had mutations in the LSS gene that codes for a protein known as lanosterol synthase. This protein is critical for the production of lanosterol, a molecule derived from cholesterol that is common in the lens².

Because lanosterol is abundant in the lens and these people had problems making the molecule, the researchers conducting the study delivering lanosterol by eye drop could fix the cataract. When they tried the eye drops in rabbit lenses, the cataracts dissolved in a matter of hours².

Excited by these results, the researchers decided to test the same eye drops in older dogs. Dogs, like humans, can have either congenital cataracts or develop them with age⁵. Also, like humans in underdeveloped parts of the world, dogs aren’t normally treated for cataracts by surgery, either because of cost or because veterinary ophthalmologists aren’t common. When the researchers tried the lanosterol eye drops in elderly dogs with cataracts, the dogs’ cataracts also improved².

In many ways, it’s hard to overstate how important this study is. Although most people with cataracts don’t have mutations in the LSS gene or have problems with lanosterol synthesis, the fact these eye drops helped aging dogs suggests the eye drops may also work in aging humans.

Because of the time it takes to get FDA approval to start clinical trials and enroll patients, we probably won’t know whether they work in humans for years. That being said, the researchers conducting this study did a fantastic job. I am very encouraged by this study and hope this will lead to a better, more widely available treatment for an incredibly common cause of blindness.

Correction: This post originally reported lanosterol eye drops were administered to engineered mice. In fact, the drops were administered to rabbits.

References

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2666974/pdf/nihms84083.pdf

http://www.nature.com/nature/journal/v523/n7562/full/nature14650.html

http://www.ncbi.nlm.nih.gov/pubmed/23224414

http://www.who.int/blindness/causes/en/

https://www.aspca.org/pet-care/dog-care/cataracts