Why Pharmaceutical Companies Care About Your Saliva

Earwax stickiness. Neanderthal ancestry. Caffeine metabolism. Tasting soap when you eat cilantro. Direct-to-consumer genotyping companies like 23andme boast this kind of information in exchange for a tube of your finest spit and a chunk of change about equivalent to a week’s worth of groceries. In the process of unlocking the whimsy of the human genome, however, companies that deal in providing genetic information to consumers have amassed an enormous collection of data.

Unique genetic variants are responsible for many of our traits — including disease.

Nearly 80% of 23andme’s consumers consent to have their information used for research purposes. One of the most valuable applications for information about millions of genomes and their owners is to uncover genes that can be targeted for therapies to treat diseases. A new multi-million-dollar collaboration between pharmaceutical company GlaxoSmithKline and 23andme promises to make identification of pharmaceutical targets quicker and aid in the design of therapies that are more likely to succeed in clinical trials on an unprecedentedly large scale.

But what does this have to do with whether you like the taste of cilantro? To find out, we first need to dive in to what kind of data direct-to-consumer genotyping companies have and how they get it.

In order to keep costs lower for the company and the consumer, most direct-to-consumer genetic testing companies use a simple method called a DNA microarray to test for specific snippets of the genome that are correlated with certain characteristics.

DNA microarray chip. Spots glow when a perfect match is made between query DNA and probe DNA that is linked to the chip.
Source: NASA

To generate the DNA microarray, microscopic “spots” of DNA are linked to the surface of a tiny chip. These “probe” DNA sequences pair with specific sequences in the human genome that signify certain traits. Often, these specific sequences are portions  of the genome where one individual may differ from another by a single nucleotide. The substitution of one base pair for another at a specific site in the genome is called a single nucleotide polymorphism, or a SNP. Many SNPs are commonly associated with specific traits, and are therefore a mainstay for direct-to-consumer genotyping companies. Only a fraction of existing SNPs are known to correlate with certain traits or diseases, limiting the number of probe sequences needed to test a single individual.

The company typically requests a saliva sample, which would contain both white blood cells and skin cells from within the mouth that are suitable for purifying large quantities of DNA. Once the saliva sample is received, DNA is extracted and subjected to an amplification process which generates more copies of the DNA from the sample. The DNA is then heated so that it no longer binds to its original pairing strand. Proteins that can cut DNA are then used to chop the genome into smaller pieces. From here, the DNA fragments are tagged with a unique fluorescent molecule that can track the position of the query DNA on the microchip. The processed sample is then applied to the chip, where query DNA will pair with probe DNA if it is complementary in sequence. To obtain test results, the microchip is analyzed for bright spots, which represent a positive test result for the genetic variant at that position on the microarray. Direct-to-consumer genetic testing companies typically include a catalog of probe DNA sequences that are strongly associated with specific traits, common ancestral backgrounds, and predisposition to a small subset of diseases.

So how can this information be useful to pharmaceutical companies? The answer is in the numbers. Associating features of the genome with traits or disease requires a large sample size to give the us more confidence that the association is real, and doesn’t simply occur because of random chance. Take the example of a SNP in the genome. Each human genome has about 10 million SNPs, or about 1 SNP per 300 base pairs. Some of these SNPs are insignificant and will be averaged out in the context of 2 million genomes. However, if a SNP is significantly associated with a disease, it will be found proportionally more often in genomes of people who have or are predisposed to having a disease compared to normal individuals. Pharmaceutical companies increasingly rely on finding new drug targets to develop new therapies, and are looking deeper into the genome to find new gene targets for therapies. Where to start? Genes with variations that correlate with certain traits or diseases –the exact information you can purchase from a direct-to-consumer genotyping service.

An approach to parsing these millions of genomes is referred to as PheWAS (phenome-wide association study). This study begins by looking at a genetic variant such as a SNP, and seeks to determine whether this variant is associated with a particular trait or set of traits in the individuals who have the variant. The data collected by direct-to-consumer genotyping companies are well-suited to be analyzed by PheWAS, as the companies often collect self-reported survey information on their customers. Myriad symptoms can be linked back to a single genetic variant with the power of huge genomic datasets to jumpstart the therapies of the future.

Old approaches allowed scientists to start with a trait and find common genetic variants in individuals with this trait. Here, scientists trace facial features back to common genetic variants. Approaches like PheWAS, however, start with the genetic variant and analyze the range of traits associated with the variant in many individuals.
Source: Kaustubh Adhikari, T. F., et al. Nature Communications. (2016) (Wikimedia Commons)

Access to large databases of genotyping information may also give pharmaceutical companies further insight into more complex traits that are determined by a wide array of genes. An example of a complex trait is human height. There are a massive number of SNPs that contribute to the height of an individual. If you divide the genome up into ~30,000 equivalent-sized sections, nearly every one of these sections contributes to a person’s height. Many of the genetic variants that affect someone’s height are seemingly random and can only be identified by using large amounts of data. Similar to height, human disease is also connected to a combination of many genetic variants. It’s likely that pharmaceutical companies will begin looking not only at the genes that we think contribute to disease, but also throughout the rest of the genome for previously unknown variants that might be to blame. This information can be used to find new genes to target and help to avoid clinical pitfalls of previous drug strategies which were largely inefficient.

Despite the promises of big data in big pharma, it is unclear as yet whether or not partnerships between direct-to-consumer genotyping companies and pharmaceutical companies will be fruitful. Undoubtedly, developing drugs to treat diseases that have ineffective or nonexistent therapies is an attractive possibility. Furthermore, projects like these could promote a personalized medicine approach, where treatments are tailored to one’s specific therapeutic needs, as signified by their genome. An in-house effort within 23andme uses customer data to peg new drug targets. They claim to have uncovered 10 new targets for drug development. However, this collaboration raises the issue of consumers paying for the privilege of having their genomes used to garner profits for both their genotyping service and a pharmaceutical giant. A caveat to using such datasets is that the sample genomes mostly represent middle-to-upper-class individuals who live in Western countries, limiting the scope of the potential therapies developed as a result of the collaboration. Nevertheless, the marriage of genotype big-data and drug development holds exciting promise for the future of targeted therapies.

Peer edited by Jacob Pawlik and Giehae Choi.

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The Science Behind Spitting for your At-home Genetic Test

Conjuring up two milliliters of spit after not eating/drinking 30 minutes prior doesn’t sound taxing, but give it a try, and you’ll quickly change your mind. Four years ago, I sat in my kitchen wafting the scent of freshly baked brownies into my face in an attempt to make myself salivate. Voilá! I finally produced enough spit for my 23andMe kit and rewarded myself with a brownie. In 6-8 weeks, I would learn more about my health and ancestry, all thanks to just two milliliters of saliva. Best Christmas gift ever…thanks, mom and dad!

Popularity for these at-home genetic testing kits has soared in recent years. For example, AncestryDNA sold about 1.5 million kits in three days alone last fall. People love buying these DNA kits as a holiday gift, and it’s one of Oprah’s favorite things, so why wouldn’t you want to purchase one? Given the general affordability of these non-invasive tests and the variety of kits to choose from, it’s easy to participate in the fun.

https://commons.wikimedia.org/wiki/File:Tongue1.png & https://pixabay.com/en/genetics-chromosomes-rna-dna-156404

After scientists receive your at-home genetic kit, they isolate cells from your saliva and unravel the chromosomes in your DNA. Then they read your base pairs like a book and check for specific genetic markers that indicate risk of a certain disease. Your ancestry is determined by comparing your genetic markers to a reference database.

I’m amazed that information about my ancestors’ migration pattern is extracted from the same fluid that helped disintegrate the brownie I just ate. In addition to the enzymes that aid in digestion, human saliva contains white blood cells and cells from the inside of your cheeks. These cells are the source of DNA, which is packaged inside your chromosomes. Humans carry two sex chromosomes (XX or XY) and 22 numbered chromosomes (autosomes). Chromosomes are responsible for your inherited traits and your unique genetic blueprint. During a DNA test, scientists unravel your chromosomes and read the letters coding your DNA (base pairs) to check for specific genetic markers.

Companies perform one or multiple kinds of DNA tests, which include mitochondrial DNA (mtDNA), Y-chromosome (Y-DNA), or autosomal DNA. An mtDNA test reveals information about your maternal lineage since only women can pass on mitochondrial DNA. mtDNA codes for 37 out of the 20,000-25,000 protein-coding genes in humans. Y-DNA test is for male participants only and examines the paternal lineage. This DNA accounts for about 50-60 protein-coding genes. Autosomal DNA testing is considered the most comprehensive analysis, since autosomes include the majority of your DNA sequences and the test isn’t limited to a single lineage. However, companies don’t fully sequence your genome because then the at-home kits could no longer be affordable. Instead the tests look at about 1 million out of 3 billion base pairs.

But how reliable are these tests if less than one percent of your DNA is sequenced? When detecting genetic markers that could increase disease risk, these tests are very accurate since scientists are searching for known genes associated with a certain disease. However, the reliability of predicting your ancestry is another story.

Using DNA to determine ethnicity is difficult since ethnicity is not a trait determined by one gene or a combination of genes. Scientists analyze only some of your genome and compare those snippets of DNA to that of people with known origins. For example, Ancestry uses a reference panel that divides the world into 26 genetic regions with an average of 115 samples per region. If your results show that you’re 40% Irish, then that means 40% of your DNA snippets is most similar to a person who is completely Irish. Each company has their own reference database and algorithm to decide your ethnic makeup, so it’s likely that you would receive different results if you sent your DNA to multiple companies.

At-home genetic tests are an exciting and affordable way to explore the possibilities of your genetic makeup and can paint a general picture of your identity. While the specifics of the ethnicity results may be a bit unreliable, at least it’s a good starting point if you’re interested in building your family tree!

Peer edited by Nicole Fleming.

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No Fermentable Foods? Yes Please!

Created by Kaylee Helfrich

Many foods aren’t allowed on the low-FODMAP diet.

No bread. No sugar. No rice, potatoes, corn, soy, milk, onions, garlic, chocolate, processed meats, or alcohol. Is this a starvation diet or a method of torture? Actually, this is a diet with a 7086% success rate in relieving the symptoms of a disorder that is notoriously difficult to treat. This diet is called the “low-FODMAP” diet, which is short for “restriction of Fermentable Oligosaccharide, Disaccharide, Monosaccharide, and Polyols in the diet”. Thank goodness for the FODMAP acronym to prevent that mouthful of words!

The low-FODMAP diet treats a disorder called Irritable Bowel Syndrome (IBS), which is characterized by stomach pain, bloating, diarrhea or constipation, and general gastrointestinal discomfort. According to Dr. Miranda van Tilburg, an associate professor in medicine from UNC-Chapel Hill who studies IBS, people with IBS often have a very low quality of life. “Those with IBS frequently miss days of work and school, and anxiety and depression are very common as people worry about future symptoms and how those symptoms will impact their life,” she says.

IBS is a common disorder with a global prevalence of 10-20%. It is clinically diagnosed based on certain symptoms. Unfortunately, the exact cause of IBS is unknown, but it is thought to be triggered by multiple issues including changes in gut motility, increased sensitivity of intestinal nerves, bacterial growth in the small intestine, intestinal inflammation, and psychological factors. Although medicines exist to treat IBS, they do not always provide adequate relief and often cause unwanted side effects. Instead, a combination of diet, exercise, and even hypnotherapy often provide more relief with fewer side effects.

A large component of treatment for IBS is diet management. Tilburg points out a few well-known triggers of IBS symptoms, including spicy and fatty foods, along with incompletely absorbed carbohydrates. The low-FODMAP diet specifically addresses the latter dietary component.

What are FODMAPs, and how can a diet low in FODMAPs treat IBS symptoms? FODMAPs are carbohydrates, such as lactose, fructose, and sugar alcohols, that are difficult to absorb in the small intestine. When the FODMAPs are not absorbed, they produce intestinal water and gas. For various reasons, those with IBS often have more difficulty when consuming FODMAPs than other people.

Created by Kaylee Helfrich

FODMAPs can cause gastrointestinal discomfort via 2 methods.

The mechanism behind FODMAP-induced discomfort is twofold. First, when FODMAPs are not fully absorbed, they remain in the small intestine and attract water, which enters the small intestine in a process called osmosis. This leads to bloating as well as increased water delivery to the large intestine, which can cause diarrhea. Second, incompletely absorbed FODMAPs can be fermented by intestinal microbiota, leading to gas, which causes pain, bloating, and general discomfort.

Consequently, for some people with IBS, a diet low in these offending carbohydrates can be beneficial. In fact, six randomized controlled trials have shown benefits for IBS patients who consume a low-FODMAP diet. However, this diet is very restrictive concerning which foods can be eaten, so people can have trouble adhering to the diet if they are not properly supported by clinical guidance.

One question that many people ask is: how can someone follow a diet that cuts out virtually all of the delicious foods that are normally eaten? Although this diet is restrictive, it offers a good chance at relief for people who have usually lived with pain for years. And this diet is not meant to be followed forever. Tilburg explains that “every person’s case of IBS is unique, and every person will have different foods to which they are sensitive.” So after following the low-FODMAP diet for 2-6 weeks to reduce the food-induced symptoms, the excluded foods are slowly added back, and the patient is monitored by a dietician for adverse symptoms. If a certain food increases symptoms, then it is removed from the diet and other foods are tried instead.

Although it may seem impossible to go without your favorite chocolate cake or garlic bread, people with IBS often welcome the chance to reduce their symptoms, even if it requires a sacrifice of ice cream and deli sandwiches.

Peer edited by Alexandria Mullins.

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The Legacy of Minamata Disease


Map of Minamata Bay and River

During the 1950s, strange events began happening around Minamata Bay, located in the Kumamoto Prefecture of Japan. Fish floated belly-up and birds collapsed while flying. Cats convulsed, salivated excessively, jumped into the sea and drowned, or merely dropped dead. Eventually, a young girl was brought to a physician because she was having difficulty walking and talking, and it was discovered that her sister and other neighborhood children were showing the same symptoms. It wasn’t long until the physician declared that “an unclarified disease of the central nervous system has broken out.”

This mysterious disorder was officially recognized in 1956 and later termed Minamata Disease. In 1958, two doctors from the Kumamoto University published a report in The Lancet that described the disease as widespread degeneration of the nervous system, particularly in the cerebellum. Although they could not pinpoint the underlying cause, they noted that fisherman and their families were those that were primarily affected. This lead them to suggest that a toxic agent from the waste flowing into Minamata Bay from the nearby fertilizer factory was the cause. Many years before, in 1908, the Chisso Corporation opened a chemical factory in Minamata. The factory disposed of its waste into Minamata Bay and later to the mouth of the Minamata River, leading to the contamination of the entire Shiranui Sea. A year after The Lancet article was published, methylmercury, generated by acetaldehyde production at the factory, was identified to be the toxic agent. When the citizens of Minamata consumed fish and shellfish from the sea, they were poisoned by the methylmercury and the epidemic took hold. To date, over two thousand people have been affected by Minamata Disease.

In 1959, Chisso Corporation was ordered to switch the flow of its waste from the river back to the bay. In a display of grandeur, the Chisso Corporation also unveiled a newly installed water purification tank, which lead most people to believe Minamata Disease was resolved. However, the Chisso Corporation misled the public as the purification tank was not removing methylmercury from the waste. As a result, Minamata Disease continued to ravage the community in the years following. It wasn’t until 1968 that the government released an official conclusion that methylmercury, originating from the factory, caused the disease and that Chisso Corporation halted release of methylmercury into the sea. After hundreds lost their lives and years of lengthy legal battles, the Chisso Corporation and the state have paid millions of dollars to the Minamata disease victims. Additionally, in response to the epidemic, numerous environmental policy changes occurred. Japan set safe regulatory standards for mercury and methylmercury levels in fish and shellfish and also instituted clean up efforts in Minamata Bay. In 1997, Minamata Bay was officially declared safe and fishing efforts resumed. However, the outbreak of Minamata Disease remains one of the most influential environmental disasters to occur in Japan to date and is a reminder of the potential devastating effects of pollution.

Peer edited by Kelsey Noll.

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