I’m a bourbon researcher and chemistry professor who teaches classes on fermentation, and I’m a bourbon connoisseur myself. The complex science behind this aromatic beverage reveals why there are so many distinct bourbons, despite the strict rules around its manufacture.
All whiskeys have what’s called a mash bill. The mash bill refers to the recipe of grains that makes up the spirit’s flavor foundation. To be classified as bourbon, a spirit’s mash bill must have at least 51% corn – the corn gives it that characteristic sweetness.
Almost all bourbons also have malted barley, which lends a nutty, smoky flavor and provides enzymes that turn starches into sugars later in the production process.
Many distillers also use rye and wheat to flavor their bourbons. Rye makes the bourbon spicy, while wheat produces a softer, sweeter flavor. Others might use grains like rice or quinoa – but each grain chosen, and the amount of each, affects the flavor down the line.
Once distillers grind the grains from the mash bill and mix them with heated water, they add yeast to the mash. This process is called “pitching the yeast.” The yeast consumes sugars and produces ethyl alcohol and carbon dioxide as byproducts during the process called fermentation – that’s how the bourbon becomes alcoholic.
The fermented mash is now called “beer.” While similar in structure and taste to the beer you might buy in a six-pack, this product still has a way to go before it reaches its final form.
Yeast fermentation yields other byproducts besides alcohol and carbon dioxide, including flavor compounds called congeners. Congeners can be esters, which produce a fruity or floral flavor, or complex alcohols, which can taste strong and aromatic.
The longer the fermentation period, the longer the yeast has to create more flavorful byproducts, which enhances the complexity of the spirit’s final taste. And different yeasts produce different amounts of congeners.
During distillation, distillers separate the alcohol and congeners from the fermented mash of grains, resulting in a liquid spirit. To do this, they use pot or column stills, which are large kettles or columns, respectively, often made at least partially of copper. These stills heat the beer and any congeners that have a boiling point of less than 350 degrees Fahrenheit (176 degrees Celsius) to form a vapor.
Pot stills in a distillery. FocusEye/E+ via Getty Images
The type of still will influence the beverages’ final flavor, because pot stills often do not separate the congeners as precisely as column stills do. Pot stills result in a spirit that often contains a more complex mixture of congeners.
The desired vapors that exit the still are condensed back to liquid form, and this product is called the distillate.
A column still. MattBarlow92/Wikimedia Commons
Different chemical compounds have different boiling points, so distillers can separate the different chemicals by collecting the distillate at different temperatures. So in the case of the pot still, as the kettle is heated, chemicals that have lower boiling points are collected first. As the kettle heats further, chemicals with higher boiling points vaporize and then are condensed and collected.
By the end of the distillation process with a pot still, the distillate has been divided into a few fractions. One of these fractions is called the “hearts,” containing mostly ethanol and water, but also small amounts of congeners, which play a big role in the final flavor of the product.
After distillation, the “hearts” fraction (which is clear and resembles water) is placed in a charred oak barrel for the aging process. Here, the bourbon interacts with chemicals in the barrel’s wood, and about 70% of the bourbon’s final flavor is determined by this step. The bourbon gets all its amber color during the aging process.
Bourbon may rest in the barrel for several years. During the summer, when the temperature is hot, the distillate can pass through the inner charred layer of the barrel. The charred wood acts like a filter and strains out some of the chemicals before the distillate seeps into the wood. These chemicals bind to the charred layer and do not release, kind of like a water filter.
Barrels of bourbon age in a rickhouse, where they take on flavors from the barrel’s wood. The_Goat_Path/iStock via Getty Images
Under the charred layer of the barrel is a “red line,” a layer where the oak was toasted during the charring process of making the barrel. The toasting process breaks down starch and other polymers, called lignins and tannins, in the oak.
When the distillate seeps to the red-line layer, it dissolves the sugars in the barrel, as well as lignin byproducts and tannins.
During the cold winter months, the distillate retreats back into the barrel, but it takes with it these sugars, tannins and lignin byproducts from the wood, which enhance the flavors. If you disassemble a barrel after it has aged bourbon, you can see a “solvent line,” which shows how far into the wood the distillate penetrated. The type of oak barrel can have a profound effect on the final taste, along with the barrel’s size and how charred it is.
For most distilleries, barrels are stored in large buildings called rickhouses. Ethyl alcohol and water in the distillate evaporate out of the barrel, and the humidity in that part of the rickhouse plays a big role.
Lower humidity often leads to higher-proof bourbon, as more water than ethanol leaves the barrel. In addition, air enters the barrel, and oxygen from the air reacts with some of the chemicals in the bourbon, creating new flavor chemicals. These reactions tend to soften the taste of the final product.
There are thousands of bourbons on the market, and they can be distinguished by their unique flavors and aromas. The variety of brands reflects the many choices that distillers make on the mash bill, fermentation and distillation conditions, and aging process. No two bourbons are quite the same.
Michael W. Crowder, Professor of Chemistry and Biochemistry, Miami University
This article is republished from The Conversation under a Creative Commons license. Read the original article.
I am a neurologist and neuroscientist who has spent my career studying Alzheimer’s disease and dementia both in the laboratory and in the clinic. Determining how genes affect brain chemistry is vital to understanding how Alzheimer’s disease progresses and devising interventions to prevent or delay cognitive decline.
In the early 1990s, scientists proposed the amyloid hypothesis to explain how Alzheimer’s disease develops. The first neuropathological changes detected in the brain of Alzheimer’s disease patients were the formation of amyloid plaques – clumps of protein pieces called beta-amyloid. Other changes in the Alzheimer’s brain, such as the accumulation of another type of abnormal protein called neurofibrillary tangles, were thought to develop later in the course of the disease.
Beta-amyloid begins to accumulate in the brain up to 15 years before symptoms emerge. Symptoms correlate with the number of neurofibrillary tangles in the brain – the more tangles, the worse the cognition. Researchers have tried to determine whether preventing or removing amyloid plaques from the brain would be an effective treatment.
Alzheimer’s disease results from the accumulation of abnormal proteins in the brain.
Imagine the excitement of the scientific community in the 1990s when researchers identified three different genes causing familial Alzheimer’s disease – and all three were involved with beta-amyloid.
The first was the amyloid precursor protein gene. This gene directs cells to produce the amyloid precursor protein, which breaks down into smaller fragments, including the beta-amyloid that forms amyloid plaques in the brain.
The second gene was termed presenilin 1, or PSEN-1, a protein needed to cut the precursor protein into beta-amyloid.
The third gene, presenilin 2, or PSEN-2, is closely related to PSEN-1 but found in a smaller number of families with familial Alzheimer’s disease.
These findings added strength to the amyloid hypothesis explanation of the disease. However, uncertainty and opposition to the amyloid hypothesis have developed over the past several decades. This was in part tied to a recognition that several other processes – neurofibrillary tangles, inflammation and immune system activation – are also involved in the neurodegeneration seen in Alzheimer’s.
The hypothesis also got significant pushback after many clinical trials attempting to block the effects of amyloid or remove it from the brain were unsuccessful. In some cases, treatments had significant side effects. Some researchers have come up with strong defenses of the hypothesis. But until a clinical trial based on the amyloid hypothesis could show definitive results, uncertainty would remain.
The vast majority – more than 90% – of Alzheimer’s cases occur in late life, with disease prevalence increasing progressively from age 65 and up. Such cases are mostly sporadic, with no clear family history of Alzheimer’s.
However, a relatively small number of families have one of the three known genetic mutations that cause the disease to be passed down. In familial Alzheimer’s, 50% of each generation will inherit the mutated gene and develop the disease much earlier, usually from their 30s to early 50s.
In 2019 and 2023, researchers identified changes in at least two other genes that markedly delayed the onset of disease symptoms in people with familial Alzheimer’s disease mutations. These mutated genes were found in a very large family in Colombia whose members tended to develop Alzheimer’s symptoms by their 40s.
A woman in the family carrying a mutated PSEN-1 gene did not have any cognitive symptoms until she was in her 70s. A genetic analysis showed that she had an additional mutation in a variant of the gene that codes for a protein called apolipoprotein E, or ApoE. Researchers believe the mutation, called the Christchurch variant – named after the city in New Zealand where the mutation was first discovered – is responsible for interfering with and slowing down her disease.
Importantly, her brain had a great deal of amyloid plaque but very few neurofibrillary tangles. This suggests that the link between the two was broken and that the suppressed number of neurofibrillary tangles also slowed down cognitive loss.
Researchers have studied certain families in Colombia with rare genetic variants that slow the progression of Alzheimer’s disease.
In May 2023, researchers reported that two siblings in the same large family also did not develop memory problems until their 60s or late 70s and were found to carry a mutation in a gene that codes for a protein called reelin. Studies in mice suggest that reelin has protective effects against amyloid plaque deposition in the brain. In these patients’ brains, as with the patient who had the Christchurch variant, there were extensive amyloid plaques but very few neurofibrillary tangles. This observation confirmed that the tangles are responsible for the cognitive loss and that there are several ways to “disconnect” amyloid and neurofibrillary tangle accumulation.
Finding medicines that might mimic the protective effects of the Christchurch variant or the reelin mutation could help delay Alzheimer’s disease symptoms for all patients. Since the vast majority of nonfamilial Alzheimer’s manifests after age 70 or 75, a 10-year delay in the emergence of first symptoms of Alzheimer’s could have a massive effect in decreasing the prevalence of the disease.
These findings demonstrate that Alzheimer’s can be slowed and will hopefully lead to additional new therapies that can someday not only treat the disease but prevent it as well.
Despite over 20 years of doubts and therapy failures, the past several years have seen positive results from three different treatments – aducanumab, lecanemab and donanemab – that remove amyloid plaques and slow loss of cognitive function to some extent. Although there is still discussion of how much slowing of decline is clinically significant, these successes provide support for the amyloid hypothesis. They also suggest that other strategies will be needed for optimal treatment.
The FDA approved the Alzheimer’s drug aducanumab (Aduhelm) in June 2021, to much controversy.
The U.S. Food and Drug Administration’s 2021 approval of the first antibody treatment for Alzheimer’s, aducanumab, sold under the brand name Aduhelm, was controversial. Only one of the two clinical trials testing its safety and effectiveness in people yielded positive results. The FDA approved the drug on the basis of that single study through an accelerated approval process in which treatments meeting an unmet clinical need can receive expedited approval.
The second antibody, lecanemab, sold as Leqembi, was approved in January 2023 via the same accelerated approval pathway. It was then fully approved in July 2023.
The third antibody, donanemab, completed a successful phase three clinical trial and is awaiting more safety data. When that is submitted to the FDA, the agency will consider the drug for approval.
Steven DeKosky, Professor of Neurology and Neuroscience, University of Florida
This article is republished from The Conversation under a Creative Commons license. Read the original article.
As pharmacists who see patients who have stopped multiple medications because of side effects or ineffectiveness, we believe pharmacogenomic testing has the potential to help guide health care professionals to more precise dosing and prescribing.
PGx tests look for variations within the genes of your DNA to predict drug response. For instance, the presence of one genetic variant might predict that the specific protein it codes for is unable to break down a particular medication. This could potentially lead to increased drug levels in your body and an increased risk of side effects. The presence of another genetic variant might predict the opposite: It might predict that the protein it codes for is breaking down a medication more rapidly than expected, which may decrease the drug’s effectiveness.
For example, citalopram is an antidepressant broken down by a protein called CYP2C19. Patients with genetic variants that code for a version of this protein with a reduced ability to break down the drug may have an increased risk of side effects.
PGx is a form of personalized or precision medicine.
Currently, there are over 80 medications with prescribing recommendations based on PGx results, including treatments for depression, cancer and heart disease. There are commercially available PGx tests that patients can have sent directly to their doorstep with or without the involvement of a health care professional. These direct-to-consumer PGx tests collect DNA from either a saliva sample or cheek swab that is then sent to the laboratory. Results can take anywhere from a few days to a few weeks depending on the company.
Some companies require a consultation with a health care provider, often a pharmacist or genetic counselor, who can facilitate a test order and discuss any medication changes once the results come back.
PGx testing will not be able to predict how you will respond to all medications for several reasons.
First, most PGx tests do not look for every possible variant of every gene in the human genome. Instead, they look only at a limited number of genes and variants strongly linked to specific drugs. PGx tests can predict how you will respond only to medications associated with the genes it tests for.
Some drugs are broken down in very complicated pathways entailing multiple proteins and byproducts, and the usefulness of PGx testing for them remains unclear. For example, the antidepressant bupropion has three major pathways involved in its breakdown and forms three active byproducts that can interact with other drugs or body processes. This makes predicting how you will respond to the drug much more challenging because there is more than one variable involved. In many cases, there also isn’t conclusive data to confidently predict the general function of a protein and how it would affect your response to a drug.
The applicability of PGx test results is additionally limited by a lack of diversity of study participants. Typically, populations of European ancestry are overrepresented in clinical trials. An ongoing research initiative by the National Institutes of Health called the All of Us Research Program aims to address this issue by collecting genetic samples from people of diverse backgrounds.
The All of Us research program seeks to conduct research that is more representative of a diverse population.
Another limitation of direct-to-consumer PGx tests is that they can predict drug response based only on your genetics. Lifestyle and environmental factors such as your age, liver or kidney function, tobacco use, drug interactions and other diseases can heavily influence how you may respond to medication. For example, leafy greens with high amounts of vitamin K can lower the effectiveness of the blood thinner warfarin. But PGx tests don’t take these factors into account.
Finally, your PGx results may predict that you may respond to medications differently, but this does not guarantee that the medication won’t have its intended effect. In other words, PGx testing is predictive rather than deterministic.
PGx testing carries the risk of not telling the whole story of drug response. If variations within the gene are not found, the testing company often assumes the proteins those genes code for function normally. Because of this assumption, someone carrying a rare or unknown variant may receive inaccurate results.
It may be tempting for some people to see their results and want to change their dose or discontinue their medications. However, this can be dangerous. Abruptly stopping some medications may cause withdrawal effects. Never change the way you take your medications without consulting your pharmacist and physician first.
Sharing your PGx test results with all the clinicians involved in your care can help prevent medication failure and improve safety. Pharmacists are increasingly trained in pharmacogenomics and can serve as a resource to address medication-related questions or concerns.
PGx tests that are not authorized by the Food and Drug Administration cannot be clinically interpreted and therefore cannot be used to inform prescribing. Results from these tests should not be added to your medical record.
Direct-to-consumer PGx testing can empower patients to advocate for themselves and be an active participant in their health care by increasing access to and knowledge of their genetic information.
Patients’ knowledge of their PGx genetic profile has the potential to improve treatment safety. For example, a 2023 study of over 6,000 patients in Europe found that those who used their PGx results to guide medication therapy were 30% less likely to experience adverse drug reactions.
Most PGx test results stay valid throughout a patient’s life, and retesting is not needed unless additional genes or variants need to be evaluated. As more research on gene variants is conducted, prescribing recommendations may be updated.
Overall, genetic information from direct-to-consumer PGx tests can help you collaborate with health care professionals to select more effective medications with a lower risk of side effects.
Kayla B. Rowe, Fellow in Clinical Pharmacogenomics, University of Pittsburgh; Lucas Berenbrok, Associate Professor of Pharmacy and Therapeutics, University of Pittsburgh, and Philip Empey, Associate Professor of Pharmacogenomics, University of Pittsburgh
This article is republished from The Conversation under a Creative Commons license. Read the original article.
