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Enzymes are the engines of life − machine learning tools could help scientists design new ones to tackle disease and climate change

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theconversation.com – Sam Pellock, Postdoctoral Scholar in Biochemistry, University of Washington – 2025-02-13 13:02:00

Enzymes are the engines of life − machine learning tools could help scientists design new ones to tackle disease and climate change

Enzymes have complicated molecular structures that are hard to replicate.
Design Cells/iStock via Getty Images Plus

Sam Pellock, University of Washington

Enzymes are molecular machines that carry out the chemical reactions that sustain all life, an ability that has captured the attention of scientists like me.

Consider muscle movement. Your body releases a molecule called acetylcholine to trigger your muscle cells to contract. If acetylcholine sticks around for too long, it can paralyze your muscles – including your heart muscle cells – and, well, that’s that. This is where the enzyme acetylcholinesterase comes in. This enzyme can break down thousands of acetylcholine molecules per second to ensure muscle contraction is stopped, paralysis avoided and life continued. Without this enzyme, it would take a month for a molecule of acetylcholine to break down on its own – about 10 billion times slower.

You can imagine why enzymes are of particular interest to scientists looking to solve modern problems. What if there were a way to break down plastic, capture carbon dioxide or destroy cancer cells as fast as acetylcholinesterase breaks down acetylcholine? If the world needs to take action quickly, enzymes are a compelling candidate for the job – if only researchers could design them to handle those challenges on demand.

Designing enzymes, unfortunately, is very hard. It’s like working with an atom-sized Lego set, but the instructions were lost and the thing won’t hold together unless it’s assembled perfectly. Newly published research from our team suggests that machine learning can act as the architect on this Lego set, helping scientists build these complex molecular structures accurately.

What’s an enzyme?

Let’s take a closer look at what makes up an enzyme.

Enzymes are proteins – large molecules that do the behind-the-scenes work that keep all living things alive. These proteins are made up of amino acids, a set of building blocks that can be stitched together to form long strings that get knotted up into specific shapes.

The specific structure of a protein is key to its function in the same way that the shapes of everyday objects are. For example, much like a spoon is designed to hold liquid in a way that a knife simply can’t, the enzymes involved in moving your muscles aren’t well suited for photosynthesis in plants.

For an enzyme to function, it adopts a shape that perfectly matches the molecule it processes, much like a lock matches a key. The unique grooves in the enzyme – the lock – that interact with the target molecule – the key – are found in a region of the enzyme known as the active site.

Diagram showing a substrate binding to an enzyme, changing both the enzyme and its own shape, then getting released as two new products
The induced fit model of enzymes states that both the enzyme and its substrate change shape when they interact.
OpenStax, CC BY-SA

The active site of the enzyme precisely orients amino acids to interact with the target molecule when it enters. This makes it easier for the molecule to undergo a chemical reaction to turn into a different one, making the process go faster. After the chemical reaction is done, the new molecule is released and the enzyme is ready to process another.

How do you design an enzyme?

Scientists have spent decades trying to design their own enzymes to make new molecules, materials or therapeutics. But making enzymes that look like and go as fast as those found in nature is incredibly difficult.

Enzymes have complex, irregular shapes that are made up of hundreds of amino acids. Each of these building blocks needs to be placed perfectly or else the enzyme will slow down or completely shut off. The difference between a speed racer and slowpoke enzyme can be a distance of less than the width of a single atom.

Initially, scientists focused on modifying the amino acid sequences of existing enzymes to improve their speed or stability. Early successes with this approach primarily improved the stability of enzymes, enabling them to catalyze chemical reactions at a higher range of temperatures. But this approach was less useful for improving the speed of enzymes. To this day, designing new enzymes by modifying individual amino acids is generally not an effective way to improve natural enzymes.

Clump of spirals and threads, with a small molecule at its center
This model of acetylcholinesterase shows acetylcholine (green) bound to its active site.
Sam Pellock, CC BY-SA

Researchers found that using a process called directed evolution, in which the amino acid sequence of an enzyme is randomly changed until it can perform a desired function, proved much more fruitful. For example, studies have shown that directed evolution can improve chemical reaction speed, thermostability, and even generate enzymes with properties that aren’t seen in nature. However, this approach is typically labor-intensive: You have to screen many mutants to find one that does what you want. In some cases, if there’s no good enzyme to start from, this method can fail to work at all.

Both of these approaches are limited by their reliance on natural enzymes. That is, restricting your design to the shapes of natural proteins likely limits the kinds of chemistry that enzymes can facilitate. Remember, you can’t eat soup with a knife.

Is it possible to make enzymes from scratch, rather than modify nature’s recipe? Yes, with computers.

Designing enzymes with computers

The first attempts to computationally design enzymes still largely relied on natural enzymes as a starting point, focusing on placing enzyme active sites into natural proteins.

This approach is akin to trying to find a suit at a thrift store: It is unlikely you will find a perfect fit because the geometry of an enzyme’s active site (your body in this analogy) is highly specific, so a random protein with a rigidly fixed structure (a suit with random measurements) is unlikely to perfectly accommodate it. The resulting enzymes from these efforts performed much more slowly than those found in nature, requiring further optimization with directed evolution to reach speeds common among natural enzymes.

Recent advances in deep learning have dramatically changed the landscape of designing enzymes with computers. Enzymes can now be generated in much the same way that AI models such as ChatGPT and DALL-E generate text or images, and you don’t need to use native protein structures to support your active site.

YouTube video
AI tools are helping researchers design new proteins.

Our team showed that when we prompt an AI model, called RFdiffusion, with the structure and amino acid sequence of an active site, it can generate the rest of the enzyme structure that would perfectly support it. This is equivalent to prompting ChatGPT to write an entire short story based on a prompt that only says to include the line “And sadly, the eggs never showed up.”

We used this AI model specifically to generate enzymes called serine hydrolases, a group of proteins that have potential applications in medicine and plastic recycling. After designing the enzymes, we mixed them with their intended molecular target to see whether they could catalyze its breakdown. Encouragingly, many of the designs we tested were able to break down the molecule, and better than previously designed enzymes for the same reaction.

To see how accurate our computational designs were, we used a method called X-ray crystallography to determine the shapes of these enzymes. We found that many of them were a nearly perfect match to what we digitally designed.

Our findings mark a key advance in enzyme design, highlighting how AI can help scientists start to tackle complex problems. Machine learning tools could help more researchers access enzyme design and tap into the full potential of enzymes to solve modern-day problems.The Conversation

Sam Pellock, Postdoctoral Scholar in Biochemistry, University of Washington

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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Trans people affirmed their gender without medical help in medieval Europe − history shows how identity transcends medicine and law

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theconversation.com – Sarah Barringer, Ph.D. Candidate in English, University of Iowa – 2025-02-18 07:36:00

Trans people affirmed their gender without medical help in medieval Europe − history shows how identity transcends medicine and law

The Lady and the Unicorn: Sight.
Unknown/Musée de Cluny, Paris via Didier Descouens/Wikimedia Commons

Sarah Barringer, University of Iowa

Restrictions on medical care for transgender youth assume that without the ability to medically transition, trans people will vanish.

As of 2024, 26 U.S. states have banned gender-affirming care for young people. Less than a month into office, President Donald Trump issued numerous executive orders targeting transgender people, including a mandate to use “sex” instead of “gender” on passports, visas and global entry cards, as well as a ban on gender-affirming care for young people. These actions foreground the upcoming Supreme Court case of U.S. vs. Skrmetti which promises to shape the future of gender-affirming health care in the U.S., including restrictions or bans.

History, however, shows that withholding health care does not make transgender people go away. Scholarship of medieval literature and historical records reveals how transgender people transitioned even without a robust medical system – instead, they changed their clothes, name and social position.

Surgery in medieval times

Surgery was not a widespread practice in the medieval period. While it gained some traction in the 1300s, surgery was limited to southern France and northern Italy. Even there, surgery was dangerous and the risk of infection high.

Cutting off fleshy bits is an old practice and, potential dangers aside, removing a penis or breasts wasn’t impossible. But amputating functioning limbs was nearly always a form of punishment. Medieval people, including surgeons and patients, likely would not have had positive views of surgery that involved removing working body parts.

Watercolor diagram of various implements resembling scalpels
Illustration from a Latin translation of Albucasis’ Chirurgia, depicting surgical instruments.
Wellcome Collection

Surgeons in the 14th century were increasingly thinking about how to perform surgery on those with both male and female genitalia – people now called intersex. But they thought about this in terms of “correcting” genitalia to make it more apparently male or female – an attitude still present today. Historically, the procedure was probably performed on adults, but today it is usually performed on children. Both then and now, the surgery often disregards the patient’s wishes and is not medically necessary, at times leading to complications later. For patients deemed female, excess flesh could be cut away, and for patients deemed male, the vulva could be cauterized to close it.

There is, however, at least one historical example of a transgender individual receiving surgery. In 1300, near Bern, Switzerland, an unnamed woman was legally separated from her husband because she was unable to have sex with him. Soon after, the woman headed to Bologna, which was the surgery capital of Europe at the time. There, a surgeon cut open the woman’s vulva, revealing a penis and testicles. The account ends, “Back home, he took a wife, did rural work, and had legitimate and sufficient intercourse with his wife.”

The story presents the possibility of medical transition, possibly even a desire for it. But given the limits of surgical techniques and ideologies at the time, these forms of medical transition were unlikely to be common.

Transitioning without medicine

To transition without medicine, medieval transgender people relied on changes they could make themselves. They cut their hair, put on different clothes, changed their names, and found new places in society.

In 1388, a young woman named Catherine in Rottweil, Germany, “put on men’s clothes, declared herself to be a man, and called herself John.” John went on to marry a woman and later developed breasts. This caused some initial consternation – the city council of Rottweil sent John and his wife to court. However, the court did not see breasts as inhibiting John’s masculinity and the couple went home without facing any charges.

In 1395, a transgender woman named Eleanor Rykener appeared before a court in London, England, after she was caught working as a prostitute. The court clerk wrote “that a certain Anna … first taught [her] to practice this detestable vice in the manner of a woman. [She] further said that a certain Elizabeth Bronderer first dressed [her] in women’s clothing” and later she took on work as an embroideress and tapster, a sort of bartender. The account is Rykener’s own, but the court clerk editorialized it, notably adding the phrase “detestable vice” in reference to prostitution.

Medieval manuscript illustration of two people embracing in bed
Detail of lovers in bed, Aldobrandino of Siena, Le Régime du corps, northern France. 13th century.
British Library Catalogue of Illuminated Manuscripts/Sloane MS 2435, f. 9v.

Rykener’s account reveals that there were a number of people interested in helping her transition – people who helped her dress, taught her how to behave, provided her employment and supported her choice of a new name. Community was a more important part of her transition than transforming her body. Based on the record, she apparently did not make an effort to create breasts.

Another account appeared in 1355 in Venice, Italy, concerning Rolandina Ronchaia. While John declared himself male, and Rykener was very active in her transition, Ronchaia’s transition was spurred on by the perceptions of others. She argued that she had always had a “feminine face, voice and gestures,” and was often mistaken for a woman. She also had breasts, “in women’s fashion.” One night, a man came to have sex with her, and Ronchaia, “wishing to connect like a woman, hid [her] own penis and took the man’s penis.” After that, she moved to Venice, where, although she continued to wear men’s clothes, she was still perceived as a woman.

Ronchaia’s account is unique because it emphasizes her body and her desire to change it by hiding her penis. But this was still a matter of what she herself could do to express her gender, rather than a medical transition.

A long transgender history

The accounts of medieval transgender individuals are limited – not only in number but in length. A lot of things did not get written down, and people were not talking about transgender people the way we are now.

Historical accounts of transgender individuals are almost always in court records, which reflect the concerns of the court more clearly than the concerns of its subjects. The court was especially worried about sexual activity between men, which both overemphasizes the importance of sex in medieval transgender people’s lives and often obscures that these accounts are even about transgender people. Eleanor Ryekener’s account frequently misgenders her and refers to her as “John.”

But it’s clear that transgender people existed in the medieval period, even when medical care was unavailable to them.

Yellowed page of manuscript with small, inked script
A court document from the interrogation of John Rykener.
Internet Medieval Source Book/Wikimedia Commons

It is also the case that many of these individuals – Rykener is a likely exception – were probably intersex, and their experience would be different from those who were not. Intersex people were legally recognized and allowed some leeway if they chose to transition as an adult. This is starkly apparent in an account from Lille, France, in 1458, where a transgender woman was accused of sodomy and burned at the stake. She claimed “to have both sexes,” but the account says this was not the case. While being demonstrably intersex may not have saved her, that she claimed she was is telling.

Gender transition has a long history, going even further back than the medieval period. Then as now, the local community played a vital role in aiding an individual’s transition. Unlike the medieval period, most modern societies have far greater access to medical care. Despite current restrictions, transgender people have far more options for transition than they once did.

Medieval modes of transitioning are not a solution to current denials of medical care. But medieval transgender lives do illuminate that transgender people will not vanish even when the legal and medical systems strive to erase them.The Conversation

Sarah Barringer, Ph.D. Candidate in English, University of Iowa

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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Why community pharmacies are closing – and what to do if your neighborhood location shutters

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theconversation.com – Lucas A. Berenbrok, Associate Professor of Pharmacy and Therapeutics, University of Pittsburgh – 2025-02-18 07:36:00

Why community pharmacies are closing – and what to do if your neighborhood location shutters

Lucas A. Berenbrok, University of Pittsburgh; Michael Murphy, The Ohio State University, and Sophia Herbert, University of Pittsburgh

Neighborhood pharmacies are rapidly shuttering.

Not long ago, Walgreens, one of the nation’s biggest pharmacy chains, announced plans to close 1,200 stores over the next three years. That’s part of a larger trend that has seen nearly 7,000 pharmacy locations close since 2019, with more expected in the coming years.

Many community pharmacies are struggling to stay open due to an overburdened workforce, shrinking reimbursement rates for prescription drugs and limited opportunities to bill insurers for services beyond dispensing medications.

As trained pharmacists who advocate for and take care of patients in community settings, we’ve witnessed this decline firsthand. The loss of local pharmacies threatens individual and community access to medications, pharmacist expertise and essential public health resources.

The changing role of pharmacies

Community pharmacies – which include independently owned, corporate-chain and other retail pharmacies in neighborhood settings – have changed a lot over the past decades. What once were simple medication pickup points have evolved into hubs for health and wellness. Beyond dispensing prescriptions, pharmacists today provide vaccinations, testing and treatment for infectious diseases, access to hormonal birth control and other clinical services they’re empowered to provide by federal and state laws.

Given their importance, then, why have so many community pharmacies been closing?

There are many reasons, but the most important is reduced reimbursement for prescription drugs. Most community pharmacies operate under a business model centered on dispensing medications that relies on insurer reimbursements and cash payments from patients. Minor revenue comes from front-end sales of over-the-counter products and other items.

However, pharmacy benefit managers – companies that manage prescription drug benefits for insurers and employers – have aggressively cut reimbursement rates in an effort to lower drug costs in recent years. As a result, pharmacists often have to dispense prescription drugs at very low margins or even at a loss. In some cases, pharmacists are forced to transfer prescriptions to other pharmacies willing to absorb the financial hit. Other times, pharmacists choose not to stock these drugs at all.

And it’s not just mom-and-pop operations feeling the pinch. Over the past four years, the three largest pharmacy chains have announced plans to close hundreds of stores nationwide. CVS kicked off the trend in 2021 by announcing plans to close 900 pharmacy locations. In late 2023, Rite Aid said that thousands of its stores would be at risk for closure due to bankruptcy. And late in 2024, Walgreens announced its plans to close 1,200 stores over the next three years.

To make matters worse, pharmacists, like many other health care providers, have been facing burnout due to high stress and the lasting effects of the COVID-19 pandemic. At the same time, pharmacy school enrollment has declined, worsening the workforce shortage just as an impending shortfall of primary care physicians looms.

Why pharmacy accessibility matters

The increasing closure of community pharmacies has far-reaching consequences for millions of Americans. That’s because neighborhood pharmacies are one of the most accessible health care locations in the country, with an estimated 90% of Americans living within 5 miles of one.

However, research shows that “pharmacy deserts” are more common in marginalized communities, where people need accessible health care the most. For example, people who live in pharmacy deserts are also more likely to have a disability that makes it hard or impossible to walk. Many of these areas are also classified as medically underserved areas or health professional shortage areas. As pharmacy closures accelerate, America’s health disparities could get even worse.

So if your neighborhood pharmacy closes, what should you do?

While convenience and location matter, you might want to consider other factors that can help you meet your health care needs. For example, some pharmacies have staff who speak your native language, independent pharmacy business owners may be active in your community, and many locations offer over-the-counter products like hormonal contraception, the overdose-reversal drug naloxone and hearing aids.

You may also consider locations – especially corporate-owned pharmacies – that also offer urgent care or primary care services. In addition, most pharmacies offer vaccinations, and some offer test-and-treat services for infectious diseases, diabetes education and help with quitting smoking.

What to ask if your pharmacy closes

If your preferred pharmacy closes and you need to find another one, keep the following questions in mind:

What will happen to your old prescriptions? When a pharmacy closes, another pharmacy may buy its prescriptions. Ask your pharmacist if your prescriptions will be automatically transferred to a nearby pharmacy, and when this will occur.

What’s the staffing situation like at other pharmacies? This is an important factor in choosing a new pharmacy. What are the wait times? Can the team accommodate special situations like emergency refills or early refills before vacations? Does the pharmacist have a relationship with your primary care physician and your other prescribers?

Which pharmacies accept your insurance? A simple call to your insurer can help you understand where your prescriptions are covered at the lowest cost. And if you take a medication that’s not covered by insurance, or if you’re uninsured, you should ask if the pharmacy can help you by offering member pricing or manufacturer coupons and discounts.

What are your accessibility needs? Pharmacies often offer services to make your care more accessible and convenient. These may include medication packaging services, drive-thru windows and home delivery. And if you’re considering switching to a mail-order pharmacy, you should ask if it has a pharmacist to answer questions by phone or during telehealth visits.

Remember that it’s best to have all your prescriptions filled at the same pharmacy chain or location so that your pharmacist can perform a safety check with your complete medication list. Drug interactions can be dangerous.

Community pharmacies have been staples of neighborhoods for more than a century. Unfortunately, current trends in pharmacy closures pose real threats to public health. We hope lawmakers address the underlying systemic issues so more Americans don’t lose access to their medications, health services and pharmacists.The Conversation

Lucas A. Berenbrok, Associate Professor of Pharmacy and Therapeutics, University of Pittsburgh; Michael Murphy, Assistant Professor of Pharmacy Practice and Science, The Ohio State University, and Sophia Herbert, Assistant Professor of Pharmacy, University of Pittsburgh

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Many gluten-free foods are high in calories and sugar, low on fiber and protein, and they cost more − new research

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theconversation.com – Sachin Rustgi, Associate Professor of Molecular Breeding, Clemson University – 2025-02-18 07:36:00

Many gluten-free foods are high in calories and sugar, low on fiber and protein, and they cost more − new research

The vast majority of Americans are not sensitive to foods containing gluten.
Westend61 via Getty Images

Sachin Rustgi, Clemson University

U.S. consumers often pay more for gluten-free products, yet these items typically provide less protein and more sugar and calories compared with gluten-containing alternatives. That is the key finding of my new study, published in the journal Plant Foods for Human Nutrition.

This study compared gluten-free products with their gluten-containing counterparts, and the findings suggested that many perceived benefits of gluten-free products – such as weight control and diabetes management – are exaggerated.

Currently, many gluten-free products lack dietary fiber, protein and essential nutrients. Manufacturers often add supplements to compensate, but the incorporation of dietary fibers during processing can hinder protein digestion.

In addition, gluten-free products generally contain higher sugar levels compared with other products containing gluten. Long-term adherence to a gluten-free diet has been associated with increased body mass index, or BMI, and nutritional deficiencies.

Gluten-free products – defined in the U.S. as those that contain less than or equal to 20 parts per million of gluten – largely lack wheat, rye, barley and sometimes oats, all rich sources of arabinoxylan, a crucial nonstarch polysaccharide. Arabinoxylan provides several health benefits, including promoting beneficial gut bacteria, enhancing digestion, regulating blood sugar levels and supporting a balanced gut microbiota.

Our study also pointed out that it is difficult to find a gluten-free product that excels in all nutritional areas, such as high protein and fiber content with low carbohydrates and sugar.

On the other hand, gluten-free seeded bread contains significantly more fiber – 38.24 grams per 100 grams – than its gluten-containing counterparts. This is likely due to efforts by manufacturers to address fiber deficiencies by using ingredients such as pseudo-cereals, such as amaranth and quinoa hydrocolloids – meaning water-soluble macromolecules used in gluten-free baked goods made with quinoa flour.

These improvements, however, vary by manufacturer and region. For example, gluten-free products in Spain tend to have lower fiber content than their gluten-containing counterparts.

Why it matters

The term “gluten-free diet” has become a buzzword, much like “organic,” and is now a part of everyday life for many people, often without a full understanding of its actual benefits. While a gluten-free diet is a medical necessity for people who are sensitive to gluten, a condition called celiac disease, or for those with wheat allergies, others adopt a gluten-free diet due to perceived health benefits or because it’s a trend.

In 2024, the global gluten-free product market was valued at US$7.28 billion and projected to reach $13.81 billion by 2032. The U.S. market share is estimated to be $5.9 billion – a little less than half of the global figure.

Approximately 25% of the U.S. population consumes gluten-free products. This figure is far higher than the the roughly 6% of people with non-celiac wheat sensitivity, 1% of people with celiac disease and even lower percentages of people with wheat allergies.

This suggests that many people adopt gluten-free diets for reasons other than medical necessity, which may not offer health or financial benefits.

YouTube video
Symptoms of celiac disease and gluten intolerance include stomach pain and bloating.

What’s next

Investment in research and development is essential to create more nutritionally balanced gluten-free products using locally available ingredients. This will require human feeding trials with different formulations of gluten-free products to ensure that these products meet nutritional needs without adverse effects.

Collaborations between governments could help secure subsidies, which would reduce production costs and make these products more affordable. Although the initial costs of research and maintaining a gluten-free production line are high, using local ingredients and financial incentives can make these products more cost-competitive compared with their gluten-containing counterparts.

Public education is also important to keep people informed about the pros and cons associated with a gluten-free diet.

The Research Brief is a short take on interesting academic work.The Conversation

Sachin Rustgi, Associate Professor of Molecular Breeding, Clemson University

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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