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As an older father with young kids, I'm vigilant about my health, which led me to get a coronary scan in 2016, the same procedure my mother had. I was 47 and exercised fanatically. My physician thought I was crazy and refused to approve the procedure for insurance coverage. So I paid $270 to a medical-imaging outfit in Boulder, where I live, to get it done. I had smidgens of plaque in two arteries, including the left anterior descending. My doctor was surprised, but my risk was considered negligible – a 3.5 per cent chance of an event within five years, based on a similar algorithm, developed by the American College of Cardiology, to the one that had established my mother's odds. "You are already doing everything right," he assured me. And yet my mother had been, too.

Six weeks after her death, I visited Nelson Trujillo, a prominent cardiologist in Boulder, Colorado. Coronary scans showed only hard plaque, he said; they don't reveal whether it's softening and ready to rupture "like a big pimple", in his words. If it pops, its fragments could clog an artery, which would be dangerous, if not lethal. A coronary angiogram, done with a CT scanner, can detect soft plaque. But because a CT scan is expensive and exposes the patient to radiation, it's rarely performed on someone whose probability of having a heart attack is low.

Trujillo had a recommendation. A privately held biotech company in town called SomaLogic was conducting a trial for a new blood-screening process to gauge cardiovascular health, and Trujillo happened to be leading the study. "You are the perfect candidate!" he said with child-like enthusiasm. Cardiologists make clinical decisions based on statistical factors gleaned from broad population studies. "We're always comparing you to big groups of people," Trujillo told me. "The problem is, we know that sometimes we're wrong. We have a miss rate – those six guys out of a hundred who we say are OK but who are not. I wanted to know who those six people were."

The test promised to search my blood for nine proteins associated with cardiovascular health. There are 20,000 or so known proteins in the human proteome, as the collective sum of proteins in any organism is called. Because it can signal when something is amiss inside a body, the proteome has the potential to serve as a diagnostic system – like the ones in modern cars that alert mechanics when a fuel injector is plugged or a timing belt needs replacing. The SomaLogic screen wouldn't merely compare my health stats with those of other men like me, it would take a snapshot of what was happening inside my body at that moment. "It's not odds-based on people who look like you," Trujillo told me. "It's odds-based on you specifically."

 

Proteomics, or the study of proteins, has long offered the ability to identify many biological processes. But until recently, the sheer number of proteins and the complexity of their interactions made screenings impractical, if not impossible. Now, with the advent of more powerful computers and a form of artificial intelligence called machine learning, medical experts are imagining a future where proteomics will realise its power to tell us, to an incredible degree, what's happening inside our bodies. As Omid Farokhzad, a professor and physician recently at Harvard Medical School, puts it: "We'll be able to diagnose diseases such as cancers and Alzheimer's years before symptoms."

For a physician like Trujillo, who is still working with SomaLogic to give the protein test to patients, the promise of proteomics is already here. "I used to say to somebody like your Mom, 'You don't have much heart disease; you don't need anything'. But that was BS, I couldn't reassure her one way or the other," he said. "This is where proteomics comes in – and where it's fundamentally different than anything else we have." Proteomics might have saved her life – and it may yet save mine.

Constant flux

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Genes tend to get more attention, but proteins might really deserve the limelight. As the workhorses in the human body, proteins play a role in nearly all its biological processes. They make antibodies to battle infections. They grow bone and muscle and convert what you eat into nutrients. Proteins are constructed inside cells, from building blocks called amino acids. Humans have 20 commonly occurring amino acids: we produce 11 naturally and obtain nine more from what we eat (which is why high-protein foods are essential to our diet). The blueprints for proteins are stored inside genes, which contain DNA and RNA. RNA is like a courier, delivering the instructions from genes to cells for making proteins from specified assortments of amino acids.

Our proteins are in constant flux. They can appear and disappear, or shift in concentration, in response to our external environment or internal physiology. Our proteome reacts to what we eat, when we sleep, how we exercise, the smoke we inhale, the alcohol we drink. My proteins look different after I run 10 kilometres than they do before the race; they change when I get the flu; they are altered by stress and emotions.

 

Researchers are learning that diseases have unique proteomic patterns. An ailment like colon cancer might involve interactions with hundreds of proteins. Stephen Williams, the chief medical officer of SomaLogic, told me about a recent experiment that turned up at least 1000 proteins associated with diabetes.

Proteins and genes have very different things to say about our health. Genes are static. We live and die with the same set we're born with: about 20,000 in the human genome that make proteins. Certain diseases are linked directly to genes, like those for breast cancer and Alzheimer's. But genes can inform us only of our odds. If my DNA resembles that of other men who have prostate cancer, that means I have a greater risk of suffering a similar fate. My genes can't tell me that I actually have cancer, or that I will, however, only that I have a predisposition for it.

Proteins can confirm an illness is under way, and they often appear in our blood long before we feel sick – months or years before symptoms, when many diseases are still curable. "In the vast majority of cases, it's the proteins we can measure before anything else," says Joshua LaBaer, who founded the Harvard Institute of Proteomics and now directs the Biodesign Institute at Arizona State University, where he is a professor.

This kind of information is invaluable to doctors, who want to know what is going wrong in real time, not what might happen in the future – and it's also why they haven't learnt as much from genomics as they had originally hoped. "We've looked a lot at genes in the past 15 years," says Jon Heimer, the chief executive of Olink Proteomics, a biotech firm based in Uppsala, Sweden, that sells protein panels to scan for ailments ranging from organ damage to inflammation. "But it makes more sense to look at proteins, because they are the biological machinery of human beings."

 

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Today, physicians rely largely on pattern recognition to make clinical diagnoses: they match observed symptoms with associated ailments. But there's a pitfall to this approach – symptoms are sometimes absent. Our bodies can function well when they're ill, even gravely so. It's an evolutionary survival mechanism that prevented my mother's heart from divulging any clues to its infirmity until it failed.

In general, we don't go to the doctor until we're feeling lousy – a persistent cough, say, or a throbbing headache. But there are deadly conditions that don't always exhibit conspicuous signs. Cardiovascular disease, stroke, cancer, Alzheimer's, diabetes and kidney dysfunction – six of the top 10 things that kill people in the US, accounting for 1.6 million deaths annually, according to the Centres for Disease Control and Prevention – can all manifest without symptoms. But proteins often show up first.

Hundreds of ailments, like strep throat, flu and HIV, among others, are already diagnosed through single-protein tests. The prostate-specific antigen protein, or PSA, can indicate if a man has prostate cancer. The blood drawn at your annual physical is analysed for a variety of its proteins, like hemoglobin and lipoproteins, which flag cholesterol levels. Perhaps the most common (and reliable) test is the pregnancy pee stick, which measures human chorionic gonadotropin, or hCG, a hormonal protein produced by the placenta.

But complex disease fingerprints with swarms of proteins are exceptionally difficult (and time-consuming) to spot using conventional "wet lab" methods. "To your eyes and my eyes, we won't catch them," says Farokhzad, who helped start Seer, a biotech firm, in 2017 to spin off his academic research into marketable protein tests. "But to sophisticated machine-learning algorithms, these things pop out like daylight." Once algorithms have identified these fingerprints, researchers can use them to develop tests like the one I took for my heart.

Scientists have discovered that exercise can change proteins in our bodies. AP

"Diagnostic medicine has always been about proteins," says Philip Ma, Seer's president and chief business officer. "All proteomics is allowing you to do is to look at them in bunches instead of one at a time."

Unicorn status

Larry Gold, a founder of SomaLogic, has wispy white hair and a bushy moustache. He looks a bit like Mark Twain. "We got our unicorn status," he says, when we meet at his office in June, modelling a knit cap with a rainbow-banded horn protruding from its crown. "I guess that's kind of a big deal." The designation is given to privately held companies valued at more than $1 billion. He is wearing blue jeans and a long-sleeve black T-shirt. He has 30 more identical ones he keeps stacked in a drawer and in regular rotation. "I don't care what I look like," Gold says. "But I have a dress-up outfit somewhere in my closet for raising money."

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Gold, 77, moved to Boulder after securing a professorship at the University of Colorado, a few years after earning a PhD in biochemistry from the University of Connecticut. He ran his own lab – now adjacent to the 34,000 square metre Gold Biosciences Building – and still teaches there occasionally. During the 1980s, one of his graduate students was a scientist named Craig Tuerk, currently a biochemistry professor at Morehead State University in Kentucky. At the time, there were several methods to determine the presence of a single type of protein, among them the use of antibodies, which Gold and Tuerk were familiar with. A protein of interest can be injected into an animal, like a mouse, whereupon its immune system will make antibodies to fight the invading molecule. These "binding antibodies" attach themselves like Lego bricks to the protein, which becomes easier to spot as a result. The mouse antibodies are subsequently harvested for research and can be used to develop diagnostic screenings.

In 1989, four years after joining Gold's lab, Tuerk was conducting research for his PhD thesis on viral DNA. While experimenting with a type of virus that infects bacteria, Tuerk noticed strands from the virus's RNA had somehow bound themselves to specific proteins. DNA and RNA are nucleic acids. What Tuerk had discovered accidentally was a way to identify immense numbers of proteins at once with nucleic acids instead of antibodies, using a molecule found on both DNA and RNA called an aptamer. It was a momentous breakthrough. "We didn't start dancing because we were being sciencey types," Gold says. They did, however, immediately begin drafting a patent, which Gold stayed up all night to write. The next evening, a biotech entrepreneur named David Brunel invited Gold over for Thanksgiving dinner. "I fell asleep on the floor of David's house," Gold says. "People were walking over me."

Brunel later invested in SomaLogic, and Gold has put at least $US20 million ($28 million) of his money into the firm, made from the sale of two companies he founded previously. At his venture before SomaLogic, during the early 1990s, Gold helped develop the first Food and Drug Administration-approved aptamer-derived medication, for macular degeneration, which had roughly $US200 million in sales in its first year on the market. Even then, Gold had bigger plans for aptamers – to use them to analyse proteins on an unprecedented scale. He would glean patterns from the data that could diagnose diseases. It was possible to do the same thing with antibodies, but that would require luck and patience, like trying to catalogue every fish in the ocean with a net that captured only a single species at a time. And even then, in those years – right about the time when Marc Wilkins, a graduate student at Macquarie University in Australia, coined the word "proteomics" – it might have taken months for researchers to make sense of the voluminous data. Proteins are folded into intricate three-dimensional structures. Mapping one was challenging enough; mapping thousands was all but unmanageable.

"Antibodies are used mostly to measure one protein," Gold says. "They would never scale to what I thought proteomics would have to do to make it significant in healthcare" – that is, generate information quickly and cheaply enough to be practical for doctors to use in daily clinical practice. "I had this idea that if you measured enough proteins, you'd be able to get insights into human biology that were hard to get any other way."

SOMAscan is the manifestation of his vision. It's a twofold technology platform, combining machine learning with a chemical process to isolate 5000 proteins from a drop of blood. Williams says this scan has found fingerprint-like patterns for more than 50 diseases, including lung and pancreatic cancer, both notorious for their dismal survival rates.

What these fingerprints convey can be grouped into three categories: probability (your odds of getting sick), current state (you're already sick but don't know it) and trajectory (how soon you'll get worse). "There are patterns that do each of these jobs," Williams tells me, adding that his ultimate goal is to find all these patterns, for any condition, in a single scan, and also measure whether they change in response to lifestyle improvements or medication.

"We'll be able to diagnose diseases such as cancers and Alzheimer's years before symptoms," says Omid Farokhzad, a professor and physician at Harvard Medical School. Not for syndication

Ethical obstacle

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Proteomics has faced something of a chicken-or-egg dilemma. Doctors won't embrace the technology until they are sure that protein screenings provide reliable results, but improving reliability is largely contingent on widespread adoption. Put another way, the greater the number of patients who are tested, the more accurate the fingerprints become.

Before it had patients whose proteins it could analyse, SomaLogic began building its disease database with bio-banks, which store frozen blood and tissue for research. Using specimens from these repositories – the ones at the National Institutes of Health and many research hospitals are made accessible to scientists – the company began to hone its machine-learning algorithm, training it to search for key protein configurations. Donors to bio-banks are anonymous, but their health data is not. By cross-indexing newly identified protein patterns with medical histories, researchers might find a new disease fingerprint in a subset of donors who had liver cancer, for example. SomaLogic can duplicate or confirm these findings by scanning different samples and using different bio-banks, which the company is doing now.

Ideally, SomaLogic would run blind trials, the gold standard for validating medical drugs and diagnostics. But there is an ethical obstacle to doing so. SomaLogic typically focuses on a single disease when it's evaluating a disease fingerprint in the real world, which is what Gold enlisted Trujillo to do with the heart test in 2016. For a blind trial, Trujillo would have had to randomly select some of his patients with a high-risk fingerprint and then – without informing them of the looming threat – wait to see if they had a heart attack.

Trujillo's work is limited to his patient pool, about 180 people so far. But SomaLogic's continuing studies typically entail thousands of patients, whose proteomes are sampled and tracked longitudinally. In lieu of a trial, SomaLogic is able to confirm data retrospectively. Over the span of, say, a lung-cancer study, some people in the cohort will get other ailments. If one of those subjects in the lung cancer study develops diabetes, for instance, SomaLogic can check whether she carried the fingerprint for that disease when her blood was drawn years earlier.

Once a fingerprint is found, it can still need refining. The cardiovascular test from SomaLogic intrigued Robert Gerszten, the chief of cardiovascular medicine at Boston's Beth Israel Deaconess Medical Centre and also a Harvard Medical School professor. Gerszten had patients with a condition called hypertrophic cardiomyopathy, which causes the heart muscle to thicken abnormally. It can be treated by medically inducing a heart attack, which thins the affected tissue. "It's one of the few examples where you know the person is going to have a big heart attack," Gerszten says. He sampled blood from his patients with hypertrophic cardiomyopathy both before and after the procedure, as well as from people who'd had ordinary heart attacks.

Not only did Gerszten find proteins that matched with those that SomaLogic had identified, he also came across ones never previously tied to cardiovascular health. "We found dozens and dozens of new proteins that no one had discovered," he says. While Gerszten had helped validate the protein-screening panels could presage heart attacks, he also illustrated that the underlying biology was remarkably more complicated.

Complicating factors

Other factors also hinder proteomic investigation. One is a statistical anomaly known as "overfitting," which happens when trying to match a disease that involves scads of proteins with too few patients. As LaBaer puts it: "There is a chance you're going to find a set of markers that look real but are not." Another is the tendency of proteins to interact with other molecules and change after they're formed, a process known as post-translational modification. "There is a landscape of these modifications – a real zoo of molecules – most of which we don't understand what their effect is," says Steven Carr, senior director of proteomics at the Broad Institute of MIT and Harvard. Scientists don't always know whether it's the actual proteins or the modified ones that are associated with trouble. Nor can they be sure if a blood test is necessarily distinguishing between these two protein structures – one of which may be malicious and the other benign – or even capable of detecting certain modified proteins at all. "Not everyone who has these proteins might get that disease," Carr says. "And some who have the disease might not have that particular form of proteins."

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SomaLogic's hunt for proteins starts in a sparse room at its headquarters, in 2.4 metre-tall upright freezers set to minus 80 degrees. They are filled with small trays holding dozens of 2.5cm-long plastic tubes, each containing a drop of serum (the clear liquid remaining after clotting compounds are removed from blood). At any given time, there are about 300,000 samples on site, stored in 13 freezers. Technicians oversee robotic arms programmed to add aptamers to the samples, with a fluorescent light-refracting tag. (SomaLogic has engineered 5000 aptamers and rechristened them SOMAmers.) After more robotic juggling, the serum solution from the tubes is placed onto glass slides, and an imaging device measures the light intensity passing through the fluorescent aptamer to assess which proteins are present and in what concentrations. It's here the biological information is converted into digital data.

Perhaps the most common (and reliable) test is the pregnancy pee stick, which measures human chorionic gonadotropin, or hCG, a hormonal protein produced by the placenta. SHUTTERSTOCK

It takes 30 hours to acquire protein data from one sample, and the lab processes about 680 a day. The raw data – totaling about four million protein measurements every 24 hours – is fed into machine-learning algorithms, which are revised constantly based on the various disease patterns they're interested in investigating.

While allocating most resources to the big three – cancer, heart disease and diabetes – SomaLogic also delves into realms that traditionally haven't been studied with proteomics, such as smoking, social deprivation, excessive alcohol consumption and fitness. There are hundreds of proteins common among tobacco smokers, which Williams speculates could be used to expose those suspected of smoking who deny it. "It's the worst lifestyle health risk you can get," he says. "But people lie about it."

SomaLogic will start its first large-scale beta test this year, collaborating with the Leeds Centre for Personalised Medicine and Health in Britain. Williams told me the project is starting with a diabetes trial, with other diseases to follow. More than a third of British residents are pre-diabetic – meaning they are not exhibiting symptoms but are at risk of developing the disease. "We don't want those people to become diabetic," Williams says. "But we don't really know who is susceptible."

SomaLogic will collect blood samples from patients in Leeds then zero in on those whose protein fingerprints suggest diabetes is imminent (the company recently set up a 900-square-metre lab in Oxford to process samples). Physicians, in turn, will instruct patients in strategies that have proved to pre-empt the need for diabetic medication, like exercise, weight loss and nutrition counselling. "The point is that this information may motivate people straightaway," Williams says.

Gold wants SOMAscan to evolve into something he calls the "wellness chip", a do-it-all protein screening to replace annual physicals, which several studies have suggested rarely benefit health. In May, at an annual healthcare and science symposium that Gold hosts at the University of Colorado, SomaLogic's chief corporate strategist, Mark Messenbaugh, displayed a slide during his lecture that showed a toilet equipped with a SOMAscan chip and captioned: "Our Ultimate Goal – SOMAwhiz." He wasn't joking. Williams confirmed the company was adapting its technology for "a non-invasive home-collected urine test" to look for many of the same disease fingerprints found by SOMAscan.

Eventually, SomaLogic hopes to sell its blood and urine scans directly to consumers, for as little as $US100 per test, Gold says. But there is a fear percolating among some scientists and healthcare providers about what patients will do with the data. Will they demand treatment from their doctors based solely on a proteomic scan? More important, will their doctors comply?

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"There are consequences to these measurements," Carr says. "There are interventions taken, drugs people are put on, additional testing. That costs money, and it raises the anxiety level of those being tested. So you damn well better be sure you're measuring what you say you're measuring – and know that it matters – before you employ it in a clinical setting."

Personalised care

When my results come back from SomaLogic, a month after my blood was drawn, they tell me I have an 11 per cent chance of a cardiac event within five years – more than three times as high as the coronary calcium scan and associated algorithm had forecast. Trujillo insists I start taking a statin drug to halt further plaque build-up.

Proteins can confirm an illness is under way, and they often appear in our blood long before we feel sick – months or years before symptoms, when many diseases are still curable. Rebecca Hallas

Because proteins react to external inputs, Trujillo asks everyone who gets the heart screening to redo it a year later. From what we know about the proteome, any actions taken to prevent a heart attack – dietary improvements, exercise, medications – should nudge the odds lower. For now, it's too early to draw conclusions from Trujillo's follow-up data. But, he says, "the results have really allowed me to personalise care. They have motivated people to change their lifestyle or take medication."

I tell Gold my anniversary date for the heart test is approaching and I would soon be providing a second blood sample to Trujillo. He warns me that my risk might not fall precipitously, as evolving proteomic research is showing that cardiovascular disease, like many other ailments, is a more intricate biological puzzle than once thought. The results from my second test confirm as much: I did not drop a single percentage point. I had spent a year on statins, mostly eliminated red meat from my diet and added high-intensity interval training to my workouts. I also did a five-day fast that Trujillo recommended for reducing inflammation – a well-known contributor to heart disease – and in the course of it lost 3.5 kilograms. None of it appeared to help.

Trujillo was untroubled. "My work has led to a page of questions as it relates to how to use this test going forward," he says. "Is it God's word? Not even close. It's just part of the armamentarium." Trujillo reckons fathoming the proteome might spawn new mysteries while solving others.

Gold echoes a similar sentiment when we talk. "We know more about the proteome here than anyone on earth, and we think it's a treasure trove of understanding human biology," he says. "But I won't lie about it. The science is hard – harder than I thought."

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Gold wants SOMAscan to evolve into something he calls the "wellness chip", a do-it-all protein screening to replace annual physicals. laboratory / Alamy Stock Photo

Australian proteome expert Marc Wilkins, right, pictured in 2001 with IBM CEO Philip Bullock and Keith Williams, CEO of Proteome Systems, which was renamed Tyrian Diagnostics in 2008.  tanya lake

A coronary angiogram, done with a CT scanner, can detect soft plaque. But because a CT scan is expensive and exposes the patient to radiation, it's rarely performed on someone whose probability of having a heart attack is low. Daniel Acker

Humans have 20 commonly occurring amino acids: we produce 11 naturally and obtain nine more from what we eat (which is why high-protein foods are essential to our diet). iStock

The New York Times

Source : https://www.afr.com/lifestyle/health/forget-genes-proteins-could-hold-the-key-to-our-health-20181120-h183m6

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