Precision Medicine and Rube Goldberg

Precision Medicine and Rube Goldberg

The American cartoonist and inventor Rube Goldberg was best known for his series of cartoons featuring absurdly intricate contraptions designed to perform mundane tasks. The humor comes from the apparent simplicity of the task: Why not just take the egg into one’s own hands and crack it open? However, Rube Goldberg was onto something: We humans are living Rube Goldberg machines. That simple act of cracking open an egg requires an inordinately complex sequence of events to occur within our bodies.

We know that such a simple act requires exquisite coordination between body and brain. However, this interaction is just the surface. If we probe deeper (to the molecular level), we can see an orchestra of DNA, RNA, and proteins working in harmony to carry out the egg-breaking. When everything works in a harmonious balance, we are fine. When discord arises, disease often results. By probing the different players of the molecular biology trilogy, unique understandings about the disease can be gleaned and harnessed for the implementation of precision medicine.

Yet, we must be cautious about which molecules we monitor for precision medicine because the realization of our own inherent complexity holds especially true in the doctor’s office. Take cancer treatment as an example. Not only are cancer genomes highly variable (Tomasetti, Vogelstein, & Parmigiani, 2013; Vogelstein et al., 2013), but cancers can be affected by numerous molecular pathways (Loeb & Loeb, 2000). As a result, successful treatments for one type of cancer do not always work efficiently for other cancers — or even other tumors of the same type of cancer!! — even though they share the same mutations (Kobayashi & Mitsudomi, 2016; Kopetz et al., 2010; Prahallad et al., 2012).

To develop medicines with greater precision, we certainly should tap into the data geyser born from the omics revolution. Before tapping in, however, we need to determine just what information we really need and how to put it together. This knowledge makes the path clearer for harnessing the wealth of data to make the vision of precision medicine a reality.

Historically, research fixated on specific pathways or individual proteins, but this approach has nearly maxed out the potential benefits regarding our understanding or providing new treatments for cancer (Sapiezynski, Taratula, Rodriguez-Rodriguez, & Minko, 2016). For the next generation of medicines/treatments, we will need to look at how numerous pathways influence one another and how they may differ among individuals. Already, this realization has birthed yet another omics, known as interactomics.

What in the world is interactomics? In essence, it’s about looking at how all the proteins interact with one another and how the interactions change in real-time in response to cues from the environment, etc. (Fessenden, 2017). It’s akin to playing the “Six Degrees of Kevin Bacon” game, but with proteins. For many researchers, interactomics could be a powerful tool for precisely understanding how a faulty protein can cause problems in other molecular pathways, which can give rise to diseases (Fessenden, 2017).

Looking at the protein version of the Kevin Bacon game is another reminder of our biological Rube Goldberg machines’ complexity. It is also a wonderful step to a deeper and sounder understanding of the body’s mechanical workings, which could be a boon for precision medicine. To properly tackle the ginormous challenge of generating a sounder understanding, however, will take a massively coordinated effort of the pharmaceutical industry, research community, and medical community.

 

References

Fessenden, M. (2017). Protein maps chart the causes of disease. Nature, 549(7671), 293-295. doi:10.1038/549293a

Kobayashi, Y., & Mitsudomi, T. (2016). Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy. Cancer Sci, 107(9), 1179-1186. doi:10.1111/cas.12996

Kopetz, S., Desai, J., Chan, E., Hecht, J. R., O’Dwyer, P. J., Lee, R. J., . . . Saltz, L. (2010). PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors. Journal of Clinical Oncology, 28(15_suppl), 3534-3534. doi:10.1200/jco.2010.28.15_suppl.3534

Loeb, K. R., & Loeb, L. A. (2000). Significance of multiple mutations in cancer. Carcinogenesis, 21(3), 379-385.

Prahallad, A., Sun, C., Huang, S., Di Nicolantonio, F., Salazar, R., Zecchin, D., . . . Bernards, R. (2012). Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature, 483(7387), 100-103. doi:10.1038/nature10868

Sapiezynski, J., Taratula, O., Rodriguez-Rodriguez, L., & Minko, T. (2016). Precision targeted therapy of ovarian cancer. J Control Release, 243, 250-268. doi:10.1016/j.jconrel.2016.10.014

Tomasetti, C., Vogelstein, B., & Parmigiani, G. (2013). Half or more of the somatic mutations in cancers of self-renewing tissues originate prior to tumor initiation. Proc Natl Acad Sci U S A, 110(6), 1999-2004. doi:10.1073/pnas.1221068110

Vogelstein, B., Papadopoulos, N., Velculescu, V. E., Zhou, S., Diaz, L. A., Jr., & Kinzler, K. W. (2013). Cancer genome landscapes. Science, 339(6127), 1546-1558. doi:10.1126/science.1235122

 

SomaLogic closes $200M financing round

Nan Fung Life Sciences and Madryn Asset Management join iCarbonX in investing to accelerate SomaLogic’s unique precision health insights delivery business

January 3, 2018 – Boulder, CO – SomaLogic announced today that it has capped its $200 million funding round, anchored by iCarbonX with substantial investments from Nan Fung Life Sciences and Madryn Asset Management. The successful round will accelerate SomaLogic’s goal of becoming the world’s leading provider of precision digital health insights.

SomaLogic uniquely and precisely measures thousands of human proteins rather than genes, and turns those measurements into insights that empower people to purposefully and meaningfully manage their individual health and wellness. SomaLogic’s “SOMAscan®” technology, which currently measures 5,000 proteins in a single sample, has successfully analyzed over 150,000 samples across more than 50 diseases or conditions, with plans for an additional 1 million more samples by the end of 2020. The continuously growing power of the SOMAscan technology, the massive proprietary data sets being accumulated and analyzed, and the strategy for turning those assets into a successful health insight company have together caught the attention of leading investors in emerging digital health markets.

“We are delighted to expand our relationship with SomaLogic and continue to support the company’s growth,” said Avinash Amin, Managing Partner at Madryn Asset Management. “We believe SomaLogic’s proteomics technology provides the basis for unique and differentiated insights into human health and disease, with broad implications for diagnosis and treatment.”

Understanding the changes over time in bodily proteins is being increasingly recognized by the medical community as essential to the effective personalized maintenance of health and management of disease. Unlike genes, proteins respond dynamically to changes in the body and the environment, offering meaningful and actionable health information in real-time.

“These new investments by Nan Fung and Madryn, two elite, global healthcare investors, are yet another huge vote of confidence in our strategic direction and the deep intrinsic value of our technology,” said Al Reynolds, SomaLogic’s CEO. “We are delighted that they recognize the huge potential of our technology to radically transform healthcare, and are joining us as valued partners to accelerate that goal.”

Specific financial details were not disclosed.

SomaLogic Contact
Laura S. Mizoue, Ph.D.
Communications Specialist
T: 720-417-7509
lmizoue@somalogic.com

About SomaLogic:
SomaLogic delivers meaningful and actionable health-management insights that empower individuals worldwide to continuously optimize their personal health and wellness throughout their lives.
These essential insights, provided through a global network of partners and users, are derived from precise, proprietary, and personalized measurement of critical changes in an individual’s proteins throughout life. For more information, visit http://www.somalogic.com/.

About Nan Fung Group:
Founded in 1954, Nan Fung Group is a conglomerate based in Hong Kong with global interests in real estate development and investment, financial investment, hotels and shipping. The Group continues to diversify its business and growth globally with interests in a diverse range of business partnerships, including life sciences.

About Nan Fung Life Sciences:
Nan Fung Life Sciences, part of Nan Fung Group, is a global life science investment platform with a significant presence in the US and Greater China.
Leveraging on the Group’s strong capital position, it has a long-term commitment to life sciences through direct investments and fund investments covering the full spectrum of the industry (including therapeutics, medical devices and diagnostics) and across different development stages.

About Madryn Asset Management, LP:
Madryn Asset Management, LP is a leading alternative asset management firm that invests in innovative healthcare companies specializing in unique and transformative products, technologies, and services. The firm draws on its extensive and diverse experience spanning the investment management and healthcare industries, and employs an independent research process based on original insights to target attractive economic opportunities that deliver strong risk-adjusted and absolute returns for its limited partners while creating long-term value in support of its portfolio companies. For additional information, please visit www.madrynlp.com.

 

An Alternative to Alternative: Assessing the Validity of Information or Knowledge

An Alternative to Alternative: Assessing the Validity of Information or Knowledge

News Flash! The wedding between Big Foot and The Loch Ness Monster to be the event of the century! It’s going to be huuuuge! A-list celebrities plan on attending…

Now, is that a true news item or a false one? Before you hit the buzzer and say it is false, consider for a second that it just might be true. People can and do give themselves or their children unique monikers (Big Foot Smith is not outside of belief). The point is, we do not know many things for certain, but we can deduce validity — at least in part — from the source of the info. However, it can be a difficult task even for professional seekers of truth, e.g., scientists.

Traditionally, scientists turn to scholarly journals for valid information. In the olden days, researchers would dive into the bowels of the library to find the journal issue carrying a sought-after article, or send an undergrad to fetch it. Not anymore. Today, a few internet clicks and POOF! Millions of hits in mere seconds. Though it has become easier to access information, it can sometimes be more difficult to discern the legitimacy of the information or the source.

A great example of discerning legitimacy comes in the form of so-called “predatory journals.” What is a predatory journal? It is a journal that exists solely for profit making rather than disseminating knowledge. For a fee, the predatory journal publishes pretty much anything thrown at them, without thorough review of the findings. It can be difficult to spot these predators for they go by titles that sound legit, and can (and do) fool even the most senior of scientists (Cobey, 2017).

How can scientists (and the rest of us) evade these noxious predators? Confirming that a journal is listed in the PubMed database, which has banned some predatory journals, is one strategy (Deprez and Chen, 2017). Other databases such as Journal Citation Reports or Directory of Open Access Journals might be useful (Moher et al., 2017). Looking at impact factors, questioning librarians, or seeing if the journal has any characteristics that have been attributed to a predatory journal (Moher et al., 2017) may also help get to the valid data/knowledge.

However, predatory journals are not the only sources of suspect information. Digital apps and other software can crunch away data and offer something “insightful.” Yet, these data and the resulting findings are not always useable or accurate. For instance, the software that converts experimental data into a DNA sequence has about a 50% reproducibility rate (Keshavan, 2017). Think about it. Your genetic test results might be different if the samples were re-analyzed. If these results were used to decide medical treatment, the treatment might be inappropriate 50% of the time! To rein in the variability seen in DNA sequencing, the FDA is taking action. Though still short of implementing regulations, the FDA beseeches the sequencing companies to scrutinize their software and improve it (Keshavan, 2017).

So, how are consumers using results from genetic tests?  Recently, a survey showed how much consumers actually used the knowledge acquired from commercial tests (Barton, 2017). Consumers can be told of their risk for cancer based on genetic tests that look for single point mutations. These tests did not greatly sway health-related behaviors in either a negative direction or positive direction for many of the participants (except in the case for prostate cancer tests) (Barton, 2017). On the bright side, it would appear that the news is not causing everyone (except for those with worrisome test scores for prostate cancer) to rush and get potentially unnecessary diagnostic tests done, which can carry their own set of problems.

Where do we go from here? With the sheer crush of data available it seems like it is almost impossible avoid predators and wring credible and reproducible information/knowledge from the internet or companies. Yet, it is not. We need to just take the time to carefully scrutinize the information/ knowledge, investigate the publishing practices of journals, query how a company validates their results, put the claims in the context of other knowledge, etc. This is not always easy because we do not always have the time to do this well, and still read entertaining stories on the internet, such as the Big Foot and Loch Ness Monster nuptials.

 

References

Barton, M. K. (2017). Health behaviors not significantly changed by direct-to-consumer genetic testing. CA Cancer J Clin, 67(3), 175-176. doi:10.3322/caac.21368

Cobey, K. (2017). Illegitimate journals scam even senior scientists. Nature, 549(7670), 7. doi:10.1038/549007a

Deprez E. and Chen C. (2017, August 29). Medical journals have a fake news problem. Bloomberg. Retrieved from https://www.bloomberg.com/news/features/2017-08-29/medical-journals-have-a-fake-news-problem.

Keshavan, M. (2017, August 1). FDA pushes to bring order to the chaotic world of DNA sequencing. Statnews. Retrieved from https://www.statnews.com/2017/08/01/fda-dna-sequencing/

Moher, D., Shamseer, L., Cobey, K. D., Lalu, M. M., Galipeau, J., Avey, M. T., . . . Ziai, H. (2017). Stop this waste of people, animals and money. Nature, 549(7670), 23-25. doi:10.1038/549023a

 

Large-scale profiling of blood proteins identifies new markers of heart damage

A new report published online in the American Heart Association journal Circulation describes the successful measurement of changes in blood proteins at a previously unattainable scale. The results revealed a large number of proteins that increased significantly soon after a heart attack—some that are well-known markers of myocardial damage but many that are completely new. This proof-of-principle study demonstrates that comprehensive protein profiling to diagnose and treat human health and disease is on the horizon.

The types and levels of many proteins that circulate through the body are constantly changing in response to changes in real-time health status. Until recently, this gold mine of information has remained largely untapped because conventional technologies can’t measure thousands of proteins present in vastly different concentrations in complex mixtures such as blood.

In this study, researchers at the Novartis Institute for BioMedical Research, Beth Israel Deaconess Medical Center and Brigham and Women’s Hospital used the SOMAscan platform to measure the levels of ~5,000 proteins in blood samples taken from patients undergoing a “planned” heart attack, a medical procedure that can help reduce severely overgrown heart muscle (hypertrophic cardiomyopathy). They analyzed plasma taken before and at different time points after the procedure, looking for proteins whose levels changed significantly. Their results not only confirmed findings from an earlier study that used an earlier, smaller version of the SOMAscan platform (ref: Ngo, D et al. (2016) “Aptamer-Based Proteomic Profiling Reveals Novel Candidate Biomarkers and Pathways in Cardiovascular Disease.” Circulation 134(4): 270-285.), but also identified nearly 150 new proteins, many of which had not been previously associated with heart damage. Twenty-nine of the proteinswere also elevated in patients who suffered “unplanned” heart attacks.

This article is the first published description of large-scale protein profiling at a level that has not previously been reported. The expanded SOMAscan assay platform provides opportunities for unbiased discovery of disease markers to improve diagnosis, predict future events, monitor responses to therapies and identify targets for drug development. Ongoing studies by these authors are applying this expanded SOMAscan platform to larger groups of patients.

Jacob, J et al. (2017) “Application of Large Scale Aptamer-Based Proteomic Profiling to “Planned” Myocardial Infarctions.” Circulation, epub ahead of print.

Larry Gold named to 2017 National Academy of Inventors

The National Academy of Inventors (NAI) has named Larry Gold, the founder and chairman of the board of SomaLogic, as one of its 2017 fellows.

Election to NAI Fellow status is the highest professional distinction given to academic inventors. NAI Fellows are inventors on U.S. patents and were nominated by their peers for their spirit of innovation and creation of new technologies that have significantly impacted society.

Dr. Gold has been a professor in the department of Molecular, Cellular and Developmental Biology at the University of Colorado, Boulder since 1970 and is an elected fellow of the National Academy of Sciences and the American Academy of Arts and Sciences. A bioscience industry pioneer, Dr. Gold founded two other biotech companies prior to SomaLogic.

The NAI elected 155 fellows to the class of 2017. The induction ceremony will be in April as part of the Seventh Annual NAI conference in Washington, D.C.

 

Click here to read the story from the University of Colorado, Boulder.
Click here for more information on the National Academy of Inventors

Who to Heed for Medical Advice?

By guest blogger: N. T. Feles

I am new to this whole blogging gig, but excited for the opportunity. You see, I come from a long line of writers. Though many members in my family choose to pen their thoughts using clay as a medium, my distant cousin — who wrote an influential physics paper (Hetherington & Willard, 1975) — and I have chosen a different media: keyboards.

What does one blog about? I guess I could just say what is on my mind. Lately, I have been fascinated by how pseudoscience dictates courses of action that can have a profound impact on health. I would really love to know why people are turning away from science and embracing the absurd.

Pawing through the internet, I see products, services and news stories that leave me speechless. For instance, people listening to Hollywood types and forgoing lifesaving vaccinations for fear of developing neurological problems, an urban myth that has been disproven by science. Promotion (and presumed purchases) of gemstone eggs that can promote health. Crystal cleanses that can remove toxins from your body. (I thought this was the job of your kidneys and liver?) Supplements made from plant extracts touted as being able to restore hormone balance, etc.

Know what these situations remind me of? The era before government regulation, when people could hawk bogus treatments and make outlandish claims about their curative effects. Thank goodness for regulations. Now, we have a set of standards to ensure that approved medications are safe and can do what the manufacturers’ say. If only we had this with vitamin and supplement markets, which are still not regulated and where untested claims are still being made and believed.

I know humans can be smart and make good decisions. So, why do they fall for these hokey claims? I am neither a psychiatrist nor a psychologist, but I can guess. As I clawed through the literature, I happened upon an article that explains the power that celebrities hold. Some of the reasons are obvious, such as celebrities being the leaders of our cultural herd and many people wanting to emulate them (Not I. I am not a herd animal.) (Hoffman & Tan, 2013). But the authors also dive into rationale that made my furry chin drop. Why? Apparently, people think if a “trustworthy” celebrity is successful (i.e., paid millions or received a tiny golden statue in the film industry awards ceremony), then it means that person will automatically be successful in other ventures such as medicine, a phenomenon known as the halo effect (Hoffman & Tan, 2013).

Somehow, I do not see someone who got a tiny golden statue for playing some famous person’s love interest getting anywhere near me with a scalpel and anesthesia! Unless, of course, that person received years of practical training from a credited medical school. Which I doubt they did. Anyway, the article is eye opening and worth reading and sending to others.

So, what can be done to get people to listen more to competent professional experts instead of celebrities who deem the next unfortunate animal to be the “it” pet or preach bad medical advice? This is a hard one. The easiest thing to do would be to tell them that they are wrong for following a celebrity’s advice on a medical thing. Surprisingly, this is likely to backfire and make the person further believe the fallible medical advice (Shermer, 2017).

In an altruistic universe, celebrities would be very mindful that with their great powers of influence, comes great responsibility. They would be sure to promote sound medical advice that helps their fans and not just someone’s pocket books. It is reassuring that some celebrities do realize this and do promote the correct medical information (Hoffman & Tan, 2013). We just need more celebrities to do it.

In that same universe, perhaps celebrities would be selected for their wisdom, education or humanitarian endeavors. I do not know if someone overheard me, but a recent commercial provided a glimpse into this alternative reality. The commercial featured Mildred Dresselhaus, a notable scientist, as an A-list celebrity. People clamored to hear her talks, named their children after her, asked for her autograph, etc. How neat would it be it were not fictional? I wonder if Dr. Dresselhaus would have promoted better medical advice?

Well, I am tired of standing on my soap box and about to miss out on my 20 hours of sleep. This blogging thing was fun, but are you going to take my word about what was said? I am not a puppy wielding celebrity, but a cat named Noodle. Then again, I do know how to persuade humans to heed what I say: the science backs me up (McComb, Taylor, Wilson, & Charlton, 2009).

 

References 

Hetherington, J.H. & Willard, F. D. C. (1975). Two-, Three-, and Four-Atom Exchange Effects in bcc 3He. Phys. Rev. Lett. 35, 1442.

Hoffman, S.J. & Tan, C. (2013). Following celebrities’ medical advice: meta-narrative analysis. BMJ. 347:f7151 doi: 10.1136/bmj.f7151

McComb, K., Taylor, A. M., Wilson, C., & Charlton, B. D. (2009). The cry embedded within the purr. Curr Biol, 19(13), R507-508. doi:10.1016/j.cub.2009.05.033

Shermer, M. (2017, January). How to Convince Someone When Facts Fail. Scientific American. Retrieved from https://www.scientificamerican.com/article/how-to-convince-someone-when-facts-fail/

 

The Right Data and Critical Thinking are Key for Precision Medicine Success

The Right Data and Critical Thinking are Key for Precision Medicine Success

“Precision medicine” carries so much promise and engenders so much enthusiasm: medical care precisely assigned based on something that is measured about you uniquely. That sounds cool and so doable with today’s technology. Yet, we need to exercise caution in these early, heady days. If we do not, we will wind up overwhelmed, stuck on data that is not entirely useful, or attempt shortcuts that don’t improve medical care. As a result, the promise of precision medicine will not be realized. When it comes to our health, we will not be empowered. Let me explain.

Many things pertaining to health can be tracked/measured/tested on an almost daily basis or by the second: body mass index, calories consumed/burned, heart-rate, oxygen-levels, blood pressure, brain waves/activity, hours slept, exercise, diet, mutations, genes, proteins, RNA, cells, weight, height, respiration, body temperature, fertility status, glucose levels, sunlight exposure, electrolyte levels, pH of sweat/urine, numerous characteristics of blood, urine and fecal matter… Think about all the data being generated by this list that together describes you. And this is only the tip of the iceberg! This Mount Everest-size pile of information could very well (and does) overwhelm people who do not know what to do with it all, including our doctors (Standen, 2015).

Gorging at the data/ information buffet alone will not empower us to manage our health. Instead, we need to think critically about what we need know to answer a health question. Here is a case in point. Already, it is becoming clearer that genetics alone cannot be used to foresee susceptibility to diseases (refer to previous blogs). The groupie following is waning for the mantra that unlocking our genetic code will improve our understanding of disease and will revolutionize the way we think and approach healthcare (Joyner, 2016). Although genomics can provide beneficial information relevant to patient care, it is not successful in all cases. As an example, let us examine warfarin (a blood thinning drug that can be broken down at different rates in patients). Two genes were identified that contributed to warfarin metabolism (Drew, 2016). When patients were given the proper dose based on their genetics, the results showed no improvement in the patients’ response (Drew, 2016). Drats!

On the bright side, we are getting closer to living the precision medicine promise. From these experiences, we are gaining wisdom (i.e., a deeper understanding about the application of information (Rowley, 2007)). However, this is taking a lot of time. What if we could use technology to speed up the process? Would that help empower us sooner? Again, nope! Recently, Watson (IBM’s artificial intelligence) was fed a monstrous amount of material and expected to recommend cancer treatments to doctors (Ross and Swetlitz, 2017). Well, the supercomputer floundered and recommended treatments that would not have necessarily helped the patients (Ross and Swetlitz, 2017). What happened? Well, it is reported that the imported material had been biased by those who fed it to Watson (Ross and Swetlitz, 2017).

So how do we realize the promise of precision medicine? Until Watson (or some other nifty artificial intelligence) advances to the point of making sense and infers something unbiased and insightful from the big-heap-of-data/knowledge for us, we must focus and be sure to collect the right data that will be meaningful for an intended purpose. We should avoid at all costs the temptation to binge at the data/information buffet or continue trying to get a failing idea to work. As Eric Topol, a famed cardiologist and advocate for precision medicine, put it best, “We need to go beyond ‘big’ and go deep” (Dusneck, 2017). By thinking critically about what data we need to answer a health question, we can be empowered. Precision medicine may then become reality.

 

References

Drew, L. (2016). Pharmacogenetics: The right drug for you. Nature, 537(7619), S60-62. doi:10.1038/537S60a

Dusneck, J. (2017, May 25) Cardiologist Eric Topol on why we need to map the human body and “go deep” with big data. Scope. Retrieved from http://scopeblog.stanford.edu/2017/05/25/cardiologist-eric-topol-on-why-we-need-to-map-the-human-body-and-go-deep-with-big-data/.

Joyner, M. J. (2016). Precision Medicine, Cardiovascular Disease and Hunting Elephants. Prog Cardiovasc Dis, 58(6), 651-660. doi:10.1016/j.pcad.2016.02.004

Ross, C. and Swetlitz, I. (2017, September 5) IBM pitched its Watson supercomputer as a revolution in cancer care. It’s nowhere close. Stat. Retrieved from https://www.statnews.com/2017/09/05/watson-ibm-cancer/.

Rowley, J. (2007). The wisdom hierarchy: representations of the DIKW hierarchy. Journal of Information Science, 33 (2), 163–180.

Standen, A. (2015, January 19) Sure You Can Track Your Health Data, But Can Your Doctor Use It? NPR. Retrieve from http://www.npr.org/sections/health-shots/2015/01/19/377486437/sure-you-can-track-your-health-data-but-can-your-doctor-use-it.

 

An immune system timeline for tuberculosis progression

An international team of researchers has defined the series of immune system changes that occur when tuberculosis (TB) transitions from a non-infectious state to active disease. The results, published online in PLOS pathogens, highlight changes in inflammatory processes that can be detected in the blood long before clinical symptoms arise. These findings have important implications for developing diagnostics, vaccines and treatments to battle the TB epidemic.

An estimated 1.7 billion people—one quarter of the world’s population—are infected with the bacterium that causes TB, but only ~10% develop active pulmonary disease. In the article, scientists from the South African TB Vaccine Initiative, the University of Cape Town, the Center for Infectious Disease Research and SomaLogic looked for changes in various molecules in blood that together could predict the risk of TB progression. The time between the initial blood collection and TB diagnosis ranged from 1 to 894 days, so the investigators could construct a timeline of changes that occurred as the disease evolved.

The blood analyses revealed that TB progression associated with sequential modifications of immunological processes. Some of these processes, such as type I/II interferon signaling and complement cascade, were elevated as early as 18 months before TB diagnosis.

Understanding the biology of progression from infection to active pulmonary TB opens the door to blood-based tests that may determine those who are at risk of developing active disease and who need early treatment. These findings could also help development of better vaccines and host-directed therapies that accelerate eradication of TB infection.

Ref: Scriba, TJ et al. (2017) “Sequential inflammatory processes define human progression from M. tuberculosis infection to tuberculosis disease”PLOS Pathogens 13(11): e1006687.

Protein profiling reveals immune system dysfunction in Down syndrome

An article published online in Scientific Reports shows that Down syndrome may be a form of chronic immune disorder. In the largest and most comprehensive study of its kind to date, investigators at the Crnic Institute for Down Syndrome, the Sie Center for Down Syndrome, the University of Colorado, and Somalogic measured the levels of over 3500 proteins in the blood of Down syndrome patients and compared them to non-Down syndrome controls. Their results provide a new framework for understanding the physiological mechanisms that drive the altered disease susceptibilities seen in individuals with Down syndrome, and suggest that individuals with Down syndrome could benefit from therapies that decrease or modulate immune responses.

Down syndrome, or Trisomy 21, is caused by having three copies of chromosome 21 instead of two. Although the genetics of Down syndrome have been known for 60 years, it is still unclear how having the extra chromosome leads to various Down syndrome traits, including changes in common disease susceptibilities (e.g., Down syndrome individuals are more likely to develop Alzheimer’s, leukemia and autoimmune disorders, but less likely to develop solid tumors and cardiovascular disease). Understanding the biology that underlies these differences could inform a wide range of medical conditions that affect not only Down syndrome individuals, but the entire population.

The researchers used the SOMAscan assay to compare levels of blood proteins in 165 individuals with Down syndrome and 98 controls, and they identified 299 proteins that differed significantly between the two groups. Surprisingly, most of these proteins are not encoded by genes located on chromosome 21, but are associated with immune system control. Down syndrome individuals appear to have something that resembles an autoinflammatory condition, with elevated levels of proteins that promote inflammation but deficiencies in proteins that help eliminate foreign pathogens. The findings provide a new way to think about Down syndrome and possible targets of therapies to improve the health and lifespan of those with Down syndrome as well as the general population.

Sullivan, KD et al. (2017) “Trisomy 21 causes changes in the circulating proteome indicative of chronic autoinflammation” Scientific Reports 7(1): 14818.

 

Holding onto the Edge: A New Look at How a SOMAmer Binds

Holding onto the Edge: A New Look at How a SOMAmer Binds

A few fingers there, a couple more fingers over there and a couple well placed feet are all that separate rock climbers from the canyon floor hundreds of feet below. With the ease and grace of spiders, the experienced climbers maneuver quickly over the nearly smooth vertical rock face. What supernatural power do they have that keeps them from succumbing to gravity’s will? None. The climbers have instead developed the muscular strength, the know-how to maximize their grip and a few other handy tools to make the daunting feat easier.

SOMAmers are the elite rock climbers of the aptamer* world. They bear a set of “tools” that give them the advantage of gripping onto proteins in ways that other aptamers cannot. These tools include specialized chemical groups that provide the extra “sticky” factor necessary for SOMAmers to find new holds on their targeted proteins and latch on for an incredibly long period of time.

In recent years, a few papers have detailed how SOMAmers put these tools to work. A new discovery from Dr. Anna Marie Pyle’s lab at Yale University (in a collaboration with SomaLogic) has expanded our insight into how these super-aptamer rock climbers hold onto the rocky outcrops of proteins. They revealed the three-dimensional structure of a SOMAmer bound to interleukin 1α (IL-1α), a very difficult protein to bind with a traditional aptamer (Ren, Gelinas, von Carlowitz, Janjic, & Pyle, 2017). This detailed look at how the SOMAmer interacts with IL-1α revealed not only unique SOMAmer attributes, but also a view of IL-1α that had never been seen.

The structure of the IL-1α binder is truly unique, bearing little resemblance to anything that one might expect when told a SOMAmer is made from mostly DNA. The tiny SOMAmer looks like a ladder thrown off the side of a mountain and trampled by a herd of elephants. This contorted shape is thanks in part to the “tools” the SOMAmer possesses. Unlike other structures of SOMAmers in the literature, this one uses a fancy chemical attachment called “2Naphthyl” (Ren et al., 2017). In the structure, these 2Naphthyl tools form a building block (seen in other SOMAmer structures that use different “tools”) reminiscent of a miniature “zipper” that helps maintain the unusual bent shape (Ren et al., 2017). Aside from the little zipper, what’s really neat about this structure is its unexpectedness in this kind of molecule. It is a new take on “G-quadruplexes (Ren et al., 2017),” which are found throughout nature.

Given this unique and tortuous configuration, how does the SOMAmer hold onto its protein partner? Well, it turns out that the bent ladder structure created a “hand,” with the 2Naphthyl groups forming a sticky pocket in the palm of the hand that provided the bulk of the interaction’s strength (Ren et al., 2017). Additional contacts were made between negatively charged and positively charged atoms in the “fingers” (Ren et al., 2017).

As mentioned above, this unusual structure reveals a lot about the protein as well. Up until now, the research community was aware of the general structure of IL-1α, but knew none of the fine details (Ren et al., 2017). The inclusion of the SOMAmer hand in visualizing the structure helped pull the protein together to form an exquisite crystal that revealed the missing fine details. The research community now sees the elusive sidechains of IL-1α, which in turn illuminate the biology of inflammation and cancer development (Ren et al., 2017). As an extra bonus, the little SOMAmer could also inhibit the protein’s normal function; thus, making it a potential therapeutic for future development (Ren et al., 2017).

With a few tools and the ability to adopt contorted shapes, this tiny hand-like SOMAmer and others can tackle the most difficult of proteins and find great places to hold on. This sticky grip makes it possible to reach new vantage points not achievable by other types of technology. What can be seen from these lofty vantage points? Akin to the beautiful vistas bestowed to rock climbers, we will be able to gaze at never-before-seen vistas of our health.

*(a string of nucleic acids designed to bind to stuff)

References

 

Ren, X., Gelinas, A. D., von Carlowitz, I., Janjic, N., & Pyle, A. M. (2017). Structural basis for IL-1alpha recognition by a modified DNA aptamer that specifically inhibits IL-1alpha signaling. Nat Commun, 8(1), 810. doi:10.1038/s41467-017-00864-2