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Giving Thanks for Biomedical Research

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This Thanksgiving, Americans have an abundance of reasons to be grateful—loving family and good food often come to mind. Here’s one more to add to the list: exciting progress in biomedical research. To check out some of that progress, I encourage you to watch this short video, produced by NIH’s National Institute of Biomedical Imaging and Engineering (NIBIB), that showcases a few cool gadgets and devices now under development.

Among the technological innovations is a wearable ultrasound patch for monitoring blood pressure [1]. The patch was developed by a research team led by Sheng Xu and Chonghe Wang, University of California San Diego, La Jolla. When this small patch is worn on the neck, it measures blood pressure in the central arteries and veins by emitting continuous ultrasound waves.

Other great technologies featured in the video include:

Laser-Powered Glucose Meter. Peter So and Jeon Woong Kang, researchers at Massachusetts Institute of Technology (MIT), Cambridge, and their collaborators at MIT and University of Missouri, Columbia have developed a laser-powered device that measures glucose through the skin [2]. They report that this device potentially could provide accurate, continuous glucose monitoring for people with diabetes without the painful finger pricks.

15-Second Breast Scanner. Lihong Wang, a researcher at California Institute of Technology, Pasadena, and colleagues have combined laser light and sound waves to create a rapid, noninvasive, painless breast scan. It can be performed while a woman rests comfortably on a table without the radiation or compression of a standard mammogram [3].

White Blood Cell Counter. Carlos Castro-Gonzalez, then a postdoc at Massachusetts Institute of Technology, Cambridge, and colleagues developed a portable, non-invasive home monitor to count white blood cells as they pass through capillaries inside a finger [4]. The test, which takes about 1 minute, can be carried out at home, and will help those undergoing chemotherapy to determine whether their white cell count has dropped too low for the next dose, avoiding risk for treatment-compromising infections.

Neural-Enabled Prosthetic Hand (NEPH). Ranu Jung, a researcher at Florida International University, Miami, and colleagues have developed a prosthetic hand that restores a sense of touch, grip, and finger control for amputees [5]. NEPH is a fully implantable, wirelessly controlled system that directly stimulates nerves. More than two years ago, the FDA approved a first-in-human trial of the NEPH system.

If you want to check out more taxpayer-supported innovations, take a look at NIBIB’s two previous videos from 2013 and 2018 As always, let me offer thanks to you from the NIH family—and from all Americans who care about the future of their health—for your continued support. Happy Thanksgiving!

References:

[1] Monitoring of the central blood pressure waveform via a conformal ultrasonic device. Wang C, Li X, Hu H, Zhang, L, Huang Z, Lin M, Zhang Z, Yun Z, Huang B, Gong H, Bhaskaran S, Gu Y, Makihata M, Guo Y, Lei Y, Chen Y, Wang C, Li Y, Zhang T, Chen Z, Pisano AP, Zhang L, Zhou Q, Xu S. Nature Biomedical Engineering. September 2018, 687-695.

[2] Evaluation of accuracy dependence of Raman spectroscopic models on the ratio of calibration and validation points for non-invasive glucose sensing. Singh SP, Mukherjee S, Galindo LH, So PTC, Dasari RR, Khan UZ, Kannan R, Upendran A, Kang JW. Anal Bioanal Chem. 2018 Oct;410(25):6469-6475.

[3] Single-breath-hold photoacoustic computed tomography of the breast. Lin L, Hu P, Shi J, Appleton CM, Maslov K, Li L, Zhang R, Wang LV. Nat Commun. 2018 Jun 15;9(1):2352.

[4] Non-invasive detection of severe neutropenia in chemotherapy patients by optical imaging of nailfold microcirculation. Bourquard A, Pablo-Trinidad A, Butterworth I, Sánchez-Ferro Á, Cerrato C, Humala K, Fabra Urdiola M, Del Rio C, Valles B, Tucker-Schwartz JM, Lee ES, Vakoc BJ9, Padera TP, Ledesma-Carbayo MJ, Chen YB, Hochberg EP, Gray ML, Castro-González C. Sci Rep. 2018 Mar 28;8(1):5301.

[5] Enhancing Sensorimotor Integration Using a Neural Enabled Prosthetic Hand System

Links:

Sheng Xu Lab (University of California San Diego, La Jolla)

So Lab (Massachusetts Institute of Technology, Cambridge)

Lihong Wang (California Institute of Technology, Pasadena)

Video: Lihong Wang: Better Cancer Screenings

Carlos Castro-Gonzalez (Madrid-MIT M + Visión Consortium, Cambridge, MA)

Video: Carlos Castro-Gonzalez (YouTube)

Ranu Jung (Florida International University, Miami)

Video: New Prosthetic System Restores Sense of Touch (Florida International)

NIH Support: National Institute of Biomedical Imaging and Bioengineering; National Institute of Neurological Diseases and Stroke; National Heart, Lung, and Blood Institute; National Cancer Institute; Common Fund


Study Suggests Repurposed Drugs Might Treat Aggressive Lung Cancer

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Small cell lung cancer cells
Caption: Small cell lung cancer cells (red) spreading via blood vessels (white) from the lung to the liver of a genetically-engineered mouse model.
Credit: Leanne Li, Koch Institute at MIT

Despite continued progress in treatment and prevention, lung cancer remains our nation’s leading cause of cancer death. In fact, more Americans die of lung cancer each year than of breast, colon, and prostate cancers combined [1,2]. While cigarette smoking is a major cause, lung cancer also occurs in non-smokers. I’m pleased to report discovery of what we hope will be a much-needed drug target for a highly aggressive, difficult-to-treat form of the disease, called small cell lung cancer (SCLC).

Using gene-editing technology to conduct a systematic, large-scale search for druggable vulnerabilities in certain types of cancer cells grown in lab dishes, NIH-funded researchers recently identified a metabolic pathway that appears to play a key role in SCLC. What makes this news even more encouraging is drugs that block this pathway already exist. That includes one in clinical testing for other types of cancer, and another that’s FDA-approved and has been safely used for more than 20 years to treat people with rheumatoid arthritis.

The new work comes from the lab of Tyler Jacks, Massachusetts Institute of Technology (MIT), Cambridge. The Jacks lab, which is dedicated to understanding the genetic events that lead to cancer, develops mouse models engineered to carry the same genetic mutations that turn up in human cancers.

In work described in Science Translational Medicine, the team, co-led by Leanne Li and Sheng Rong Ng, applied CRISPR gene-editing tools to cells grown from some of their mouse models. Aiming high in terms of scale, researchers used CRISPR to knock out systematically, one by one, each of about 5,000 genes in cells from the SCLC mouse model, as well in cells from mouse models of other types of lung and pancreatic cancers. They looked to see what gene knockouts would slow down or kill the cancer cells, because that would be a good indication that the protein products of these genes, or the pathways they mediated, would be potential drug targets.

Out of those thousands of genes, one rose to the top of the list. It encodes an enzyme called DHODH (dihydroorotate dehydrogenase). This enzyme plays an important role in synthesizing pyrimidine, which is a major building block in DNA and RNA. Cytosine and thymine, the C and T in the four-letter DNA code, are pyrimidines; so is uracil, the U in RNA that takes the place of T in DNA. Because cancer cells are constantly dividing, there is a continual need to synthesize new DNA and RNA molecules to support the production of new daughter cells. And that means, unlike healthy cells, cancer cells require a steady supply of pyrimidine.

It turns out that the SCLC cells have an unexpected weakness relative to other cancer cells: they don’t produce as much pyrimidine. As a result, the researchers found blocking DHODH left the cells short on pyrimidine, leading to reduced growth and survival of the cancer.

This was especially good news because DHODH-blocking drugs, including one called brequinar, have already been tested in clinical trials for other cancers. In fact, brequinar is now being explored as a potential treatment for acute myeloid leukemia.

Might brequinar also hold promise for treating SCLC? To explore further, the researchers looked again to their genetic mouse model of SCLC. Their studies showed that mice treated with brequinar lived about 40 days longer than control animals. That’s a significant survival benefit in this system.

Brequinar treatment appeared to work even better when combined with other approved cancer drugs in mice that had SCLC cells transplanted into them. Further study in mice carrying SCLC tumors derived from four human patients added to this evidence. Two of the four human tumors shrunk in mice treated with brequinar.

Of course, mice are not people. But the findings suggest that brequinar or another DHODH blocker might hold promise as a new way to treat SCLC. While more study is needed to understand even better how brequinar works and explore potentially promising drug combinations, the fact that this drug is already in human testing for another indication suggests that a clinical trial to explore its use for SCLC might happen more quickly.

More broadly, the new findings show the promise of gene-editing technology as a research tool for uncovering elusive cancer targets. Such hard-fought discoveries will help to advance precise approaches to the treatment of even the most aggressive cancer types. And that should come as encouraging news to all those who are hoping to find new answers for hard-to-treat cancers.

References:

[1] Cancer Stat Facts: Lung and Bronchus Cancer (National Cancer Institute/NIH)

[2] Key Statistics for Lung Cancer (American Cancer Society)

[3] Identification of DHODH as a therapeutic target in small cell lung cancer. Li L, Ng SR, Colón CI, Drapkin BJ, Hsu PP, Li Z, Nabel CS, Lewis CA, Romero R, Mercer KL, Bhutkar A, Phat S, Myers DT, Muzumdar MD, Westcott PMK, Beytagh MC, Farago AF, Vander Heiden MG, Dyson NJ, Jacks T. Sci Transl Med. 2019 Nov 6;11(517).

Links:

Small Cell Lung Cancer Treatment (NCI/NIH)

Video: Introduction to Genome Editing Using CRISPR Cas9 (NIH)

Tyler Jacks (Massachusetts Institute of Technology, Cambridge)

NIH Support: National Cancer Institute


Caught on Video: Cancer Cells in Act of Cannibalism

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Tumors rely on a variety of tricks to grow, spread, and resist our best attempts to destroy them. Now comes word of yet another of cancer’s surprising stunts: when chemotherapy treatment hits hard, some cancer cells survive by cannibalizing other cancer cells.

Researchers recently caught this ghoulish behavior on video. In what, during this Halloween season, might look a little bit like The Blob, you can see a down-for-the-count breast cancer cell (green), treated earlier with the chemotherapy drug doxorubicin, gobbling up a neighboring cancer cell (red). The surviving cell delivers its meal to internal compartments called lysosomes, which digest it in a last-ditch effort to get some nourishment and keep going despite what should have been a lethal dose of a cancer drug.

Crystal Tonnessen-Murray, a postdoctoral researcher in the lab of James Jackson, Tulane University School of Medicine, New Orleans, captured these dramatic interactions using time-lapse and confocal microscopy. When Tonnessen-Murray saw the action, she almost couldn’t believe her eyes. Tumor cells eating tumor cells wasn’t something that she’d learned about in school.

As the NIH-funded team described in the Journal of Cell Biology, these chemotherapy-treated breast cancer cells were not only cannibalizing their neighbors, they were doing it with remarkable frequency [1]. But why?

A possible explanation is that some cancer cells resist chemotherapy by going dormant and not dividing. The new study suggests that while in this dormant state, cannibalism is one way that tumor cells can keep going.

The study also found that these acts of cancer cell cannibalism depend on genetic programs closely resembling those of immune cells called macrophages. These scavenging cells perform their important protective roles by gobbling up invading bacteria, viruses, and other infectious microbes. Drug-resistant breast cancer cells have apparently co-opted similar programs in response to chemotherapy but, in this case, to eat their own neighbors.

Tonnessen-Murray’s team confirmed that cannibalizing cancer cells have a survival advantage. The findings suggest that treatments designed to block the cells’ cannibalistic tendencies might hold promise as a new way to treat otherwise hard-to-treat cancers. That’s a possibility the researchers are now exploring, although they report that stopping the cells from this dramatic survival act remains difficult.

Reference:

[1] Chemotherapy-induced senescent cancer cells engulf other cells to enhance their survival. Tonnessen-Murray CA, Frey WD, Rao SG, Shahbandi A, Ungerleider NA, Olayiwola JO, Murray LB, Vinson BT, Chrisey DB, Lord CJ, Jackson JG. J Cell Biol. 2019 Sep 17.

Links:

Breast Cancer (National Cancer Institute/NIH)

James Jackson (Tulane University School of Medicine, New Orleans)

NIH Support: National Institute of General Medical Sciences


Panel Finds Exercise May Lower Cancer Risk, Improve Outcomes

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Mature woman doing moderate exercise
Credit: gettyimages/vgajic

Exercise can work wonders for your health, including strengthening muscles and bones, and boosting metabolism, mood, and memory skills. Now comes word that staying active may also help to lower your odds of developing cancer. 

After reviewing the scientific evidence, a panel of experts recently concluded that physical activity is associated with reduced risks for seven common types of cancer: colon, breast, kidney, endometrial, bladder, stomach, and esophageal adenocarcinoma. What’s more, the experts found that exercise—both before and after a cancer diagnosis—was linked to improved survival among people with breast, colorectal, or prostate cancers.

About a decade ago, the American College of Sports Medicine (ACSM) convened its first panel of experts to review the evidence on the role of exercise in cancer. At the time, there was limited evidence to suggest a connection between exercise and a reduced risk for breast, colon, and perhaps a few other cancer types. There also were some hints that exercise might help to improve survival among people with a diagnosis of cancer.

Today, the evidence linking exercise and cancer has grown considerably. That’s why the ACSM last year convened a group of 40 experts to perform a comprehensive review of the research literature and summarize the level of the evidence. The team, including Charles Matthews and Frank Perna with the NIH’s National Cancer Institute, reported its findings and associated guidelines and recommendations in three papers just published in Medicine & Science in Sports & Exercise and CA: A Cancer Journal for Clinicians [1,2,3].

Here are some additional highlights from the papers:

Ÿ There’s moderate evidence to support an association between exercise and reduced risk for some other cancer types, including cancers of the lung and liver.

Ÿ While the optimal amount of exercise needed to reduce cancer risk is still unclear, being physically active is clearly one of the most important steps in general that people of all ages and abilities can take.

Ÿ Is sitting the new smoking? Reducing the amount of time spent sitting also may help to lower the risk of some cancers, including endometrial, colon, and lung cancers. However, there’s not enough evidence to draw clear conclusions yet.

Ÿ Every cancer survivor should, within reason, “avoid inactivity.” There’s plenty of evidence to show that aerobic and resistance exercise training improves many cancer-related health outcomes, reducing anxiety, depression, and fatigue while improving physical functioning and quality of life.

Ÿ Physical activity before and after a diagnosis of cancer also may help to improve survival in some cancers, with perhaps the greatest benefits coming from exercise during and/or after cancer treatment.

Based on the evidence, the panel recommends that cancer survivors engage in moderate-intensity exercise, including aerobic and resistance training, at least two to three times a week. They should exercise for about 30 minutes per session.

The recommendation is based on added confirmation that exercise is generally safe for cancer survivors. The data indicate exercise can lead to improvements in anxiety, depression, fatigue, overall quality of life, and in some cases survival.

The panel also recommends that treatment teams and fitness professionals more systematically incorporate “exercise prescriptions” into cancer care. They should develop the resources to design exercise prescriptions that deliver the right amount of exercise to meet the specific needs, preferences, and abilities of people with cancer.

The ACSM has launched the “Moving Through Cancer” initiative. This initiative will help raise awareness about the importance of exercise during cancer treatment and help support doctors in advising their patients on those benefits.

It’s worth noting that there are still many fascinating questions to explore. While exercise is known to support better health in a variety of ways, correlation is not the same as causation. Questions remain about the underlying mechanisms that may help to explain the observed associations between physical activity, lowered cancer risk, and improved cancer survival.

An intensive NIH research effort, called the Molecular Transducers of Physical Activity Consortium (MoTrPAC), is underway to identify molecular mechanisms that might explain the wide-ranging benefits of physical exercise. It might well shed light on cancer, too.

As that evidence continues to come in, the findings are yet another reminder of the importance of exercise to our health. Everybody—people who are healthy, those with cancer, and cancer survivors alike—should make an extra effort to remain as physically active as our ages, abilities, and current health will allow. If I needed any more motivation to keep up my program of vigorous exercise twice a week, guided by an experienced trainer, here it is!

References:

[1] Exercise Is Medicine in Oncology: Engaging Clinicians to Help Patients Move Through Cancer. Schmitz KH, Campbell AM, Stuiver MM, Pinto BM, Schwartz AL, Morris GS, Ligibel JA, Cheville A, Galvão, DA, Alfano CM, Patel AV, Hue T, Gerber LH, Sallis R, Gusani NJ, Stout NL, Chan L, Flowers F, Doyle C, Helmrich S, Bain W, Sokolof J, Winters-Stone KM, Campbell KL, Matthews CE.  CA Cancer J Clin. 2019 Oct 16 [Epub ahead of publication]

[2] American College of Sports Medicine Roundtable Report on Physical Activity, Sedentary Behavior, and Cancer Prevention and Control. Patel AV, Friedenreich CM, Moore SC, Hayes SC, Silver JK, Campbell KL, Gerber LH, George SM, Fulton JE, Denlinger C, Morris GS, Hue T, Schmitz KH, Matthews CE. Med Sci Sports Exerc. 2019 Oct 16. [Epub ahead of publication]

[3] Exercise Guidelines for Cancer Survivors: Consensus Statement from International Multidisciplinary Roundtable. Campbell KL, Winters-Stone KM, Wiskemann J, May AM, Schwartz AL, Courneya KS, Zucker DS, Matthews CE, Ligibel JA, Gerber LH, Morris GS, Patel AV, Hue TF, Perna FM, Schmitz KH. Med Sci Sports Exerc. 2019 Oct 16. [Epub ahead of publication]

Links:

Physical Activity and Cancer (National Cancer Institute/NIH)

Moving Through Cancer (American College of Sports Medicine, Indianapolis, IN)

American College of Sports Medicine

Charles Matthews (NCI)

Frank Perna (NCI)

NIH Support: National Cancer Institute


Finding New Genetic Mutations Amid Healthy Cells

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Po-Ruh Loh
Po-Ru Loh Courtesy of Loh Lab

You might recall learning in biology class that the cells constantly replicating and dividing in our bodies all carry the same DNA, inherited in equal parts from each parent. But it’s become increasingly clear in recent years that even seemingly healthy tissues contain neighborhoods of cells bearing their own acquired genetic mutations. The question is: What do all those altered cells mean for our health?

With support from a 2018 NIH Director’s New Innovator Award, Po-Ru Loh, Harvard Medical School, Boston, is on a quest to find out, though without the need for sequencing lots of DNA in his own lab. Loh will instead develop ultrasensitive computational tools to pick up on those often-subtle alterations within the vast troves of genomic data already stored in databases around the world.

How is that possible? The math behind it might be complex, but the underlying idea is surprisingly simple. His algorithms look for spots in the genome where a slight imbalance exists in the quantity of DNA inherited from mom versus dad.

Actually, Loh can’t tell from the data which parent provided any snippet of chromosomal DNA. But looking at DNA sequenced from a mixture of many cells, he can infer which stretches of DNA were most likely inherited together from a single parent.

Any slight skew in those quantities point the way to genomic territory where a tiny portion of chromosomal DNA either went missing or became duplicated in some cells. This common occurrence, especially in older adults, leads to a condition called genetic mosaicism, meaning that, contrary to most biology textbooks, all cells aren’t exactly the same.

By detecting those subtle imbalances in the data, Loh can pinpoint small DNA alterations, even when they occur in 1 in 1,000 cells collected from a person’s bloodstream, saliva, or tissues. That’s the kind of sensitivity that most scientists would not have thought possible.

Loh has already begun putting his new computational approach to work, as reported in Nature last year [1]. In DNA data from blood samples of more than 150,000 participants in the United Kingdom Biobank, his method uncovered well over 8,000 mosaic chromosomal alterations.

The study showed that some of those alterations were associated with an increased risk of developing blood cancers. However, it’s important to note that most people with evidence of mosaicism won’t go on to develop cancer. The researchers also made the unexpected discovery that some individuals carried genetic variants that made them more prone than others to pick up new mutations in their blood cells.

What’s especially exciting is Loh’s computational tools now make it possible to search for signs of mosaicism within all the genetic data that’s ever been generated. Even more importantly, these tools will allow Loh and other researchers to ask and answer important questions about the consequences of mosaicism for a wide range of diseases.

Reference:

[1] Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations. Loh PR, Genovese G, Handsaker RE, Finucane HK, Reshef YA, Palamara PF, Birmann BM, Talkowski ME, Bakhoum SF, McCarroll SA, Price AL. Nature. 2018 Jul;559(7714):350-355.

Links:

Loh Lab (Harvard Medical School, Boston)

Loh Project Information (NIH RePORTER)

NIH Director’s New Innovator Award (Common Fund)

NIH Support: Common Fund; National Institute of Environmental Health Sciences


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