Sanford Magazine

Sanford Health

AT T H E F O R E F R O N T O F

DISCOVERY 2014-2015

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Denny Sanford Denny Sanford is the preeminent health care philanthropist in the U.S., donating more than $1 billion to health care and medical research efforts.

In 2007, a transformational gift of $400 million by Denny Sanford provided for an expansion of children’s initiatives at Sanford Health, and has created significant momentum in making Sanford Health one of the premiere research institutions in the United States. Key programs include developing a cure for type 1 diabetes through The Sanford Project and providing health care to children and families in underserved communities across the world through Sanford World Clinic.

Most recently, subsequent gifts of more than $200 million by Mr. Sanford have paved the way to establish Edith Sanford Breast Center and Sanford Imagenetics.

Denny Sanford is making the impossible possible through his generosity and belief in Sanford Health’s dedication to the work of health and healing.

LETTER FROM DR. HOYME Dear Reader, Thank you for picking up this publication. In these next few pages, you will have the opportunity to learn more about the remarkable work being done to further medical knowledge right here at Sanford Health.

We invite you to look inside the walls of our robust research programs to see why research matters.

We have selected 13 research endeavors that are making significant contributions to the global medical community; each has the potential to significantly alter the landscape of medical care. From searching for a cure for type 1 diabetes to seeing how cattle can be used to treat human diseases, you will discover how diverse our projects are and the integral part they play in the overall care of our patients at Sanford Health. We also want to introduce you to our scientists, research staff and physicians, remarkable people who work diligently every day to solve crucial health problems that face our country and the world.

And while this is just a fraction of the research that occurs here, none of it would be possible without the generosity of one man. Denny Sanford has shared his wealth on a grand scale, and we here at Sanford Health are so thankful to benefit from that generosity. Mr. Sanford is dedicated to donating to cutting edge projects in biomedical research that have the potential to fundamentally change healthcare for the betterment of all people. Thanks to his gifts, we can help accomplish his goals.

This is an amazing time in the world of medicine. There is so much to learn and discover. Sanford Health is proud to play a role in those breakthroughs that will improve the human condition. So please continue reading to see how Sanford Health is truly at the forefront of discovery!

Sincerely,

H. Eugene Hoyme, MD President, Sanford Research Chief Academic Officer, Sanford Health 2 | AT THE FOREFRONT OF DISCOVERY | 2014-2015

L E V ER AGING GENE T IC S FOR INNO VAT I V E C A RE 04 M AKE YOUR MARK Discovering genetic markers in breast cancer and how you can contribute to medical research 08 SIDE EFFECTS Pharmacogenetics and the emerging changes for prescription medication 12 A NSWERS FROM THE FAMILY TREE H ow understanding your genetic makeup improves your medical care

IMP RO V ING F E TA L DE V ELOP MEN T 16 SEARCHING FOR ANSWERS One in 160 pregnancies end in stillbirth 20 J UST ONE DRINK Prevalence, prevention, and the early identification of Fetal Alcohol Syndrome

THE BIG-PICTURE PROJECT, page 48

A DVA NCING INFA N T & CHIL D HE A LT H

S T RENG T HENING OUR IMMUNI T Y

24 UNLOCKING THE UNKNOWN Batten disease and other rare diseases

36 MORE THAN MILK 44 THE NEXT PHASE Cows help Sanford How the Sanford Project researchers create is making progress disease-fighting antibodies toward a discovery

28 THE DHA GAP Helping premature babies get back on track

40 THE NEW CANCER EPIDEMIC Sanford achieves one of the highest oropharyngeal cancer survival rates in the nation

32 CONCUSSIONS & KIDS Get in the game: Keeping kids safe in sports at a time when concussions are on the rise

C URING & T RE AT ING CHRONIC DI SE A SE 52 A JOURNEY OF FIRSTS H ow a new device could reshape the treatment of aortic aneurysms

48 THE BIGPICTURE PROJECT Uncovering the interactions of proteins and how they affect disease

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“We have the capability to sequence your entire genome and get ideas on what may be causing the mutations and what may be causing the cancer.”

DAVID PEARCE, PHD

(above)

DAVID PEARCE, PHD Chief Operating Officer and Vice President, Sanford Research

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Discovering genetic markers in breast cancer and how you can contribute to medical research

The human body is a complex thing. Its parts are numerous, multifaceted, and often multifunctional. It is difficult enough to understand when things are working perfectly; it is another whole endeavor to piece things together when they go wrong.

Breast cancer is the most common cancer among U.S. women. One woman is diagnosed with it every two minutes, and one dies from it every 13 minutes. And like most things dealing with the human body, it is complex.

“We know there are certain changes in the DNA sequence,” remarks David Pearce, PhD, Sanford Research chief operating officer and vice president. “Out of those 3.2 billion base pairs of genetic code, there may be some certain changes in individuals that make them more susceptible to cancer. We also know that environment has a heavy play on cancer development.”

Smoking, being exposed to toxins or being overweight are all environmental factors that can contribute to the growth of cancer. But Dr. Pearce explains that the development of cancer is so complex that there may be other elements connected to cancer that haven’t been identified yet. So while there are many combinations of factors that could lead to breast cancer, researchers do know what happens when the catalyst occurs.

“A single cell would normally divide and regenerate,” explains Dr. Pearce.

“With cancer, something reprograms that cell to start growing in a different way. It essentially switches the cell on to do something it just shouldn’t do. It grows and it grows and it grows when it’s not supposed to.”

L E V E R A G IN G G E N E T I C S F O R IN N O VAT I V E C A R E

Make your Mark

A S T O R E H O US E OF SAMPLES To get a better idea of where these mutations originate from, Sanford researchers need to look at a large number of samples. That is where the Sanford Health BioBank comes into the picture.

Sanford’s on-site biobank includes a robotic sample processing system, one of only a small handful of similar systems being used around the globe.

“We can speed up the pace of research,” says Chun-Hung Chan, PhD, director of the Sanford Health BioBank. “If a researcher needs a large amount of breast cancer samples, it could take a long time to recruit those people, especially in a rural setting like South Dakota or North Dakota. But with us, if we already have the samples, then we can give them to our researcher in a matter of weeks.”

START THE SEQUENCE In 2011, Sanford Health received a $100 million gift from Denny Sanford to establish Edith Sanford Breast Center, named after his mother who he lost to breast cancer at the age of just 2. The focus of the initiative is to pursue cutting-edge forward genomic research and identify more of the breast cancer markers in our DNA. “We have the capability to sequence every one of your base pairs,” remarks Dr. Pearce. “That’s the infrastructure we’ve been developing here. We have a machine that can sequence all 3.2 billion of them. We have the ability to sequence it and get ideas of what may be causing the mutations and what may be causing the cancer.”

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(above)

CHUN-HUNG CHAN, PHD BioBank Director, Sanford Research

Dr. Chan and the BioBank staff gather samples throughout the Sanford Health footprint from patients who are willing to donate and help further research efforts. The process of donating is very simple and is done without extra effort from the patient.

“What we essentially try to do is integrate our process with normal clinical operations,” explains Dr. Chan. “We do not want to poke people only for our purpose. The lab will be drawing blood for a diagnostic report, and if the patient agrees, they will take a few extra tubes that will come to us.”

Through these methods, the BioBank has thousands of samples ready to help aid in research. However, Dr. Chan says that they are very particular as to who has access to the samples and how they are used.

“Ultimately we have a responsibility to our patients,” says Dr. Chan.

“They’ve entrusted us to use their samples in a meaningful manner.

We specified that they would go to health research to further Sanford’s mission of improving the human condition. So if we were presented with a sample request that isn’t within the spirit of our mission, we wouldn’t allow our samples to be used.”

R I SK A SS E SSM E N T Through the analysis of samples, researchers can hopefully start to identify more and more DNA indicators of breast cancer. That information could help more women when it comes prevention and early diagnosis.

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“The most aggressive forms of breast cancer occur over a three-month window,” states Dr. Pearce. “You could have your breast exam and then two days later start developing a tumor. But if we know that you could be susceptible to that, then we can implement proper screening and catch it early on.”

This investment and dedication to discovering answers is gearing Sanford to become a national resource for researchers. That is something that not only will further the understanding of breast and other types of cancers, but will also help patients right here in Sioux Falls.

“With sequencing and sampling, combined with our research, we’ve built significant capacity by investing in the equipment to do it here,” states Dr. Pearce. “And more importantly, we’ve invested in and recruited the individuals that can take the information from a machine and apply it to a patient.”

Gene A b nor m a l itie s and Brea s t C ancer

Inherited Cases About 5 to 10 percent of breast cancers are thought to be hereditary, caused by abnormal genes passed from parent to child.

Most inherited cases of breast cancer are associated with two genes: BRCA1 (BReast CAncer gene one) and BRCA2 (BReast CAncer gene two). Mutations in these genes have shown a correlation to breast cancer.

SNP Mutations However, Dr. Pearce explains that while your chances of getting breast cancer increase with that mutation present, researchers are learning that other mutations in pieces of chromosomes – called SNPs (single nucleotide polymorphisms) – are also linked to higher breast cancer risk in women with an abnormal BRCA1 gene, as well as women who didn’t inherit an abnormal breast cancer gene.

Uncommon Gene Abnormalities Changes in other genes are also associated with breast cancer. These abnormal genes are much less common and do not increase risk as much as abnormal BRCA1 and BRCA2 genes, including ATM, p53, CHEK2, PTEN, CDH1, and PALB2.

Gene Abnormality Risks You are substantially more likely to have an abnormal breast cancer gene if: • You have blood relatives (grandmothers, mother, sisters, aunts) on either your mother’s or father’s side of the family who had breast cancer diagnosed before age 50 • There is both breast and ovarian cancer in your family, particularly in a single individual • There are other gland-related cancers in your family such as pancreatic, colon, and thyroid cancers • Women in your family have had cancer in both breasts • A man in your family has had breast cancer

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8 | AT THE FOREFRONT OF DISCOVERY | 2014-2015

(left and right)

R USS W I LK E , M D Internal Medicine, Sanford Health

Side Effects

Pharmacogenetics and the emerging changes for

prescription medication

You get a prescription from the doctor. You fill it at the pharmacy and begin the daily routine of taking your medication. A lot of the time it works and you feel better, but many times patients can have side effects. The question is why.

Why do certain drugs work for certain people and not for others?

The answers lie in the field of pharmacogenetics.

“We all respond to drugs differently,” says Russ Wilke, MD. “If we vary genetically in our ability to metabolize any given drug, this variation affects the levels of the drug in our blood and tissues. For some drugs, this can have a measurable impact on clinical outcomes. Examples include cancer drugs and blood thinners.”

Dr. Wilke practices internal medicine at Sanford Health in Fargo, ND, where he also holds an appointment as a clinical professor of medicine at the University of North Dakota. He has been a general internist for nearly two decades, and for much of that time he ran a research program focused on identifying genetic predictors of drug outcomes, a field known as pharmacogenetics. Prior to joining Sanford, Dr. Wilke was director of genomics and cardiovascular risk at Vanderbilt University in Nashville, Tennessee.

“Using genetics to guide how we prescribe certain medications helps us determine how each individual patient will be affected by a drug at the point of prescribing,” says Dr. Wilke. “Using this approach, we may be able to help some patients avoid potentially severe side effects.”

I t m a k e s s en s e There is no blanket drug that is safe for everyone. Many drugs are metabolized (broken down) by enzymes in our livers.

The function of these enzymes vary genetically. Some of them vary a lot. For some drug-metabolizing enzymes, one in 10 people can have a genetic variant in their DNA that may change their response to a drug metabolized by that enzyme.

Common drugs, like warfarin (Coumadin) and clopidogrel (Plavix), are metabolized by liver enzymes that vary genetically.

Clinical investigators working in the field of pharmacogenetics examine how these gene variations change the way patients respond to these blood thinners in a clinical setting.

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While the world of medicine still has a long way to go, Dr. Wilke and the rest of the Sanford Health team will be on the forefront with a new program called Imagenetics (Internal Medicine and Genetics). Earlier this year, Sanford Health announced Sanford Imagenetics – the first program of its kind in the nation to fully integrate genetics and genomic medicine into primary care for adults.

It allows Sanford to merge medicine and science in a way that other health systems are not able to because of the generosity of Denny Sanford, who gifted $125 million to build the program.

(above)

CATHERINE HA JEK, MD Internal Medicine, Sanford Health

Doctors and scientists at Sanford Health will be determining if this approach can be applied to medications used to manage common problems like diabetes, high blood pressure, and elevated cholesterol levels. A lot of Dr. Wilke’s work has been in the field of statin drugs. These medications are used to lower LDL cholesterol levels (i.e. the bad cholesterol levels), and they reduce cardiovascular disease in patients at risk. Statins are some of the most frequently prescribed drugs in the U.S. “These drugs are very safe,” reminds Dr. Wilke. “Millions of people take them every day, and they are hugely efficacious at reducing the burden of heart disease and stroke in our country.” However, Dr. Wilke explains that certain people can experience muscle side effects. Most muscle side effects are very mild, but in rare circumstances (less than 1 in 1,000) patients can experience muscle damage – a condition known as myopathy. “Genetic predictors may soon be available clinically to identify a subset of patients at risk for developing the more severe statin-related muscle side effects.”

A ne w era Sanford’s approach to pharmacogenetics will be to make the genetic information available to the clinician up front, before a medication is prescribed. At present, a lot of genetic testing is done reactively (after the drug has been selected) because of potential cost implications. However, Sanford internist and intensivist, Anthony Tello, MD, sees a near future where a patient’s genetic information is included in his or her medical record pre-emptively, to predict and prevent potential side effects.

“Imagine that you go to type in a prescription,” explains Dr. Tello, “and the electronic medical record recognizes that your patient’s genetic code isn’t quite compatible with that medicine. It will pull that information forward in real time and prompt you to consider changing the dose or prescribing an alternative medication.”

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Sanford Health is expanding the integration of genetic counselors across its entire system of care, increasing the number of available genetic tests, and leveraging detailed family histories to deliver health care with even greater precision. Combined with gene-based drug dosing where applicable, this will allow physicians to predict future health concerns and reduce drug side-effects through a personalized health care plan.

Denny Sanford’s gift will also support the expansion of ongoing research initiatives to uncover new disease – causing biomarkers and develop academic programs to ensure that our next generation of clinicians is trained in the emerging field of genetics. “This is truly an amazing gift,” says Dr. Wilke. “It will spark a paradigm shift in routine clinical care, helping doctors to have a deeper understanding of their patients, and patients to have a better understanding of their health care.”

SANFORD IMAGENETICS

Thanks to Denny Sanford’s generosity, Sanford Health has launched Sanford Imagenetics – the first program of its kind in the nation to fully integrate genetics and genomic medicine into primary care for adults.

In the coming months, Sanford Health will begin translating its patients’ genetic makeup to prescribe certain medications with even greater precision. It will be the first step toward offering more effective treatments, predicting future health concerns, and preventing disease with a personalized health care plan.

Sanford Health is recruiting the best and brightest in the fields of genetics and, by partnering with area educational institutions, will train the next generation of physicians, nurses and scientists in genomic medicine.

Sanford Imagenetics will accelerate scientific discovery of how DNA affects health and healing, and apply that understanding to benefit patients.

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Answers from the

Family Tree How understanding your genetic make-up improves your medical care

It’s a small thing, smaller than small actually. Microscopic would be more of an accurate description. And although it is invisible to the naked eye, its work is written all over your face.

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“We can give patients a detailed explanation of what is happening and what it can mean for them when it comes to prevention, earlier diagnosis, or more targeted treatments.”

QUINN STEIN, MS

(above and left)

Q U I N N S T E I N , MS Genetic Counselor, Sanford Health

Your DNA and the genes and chromosomes that they make up tell your body everything it needs to be you. From why your hair is curly to why your eyes are blue, all the answers lie in your genetic make-up. Your genes also play a big role when it comes to your health. But sometimes genes can get scrambled, and it can cause a mutation in your DNA sequence. When that happens, it can disrupt normal development or cause a medical condition.

These mutations can manifest at birth or they might appear later in life.

They could lead to anything from Cystic Fibrosis to a predisposition for breast cancer. Over 4,000 diseases are the result of these altered genes.

Knowing what that means for you can be confusing and overwhelming.

H e l p m e u nder s tand Enter Sanford Health genetic counselors. The team of clinical genetic experts guides patients through the intricacies of their genetic code.

“We are really all about educating the patient,” says Genetic Counselor Quinn Stein, MS. “We want them to make informed decisions when it comes to their health care.”

Stein and the team of genetic counselors at Sanford meet with patients following a referral.

Many of these patients have been diagnosed with cancer and are looking for what that means for them and their families.

“Let’s say a woman is diagnosed with breast cancer,” says Stein. “We want to know if her cancer was related to a gene she inherited so other family members can use the information as part of their preventative care plan. For example she may have a sister or a daughter, and through genetic testing they can get those answers.”

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This knowledge also helps doctors. Knowing what possibly caused the cancer to occur can affect the type of procedure prescribed.

“Knowing whether it is genetic or not is huge,” says Stein. “That can mean the difference between a simple lumpectomy and a double mastectomy.”

But genetic counseling isn’t just reserved to cancer diagnoses. Stein also works with patients who struggle with trying to have a child.

“Having a miscarriage is such an emotional and sad thing for families, and often times a woman will experience guilt or think that it’s something she did wrong,” says Stein. “But we can test for what caused it. And in 80 percent of cases, we can find out why it happened and whether it is likely to happen again. That can bring a lot of closure to the family.”

T he f u t u re i s here This type of medicine that uses genetics as a base is a rapidly expanding field.

“Genetics is big and fashionable in medicine right now,” says Stein. “It’s moving at such a fast pace. It’s a pretty dynamic field.”

And nowhere is that more true than at Sanford Health. The newly announced Sanford Imagenetics program is recruiting additional genetic counselors and integrating them into the clinical setting where they will be more readily accessible.

This will be a first in health care.

“This is a new experiment,” says Stein.

“This model hasn’t been done before and that’s exciting. We are figuring this out together with our doctors and patients.”

And while this is a new venture, Stein wants to assure patients that this will only increase their quality of care. “We can give patients a detailed explanation of what is happening and what it can mean for them when it comes to prevention, earlier diagnosis or more targeted treatments.”

(left to right)

J E SS E D I R KS E N , M D Surgeon, Sanford Health

KRISTEN DEBERG Genetic Counselor, Sanford Health 14 | AT THE FOREFRONT OF DISCOVERY | 2014-2015

Sanford H ea l th Mo l ec u l ar La b

Is genetic testing performed on-site?

Genetic testing is a great tool doctors can use to get a more accurate picture of what is happening in the body; however, it can be expensive. Previously, Sanford had to send much of the DNA samples off-site to be tested in labs around the country. But as part of the new Imagenetics initiative, Sanford will be home to its own molecular lab. This will give doctors and genetic counselors direct access to those performing the tests, allowing for faster results and the convenience of having a facility on campus.

Do my genes say all that?

Genes give us a lot of information, but they aren’t the only things that matter. Your family medical history and certain aspects of your lifestyle all play an important role in your health. So while you might not have a genetic predisposition for skin cancer, never wearing sunscreen, for example, will increase your risk. Your genes can give you answers, but the environment around you is also a key piece of the genetic puzzle.

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A MY E LL I O T T , P H D Director and Senior Scientist, Sanford Research’s Center for Health Outcomes and Prevention Research

SEARCHING FOR ANSWERS

One in 160 pregnancies end in

Stillbirth

IM P R O V IN G F E TA L D E V E L O P M E N T

(left)

You’ve waited nine months. You’re excited to see the color of her eyes or if she has her dad’s nose. It should be a time of joy and celebration. But sadly, not every pregnancy ends happily. One in every 160 pregnancies will end in a stillbirth.

“Stillbirths are so unique,” explains Amy Elliott, PhD. “A family that is going through that situation, they are simultaneously experiencing birth and death at the same time. It is a horrible juxtaposition.”

A stillbirth is when the fetus dies in the womb at any point after 20 weeks gestation. It can happen for a number of reasons: a birth defect, a genetic problem with the mother or an issue with the placenta. But amazingly, the cause of more than 50 percent of all stillbirths is unknown.

“One of the things we are trying to do within our research is to see if some of those unknowns can be explained,” says Dr. Elliott. “We are trying to figure out why this happened. What are ways that this can be prevented?”

This type of research doesn’t happen in a lab though. It takes place in hospitals and clinics where Dr. Elliott’s team is working right alongside the expecting women.

“Our research is very patient focused,” says Dr. Elliott. “We are working directly with women at prenatal clinics.

That’s where we meet with them and collect the information.”

GATHERING INFORMATION Dr. Elliott and her team of researchers are participating in a global study, funded by the National Institutes of Health called Safe Passage, to discover just that. They have enrolled around 5,400 moms-to-be in four sites across North and South Dakota. Sanford Research is the only United States site investigating this type of data. While most of the babies in the group are carried to full-term and are born perfectly healthy, the study focuses on those who sadly do not make it.

“With that information, we will be able to find risk factors which can determine who may be at risk for a stillbirth,” says Dr. Elliott. “Once we know what those signs are during pregnancy then clinicians can pick up on that and design intervention programs to help prevent it from happening.”

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T O UG H D E C I S I O N S As a trained child clinical psychologist, Dr. Elliott knows that the loss of a child can have traumatic effects on the family.

“Women get past their first trimester and think they are in the clear,” says Dr. Elliott. “It is just devastating for these families.”

After a stillbirth, many families just want to bury their child and try to move on. However, one of the best ways to determine what happened is to perform an autopsy, which can be a hard thing to ask of a grieving family.

“We work very closely with our research teams on how to deal with people who are handling grief,” says Dr. Elliott. “How do you talk to families about participating in a research study on the most horrible day of their lives? It’s the last thing anybody wants to talk about.”

Although it is a tough decision, Dr. Elliott says that the parents understand that the information gathered can provide important answers down the road.

“When it comes down to it, they want to help ensure other families do not have to experience what they did,” says Dr. Elliott.

IMPROVING THE ODDS But this research, though focused on stillbirths, can also help improve care across the spectrum of medicine.

“Research is happening here to help better identify individuals at risk for having a stillbirth delivery,” explains Dr. Elliott.

“But that information can help improve care practices, not just here but internationally. Our research is contributing to that body of literature to help improve health and well-being.”

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“ Once we know what those signs are during pregnancy then clinicians can pick up on that and design intervention programs to help prevent it from happening.”

AMY ELLIOT T, PHD

PREGNANCY R I SK F A C T O R S

Factors that place a pregnancy at risk can be divided into four categories: 1. E xisting Health Conditions Existing health conditions, including but not limited to high blood pressure, polycystic ovary syndrome, diabetes, kidney disease, autoimmune disease, thyroid disease, infertility, obesity and HIV/AIDS can impact pregnancy and result in increased risks.

2. Age Pregnant teens are more likely to develop high blood pressure and anemia (lack of healthy red blood cells), and go into labor earlier than women who are older. Older first-time mothers (i.e. first-time pregnancy after age 35) may have normal pregnancies, but research indicates that these women are at increased risk of having a cesarean delivery and delivery complications.

3. Lifestyle Factors Lifestyle factors create increased risks during pregnancy. Women who drink during pregnancy are more likely to have a miscarriage or stillbirth. Smoking during pregnancy puts the fetus at risk for pre-term birth, certain birth defects and SIDS. 4. Conditions of Pregnancy Specific conditions of pregnancy, including multiple gestation (pregnancy with twins, triplets, or more) and uncontrolled gestational diabetes, increase the risk of infants being born prematurely.

Preeclampsia is a syndrome marked by a sudden increase in the blood pressure of a pregnant woman after the 20th week of pregnancy. When left untreated, the condition can be fatal for the mother and/or the fetus and result in long-term health problems.

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Just One Drink...

Prevalence, prevention and the early identification of

Fetal Alcohol Syndrome

There is a painting that hangs in an office at the Sanford Research Center. It’s just a small square no more than ten inches across surrounded by wood that has been painted black. On the canvas the artist has depicted the faces of two young boys. Their arms slung around one another, they look as if they could be brothers. But something sets them apart from one another. One has Fetal Alcohol Syndrome and one does not.

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“Prevention is challenging, but if we can diagnose it early, then we can institute intervention and educational programs that help in the long run with making the life of the child better.”

EUGENE HOYME, MD

(above and left)

E UG E N E H O YM E , M D

The painting belongs to Eugene Hoyme, MD, president of Sanford Research and chief academic officer for Sanford Health. Dr. Hoyme picked it up on one of his many trips to South Africa. He has spent the past 17 years making annual trips to the African nation where the prevalence of Fetal Alcohol Spectrum Disorders, or FASD, is the highest in the world.

President, Sanford Research Chief Academic Officer, Sanford Health

“Everybody drinks there because of how deeply engrained it is within their culture,” says Dr. Hoyme.

It’s that culture of drinking that is causing 8 to 10 percent of kids born to farm workers in the Western Cape Province near Cape Town to be born with FASD. It’s a staggering stat and sadly one that is totally preventable.

Brain deve l op m ent and a l coho l don ’ t m i x Many women have heard it before: Don’t drink while you’re pregnant. The effects of alcohol on a developing fetus can be dangerous.

“If a woman drinks regularly during pregnancy, there is about a 50 percent chance that the child will have negative effects,” states Dr. Hoyme. “The extent of those effects depends on how much the mother drinks and at what point in her pregnancy she drinks.”

If a woman drinks heavily at the start of her pregnancy, the baby will be more at risk for physical deformities and neurological issues. If she drinks later on, most of the facial features will already be developed and the effects will largely be on the baby’s brain development.

A child with FASD will face a number of obstacles in life, both physical and mental.

They are typically little for their age with smaller heads. They can have issues with balance and motor coordination and often appear clumsy or off-balance. Typically, people with FASD have lower IQs, have a hard time adapting to situations, display hyperactivity and attention deficits, and have difficulties in processing information.

However, with help, people with FASD can live happy and productive lives.

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A s t u d y at ho m e Through Dr. Hoyme’s global research and commitment in the field of early detection of FASD, Sioux Falls was selected as one of four American communities to participate in a FASD prevalence study: the first of its kind in the nation.

E ar l y intervention The only way to prevent FASD is to not drink during pregnancy.

However that can sometimes be a hard ideal to project.

“If the husband is a heavy drinker, it’s likely that the wife will be a drinker as well. You see a lot of binge drinking on the weekends and that is hard to combat,” says Dr. Hoyme.

While education is a major part of Dr. Hoyme’s work in South Africa, he has focused mostly on identifying which children have FASD. “Prevention is challenging,” reminds Dr. Hoyme. “But if we can diagnose it early, then we can institute intervention and educational programs that help in the long run with making the life of the child better.”

In South Africa, Dr. Hoyme and his team go into the school system and work with first-graders. They measure the size of their heads, look for any identifying facial features, and other physical and behavioral characteristics that would indicate the presence of alcohol during fetal development. This list of markers for FASD has become known as the “Hoyme criteria.”

“This is a difficult diagnosis because there is not a single unique marker,” states Dr. Hoyme. “It’s not a genetic problem. There is not a blood test that you can do. It really is a clinical diagnosis based on characteristics of the child.”

Dr. Hoyme and a large team of doctors and researchers received permission from all of the elementary schools in Sioux Falls to examine first-graders throughout the city. They performed the same evaluation used in South Africa, looking for the children that appeared small and underweight for their age. After identifying the children who may have growth problems, Dr. Hoyme’s team began contacting parents for consent to continue studying their children.

Seventy percent of parents agreed, and the children were given an in-depth exam from a doctor experienced in identifying kids with developmental disabilities.

The children underwent thorough psychological testing, and the mothers of the children were also interviewed.

“We asked them about their health,” explains Dr. Hoyme. “We talked about their family history, medications, smoking and drinking. And that can be hard, since a lot of woman do not want to admit that they drank while pregnant.”

The results of the study are currently being reviewed for publication, but Dr. Hoyme feels they will surprise a lot of people.

“FASD is much more common in the United States than you may think,” says Dr. Hoyme. “We have found that it is blind to race and blind to income. It has to do with how much the mother drank, not how much money she makes, where she lives or what kind of alcohol she drank.”

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A SK D R . H O YM E

What is fetal alcohol syndrome?

Fetal alcohol syndrome is a group of abnormalities in babies born to mothers who consume alcohol during pregnancy.

It is the most common known nongenetic (non-inherited) cause of mental retardation in the United States.

How many children are born each year with fetal alcohol syndrome?

About 40,000 babies (or 10 in 1,000 births) are born with FAS each year in the United States. Even more are born with partial fetal alcohol syndrome or alcohol-related neurodevelopmental disorder. Sanford’s research in Sioux Falls and other American communities will help provide better prevalence rates.

Before I found out I was pregnant, I got drunk one time. Did I hurt my baby?

If it was a one-time thing, your baby is probably going to be okay. But what you do not want to do is drink regularly, or binge drink, during pregnancy. Once you find out you’re pregnant, you should stop drinking.

Even better, if you are planning a pregnancy or are not using birth control and are sexually active, you should not drink alcohol.

What amount of alcohol is safe during pregnancy?

We do not have the answer to “how much is too much;” therefore, women shouldn’t drink at all during pregnancy. What we do know is that drinking results in fetal brain damage, and we do not know what amounts, if any, are safe. Why take the risk? Staying away from alcohol completely gives your child the best chance at optimal development and long-term health.

Is drinking that big of a deal?

Of all of the environmental exposures, medications, illegal drugs, and whatever else women might be exposed to during pregnancy, alcohol is the most dangerous.

IMPROVING FETAL DEVELOPMENT | 23

Unlocking the Unknown

Batten disease and other rare diseases

It comes out of nowhere. The vision of a healthy 5-year-old child starts to deteriorate.

Soon they lose motor function. By the age of 10 they begin to decline cognitively. Before they reach the age of 20, most end up bedridden in a vegetative state. It is always fatal.

At the moment there is no cure and very limited treatment options.

This is Batten disease, and this is what a team of scientists at Sanford Research are up against.

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MICHAEL KRUER, MD

(above)

FIGHTING A RARE DISEASE At the Sanford Children’s Health Research Center scientists are searching for answers to not only what causes Batten disease but also how children develop other rare diseases.

These diseases are complex, hard to identify and progress at different rates.

They also only affect a handful of the population. It is estimated that two to four out of every 100,000 children are born with Batten disease. There are only a few hundred cases in the United States, but the rarity of the disease doesn’t make it any less painful for parents.

“Most children will hit a threshold where suddenly they will go rapidly downhill and crash. It’s a horrible disease,” says Dr. David Pearce.

Dr. Pearce is the director of the Sanford Children’s Health Research Center. He has spent over a decade piecing together the complexities of Batten disease.

“It is my calling,” says Dr. Pearce. “I knew I could make an impact on something.”

A C O M P L E X P R O BL E M Batten disease is caused by a defect in one of the body’s 24,000 genes.

This defect causes problems for a specialized compartment in cells known as the lysosome. The lysosome breaks down proteins and other waste the cell doesn’t need. Dr. Pearce refers to lysosomes as the human version of a garbage disposal. But if something is wrong in the lysosome, things can get chaotic in the body.

“It cannot recycle the proteins in the cell and you get this build up of waste products in the cell,” explains Dr. Pearce. This build up is deadly to a cell.

“The brain cells are just dying and dying and dying,” says Dr. Pearce.

Unlike other cells in the body, brain cells are unable to regenerate. This causes those who have such disorders to slowly deteriorate over time, eventually losing their ability to see, walk, talk or live a normal life.

“It is very motivating,” says Dr. Pearce. “You don’t want to see another child go through that. I’ve learned so much from families living with Batten disease. It has a way of putting everything into perspective.”

MICHAEL KRUER, MD

A D VA N C IN G IN FA N T & C H IL D H E A LT H

“Our research into the basic mechanisms of the disease has actually led us in exciting and unexpected directions. We think that we may be able to repurpose existing drugs to treat some of these devastating diseases.”

Pediatric Neurologist and Associate Scientist, Sanford Children’s Health Research Center

STEPS IN THE RIGHT DIRECTION Dr. Pearce’s team is dedicated to helping those suffering from Batten disease.

After years of studying lysosomes in yeast and performing tests on mice, they have discovered new facets to this debilitating disease. Dr. Pearce’s lab has shown that Batten disease has elements of an autoimmune disease, wherein the body’s cells are essentially attacking themselves. This discovery has led to the first human clinical trial for children with Batten disease at a research center in Rochester, New York. Researchers have suppressed the immune systems in 25 children, hoping this will help curb their symptoms. Right now they are a year into the trial. And while it is too early to garner any conclusions, it’s an important start.

“We are just starting to understand the basis of these diseases now,” says Scientist Jill Weimer, PhD, who just received $1.75 million from the National Institutes of Health to study intracellular trafficking in rare diseases, including Batten disease, at Sanford. “But when you are working on a disease like this, it is probably going to take multiple treatments to crack this disease.”

ADVANCING INFANT & CHILD HEALTH | 25

Of the 7,000 known rare diseases, only 400 have FDAapproved therapies.

80% of these are diseases that are genetic, and 50% of those affected are children. 30% of these children do not live to see their 5th birthday. (above)

DAVID PEARCE, PHD

GLOBAL GENES PROJECT

Director, Sanford Children’s Health Research Center

I T ’ S A LL C O N N E C T E D But it is discoveries like this that are propelling research not just in Batten cases but across the board of rare diseases. Pediatric neurologist Michael Kruer, MD, is an associate scientist at Sanford Children’s Health Research Center. He focuses his research on childhood genetic disorders, specifically juvenile Parkinson disease and dystonia. Both of these diseases attack the parts of the brain that control the body’s movements.

“Our efforts are focused on what’s not working,” says Dr. Kruer. “We are trying to understand what protective mechanisms are malfunctioning at a cellular level in order to rescue that function and help cells survive.”

Like Batten disease, there is no cure and very few treatment options for kids with juvenile Parkinson disease and dystonia. But Dr. Kruer and his team are trying to change that.

“Our research into the basic mechanisms of the disease has actually led us in exciting and unexpected directions,” explains Dr. Kruer. “We think that we may be able to repurpose existing drugs to treat some of these devastating diseases.”

In one series of experiments, medications are being applied to cells in the lab from patients with juvenile Parkinson disease and dystonia.

Dr. Kruer is hoping to discover one that will benefit affected kids.

If these treatments work, Dr. Kruer says that it could have a major impact not only on rare diseases but also on more common ones.

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“As opposed to common conditions where many different factors are involved, with rare diseases we can often isolate a single important cellular function that is failing,” explains Dr. Kruer. “We can learn fundamental lessons from rare diseases that we can then relate back to more common diseases.”

STANDING OUT All of this information that is being gathered is getting noticed. Not just by parents of children with rare diseases, but by a larger audience.

“Nationally we are attracting the attention of a number of different rare disease organizations,” says Dr. Pearce. “We will become a center for the treatment of rare diseases. Once you get that national reputation, that enables you to build an even stronger internal capacity for your own patients.”

RARE DISEASE FAQ

How do you get Batten disease?

Batten disease stems from a problem in the genetic code. Each person receives a copy of each gene from each parent, giving you two versions of each gene. If the gene you receive from your mother is defective, your body can rely on the non-defective one given by your father. In cases like Batten, you receive a defective copy of the same gene from both parents. Parents who are carriers have a 1 in 4 chance of each passing on a defective gene to their children.

What is Dystonia?

Dystonia is a neurologic movement disorder that causes sustained involuntary muscle contractions and spasms. It affects men, women, and children of all ages and backgrounds, and may affect a single body area or multiple muscle groups.

The disorder may be hereditary or caused by other factors such as brain injury.

According to the American Association of Neurological Surgeons, as many as 250,000 people in the United States have dystonia, making it the third most common movement disorder behind essential tremor and Parkinson disease.

Are there genetic tests you can take to determine your chances of having a child with a rare disease?

Sanford’s genetics experts have access to a broad base of local, regional and world-wide testing capabilities to determine a patient’s, as well as an embryo’s, susceptibility to inherited gene mutations, thus predicting disease before it occurs and providing patients with preventative management.

Genetic counseling is used widely with patients who are thinking about becoming pregnant. Today, couples can take a universal pre-conception test that will gauge their baby’s predisposition to over 100 genetic conditions. Cystic Fibrosis is one of the most common, occurring in 1 in every 3,500 babies born. (above)

J I LL W E I M E R , P H D Scientist, Sanford Children’s Health Research Center

ADVANCING INFANT & CHILD HEALTH | 27

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The DHA Gap

Helping premature babies get back on track

The reasons are numerous and sometimes unknown, but over half a million babies in the U.S. arrive before their expected due dates.

While some babies suffer few complications, others are riddled with problems. From jaundice to underdeveloped lungs and eyes, the early life of a premature baby is an uphill battle.

Help to overcome some of the problems they face lies in a fatty acid with a long name. Docosahexaenoic acid, or DHA, is an omega-3 fatty acid that is essential in the development of many structures in the body. From the brain to the bowels, DHA helps balance out the inflammation throughout the body. And although it is important to a growing baby, humans can’t actually make it themselves.

“You have to take it in through your diet,” says Sanford Children’s pediatrician and researcher Michelle Baack, MD. “You can get it from supplements or as a precursor in some foods like flaxseed oil. But the best way to get it is through eating fish.” (above and left)

M I C H E LL E B A A C K , M D Neonatologist and Assistant Scientist, Sanford Children’s Health Research Center

ADVANCING INFANT & CHILD HEALTH | 29

Mi s s in g o u t Babies get the DHA they need in the womb through the placenta. Most of this transfer from mother to baby occurs in the third trimester, so if a baby is born too early, then it won’t get all of the DHA that it needs.

Additionally, for a period after premies are born, they also miss out on the DHA that they would normally get through breast milk.

A g rea T p l ace to s tart

“When a preemie is born, it isn’t able to eat like a full-term baby,” explains Dr. Baack. “They usually get a very small amount of essential lipids through an IV, but it doesn’t contain any preformed DHA. And many aren’t able to drink until they develop more. It may take two to four weeks for babies to start getting the full amount of breast milk or formula that they need to grow. Even then, the amount of DHA they get only helps them maintain their levels. It is not enough to help them make up the difference from when they missed out.”

This is the first trial of its kind in the world, and Dr. Baack is hoping to have the results published within the next year. The study is unique because it provides a dose of DHA that could potentially help babies safely overcome deficiency before they are able to drink formula or breast milk.

As a result of the lack of DHA, the preemie baby is at risk of poor brain and eye development and at greater risk for inflammatory lung and bowel disease as they grow. To help combat this problem, Dr. Baack and her team developed a clinical trial where babies were given a supplement of DHA through a feeding tube once a day.

“We are the first institution in the world to do something like this,” states Dr. Baack. “This is a very costeffective study that is very safe for babies. Plus, here in the Midwest where we do not eat a lot of fish, it’s a great place to do this type of study and figure out how to overcome that deficiency. It could really help improve the outcomes for a lot of babies.”

“We used a higher dose than what is offered in baby formula to compensate for what they would have been getting from their mom,” says Dr. Baack. “This helps them overcome that deficiency.”

Dr. Baack examined the DHA levels of the preemies within the first week of their life. And then checked their levels again when they reached full feedings and full term and were ready to go home. She also monitored a number of full-term babies as a control to see what a normal level looked like.

The study was done blindly. So neither Dr. Baack nor the parents knew which baby was receiving the DHA supplement and which received placebo, but all babies received the best practice standard of care. The three-year trial recently completed and finished earlier than planned.

Dr. Baack credits that to the great group of participants, in addition to the seed grant funding from Sanford Health and the Gerber Foundation that made the trial possible.

“The parents were very receptive and excited to participate,” says Dr. Baack. “We had better enrollment than expected which is always a good thing.”

“ We are the first institution in the world to do something like this...It could really improve the outcomes for a lot of babies.”

MICHELLE BA ACK, MD

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And if those results are as promising as Dr. Baack hopes, she is excited to do more tests on the impact of DHA and the amounts that transfer over from mom to baby either through the womb or through breast milk.

“The Midwest typically has very low DHA numbers,” says Dr. Baack. “We did a study in Iowa where we tested breast milk for DHA. The national average is 0.32 percent. Iowa’s average was 0.08 percent. That is as low as places in the Middle East where they have very poor nutrition. These are some of the lowest levels in the world.”

Dr. Baack hopes this study will bring the importance of DHA to the forefront and wants to begin educating everyone from moms-to-be to doctors. “We are hoping to do a study here and begin counseling moms about DHA intake,” says Dr. Baack. “That could have a significant impact on the future of maternity care, resulting in much healthier infants across the nation.”

I m prove y o u r D H A inta k e

Recommended Daily Intake DHA is important to your baby’s health and development, but where can you get it?

DHA is an omega-3 fatty acid that can be found in oily fish or omega-3-containing supplements. Dr. Baack says that the recommended daily intake for women who are pregnant or breastfeeding is 200 mg a day. Some prenatal vitamins contain DHA, but Dr. Baack says you need to check the label to make sure.

Fish as a Source You can also get the proper amount by eating two 6 oz. servings of fish every week. Certain “oily” fish, such as salmon and sardines, can markedly improve DHA levels. Lake fish, such as walleye, do not have as much DHA. Pregnant or nursing mothers, however, need to be careful to avoid a few fish that are high in mercury. These include shark, swordfish, tilefish and king mackerel. A fish that has moderate mercury levels but is, at the same time, a very good source of DHA, is albacore tuna. The U.S. Food and Drug Administration has recommended that up to half of the recommended 12 oz. of fish that nursing mothers should eat per week could come from albacore tuna.

DHA Supplements For women who do not like fish, fish oil supplements are a mercury-free source of DHA. Algal DHA supplements are a viable option for vegetarians and vegans.

Plant-derived omega-3s from flaxseed oil (alpha-linolenic acid, or ALA) will have very little effect on your DHA levels. Therefore, ALA is not an effective substitute for DHA.

ADVANCING INFANT & CHILD HEALTH | 31

Concussions & Kids Get in the game: Keeping kids safe in sports at a time when concussions are on the rise 32 | AT THE FOREFRONT OF DISCOVERY | 2014-2015

(right)

MICHAEL BERGERON, PHD Executive Director, Sanford Sports Science Institute

It is one of the world’s newer sports, but football has become part of the make-up of America.

But over the last several years, news has emerged about the dangers of living a life making plays in the end zone. Bruises, torn ligaments and the chance of a broken bone were always considered hazards of playing football, as was the occasional concussion. But where bruises will heal and bones can mend, the effects of a concussion on the brain aren’t always so easily fixed.

PROTECTING WHAT’S IMPORTANT The brain is made of soft tissue and, although it is surrounded by the skull, the brain can be easily damaged. And it doesn’t take a blackoutinducing blow to do it. Any temporary loss of brain function is considered a concussion, whether it is from a bad tackle on the 20-yard-line or whiplash from a car accident.

Michael Bergeron, PhD, and his team at Sanford Research, in collaboration with Sanford Orthopedics and Sports Medicine’s Verle Valentine, MD, are diving deeper into the problem of concussions and other sports-related injuries.

“Concussion is such an important issue for all kids playing sports and their parents,” says Dr. Bergeron. “So we are taking a close look at concussion in youth, with a particular focus on tracking concussion resolve with novel objective measures. Sanford Research has made a big commitment to uncovering new perspectives and improved clinical management of these brain injuries and related changes.”

For the past several years, they have been examining young athletes and how their brains respond to a series of neuropsychological and other clinical tests. They have tested and tracked a number of kids who have never experienced a concussion to those who have had one or more.

“Much of the research we’ve done has been in patients from the clinic,” states Dr. Bergeron. “But we’ve also done some field work with the junior football in Sioux Falls.”

These tests examine certain aspects of brain function and capacity under normal circumstances and following brain injury. This includes examining associations between head impact exposure – or resolution following a brain injury – and changes in selected clinical measures of neurologic function, including balance and oculomotor performance. This information can provide researchers with a baseline for each child, or it can be used to more objectively determine recovery from a concussion and readiness to fully return to academics and sports.

LET YOUR VOICE BE HEARD Dr. Bergeron isn’t just testing student athletes in the lab or on the field. He has become an advocate for them on Capitol Hill. Representing Sanford Health and the National Youth Sports Health & Safety Institute (NYSHSI), Dr. Bergeron spoke at a congressional briefing last fall in Washington D.C. He helped to introduce a new campaign aimed at particularly promoting earlier functional movement skills and capacity in girls that can better prepare them for athletics and physical activity in adolescence and beyond.

The GIRLS in Sports MattersSM initiative focuses on getting young girls the right education and training needed to play sports more safely. The program is designed to educate girls at an early age the best way to move while on the field.

During the crucial time between childhood and adolescence, boys and girls are at particular risk of growth-related overuse injuries. However, girls are more likely to have problems with their knees as they enter the competitive sports arena because of dysfunctional movement patterns that are adopted by girls who are not sufficiently and appropriately trained to move more optimally. Giving parents, coaches and kids this information will help prevent injuries and enable girls to stay active in sports longer, as well as encourage life-long participation in regular physical activity.

ADVANCING INFANT & CHILD HEALTH | 33

The reported number of individuals aged 19 and under treated in U.S. emergency departments for concussions and other non-fatal, sports-and recreationrelated traumatic brain injuries increased from 150,000 in 2001 to 250,000 in 2009.

I nstitute of M edicine and N ational R esearch C ouncil

A BALANCING ACT And while many of these preventable injuries, whether it is concussions or strained knees, occur on the court or field, Dr. Bergeron says that sports have numerous benefits that outweigh these risks.

“We believe that there is a huge value in sports,” says Dr. Bergeron.

“And not just in the fun and social aspect, but in setting a foundation for life. If sports participation is done in the right way, and in a complimentary way to academics and other important aspects of growing up, then sports can play a critical role in developing a wellrounded and healthy child, providing a foundation for a healthy, active lifestyle into adulthood.”

However, Dr. Bergeron points out that the number of kids who participate in athletic activities rapidly diminishes as they grow older.

“The problem is that, mostly because of parents and other adults, sports often become something else,” says Dr. Bergeron. “It becomes more of a barrier to healthy development and ultimately a burden to a child. The amount of training and conditioning, competition, and overall activity overload often becomes unsustainable.”

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For a healthier perspective, Dr. Bergeron encourages all parents of student athletes to take the NYSHSI Youth Sports Parent Pledge. The pledge reminds parents that sports should be a fun activity not a stressful one. “The responsibility for encouraging and implementing a healthier and sustainable pathway to athletic success falls on the shoulders of all stakeholders in youth sports – especially PARENTS,” says Dr. Bergeron. “Commit to making youth sports a lasting foundation for life… and fun!”

Take the pledge by going to NYSHSI.org.

(right)

T H A Y N E MU N C E , P H D Associate Director, Sanford Sports Science Institute

THE NATIONA YOUTH SPORT HE ALTH & SAFET INSTITUT YOUTH SPORT PARENT PLEDG

L S Y E S E

1. I let my child PLAY and have FUN. 2. I let my child choose the sport(s) he or she wants to play.

3. I discourage my child from playing multiple sports in the same season.

4. I let my child have at least one day off each week and some weeks off each year.

5. I listen if my child says he or she is hurt.

6. I am a fan of my child – not his or her manager.

7. I encourage fair, honorable, safe and sportsmanlike behavior in practice, competition and play.

8. I ensure that the car ride home after a game is a good one for my child.

9. I do not live my athletic dream through my child.

10. I say, “I love to watch you play!” to my child and ask, “Did you have fun?”

Take the pledge by going to NYSHSI.org.

ADVANCING INFANT & CHILD HEALTH | 35

(left)

E D D I E SULL I V A N , P H D Vice President of Business Development and Government Relations, Sanford Applied Biosciences

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Milk

S T R E N G T H E N IN G O U R IM M U N I T Y

More than

COWS HELP SANFORD RESEARCHERS CREATE DISEASE-FIGHTING ANTIBODIES

Just a short drive south from Sioux Falls a herd of cattle is munching their hay.

They look like normal dairy cows. Their white and black hides stand out in sharp contrast to the green of new spring grass. They chew their cud and moo like normal cows, but these bovines are far from average.

Dr. Eddie Sullivan and a team of scientists, researchers and veterinarians at Sanford Applied Biosciences are using these cows to change the way diseases are treated. Sanford Applied Biosciences’ research is unlike anything else that is happening in the medical community.

DEFENDERS OF THE BODY When humans get sick, they produce antibodies to fight off the infection.

These antibodies attack invading foreign objects like viruses and bacteria and work to rid your system of them. But sometimes the human immune system can get overwhelmed and needs help.

Enter Dr. Sullivan. He and his team are developing a way to produce these all-important human antibodies in cattle. They then can be used to fight everything from influenza to certain types of cancer.

“This gives us another tool in the toolbox for fighting very serious diseases,” says Dr. Sullivan. “It is a way to give physicians and patients another option on the course of treatment for disease.”

N O T Y O U R C O MM O N C O WS Creating cows with the ability to produce these antibodies has been a long process. It was started back in 1998 at the University of Massachusetts in Amherst.

“It took several years to learn how to make the human antibody genes work inside of cows,” remembers Dr. Sullivan. “So it has been a long road.”

Over the past 15 years, Dr. Sullivan and his team have genetically modified the immune systems of these cows. They have suppressed their natural immune systems and have made it resemble that of a human’s.

“Because the cows are born with the human antibody genes, they don’t reject them,” explains Dr. Sullivan. “They think that it is theirs even though it is human.”

With a herd that has the ability to produce human antibodies, the possibilities are seemingly endless. The researchers at Sanford Health can now have the cows produce antibodies for specific viral and infectious diseases. The cows are given a shot that contains a portion of a virus like the flu. The cows then begin to produce antibodies to fight off the invaders. But since they are only being injected with a component of the virus and not the actual virus, the cows do not get sick.

“These cows live a very nice life,” says Dr. Sullivan. “They have instant medical care and a vet that takes care of them day in and day out. They are well taken care of.”

STRENGTHENING OUR IMMUNITY | 37

P O W E R I N P L A SM A Since cows are much larger than humans, their systems can produce a greater volume of antibodies. The team at Sanford gets these antibodies by taking plasma.

“Sanford is on the cutting edge of disease research and treatment,” says Dr. Sullivan. “We really have the ability to go from research to bedside.”

“These cows are essentially plasma donors,” explains Dr. Sullivan.

“We extract it from them two to three times a month.”

The plasma then goes through a very stringent purifying process to extract just the antibodies and nothing else. It is these antibodies that could change the way patients with certain diseases are treated.

A GAME CHANGER Right now, Dr. Sullivan’s research is in the pre-clinical phase, but he speculates that it will be ready for clinical trials within the next 12 to 24 months. Once given FDA approval, this research could paint a whole new picture for patients.

“We could use the antibodies to treat cancer patients,” explains Dr. Sullivan. “This would be one of the natural ways that our bodies would defend itself against cancer and it would either increase the survival rate of cancer patients or would decrease the time they would have to spend on chemotherapy or radiation therapy, which of course has side effects that are very serious for patients.”

Sanford Applied Biosciences is the only facility in the world that is using a large-animal species to produce human antibodies.

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“ Sanford is on the cutting edge of disease research and treatment.

We really have the ability to go from research to bedside.”

EDDIE SULLIVAN, PHD

TARGETING DISEASE

Sanford Applied Biosciences’ extra special cows could produce antibodies for a number of different diseases and infections.

So how do Dr. Sullivan and his team pick the ones they want to target? They are working with the United States Department of Defense to pinpoint infectious disease targets that could be the most helpful to the military.

Currently they have cows producing antibodies for the flu, Hantavirus, MERS-CoV, along with several types of cancers.

What is Hantavirus?

Hantaviruses are a family of viruses that can lead to bleeding in the lungs and kidney damage.

Humans may become infected with hantaviruses through contact with rodent urine, saliva, or feces. Some strains of hantaviruses cause potentially fatal diseases in humans.

Rodents are the natural reservoir for hantaviruses. In North America, they are the deer mouse, the white-footed mouse, the rice rat, and the cotton rat.

Other known carriers include the striped field mouse, the brown or Norway rat, the bank vole, and the yellow-necked field mouse.

Dogs and cats cannot give people hantavirus infections. Since it is hard to tell if a mouse or a rat carries a hantavirus, it is best to avoid all wild mice and rats, and to safely clean up any rodent urine, droppings, or nests in your home.

STRENGTHENING OUR IMMUNITY | 39

The New Cancer Epidemic Sanford achieves one of the highest oropharyngeal cancer survival rates in the nation Cancer leaves its marks. Whether it is the loss of hair due to chemotherapy or the emotional scars of battling a disease, all that are diagnosed bear some sign of their illness. But the marks left behind from one certain type of cancer are often more severe than others.

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“For the type of care we provide at Sanford, patients used to travel out of state. We are essentially bringing the forefront of medicine to South Dakota.”

JOHN LEE, MD, FACS

(above and left)

“With head and neck cancers, it affects the part of us that allows us to eat, to vocalize, and to communicate with others,” says Sanford Ear, Nose and Throat specialist and researcher John Lee, MD, FACS. “A lot of other effects from cancer, you can cover up with a shirt or scarf. The treatment for head and neck cancer is so drastic. People do not realize how socially detrimental this type of cancer is to those who are dealing with it.”

J ohn Lee , M D , F A C S Specialist and Scientist, Sanford Health Ear, Nose and Throat

The prevalence of head and neck cancers has exploded in the last few years across the nation and even here in South Dakota. The amount of patients being treated for this at Sanford Health has gone from 9 in 2008 to 304 in 2013.

“This is really the new cancer epidemic,” says Dr. Lee. “The number of people we’ve seen with tonsillar cancer in the last few years has tripled if not quadrupled in size.”

And in most of these new cases, the cause is the human papilloma virus – known more commonly as HPV.

F u e l to the fire HPV is a DNA virus. It can affect both men and women and is essentially fuel for cancer growth. There are dozens of strains of the virus, some of which will lead to no issues and will go away on their own, while others are the reason for most cases of cervical cancer. Many of the head and neck cancer cases form from two strains of the HPV virus. And while Dr. Lee knows the culprit behind the cancer, where it’s coming from is still largely a mystery.

“At this point, the actual reason is not understood yet,” says Dr. Lee. “But we are seeing it mostly in white men who are between the ages of 55 and 60.”

A b etter w a y

Sanford ENT’s use of robotic surgery also enables patients to have a quicker recovery time with a less invasive procedure. But even with all these advancements and promising outcomes, Dr. Lee is pushing for more. “We think that there is a better way to do it,” says Dr. Lee. “We want to be able to target the specific virus and help the body clear that virally infected cell out.”

With that motivation, Dr. Lee and his team are using a drug targeting those cells. “The cancer cells require two viral proteins to grow and to live,” explains Dr. Lee. “What we have done is taken a normal virus vaccine and have put in the proteins that are required. But we’ve changed them in such a way that they can’t cause cancer. They can just cause an immune reaction.”

As the number of patient cases has increased, so has Sanford’s success in helping patients overcome the disease with Dr. Lee’s leadership. Sanford Health’s Ear, Nose and Throat (ENT) team of doctors is producing one of the best health outcome rates in the nation for head and neck cancer patients. A recent study at Sanford tracked the survival rate of head and neck cancer patients over the last five years. Two years post-treatment, 98 percent of Sanford ENT patients survived their cancer. This is compared to the national average of 72 percent according to SEER survival data tracked by the National Cancer Institute.

STRENGTHENING OUR IMMUNITY | 41

It is this immune reaction found in HPV-positive head and neck cancer patients that Dr. Lee and the other researchers working on this study are counting on to deliver some positive results.

“This is something that our lab has brought to the forefront,” says Dr. Lee. “Let’s say I’ve been therapeutically vaccinated. This vaccine will help my body get ready to clear that tumor better during radiation treatments. My immune response will be heightened.”

Currently the treatment team is testing another method to improve immune response in the tumor using a non-toxic drug called DCA. This has gone through years of testing and is just about to reach the end of a three-year human clinical trial conducted by Dr. Lee, which is the first of its kind in the nation. The study involved 50 Sanford patients. Throughout the trial, the participants received best practice care and treatment for their cancer in addition to either a dose of the new medication or a placebo over the course of eight weeks. This was a blind study where neither the patients nor the doctors knew if they were taking the placebo or the new drug. And because the study is still in progress, Dr. Lee’s team of researchers is unable to gather any data on the effectiveness of the drug, as they are still blind to who received it.

42 | AT THE FOREFRONT OF DISCOVERY | 2014-2015

C enter for di s coverie s So while it is too early to tell what the study findings will reveal, they are important steps in the world of cancer research. And these steps are being taken right here at Sanford Health.

“As a nation, we are seeing thousands of new cases like this every year and it’s been going up,” says Dr. Lee. “For the type of care we provide at Sanford, patients use to have to go out of state.

Now they just travel a few hours or across town. We are essentially bringing the forefront of medicine to South Dakota.”

H P V and cancer

How does HPV cause cancer?

HPV can cause normal cells in infected skin to turn abnormal. Most of the time, you cannot see or feel these cell changes.

In most cases, the body fights off the HPV infection naturally and infected cells then go back to normal. But in cases when the body does not fight off this virus, HPV can cause visible changes and certain types of HPV can cause an oropharyngeal cancer. Cancer caused by HPV often takes years to develop after initially getting an HPV infection. It is unclear if having HPV alone is sufficient to cause oropharyngeal cancers, or if other factors (such as smoking or chewing tobacco) interact with HPV to cause these cancers. More research is needed to understand all the factors leading to oropharyngeal cancers.

What are the signs and symptoms of oropharyngeal cancer?

Signs and symptoms may include persistent sore throat, earaches, hoarseness, enlarged lymph nodes, pain when swallowing, and unexplained weight loss. Some persons have no signs or symptoms.

HPV: Isn’t there already a vaccine for that?

At the moment, there is a vaccine recommended for young girls and boys in order to prevent the HPV strain that causes cervical cancer. This vaccine is good at preventing but does not help those who already have the disease.

The drug being used in Dr. Lee’s study is geared to those patients who already have HPV-related cancer. While the strains that cause the two different cancers are in the same family, there isn’t enough information available to determine with certainty whether the cervical HPV vaccine would benefit those with head and neck cancers; however, Dr. Lee says the best preventative approach today is to get vaccinated with the current vaccine.

STRENGTHENING OUR IMMUNITY | 43

“ What’s really exciting is the pace in which we are able to conduct research here in the Dakotas. Medical research takes significant time and patience; however, Sanford’s vast footprint, combined with extraordinary investments to its research infrastructure, allows scientists to much more quickly and seamlessly bring their research from the bench to bedside.”

ALEX RABINOVITCH, MD

44 | AT THE FOREFRONT OF DISCOVERY | 2014-2015

(right and below)

A l e x R a b inovitch , M D Todd and Linda Broin Chair and Director, The Sanford Project

Phase

How the Sanford Project is making progress toward a discovery

It was a bold statement; an ambitious goal set less than 6 years ago.

The announcement was made June 6, 2008. Sanford Health was making it their mission to discover a cure for type 1 diabetes.

C U R IN G & T R E AT IN G C H R O N I C D I S E A S E

The Next

This was the birth of The Sanford Project, and since 2009 Alex Rabinovitch, MD, has been leading the way toward that end goal. With generous support from Denny Sanford and Todd and Linda Broin, The Sanford Project has come a long way in a short time to try and make the lives of those struggling with diabetes better.

“People with type 1 diabetes, whether they be children or adults, need insulin,” says Dr. Rabinovitch. “The beta cells that produce insulin in their bodies have been destroyed by an autoimmune process. They have to inject insulin to replace that insulin that has been lost because those cells that produce it have been lost.”

focused on how to lessen the amount of insulin that needs to be injected and prevent the problems that come from dosing that cannot be as exact as what the body should be doing on its own.

This insulin is crucial to maintaining proper glucose levels in the body. When these levels are imbalanced, complications begin to occur.

“If we can bring those insulin-producing cells up even a little bit, then you would have a contribution from your own insulin production,” says Dr. Rabinovitch. “Then you wouldn’t have to inject as much insulin and still get good blood glucose control. This would hopefully improve the life of people with type 1 diabetes.”

“Kidney failure, blindness, heart attack, strokes, all of those things happen if your blood glucose goes too high,” explains Dr. Rabinovitch. “And if your blood glucose goes too low, then you would be at risk for seizures or slipping into a coma.” Avoiding these problems requires injecting exactly the right amount of insulin several times each day, a quantity that changes depending on many factors including activity and food.

S T E P S T O T he perfect c u re To fix this problem, ideally researchers would like to find a way to regenerate those insulin-producing cells in the body. This is what Dr. Rabinovitch refers to as the “perfect cure” where diabetic patients would no longer need to inject themselves at all. And while that is the ultimate goal, the team is currently

By having a little reserve insulin from the pancreas, the body can do fine tuning after a more approximate dose, building a cushion against the problems of both over- and under-dosing.

CURING & TREATING CHRONIC DISEASE | 45

What Dr. Rabinovitch and his team found from the trial is that only some of the patients who received the two medications experienced the elevated hormone levels that were predicted to help the beta cells and preserve insulin production; and that those people who responded with higher hormone levels may have had some benefit to insulin production.

This has left The Sanford Project team hungry to learn more and find an answer to “why?” The most likely answer has to do with differences among people in how fast their bodies eliminate various drugs. This phenomenon - known as pharmacogenetics - is becoming increasingly recognized as affecting many drugs.

T he ne x t s tep s

C l inica l tria l co m p l etion m ar k s m ajor m i l e s tone Searching for answers, The Sanford Project recently reached a major milestone and published the results of its first clinical trial.

Called REPAIR, this phase-two trial enrolled people who had been diagnosed with type 1 diabetes within the past six months.

They ranged between the ages of 11 and 36 and were from four different areas of the country, including Sioux Falls and Fargo.

The 69 trial participants continued taking their insulin shots as normal, but a number of them were given something else, as well.

“We treated them with two medicines that are safe and are used for other disorders,” says Dr. Rabinovitch. “One is used in type 2 diabetics, and the other is used as an antacid. The objective was to see if we could increase hormones GLP-1 and gastrin, as these hormones enhance insulin-producing cell survival and/or regeneration.”

The patients were treated and monitored over a 12-month period of time to keep track of insulin produced by their own bodies. Completing this trial required the development of not only the local, hands-on clinical research staff, but also a higher level of administration and monitoring to enable The Sanford Project to conduct this study across multiple sites.

46 | AT THE FOREFRONT OF DISCOVERY | 2014-2015

With results from the REPAIR trial in hand, Dr. Rabinovitch is already finalizing plans for a new trial. This next study will build on the REPAIR trial method and the infrastructure that has been developed.

The Sanford Project team will combine agents similar to those used in REPAIR with an additional drug that they hope will work synergistically, and then measure whether this combination can preserve insulin production from the pancreas.

Reaching this stage is very exciting for The Sanford Project team. This pursuit of a real solution to diabetes is something Dr. Rabinovitch says the people in our Sanford communities can really take pride in.

“What’s really exciting is the pace in which we are able to conduct research here in the Dakotas,” says Dr. Rabinovitch.

“Medical research takes significant time and patience; however, Sanford’s vast footprint, combined with extraordinary investments to its research infrastructure, allows scientists to much more quickly and seamlessly bring their research from the bench to bedside.”

dia b ete s b y the n u m b er s

the RATE of

TYPE 1 diabetes

INCIDENCE

AMONG CHILDREN under the age of

AS MANY AS

3 million

americans MAY HAVE

IS ESTIMATED TO INCREASE BY 3% ANNUALLY WORLDWIDE

14

TYPE 1 diabetes

the prevalence of

TYPE 1 diabetes

TYPE 1 DIABETES ACCOUNTS FOR

$14.9 BILLION

IN HEALTH CARE COSTS IN THE U.S. EACH YEAR

in americans

under the age of

ROSE BY

23% 2001

20 2009

EACH YEAR, MORE THAN

15,000 CHILDREN

15,000 ADULTS

AND

are diagnosed with

type 1 diabetes in the u.s.

THAT IS APPROXIMATELY

80 PEOPLE PER DAY.

- Stati s tic s fro m J D R F . or g

CURING & TREATING CHRONIC DISEASE | 47

48 | AT THE FOREFRONT OF DISCOVERY | 2014-2015

(left and right)

KYL E R O UX , P H D Scientist, Sanford Children’s Health Research Center

The Big-Picture Project UNCOVERING THE INTERACTIONS OF PROTEINS AND HOW THEY AFFECT DISEASE

Our bodies are filled with little machines. They can be found in virtually every structure and play a role in every activity that goes on inside us. They are proteins and there are thousands of different kinds in the human body. But despite their commonness, there still is a lot that we don’t know about them.

“What we want to know is which proteins the proteins we are interested in are hanging out with. And that can tell us a lot,” says Sanford Scientist Kyle Roux, PhD. “Most proteins work together to execute some kind of function. We may know what one protein does, but not another. But if we know that they interact we can get some sense of how the unknown protein actually functions. It’s a way to build upon what we know.”

Knowing how these proteins interact and function can lead to some big discoveries. Proteins actually play a large part in the world of inherited diseases. To understand the connection between proteins and diseases, you have to know the connection between proteins and our genes. Our genes are inherited from our parents. These genes make up our DNA, what makes us, us.

Inside the DNA is the blueprint for how to assemble proteins.

Now if there is a problem with one of the genes given to us by our parents, then that will affect how the proteins are constructed.

or abnormal levels of a protein,” explains Dr. Roux. “What I am interested in is how those defects in the proteins lead to the disease the patients has. There is a lot of knowledge about what those genetic mutations are, but unfortunately it is difficult to take that to the mechanism of how the disease actually happens. To get at that we have to understand how these proteins normally behave and then how the mutation impacts them.”

“When people have diseases that are inherited, the defect is in the gene, but you almost always end up with a defective protein

CURING & TREATING CHRONIC DISEASE | 49

A protein ’ s hi s tor y When a researcher previously wanted to examine the connections of a protein, they would isolate and examine it. But through this process they could only see the other proteins that were actually physically bound to it. That way worked, but it only showed the interactions at the point in time you isolated the cell. To better understand what these proteins do, Dr. Roux developed a method called BioID. “It allows us to generate a history of what a protein has been doing in a cell over a period of time,” explains Dr. Roux. “You can get at proteins that maybe aren’t so tightly connected, that way weaker transactions can be monitored.”

Dr. Roux can take a protein and add an enzyme to it. That enzyme becomes a sort of marker. Whenever the protein comes in contact with another protein, the enzyme marks it. That marker is called biotin, and it is something researchers can visualize.

“We can see it and we can use it to selectively isolate those proteins that are tagged with it,” says Dr. Roux. “Then we can go and identify what those proteins are. With that information we get a sense of what our protein of interest has been doing.”

Ma k in g connection s With this new information, researchers can start comparing the function of a normal protein to that of a defective one.

“If you have a cancer-related protein and you need to know why this mutation leads to cancer, that can be studied with this new method,” says Dr. Roux. “You can get a better sense of how that protein is misbehaving when it’s mutated and then design your therapy based on that information.”

This application will advance the understanding of everything from common disorders such as diabetes to rare diseases, such as progeria and dystonia. And because of the way BioID was designed, it can help track proteins in any type of cell.

“Theoretically this can happen in any cell type,” says Dr. Roux. “This format will work in everything from lung cells to kidney cells.”

And researchers are already taking advantage of Dr. Roux’s model. He published the BioID method in 2012 and opened up the reagents to the medical community at large. There are already 700 requests to use the model.

“This is more of a big-picture project,” states Dr. Roux. “I’m providing a tool that researchers all around the world will use and can apply to almost any disease.”

It’s this type of innovation and drive that will help bring about a greater understanding of diseases and with that, better ways to treat and cure them. And while Dr. Roux’s BioID method is already taking off, he is not resting on his laurels.

“My work isn’t over,” says Dr. Roux.

“I developed the method, but it’s not the end of it. I’m trying to make it better, more robust, faster and explore what else it can do.”

50 | AT THE FOREFRONT OF DISCOVERY | 2014-2015

“This is more of a big-picture project.

I’m providing a tool that researchers all around the world will use and can apply to almost any disease.”

K YLE ROUX, PHD

CURING & TREATING CHRONIC DISEASE | 51

A Journey of

Firsts

How a new device could reshape the treatment of aortic aneurysms

It is a fairly small piece of equipment. It’s white, round and depending on where it’s going has several short small tubes branching out from the bottom. In the eyes of your typical person, it doesn’t look like anything too amazing. But to people suffering from inoperable aortic aneurysms, it might be the invention that gives them the chance to live.

52 | AT THE FOREFRONT OF DISCOVERY | 2014-2015

“We have treated people successfully that have been denied at other hospitals all over the country. This type of care isn’t offered anywhere else.”

PATRICK KELLY, MD

(above and left)

P A T R I C K K E LLY , M D Vascular Surgeon, Sanford Health

Patrick Kelly, MD, is a vascular surgeon at Sanford Health. With a background in engineering, he has always had the propensity to solve structural problems. So when met with the problem of a patient that had been turned away from surgery at hospitals across the country, he wanted to solve it.

“We were presented with a patient who had a 10-centimeter aneurysm with no surgical options,” remarks Dr. Kelly. “Do you do nothing for this patient or do you actually try to figure out a way to fix this? We decided to try and come up with something and this was the result.”

A DIFFERENT DESIGN Dr. Kelly and his team designed a new kind of stent graft system for this patient. Like other stent grafts, it is used to bypass the aneurysm in the aorta and offers a new, safe path for blood to flow. However this particular one is having some pretty incredible results.

The grafts were designed where the only component that varies is the largest opening that matches the diameter of the patient’s aorta. All of the other pieces are the same size regardless of the patient’s anatomy.

“This design is so unique and different,” remarks Tyler Remund, PhD, a bioengineer on Dr. Kelly’s team. “The company that makes all these parts kind of took a step back and said ‘Why didn’t we think of that?’”

“If you look at the current technology out there, they are having major challenges keeping their branches open,” states Dr. Kelly. “We haven’t seen that. Our design is different enough that we haven’t been challenged with those issues. We have had really phenomenal stay-open rates of our branches.

That’s due to the flow dynamics of our system.”

Dr. Kelly and his team constructed the system from components already built by one manufacturer. They repurposed the parts to create something that has a greater potential to help more people.

“Hospitals need solutions available for emergencies, and these solutions cannot be built for just one person’s anatomy,” states Dr. Kelly. “You want a solution that can be truly an off-the-shelf-product that works for a wide variety of patients. Our design allows more versatility than what’s currently available on the market.”

CURING & TREATING CHRONIC DISEASE | 53

O penin g opport u nitie s With this new design, a lot of tests and diagnostics need to be done.

These tests and simulations are something that huge companies are just starting to do with their own grafts. However, they have entire departments dedicated to them. But a typical surgeon with a new invention does not have the resources or time to conduct those tests.

So to help with the project, the team reached out to some local experts.

“We are looking at a collaboration with the engineering school at South Dakota State University (SDSU), and they are going to actually examine the flow mechanics of the graft,” says Dr. Remund. “They’ll simulate with their computers blood flow through them and help us determine why our grafts do not have the same issues that others do.”

This collaboration is also going to benefit the students at SDSU, giving them a chance to be involved in something that typically isn’t done in South Dakota.

“This is a phenomenal opportunity for them,” says Dr. Remund.

“This is new stuff that people have never looked at before. For them to get that experience will be extremely beneficial.”

P atent pendin g Drs. Kelly and Remund are very excited for the next steps in their adventure.

They have patents going through approval processes on several different design variations. They are working on a contract with the Food and Drug Administration so that the device could be used in hospitals across the country.

They are also planning a clinical trial to use the device on more patients. And while their plans are big for the small device, they are beginning to realize the true magnitude of their invention.

“We have never really done anything like this before,” says Dr. Kelly. “And really no one has. It almost never happens that a doctor will go to a company and present them with an idea that will truly work.

We are going down a very unique path.” (left to right)

C H E LS E A T W A ML E Y Nurse Practitioner, Sanford Health

ROX ANNE HEITK AMP

What’s at the end of the road for Dr. Kelly’s invention is still up in the air, but one thing for certain is this type of ingenuity is helping to push Sanford to a higher level of care.

Advanced Surgical Tech, Sanford Health

P A T R I C K K E LLY , M D Vascular Surgeon, Sanford Health

54 | AT THE FOREFRONT OF DISCOVERY | 2014-2015

“We have treated people successfully that have been denied at other hospitals all over the country,” says Dr. Kelly. “This type of care isn’t offered anywhere else.”

T he pro b l e m of aortic ane u r y s m s

The aorta is the largest artery in the body and runs from the left ventricle of the heart through the abdomen where it splits into two smaller arteries just past the kidneys. But sometimes due to high blood pressure or to the hardening of the arteries, a section of the aorta wall can bulge and weaken. This is known as an aneurysm, and in worst-case scenarios, the aorta would burst causing extensive bleeding that would most likely result in death. Working to repair such a sensitive area of the body is, to say the least, difficult.

“ Imagine you had to close down and fix a road in the middle of a busy interchange, something like that would be super challenging, but doable.

This is kind of the same thing. If we have to fix an aneurysm where four or five major arteries come off, we could shut everything down and fix it, but that isn’t good for the patient. Our design allows us to fix that super highway without having to shut down any of the lanes.”

PATRICK KELLY, MD

CURING & TREATING CHRONIC DISEASE | 55

GIVE

If you are interested in providing philanthropic support for any of the research or initiatives featured in this publication, please contact the Sanford Health Foundation.

Thank you.

Sioux Falls Region: (605) 312-6700 Fargo Region: (701) 234-6246 Bismarck Region: (701) 323-8450 Bemidji Region: (218) 333-5515 foundation.sanfordhealth.org Edith Sanford Breast Foundation: (855) 463-3484 edithsanford.org To learn more about research innovation and advancements, visit www.sanfordresearch.org.