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Science Saturday: The collective wisdom of biobanks
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Biobanks preserve our body's knowledge so it can pay dividends in the future.
Since antiquity physicians have analyzed patient specimens to diagnose illness. Now, our samples can do far more than diagnose. They can help researchers understand disease mechanisms and find treatments for the unmet needs of patients.
“A biobank is a collection of biological samples from a large number of patients,” explains Stephen Thibodeau, Ph.D., the David F. and Margaret T. Grohne Director, Biorepositories Program in the Mayo Clinic Center for Individualized Medicine.
The Program, based in the John W. Marvin Building in Rochester, maintains more than 100 disease-specific repositories. It has also built a single general repository using specimens collected from more than 60,000 participants. All samples are collected with patients’ informed consent and the knowledge that they will be helping others.
“Whether you’re interested in colon cancer or Parkinson’s Disease or Alzheimer’s Disease, in order to really study and understand it, you need to collect samples from those patients,” says Dr. Thibodeau. “It can be blood, tissue, urine — anything from the patient that might help to solve [research] questions.”
The point of banking samples is to have them on hand when they’re needed for studies —leaving the doors to medical advancement wide open.
Cryogenic storage — a doorway through time
Specimens are processed, divided up among a number of small tubes, and then stored at an ultra-low temperature so at some future date they can be pulled from clouds of frigid fog and analyzed. This way, as research capabilities progress or new research questions arise, investigators have relevant samples to access.
Sometimes biobanks help with studies that extend across generations. In one case, Mayo Clinic researchers discovered a dangerous facial cancer by ‘collaborating’ with a long-retired colleague. The cancer, called biphenotypic sinonasal sarcoma, usually affects women. It causes tumors that infiltrate connective tissue in and around the nose, which were hard to diagnose because they look like a range of other types of lesions. Treatment required disfiguring surgeries.
Using biorepositories, researchers were able to determine the molecular makeup of this new class of tumor, which made diagnosis more straightforward, and pointed the way to several existing tumor-targeting drugs.
Notes from the original physician in the 1950s and stored samples from those early biopsies added to the findings of the more recent discovery and confirmed the genetic defect that triggers the cancer. Every banked sample is annotated with non-identifying donor information like age, sex, diagnosis and medication. “It’s the information about the patient — along with the access to the sample — that allows you to really make research discoveries,” says Dr. Thibodeau.
“And this is only the tip of the iceberg,” explained Andre Oliveira, M.D., Ph.D., one of the pathologists who characterized the face cancer. “Who knows what is in our repositories waiting to be discovered.”
Multiple biobanks, multiple accounts
When researchers want to establish new repositories specific to their research area — bipolar disorder or obesity, for example — the Biorepositories Program enables that, and then cares for their collections and manages sample withdrawals.
The Program also created the Mayo Clinic Biobank to address a pressing need: finding controls to use as benchmarks in research studies.
“The idea was that, in addition to the hundreds of individual collections that are out there, we established another, institutional collection that would complement what individual investigators are doing,” says Dr. Thibodeau. A large fraction of this 60,000-participant collection was gathered from generally healthy individuals.
The Program’s core facility, directed by Mine Cicek, Ph.D., manages samples for both individual repositories and the Biobank.
It’s vast — encompassing almost 60,000 square feet on the Mayo Clinic campus in Rochester, Minnesota. A staff of about a hundred people is required to handle the sheer volume of specimens going in and samples going out, even with state-of-the-art automated processing, while researchers peruse and order samples online.
The Biorepository Program at Mayo has Two Parts:
1. Mayo Biorepositories:
- 100+ repositories
- Disease or population specific
- Samples and information from patient volunteers with particular health histories
- Thousands to tens of thousands of samples per repository
- Each repository is accessible primarily to the investigator(s) who initiated it
2. Mayo Clinic Biobank
- One large repository
- Not focused on a specific disease or demographic
- A collection of samples from 60,000 participants, regardless of health history
- Approximately 1.5 million samples
- Accessible to all Mayo Clinic investigators
Honing in on health
The Biorepositories Program makes it possible to bring together information about health and lifestyle in an all new way, and to look at disease patterns over time. The greater the number of participants and the more detailed their health records, the more powerful the research study.
“Oftentimes you need [samples from] a very large number of patients, because you’re looking for small differences, and small numbers of patients don’t give you enough information,” Dr. Thibodeau explains. To illustrate, there are several dozen types of cancer, but even within types, tumors differ from one patient to another.
James Cerhan, M.D., Ph.D., and Janet Olson, Ph.D. are driving forces behind the Biobank. Like many Mayo Clinic investigators, they use epidemiologic approaches in their own research programs, which means that they study how often diseases occur in different groups of people, and why.
Dr. Cerhan, who co-directs the Biorepositories Program and co-leads the Genetic Epidemiology and Risk Assessment Program in the Mayo Clinic Cancer Center, works to identify the causes of lymphoma and other cancers to develop preventative approaches.
Dr. Olson studies the molecular and genetic underpinnings of breast cancer survival and is developing two resources specific to breast cancer: the Biospecimen Resource for Breast Disease (an individual repository) and the Mayo Clinic Breast Disease Survivors Study.
Help finding the needles in the haystacks
The work of Adrian Vella, M.D., illustrates how the Biobank can make it easier to study genes that underlie disease. Dr. Vella focuses on the chain of events leading to the development of type 2 diabetes.
And, until recently, he was in a bit of a pickle.
Almost 30 million Americans have diabetes. Many more have high blood sugar (glucose) but never actually develop the disease. To understand why, Dr. Vella had been trying for years, without success, to find patients with uncommon variants of a diabetes-associated gene called TCF7L2. When he extended his search to the Biobank, not only did he find people with the needed genotypes, he saw some surprising results.
We can carry different variants of TCF7L2 in our DNA — one is serviceable and can help protect us from developing diabetes, but the other is faulty and can predispose us to the disease. For a study that’s powerful enough to answer the ‘whys’ and ‘hows’ of this phenomenon, Dr. Vella needed to find a lot of people who’d inherited the diabetes-protective variant from both of their parents, and a lot of people who’d inherited the diabetes-predisposed variant from both parents.
Fortunately, once the Biobank was up and running, he was able to search a much broader pool of DNA samples, and quickly found the volunteers he needed.
What he discovered involves two hormones that control blood glucose levels: insulin and glucagon. If we’re healthy, a sugar binge triggers our pancreas to release more insulin and less glucagon.
As expected, when Dr. Vella and his team began to analyze their results, they found that people with the diabetes-predisposed gene variants don’t release enough insulin in response to oral glucose challenges. But they also found that these same participants released too much glucagon. The involvement of glucagon in the TCF7L2 equation is new information that’s rapidly expanding the understanding of diabetes development.
Diagnostics and prognostics
Comparing samples representing thousands of individuals makes it easier to find genetic variations associated with particular diseases, and to discover biomarkers.
Biomarkers are molecules whose levels can be measured to indicate health — and they’re among the superstars of personalized medicine. They can be used to detect and diagnose disease, sometimes even before symptoms appear. They can also help point the way to the most effective treatments, or herald healing.
With this in mind, multiple researchers came together and formed a biorepository specific to inflammatory bowel disease, managed across all of the Mayo Clinic campuses.
Inflammatory bowel disease (IBD) is an umbrella term for chronic, inflammatory conditions of the digestive tract — disorders that typically cause severe diarrhea, abdominal pain, fatigue and weight loss, and which probably arise from immune system malfunction, as well as genetic and environmental influences. About three million Americans have IBD.
Jonathan Leighton, M.D., and Shabana Pasha, M.D., co-lead the IBD biorepository-based research happening on Mayo Clinic’s campus in Arizona. Their quest is finding autoantibody biomarkers that will lead to improved care for their patients.
While antibodies are helpful proteins that our immune systems use to neutralize disease-causing pathogens, autoantibodies are harmful antibodies misdirected at our own cells. They can be used as biomarkers, explains Dr. Leighton, “to predict disease behavior, outcomes, and which drugs might be more effective in an individual patient.”
Partnering with researchers at Arizona State University, and using the IBD repository, Dr. Leighton and Dr. Pasha are successfully identifying biomarkers for Crohn’s disease and ulcerative colitis (prevalent inflammatory bowel diseases), several of which may have clinical impact in diagnosis and management.
Leaving doors wide open
The goal of personalized medicine is to make better diagnoses — to understand the genetics of each person, individually — and tailor treatment accordingly.
“Looking at the future of medicine,” says Dr. Thibodeau, “what we’re trying to do is create a facility that makes it easier for people to do their work more quickly, and that helps all investigators at Mayo do what they need to do."
- Megan McKenzie, May 2018
The All of Us Research Program
Mayo Clinic is the home of the biobank of the National Institutes of Health All of Us Research Program, which aims to advance precision medicine research by gathering biospecimens and health and lifestyle information from 1 million or more volunteers across the U.S. The All of Us Research Program is a major piece of the Precision Medicine Initiative — an unprecedented research effort aimed at applying precision medicine to all diseases.
- Mayo Clinic received a five-year, $142 million funding award from the NIH.
- Mayo Clinic’s 60,000-square-foot fully automated biorepository facility will store 34 million samples from one million participants collected across the U.S.
- Mayo Medical Laboratories network ensures short transit times for receiving specimens from nationwide collection locations.
- Mayo Clinic’s Florida campus provides sample storage for about one-quarter of the collection, to protect the national resource in the event of disaster.
The NIH opened enrollment nationwide on May 6, 2018. Visit the All of Us Research Program for more information.
