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PRECISION MEDICINE CENTER PROFILE: The Center for Individualized Medicine, Mayo Clinic by Alla Katsnelson, Ph.D
In its 150-year history, the Mayo Clinic has stayed true to its patient-centered model of care. That same vision has guided the trajectory of its precision medicine initiative, the Center for Individualized Medicine. The idea behind the Center, which launched five years ago, was to create a new entity within the institution that was positioned to engage existing centers and departments as the vision and reach of precision medicine evolved. For this reason, too, the Center was conceived as an enterprise-wide effort, involving clinicians and researchers at the Minnesota, Arizona, and Florida campuses. At the three sites combined, Mayo sees some 1.4 million patients each year, and the aim was to bring genomic medicine to as many of these patients as possible. Rather than pursuing large-scale genomics or bioinformatics efforts, says Keith Stewart, professor of medicine and the Center’s director, “we’ve been more and more focused on delivering the power of genomics to the bedside.”
We’re beginning to diversify into areas that aren’t traditional grounds for such efforts.
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PRECISION MEDICINE CENTER PROFILE: The Center for Individualized Medicine, Mayo Clinic by Alla Katsnelson, Ph.D
The Mayo Clinic’s roots in precision medicine
run deep. The institution was one of the
pioneer members of the Pharmacogenomics
Research Network, a nationwide collaboration
funded by the National Institute of General
Medical Sciences studying how genetics affects
patients’ response to medicine which ran from
2000 to 2015. It also participates in another
long-standing network, the eMERGE network,
funded by the National Human Genome
Research Institute which investigates how to
join electronic health records to genomic data
to gain insights into disease pathology and drug
response. A great deal of scientific and clinical
evidence has already demonstrated the clinical
utility of pharmacogenomics testing to help
avoid drug adverse effect and maximize drug
efficacy. That makes pharmacogenomics one of
the areas in genomic medicine that can already
be implemented in the clinic.
To achieve this goal, the Pharmacogenomics
Program, one of the Center’s six translational
programs, established a Pharmacogenomics
Task Force to identify drug-gene pairs for
which there was enough clinical utility to
develop a genetic test, says Liewei Wang,
Liewei Wang, professor of pharmacology and
the Pharmacogenomics Program’s co-director.
So far, 19 such pairs have been vetted, and tests
have been adopted in the clinic and linked
to patients’ medical records. That means if
a physician prescribes one of these drugs, he
or she will be alerted by the system to test the
patient’s genotype to make sure they don’t
carry a mutation that would alter how they
metabolize the drug or put the patient at risk
for a serious adverse drug reaction. “Mayo, and
particularly the Center for Individualized
Medicine, really put a lot of resources, effort,
and talent into developing the infrastructure
needed to implement these genetic tests and
ultimately establish a program that offers
clinical genomics for everyone,” says Wang.
“To be honest I think that no other institution
is doing it on this scale.”
This set of tests was just the first step. In order
to proactively determine patients’ pharmacog-
enomic status, Mayo sequenced a set of drug
metabolism and other “pharmacogenes” in
1013 of its patients whose samples reside in the
institution’s vast biobank. “To our surprise,
what we find is that 99% of local patients have
at least one actionable variant among the top
five pharmacogenes – five well-known genes
that metabolize more than half of all drugs
on the market,” says Wang. “The finding truly
confirms that pharmacogenomics represents
clinical genomics for everyone,” she adds. Last
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The other arm of the Clinomics program
addresses what Lazaridis calls diagnostic
odysseys – rare disease cases that are suspected
to be genetic but that have never been
diagnosed. By identifying where whole exome
sequencing might be helpful and following the
path to where it might lead, the program has
been able to provide diagnoses to some 30%
of patients, and for a small percent within
that to figure out how to treat them based
on knowledge of the genetic target. “We
know that this 30% holds very well – other
centers see the same outcomes – but the
question for us is, how can we turn this 30%
into 40% or 50%,” Lazaridis says. In many
patients for whom a diagnosis isn’t reached,
he adds, there are hints that the mutation is
a new one that has not been reported before.
“We have to functionally interpret all these
genetic variations we find for all these
unsolved cases, because that’s where lots
of discoveries will be made.”
The program started by performing clinical
grade whole exome sequencing in just 10
patients on a diagnostic odyssey in 2012 and
will complete more than 300 exomes for the
clinical care of an equal number of patients
in 2016 alone, a thirty-fold increase, Lazaridis
said. He estimates that his Individualized
Medicine Clinic has seen about 1600 patients
over the past five years, though not all have
undergone sequencing. Early on, cases
addressed by the Clinomics Program were
neurological conditions in children, but the
aim now is to expand the offering to other
conditions that might benefit from the
approach, such as gastrointestinal, cardiovas-
cular and neurological disorders. Patients seen
in childhood tend to have severe phenotypes,
but for those with milder symptoms getting a
diagnosis later in life can still be tremendously
helpful. The program also aims to expand its
base in predictive genomics, sequencing
people with common chronic conditions,
who traditionally had no strong evidence of a
genetic disease, with the goal of sequencing
10,000 exomes in the next year, Lazaridis says.
“We would like to make sequencing for clinical
care available to patients and providers – and
then it will be part of their medical record.
Our goal is to prove this information will be
useful for years to come.”
Perhaps at an earlier stage of clinical application
compared to the other five translational
programs is the Center’s Microbiome Program.
“The major effort there is to revolutionize and
transform the way we diagnose and perhaps
even manage infectious disease,” says Stewart.
Step one is replacing classic cultures with next
generation sequencing, which can more easily
identify microbial species and is more appli-
cable for assessing outbreaks and antibiotic
resistance. “Being able to use these tools to do
forensic work to figure out how a pathogen is
transmitted will really help us in the future,”
says Heidi Nelson, professor of surgery, who
directs the Center’s Microbiome Program. As for
the longer view, though it’s still in the research
phase, the Microbiome Program aims to look
more broadly at wellness and at environmental
influences on health, focusing on areas such as
bowel health, personalized nutrition, and
probiotics. “We see the potential to really
understand what is a healthy state for each
person, and to figure out the guiding principles
for balance versus imbalance,” says Nelson.
While most precision medicine initiatives
have so far focused on cancer, Mayo is reaching
into areas such as cardiovascular disease,
neurology, gastroenterology, and most recently,
hematology. “We’re beginning to diversify
into areas that aren’t traditional grounds for
such efforts,” says Stewart. The institution is
also partnering with the San Francisco-based
consumer genomics company Helix to develop
an app for consumers to use. “Through it we
think we will introduce many of them to
genomics at the consumer level, which will
increase peoples’ interest in having medical
testing done in the genomic space.”
year, the Pharmacogenomics Translational
Program expanded this sequencing project
to include 10,000 biobanked individuals.
Collaborating with the genome center at the
Baylor College of Medicine, the plan is to
sequence these genes using a CLIA-approved
assay and identify the actionable variants,
and then include this information in patients’
electronic medical records. Ultimately, the
goal is to test all of Mayo’s patients in this
prospective manner, but meanwhile the intent
of this study is to demonstrate that collecting
pharmacogenetic information would benefit
patient care, improve clinical outcomes and
save money for the health system – and
ultimately, for insurers.
The Pharmacogenomics Program is also
tackling treatment response to cancer drugs.
In one ongoing study, called BEAUTY, women
with breast cancer who are at high risk of
recurrence have their tumors sequenced; the
sequence as well as xenografting into mouse
avatars can help both discovery and trans-
lational studies to determine whether their
unique mutations can point to additional
targets for therapy. The infrastructure from
this study is also being applied to similar
studies in other cancer types, Wang says.
Cancer is also the focus of one arm of the
Clinomics Program, another translational
program at the Center for Individualized
Medicine. The idea behind the program is
to push the application of insights gleaned
through genomic medicine into clinical
practices, says the program’s director,
Konstantinos Lazaridis, professor of medicine
at Mayo. Exome sequencing in somatic and
tumor DNA of patients with advanced cancer
can reveal treatments that might target an
individual’s mutations. Liquid biopsies, too,
are a big focus for detection. “We strongly
believe that’s very much going to be a key
part of the future of how we manage cancer
patients, and we have several large initiatives
coming out in this space,” says Stewart. Alla Katsnelson, Ph.D, is an independent science writer
and editor based in western Massachusetts.