Mayo, U of M offer concrete examples of genomic-research progress

Second of two articles

If someone you love has struggled with depression or any other mental illness, you know it can be a heart-wrenching ordeal to simply acknowledge the problem and accept the need for treatment.

Stressed-out patients and their families grasp for lines of hope. But those lines can break with tragic consequences during treatment that all too often is guesswork.

Today’s installment of MinnPost’s report on the 10th anniversary of the human genome’s first draft will look at progress toward strengthening those lines for people battling addiction and mental illness.

It also will look into fascinating questions of human development — why, for example, we don’t look like poor Mr. Potato Head with mismatched ears and arms.

The medical research projects highlighted in this report are far from the only examples of genomic research under way in Minnesota. The power of the tools developed to sequence the human genome has been deployed in agriculture, anthropology, wildlife studies and many other areas.

For now, though, we’ll look at two examples.

Addiction and mental illness
People wrestling with addiction and mental illness are lucky if their first bid for recovery through drugs works half the time, said Dr. David Mrazek, who chairs the Department of Psychiatry and Psychology at the Mayo Clinic College of Medicine. He also is the author of the book “Psychiatric Pharmacogenomics.”

Dr. David Mrazek
MinnPost/Sharon Schmickle
Dr. David Mrazek

“It is terribly disappointing to get all that way to finally admitting it, dealing with your family about it, going to the doctor, taking a medicine — and then it makes you worse,” Mrazek said.

Such was the conundrum that drove Mrazek to leave a prestigious post at George Washington University, pack up his family and move to “beautiful Minnesota,” he said. The first draft of the human genome was being assembled, and Mayo had set ambitious goals to translate this new knowledge into individualized medicine. Mrazek wanted in.

Genetic variations play into each patient’s response to psychiatric drugs. A doctor must guess which of some 20 different anti-depressants might work for a given patient, or some 15 different anti-psychotic drugs — whether a mood stabilizer, therapy or some combination of drugs and therapy is the best course.

Some important genes at play in the puzzle had been identified. Mrazek wanted to translate those discoveries into practical tests “so that we could predict which patients would be most likely to respond to a particular treatment.”

Less trial and error on already fragile patients. That was the goal.

One target was a set of genes carrying the body’s instructions for metabolizing drugs. It turns out that some of us race through this process, clearing the drugs from our systems before they have time to work. Others work the drugs so slowly that they linger in their bodies and build up to the point where side effects can be serious enough to feel worse than the original problem.

Ten genes to incorporate in tests
Using techniques that were refined for genome sequencing, Mrazek and his colleagues began systematically hunting and testing genes. They’ve come up with 10 genes to incorporate in tests for determining how an individual patient would likely respond — say, to an antidepressant like Prozak.

Now Mrazak’s hunt has widened from a search for individual genes to sweeps across the genomes of individual patients.

In one study, 529 depressed patients at Mayo have been given similar medications. About 50 percent recovered after eight weeks, Mrazak said, 20 percent had their symptoms cut in half, 20 percent got just a little better and 10 percent had no improvement or actually got worse. Those who saw little or no improvement are taking a different drug or other treatments for follow-up studies.

DNA from all 529 was analyzed at 1.5 million different spots on the genome that are likely locations for variants that could help explain the responses.

Next, Mrazak expects to ramp up the study, looking everywhere on the genome’s 3 billion chemical units.

“We couldn’t have done this 10 years ago,” Mrazak said. “Because we can do it now, we are going to have a much better ability to predict how our patients will respond to drugs.”

Mary Doerge makes starter DNA for genomic studies at Mayo.
MinnPost photo by Sharon Schmickle
Mary Doerge makes starter DNA for genomic studies at Mayo.

It’s only a first step, though, in tapping the genome’s potential for improving psychiatric care and cutting the costs of medicating by trial and error, Mrazak said.

Psychiatric medicine has yet to reach a point where a genetic test could precisely diagnose an illness like schizophrenia or distinguish one form of depression from another.

“We still have to rely on talking to the patient, looking at the symptoms and making a clinical diagnosis,” he said.

Optimistic about project’s eventual results
Mrazak is optimistic that day will come when “the genome project will help us understand the cause of these illnesses.”

That’s one reason he predicts that eventually all of us will want to have our genomes sequenced.

“I bet that 20 years from now even before a baby is born the doctor and the parents will know the sequence,” he said. “It will be inexpensive, and you will be able to learn a lot about possible problems.”

It has long been known that a child is born to a mother and father who struggle with depression is at risk too, and a good family doctor will watch for symptoms.

In the post-genome future, that child could be treated before a crisis erupts.

“If we can see it in advance, we can provide effective treatments at the beginning instead of waiting until a child attempts suicide or some other horrible event when all of a sudden everybody wakes up and says, ‘Oh my gosh, he was depressed!’ “

Human development
I never lose my awe over nature’s ability to unfold life from something miniscule and compact to something large and complex.

Take a corn seed. How does one small kernel contain all of the potential it needs to utilize sunlight, water and soil nutrients in order to grow knee-high by this time of the year, tower over my head by fall — and flower in separate sexual parts with a tassel shedding pollen just in time to fertilize delicate silks and give rise to more kernels?

Think about it as you chomp into a juicy cob of corn this July 4th weekend.

It’s mindboggling. And until recently, it’s been pretty much a mystery.

What’s fascinating about corn is fascinating about all life on the planet — including animal life, and especially human life.

We’ve long known we start from a single cell formed by the union of egg and sperm. But how is that microscopic cell able to divide into parts as distinct and specialized as eyes and toes, frontal lobe and ovaries?  

The parts manual and instructions for operating all of the parts are packaged that first cell.

Thanks to the human genome sequence, Michael O’Connor and his colleagues are making unprecedented strides toward reading the manual. He heads the Department of Genetics, Cell Biology and Development at the University of Minnesota.

‘We want to understand those instructions’
“There must be programmed in that early embryo a set of instructions, blueprints of how to divide and change with time to give you the different organs,” O’Connor said. “So we want to understand those instructions. That’s our basic goal.”

A key to deciphering the instructions is eavesdropping on the signals cells send to each other.

Michael O'Connor
MinnPost/Sharon Schmickle
Michael O’Connor

“As soon as that embryo divides into two cells they begin to communicate with each other,” O’Connor said. “That communication isn’t symmetrical, and so that’s how you begin to get differences. One cell will receive one signal or more of a signal than its neighbor. So you can imagine that is going to set one cell off on a particular path while another will go a different way.”

But understanding the signals in all of their various intensities was only part of the puzzle. Scientists also needed to learn how cells perceived the signals and used them to make decisions that would spur action toward developing — say an ear instead of a kidney.

That was immensely complicated. It called for watching long line-ups of genes and observing which were turned on or off by a given signal.

“You really need the genome sequence,” O’Connor said.

Now that sequences are in hand, O’Connor and his colleagues have been able to work with long lineups not only of human genes but also of those from fruit flies and other research models.

Proportion and symmetry
One subject they’ve probed is proportion and symmetry. Most of us — whether we are short or tall, young or old — take it for granted that our arms will be roughly symmetrical.

“You don’t have a two-foot arm on one side and a 6-foot arm on the other,” O’Connor said.

But we never knew why.

“There has to be a mechanism that makes it work the right way,” O’Connor said. “We are beginning to understand that at the molecular level. … We’ve been able to come up with rules that need to be obeyed to get proper scaling.”

They also are gaining new insights into the timing of development.

“If you made a gut 10 hours before you made the right attachment points, it wouldn’t work,” O’Connor said. “You have got to make everything at the right time so all of it interconnects.”

One stage where timing plays an obvious role is puberty, when the brain signals the body it is time to transform to sexual maturity.

“For this project as well, the genome is very important because we have to understand how these brain signals are being interpreted by all of the tissues and to try to understand the response at the genome level — which genes are turning on and which genes are turning off,” O’Connor said.

Where is all of this research leading? Most of it is basic science, but it should give us “a much better understanding of birth defects because that’s development that’s gone wrong,” he said.

Signaling factors in our cells also shed light on immune responses and other functions that affect our bodies throughout our lifetimes.

In one sense, it’s futile to ask what will come of the research because knowledge of the genome has opened so many new doors that scientists still don’t know where they will lead.

“There is such an explosion of information that we haven’t learned how to use it yet,” O’Connor said. “But we will. It will just take time.”

Sharon Schmickle covers science, international affairs and other subjects.

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