Medical Minute 8-19: Making Medical History

By: Vanessa Welch Email
By: Vanessa Welch Email

Simple tasks take longer for Heather and her Brother Logan. They both have miller syndrome -- an extremely rare disorder that causes face and limb malformations.

Heather and Logan also have a lung disorder known as PCD. But both their parents are healthy. That's what led them to be scientific trailblazers -- the first family in the world to have their entire genetic code sequenced. Now -- they know for sure their problems are genetic.

"It's given us peace. It's given us answers," said Debbie Jorde, Mom.

"I was really happy. Finding out that Miller Syndrome is genetic helped resolve some feelings of not belonging," said Heather Madsen, Had Genome Sequenced.

Doctor Lynn Jorde, human genetics chair at the University of Utah, started the family's pioneering journey -- with many other scientists. He's Debbie's Husband -- the children's stepfather. Jorde's team worked about a year to pinpoint the recessive genes from each parent that caused the kids' disease. They were able to identify two genes that were the culprits. Jorde says this is often the first step toward finding the cure

"And you can't really figure out how to fix something until you know what's really broken," said Lynn Jorde, Ph.D., Human Genetics Chair
University of Utah.

The discovery doesn't change life or treatment for Heather or Logan, but making medical history, is pretty cool, too.

"It's great to have that place in the world, that my existence has a marker, a permanent marker," said Logan Madsen, Had Genome Sequenced.

For more information on other series produced by Ivanhoe Broadcast News contact John Cherry at (407) 691-1500, jcherry@ivanhoe.com.

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MEDICAL BREAKTHROUGHS - RESEARCH SUMMARY:

GENOME SEQUENCING: Genome sequencing is a process that detects the complete DNA sequence of an organism's genome at a single time. Sequencing a patient's genome, the entirety of an organism's hereditary information, to find the genetic cause of an inherited disease has just been proven to be a clinical approach in a new era of medicine. A family in Utah has recently used genome sequencing to determine the cause of a rare disease.

THE FAMILY: Heather and Logan Madsen have been involved in trailblazing research that maps their entire DNA. Heather and Logan, as well as their mother and father, have had their genomes mapped in hopes of determining the cause of their illnesses, which they have been living with their entire lives.

THE DISORDERS: Heather and Logan both have Miller syndrome, a disease that causes limb malformations and facial disfigurement. Only about 30 people in the world are known to have Miller syndrome. Heather and Logan also have a lung disorder called primary ciliary dyskinesia (PCD) in which hair-like structures that sweep mucus from the lungs fail to move properly. The odds of one person having both Miller syndrome and the lung disease were less than one in 10 billion.

FINDINGS: Scientists from the University of Washington, the University of Utah and the Institute for Systems Biology helped the family on their pioneering journey. They worked for about one year to pinpoint the recessive genes from each parent that caused the kids' disease. They were able to identify two gens that were the culprits. The researchers also found each parent passes 30 mutations to their offspring -- for a total of 60. Prior to this study, most scientists thought each parent passed 75 mutations to their children. The researchers say a big bonus to sequencing the entire family is that they can identify errors in the DNA and increase the accuracy of their data when they compare it to other family members. They say family sequencing could one day become a normal part of a person's medical history records.

COST: In 2009, the cost to have a person's genome sequenced was about $25,000. Today, it is below $5,000 per person.

FOR MORE INFORMATION, PLEASE CONTACT:
Debbie Jorde
Author, Eight Fingers and Eight Toes: Accepting Life's Challenges
eightfingerseighttoes@gmail.com
http://blog.debbiejorde.com

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Lynn Jorde, Ph.D., Human Genetics Chair, University of Utah, discusses how human genome sequencing of entire families has allowed scientists to determine the causes of mutations and, the evolution of certain diseases that were once unknown.

Can you discuss in laments terms what exactly the DNA sequencing entails in regards to the work you are currently undergoing?

Dr. Lynn Jorde: The DNA sequence is essentially a series of instructions. It’s in every one of the cells in our body, and it tells the cell how to make all of the things it makes (proteins and so forth) that gives our body structure and function.

Can you talk a little bit about the project that implemented the DNA sequencing aforementioned?

Dr. Lynn Jorde: The project that we were involved in was the sequencing for the first time of the entire DNA of a whole family – two parents and two offspring. So, we determined the entirety of the three billion bases within the four family members.

How do you do that?

Dr. Lynn Jorde: Briefly, what we do is chop the DNA into small pieces. From there, we have technology that allows us to read each and every one of the bases found within those pieces. Then, since what we have is millions upon millions of these small pieces of DNA, we have to put them back together in a process commonly referred to as alignment. What we are doing, is stitching those small pieces that have already been sequenced back together in an effort to sequence them as a whole.

How long does that take?

Dr. Lynn Jorde: Well, currently sequencing an entire human takes approximately a week or two, so it can be accomplished rather quickly, especially considering that the original Human Genome Project involved with getting the first human genome sequence took a total of about thirteen years.

When did the first human genome sequencing take place?

Dr. Lynn Jorde: It was completed in 2003.

What methods are used to extract the DNA so that you can begin the sequencing process?

Dr. Lynn Jorde: Typically (and especially when we want high quality DNA), we take a small blood sample – a couple tablespoons of blood – and then we extract DNA from that blood, and it’s that DNA that we ultimately determine the sequence of.

In regards to the two parents and their offspring, what information was discovered through the process of sequencing their DNA?

Dr. Lynn Jorde: Well, there were several things that the sequencing project led to. One, because we were looking at the entire DNA sequence, we were able to determine the human mutation rate actually for the first time in an entire family. So that is asking the question: When we do reproduce, how many new variants occur in the DNA. Furthermore, this is something that had never been done before in a human family. This is something, however, that we need to know in human genetics. How often are these variants rising? So, that study gave us the first estimate of the human mutation rate. Furthermore, this is something that scientists will be able to use in myriad contexts as well as applications. The other thing that the DNA sequencing led to for this family, was the cause of the children’s condition – Miller Syndrome – as well as a lung disease that is independent of their abovementioned condition, however, it is another genetic condition that in due course affects both of them.

What were you able to determine was the source of their condition after studying the results of the sequencing?

Dr. Lynn Jorde: For both of the conditions that the children have, the precise variant that causes the disease was determined – the one inherited from the mother, and the one inherited from the father – because both of their diseases (Miller Syndrome as well as Primary Ciliary Dyskinesia) were autosomal recessive conditions, in the sense that you have to inherit both conditions from the parents in order to express the disease.

Who came up with the idea to perform the genetic sequencing on the entire family?

Dr. Lynn Jorde: The idea of doing the whole genome sequencing came up in a discussion at had with David Galas at the Institute for Systems Biology. David was interested in sequencing a whole family, although it had never been done before, and said that, “It would be really interesting to sequence a whole family that is in some way of special interest.” I responded, “Well, we should sequence a family whose cause we have yet to be able to determine.” He then went on to ask, “Do you know a family like that?” I told him, “Yes I do.” So, that is how that started. We chose that particular family to be a part of the study due to the fact that neither the cause nor the syndrome was known.

How exciting was this for not only you, but also people around the United States who have never done (or possible considered doing so) the human genome sequencing process for an entire family?

Dr. Lynn Jorde: This is the first family ever in history to have their entire genome sequenced, and within two to three weeks of the publication of the results from the sequencing in Science last year, it was referenced in various other publications that were studying the process of human genome sequencing. The first family ever to be sequenced was then picked up by Nature Magazine, to further investigate the huge milestone made in human genome sequencing

What is the next step for the whole human genome sequencing project?

Dr. Lynn Jorde: One of the things that we are doing with this family is to look at another generation – in this case the grandparents – with Miller Syndrome. What this will allow us to do is look at the mutation rate in regards to how fast it moves for females and males. How often do changes occur when males make their reproductive cells and females make there’s? We think, and there appears to be good evidence for this, that the mutation rate seems to be a lot higher in males that that of females, however, we yet to have an exact estimate from families to support that. So, this is going to aid us in determining to what extend these changes (really evolution) occur. Is it more male driven than female driven? This is sort of the biological question that we are looking at. Now, people are doing sequencing and doing hundreds of people at that. Next year, it could be thousands as costs for this process continue to go down.

This might seem to be a rather obvious question for you, but why is this such a good thing? What will come of determining these answers by sequencing the entire human genome?

Dr. Lynn Jorde: Well, getting the entire human genome sequencing results allows us to find out the cause of a patient’s problems, because this is the blueprint – the blueprint for ourselves, he blueprint for our bodies. Moreover, even still today, with many of the diseases out there we still don’t know exactly what is going on at the most fundamental as well as biological level. Nevertheless, getting the DNA sequence (we believe in many cases) will allow us to find out exactly what is broken, and you can’t really figure out how to fix something until you know how and why it is broken.

Can you briefly discuss the costs of performing the human genome sequencing throughout the years of research?

Dr. Lynn Jorde: The cost of the first human genome sequencing (remember, this was a public effort) is estimated to have been over one billion dollars. This was in 2003. Four years later, the next genome sequencing cost one hundred million dollar. This year, we are paying on the order of five to ten thousand dollar per sequence. So, as far as I can tell, this is one of the most rapidly decreasing cost anywhere. If you look at Moore’s Law and the increase in computing power, this beats Moore’s Law completely.

Do you now see families participating in human genome sequencing for each member of the family?

Dr. Lynn Jorde: There are several families now that have been sequenced, and I think that as time goes on we will continue to see more and more of that. There is a lot of interest, certainly on the part of scientists, to do sequencing because we still have hundreds of thousands of genetic diseases whose cause is yet to be determined. This is a way to find the causes of those diseases.


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