A True and Astounding Scientific Breakthrough: Genes Changed, Christmas Disease Reversed

A True and Astounding Scientific Breakthrough:  
Genes Changed, Christmas Disease Reversed

A profound triumph was reported in the New England Journal of Medicine this week.  On December 10, 2011, investigators in London made history.

For the first time in the history of the world, a virus was altered and then given to people, successfully changing the DNA of the infected person, thereby actually reversing a genetic disease, and ending the suffering caused by the genetic disease.

The report establishes that for the duration of the change in the infected person's DNA, their genetic disease is cured.

The disease is the second most common form of hemophilia, variously known as hemophilia B, Factor IX deficiency, or Christmas disease, after the name of a 10 year old boy with the disease, Stephen Christmas.  Stephen was the first person in whom the cause of hemophilia was defined as a deficiency of a clotting factor, specifically Factor IX.

Background:  The Basics of Why and the How Blood Clots
To understand the astounding nature of this breakthrough, a little background on hemophilia.  Hemophilias are diseases of too little clotting.  Blood is a very peculiar liquid.  It has to have two opposite properties available to it, at all times.  For most of the time, blood must be very liquid, it must be able to flow.  After all, it supplies all the oxygen and nutrient to the cells of the whole body.  No flow, no life.  

But at the same time, the delivery of blood depends on intact pipes to deliver it.  Leaks in the pipes lead to loss of blood, which can ultimately end flow.  Those leaks can be small or large.  All the pipes, or blood vessels, are made of living cells, whose edges always need to be kept nice and close to prevent any blood from leaking out.  The pipes can also be injured by tears and cuts.  So when tiny leaks occur or big tears, the blood right there needs to patch the hole if blood flow is to be saved.  And so blood has the incredible ability to convert from a liquid to a solid, right where the hole is, sealing the leak, in a process called clotting.

Now, for blood to always be liquid when necessary and at the same time be able to always be a solid when necessary, the body has devised many, many processes that keep the blood liquid, and allow it flash into being solid.  The fact that many, many processes are active in both directions, allows the body to fine tune the situation to a remarkable degree of accuracy, keeping the blood liquid and flowing whenever that is required, and converting it to a solid, in just the one spot it needs to be at just the one time it needs to be, whenever or wherever a leak occurs.

One of these complex systems of checks and balances is called the coagulation cascade, and it is made up of over 13 different enzymes, each called by their Roman numeral number.  So the #5 enzyme in this cascade is called Factor V.  In order for a clot to form, a sequence of one enzyme activating another needs to be launched before the final step of a clot forming can occur.  Of course, the body has various counter measures to stop the cascade from proceeding at every step, so that the jump towards making a clot can be very carefully controlled.

Hemophilia, then, is a disease where one of these 13 or so clotting factors is missing.  There are two clotting factors whose absence makes up nearly all of hemophilia, Factor VIII and Factor IX.   In Christmas disease, the gene that makes Factor IX is defective, and the affected person makes essentially no Factor IX.  This leads to life-threatening, painful, and damaging bleeding into bones and muscles. This is the disease that the descendants of Queen Victoria had.

If the person is given Factor IX, the bleeding does not occur and the disease is controlled.  But Factor IX is not easy to get, and to prevent bleeding one has to have a steady supply.  If one depends on getting Factor IX from donated blood, that exposes a person to lots of donors and a real risk of AIDS.  In fact, hemophiliacs were the people at highest risk for getting AIDS until the blood supply could reduce the amount of AIDS to essentially zero.   

Background on Gene Therapy
Now one more piece of background before we unveil the incredible nature of this news.

Genes are bits of DNA that make proteins.  And proteins, in turn, are the main signals of the body, directing it to do nearly each and every one of its myriad chemical reactions.  In the case of hemophilia,the gene for Factor IX makes the protein Factor IX, which we just learned is an important cog in the wheel that allows blood to clot at the right time and place.

No gene for Factor IX, no Factor IX, lots of painful and destructive bleeding.
So, if one could find a way to fix the gene for Factor IX in people with Hemophilia B, or Christmas disease, they would no longer have hemophilia.   To fix such a gene, one would have to succeed in each of these steps:
  1. Insert the normal gene for Factor IX into living cells of the person with hemophilia B.
  2. The normal gene would have to be active in the cells that normally make Factor IX.
  3. The cells with the inserted gene would have to actually make normal Factor IX in sufficient quantity 
  4. The new gene making the cells make Factor IX would have to continue operating the rest of the person's life.
Notice that in contrast to interventions like transplanting there is no risk of rejection or bad side effects.  At its heart gene therapy is the most harmless of ideas.  It simply restores normal function to your cells.  

But the great challenge of gene therapy has always been, how to get a new gene operating in your cell without disrupting that cell?   The answer these scientists came up with requires one more piece of background before we unveil the extraordinary breakthrough.

Background:  How does a Virus Work and how does that help make gene therapy happen? Therapy?
Most of us know viruses as a major nuisance and creator of agonies.  Viruses make us sick, they give us colds, flus, stomach flus.   They cause warts and rashes and cold sores.  Really, what good could come from that?  What sort of good science could possibly come out of a week of sneezing and coughing, and being up all night with your suffering child?

Well, it turns out that viruses are barely alive.  One could make the case that they are more little packets of information than of life.  Every virus that we know of is a very simple package of 2 elements.  A coating of a handful of proteins and within that coating a strand of DNA or RNA.   Each of these 2 elements have one specific task to complete.  

The coating of proteins contain codes that open the door of a cell the virus.  Keep in mind every cell in every bit of life must take in certain compounds, keep out certain compounds, and secrete certain compounds if it wants to live.  Cells are extremely clever about keeping what is needed in, what is dangerous out.  The proteins on the outside of every virus, then, are proteins that talk to their target cell to talk that cell into letting the whole virus into the cell.  Now, keep in mind that one virus is about one thousandth the size of one human cell.  So from a size point of view it is nothing for one virus to enter one cell, it just needs the right key, and that is what its coating proteins are, a key.

Once inside the cell, the second element of any virus comes into play.  That element is a strand of DNA or RNA.  Either way, that strand is really a piece of information.  And in the case of viruses, the information this strand of genetic material contains is limited to 2 items:  make more coating protein, make more viral DNA/RNA.  That's it.  That's the only message a virus delivers to the cell once it is inside, make more virus.
That information gets expressed by the viral DNA/RNA inserting itself into the cell's DNA thereby forcing your cell to stop what it is doing and make viral proteins and genes. 

Now, for most cells, that's a bad message.  For once the cell has been commanded to make more viruses, it makes billions of them and the cell pops.  That's how colds work, all the cells lining your nose, throat, lungs, sometimes eyes pop.  That leaves the lining of these areas actually burned, weeping and watery, red and swollen, and they stay that way until the cells are replaced and the virus is killed.  That is, a cold.

So why use such a marauding system to help someone get well?

It turns out there is no machine for delivering a new gene to your cell's genes like a virus.  Imagine, just plop the new gene into the protein coating of a virus, let the new gene sit next to the viral DNA/RNA, then let the virus into the patient's body, and whammo, the virus inserts all its genes into your genes and your cell now has the missing gene.

That's why science turned to viruses for gene therapy, they can deliver, implant, and activate the new gene!

But, to use a virus to fix your gene now demands these steps be met:
  1. Put the desired new gene inside the protein coat of  a virus.
  2. Once assembled, this new gene-virus combo still has to be able to enter the target cells.  The target cells are the cells of the patient's body that the new gene should help restore to the lost function.  In this case, the target cells are the cells that make Factor IX in the human body, and those turn out to be liver cells.  So, it does no good to have a virus with the gene for Factor IX strapped into it, if the virus cannot get into a human liver cell.
  3. Once the new gene-virus combo is launched in the body, it would be ideal to have the virus enter the target cell, insert the new gene into that cell's genes, but stop there.  That is, let the new gene in the virus be active in the target cell, but don't let the viruses own genes activate.  If the viral gene activates we know what will happen, billions of viruses will be made and the cell just cured of its genetic defect will pop, and the patient will just end up with a cold.
The Breakthrough

Now we are ready to be amazed.  The report from the New England Journal of Medicine establishes that this all has been done in people with hemophilia.

Scientists took a virus called the adeno-associated virus.  This is very unusual virus, in that it does invade and multiply in people, but does not cause illness.  A perfect sort of virus for gene therapy.

So what happened was that scientists altered the adeno-associated virus in two ways:  they inserted a normal healthy gene for Factor IX, and they weakened or deleted the ability of the virus to cause harm to the cell.

With this new machine in hand, they simply injected a bunch of this virus into 6 people with hemophilia B, or Christmas disease.   

Here is what happened:
  • Not a single person got sick
  • Every one of the six people with hemophilia needed less Factor IX injections to remain free of bleeding.  Four of the six went off Factor IX completely for the many months of the study.
  • The immune system did notice the virus and did make antibodies to it.
To put it in the simplest possible words, if this change sticks, 4 of 6 of these first people treated will be cured of their hemophilia!  And, the other two were nearly cured!

This is the first instance in the history of the world that a person had a normal gene inserted to take over from a faulty gene, curing a serious illness, with essentially no side effects.

The door is now very much open to addressing problems caused by single gene abnormalities.  Now, most of human suffering is not due to simple, one gene problems, but many problems are, like cystic fibrosis, muscular dystrophy, sickle cell anemia, for example.  And there may be conditions of more complex genetics where altering one or two genes could make a very large difference.

Think about, 6 people who did not make enough Factor IX to prevent serious bleeding now are making it on their own with no further intervention beyond one single injection of a very weak virus that did not make them ill.

I thought it quite poignant to report this astounding breakthrough to you on the Christmas of 2011.
After all, the first disease truly reversed with one gene therapy turns out to be Christmas disease.

The promise of medical science continues to amaze.  Modern surgery transformed our ability to remove harmful entities from our body, untwist clogged structures, repair wounded or malformed parts of the body.
Antibiotics gave us the unheard of power to kill deadly bacteria and push back the scourge of infectious disease.  And now, we can for the first time meet people who had one gene changed curing a once incurable disease.  We now have our hands on the genome, and the possibilities for helping life have suddenly taken another leap forward.  I am especially pleased that the approach to touching the genome was done so responsibly and safely.  As with every advance, a dark side always threatens, the dark side of unintended consequences.  But when I look at the interventions of surgery, antibiotic, and gene therapy, we may ultimately find gene therapy the safest of them all.  It's end point is clearly the most harmless, adding a normal gene to a normal cell, really simply restoring a cell to its intended and natural function.  No surgery or even antibiotic can claim that level of process, each involve killing normal cells (cutting) or disrupting normal functions (hurting helpful bacteria in the body) as they reach their goals.  If the delivery of the healthy gene can be made fully harmless, gene therapy could be the safest intervention yet invented.

So, I wish all families today a very Merry Christmas, a Happy חנוכה (Hannukah), and starting tomorrow Kwanzaa.   This breakthrough adds more hope that 2012 will be a Happy and Healthy New Year for all of us as well.

Dr. Arthur Lavin
December 25, 2011

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