2012 in review

This was a slow year…sorry readers.  I promise to make 2013 a more productive year by writing more posts about cancer trends and medical issues including controversial issues!  Thanks for your support!

Dr C

Here’s an excerpt:

The new Boeing 787 Dreamliner can carry about 250 passengers. This blog was viewed about 1,200 times in 2012. If it were a Dreamliner, it would take about 5 trips to carry that many people.

Click here to see the complete report.

Can HIV be used as therapy for cancer?

Diagram of the HIV virus.

Diagram of the HIV virus. (Photo credit: Wikipedia)

Every so often, a report comes out in the news that grabs our attention.  Here is one of them.  The virus responsible for AIDS, a deadly disease with no real cure, has been successfully used to treat a few people with certain types of cancer.  Now wait a minute, you mean we are giving someone HIV?  Are we replacing one fatal disease (viral) for another fatal disease (cancer)?  No and no. Let me explain.

Human viruses that cause disease have successfully evolved to infect and survive in human tissues and cells.  HIV has evolved so well that it infects humans cells and avoids immune elimination and of course eventually causes death.  Other viruses are also very effective at infecting human cells and surviving to the extent that they replicate (or divide) very well in the body.  Viruses, although extremely simple in their makeup, have also evolved clever ways to manipulate the human cell’s own machinery for itself.  One of the things that the HIV viruses does very well is to integrate it’s genetic material into the human cells.  So, why not modify the virus so that it no longer kills you (we call this removing the virulent properties) but still has all the infective, survival and genetic integration properties. This is exactly what is being done.

For many years, a virus known as adenovirus has been modified to remove it’s harmful properties and keep it’s infective and replication processes.  This has been done rather successfully, but using these ‘modified viruses’ has proven rather difficult…do to a host of reasons.  What is new now is that the HIV virus was used as a viral vector in this case.  Thus, the properties that allow HIV to kill humans were removed, but the properties that allow HIV to infect human cells and integrate their genetic elements were kept.  It is perhaps not surprising that after nearly 15 years of HIV research and trillions of dollars being spent, we have now reached a stage where we know enough about the virus to start modifying it for use as therapy.

OK, so how is it being used.  Let’s first look at the cancer in question.  Leukemia is a cancer of the blood…often it is a cancer of the B cells specifically.  These B cells, instead of protecting you from pathogens by making B cells and then dying like normal cells, become transformed and keep dividing uncontrollably.  Mutations in the genome of the B cells result in a cancer of these cells that grows to such a large extent that they start preventing the normal function of the blood and the immune system.  These cancerous B cells start to overtake the body.  Getting rid of them permanently is difficult as bone marrow transplants are the best way to permanently remove them.  However, this can only be done with individuals who are healthy, and who have their cancer in remission (one must have a good heart, have a functioning normal immune system, etc.). BM transplants are still high risk and have many side effects and are very expensive, but can be life saving.  Not everyone can qualify for this procedure.  Chemotherapy often fails but is used to try and control the disease, but often as a temporary measure for many leukemias.  So, other therapies are often needed.

Using a modified and non lethal form of the HIV virus that infects T cell, scientists mixed a these cells.  However, the HIV itself was engineered to express a modified protein that allows the T cells to recognize the B cell, and then to kill it.  So, a mix of this genetically engineered HIV was allowed to infect the patients own T cells and those T cells are now able to recognize and destroy the B cells in the patient.  Confusing…yes, but don’t worry too much about the details.  In general HIV plus the patients own T cells were used to allow the T cells to kill the cancer cells.

Sounds sexy sure.  However a few things to recognize before getting too ahead of ourselves.  1) All B cells are killed not only the cancerous B cells and thus treatment makes you VERY sick as your immune system is shot for quite some time after the procedure (but this is only temporary as your immune system will recover but the cancer wont).  2) This may not work on everyone and only a small amount of people have been tested.  3) This is an example of personalized medicine and is very costly.  4) It may be years, if ever, before the FDA recognizes and approves of this type of therapy.  5) No one knows the potential dangers if any with using HIV as an infection tool.

So, interesting…let’s hope they can expand their trial and show long term studies that ‘prove’ that this works.  But for now, its a small step in the right direction!!!

 

Thank you

Dr C

Gene therapy finally gets its day!

DNA vaccine and Gene therapy techniques are si...

DNA vaccine and Gene therapy techniques are similar. (Photo credit: Wikipedia)

It is finally real.  One very specific form of gene therapy has been approved by the European drug authorities.  Actually, China has allowed some forms of gene therapy since 2003, but regulatory authority in Chinese Healthcare is not as rigorous as other countries.

What exactly constitutes gene therapy.  It is a form of treatment for any disease in which a defective gene is replaced by a functional gene through a very a specific protocol.  Simply injecting genes or using gold particle coated with gene(s) (units of DNA which code for a protein) is not enough.  Genes must be delivered into cells through certain vehicles before they can work properly.  Viruses make excellent carriers of genes because of their unique properties of 1) infecting cells and 2) getting gene products to be converted into protein products in an efficient manner.

The US and other countries with active medical research capabilities have been certainly keen to adopt gene therapy in the past.  However, as of date, there are currently NO gene therapy approved protocols/nor products in the US.  Why?  In 2000-2001 the entire human genome was sequenced and we technically at least know all the genes that humans have.  So, the issue of the gene itself is solved (theoretically).  The problem is in the delivery.  How do we get cells (and the right cells in fact) to take up the genes and most importantly convert the gene into a useful product?

That is where viruses come in.  The most useful and somewhat safe viral system developed so far is something called the adenovirus.  This virus will infect human cells and allow the inserted gene to be converted into useful protein product.  Also importantly, the virus itself does not insert the gene into the human genome.  In this way the new gene does not disrupt the existing genes or DNA material that is inside the cell.

Sounds good.  So what the problem?  Well all viruses are pathogens.  That means that part of the definition of a virus is that it infects human and has the potential to cause an infection.  Secondly, even if it has been modified extensively, it is still a virus and thus a foreign entity or organism.  One fundamental tenant of the human immune system is that foreign proteins or entities are immunoreactive.  Thus, the human immune system can mount an aggressive  response.  That response is normal, but can actually kill the patient if strong enough.  In fact, that is exactly what happened in a very well publicized gene therapy trial for a teenage boy with a very rare disease (ornithine transcarbamylase deficiency) in 1999, who was killed after mounting a huge immune response against the viral carrier of the gene being replaced.  There have been a number of other accidents and failures to various gene therapy trials and the US regulatory authorities have been extremely cautious to grant approval of any new forms of gene therapy.

There are over 2000 different types of diseases which are potentially treatable with gene therapy.   Generally any deficiency in which a single gene is responsible can be treated with gene therapy.  All one technically has to do is make sure that the cell type which carries and produced the defective gene (like the gene responsible for the disease cystic fibrosis) and use gene therapy with a corrected version of the gene that is targeted to that cell using some kind of modified virus.  The gene needs to be produced over a long time in order to be effective as a treatment.  In the case of this newly approved gene therapy by the company called uniQure Glybera allows for the expression of the new gene that codes for a lipid processing enzyme that is deficient in the patient receiving the treatment.  The gene is introduced into the muscle tissue with an adenoviral associated virus (AAV).  As the virus does not insert the gene into the human genome itself the gene only lasts in the nucleus of the cells for as long as 12 weeks and seems to minimize the diseases for almost two years.  This new therapy relied on a AAV that has been modified to be non-pathogenic, thus not causing disease.  So, the parts of the virus that causes disease has been removed, the the parts that allows the virus to act like the virus has been kept (e.g. the viral coat proteins).  Only one case of fever (often a result of immune reaction) has been reported so far, thus this new viral vector may indeed hide itself from recognition by the immune system.

So, finally gene therapy gets its share of the limelight.  Generally, it takes one successful trial of a certain drug class (in this case gene therapy using AAV) to get other agencies to approve that therapy or to get the same agency to approve of use of that therapy in different disease.  In clinical trials at the moment is this type of gene therapy for Parkinson’s disease and others.  So, who knows this approval for this one disease may point the way to more approval for other countries and other diseases where single gene replacement is curative.

Thank you and please do support me by going to my web page….www.cancermadesimple.com

Dr. C

Hallmarks of cancer

English: Cancer cells photographed by camera a...

English: Cancer cells photographed by camera attached to microscope in time-lapse manner. (Photo credit: Wikipedia)

II was inspired to add another blog today after a friend/former colleague of mine came in to see me and mentioned he had been reading my blog (thanks Allan).  So, today I have decided to embark on describing the hallmarks of cancer as we now understand them (hopefully using simple words and concepts as some of this does get kinda’ murky).

In 2000, a well known cancer scientists named R. Weinberg and his colleague published a review of the major hallmarks of all cancer cells (and thus of cancer itself).  In that original publication, he described six hallmarks, that was an increase in the previously established two.  There are now about eight that are widely accepted.  So, let’s start with the original two.

We all have normal tissues and cells in our body and many of the cells turnover relatively frequently.  Cellular turnover refers tot he process of dying and dividing cells.  Thus, new cells are made from dividing older cells and other old cells die off.  As the new cells are made, some of them may acquire new mutations.  Some of the cells may also have old mutations or may even harbor mutations that were inherited.  If these mutations affect the survival of the cells than we call them oncogenes (#1 hallmark).  If these mutations prevent the killing (or what is known as apoptosis, or programmed cell death) then the cells don’t die when they are supposed to (the #2 hallmark of cancer).  We have known for many years that all cancer cells derive from cells that keep growing and that don’t die.

Later, we started to appreciate that there were some other characteristics that we could ascribe to all cancer cells in addition to these two.  Instead of needing to turn on and off growth signals like normal cells, cancer cells are self sufficient in growth signals.  That means that the signals that make the cells grow, don’t turn off.  As long as their is cellular energy, then the cells keeps going.  That is hallmark #3.  Another attribute that all cancer cells have is that they are actually insensitive to growth signals, this is in addition to the fact they they evade death signals.  So, the signals that they receive from death inducing agents are either ignored or fuel growth or expansion. That is the 4th hallmark.  Two additional changes occur that are universal to all cancers, but some early cancers may not progress o this state.  One of these is the promotion of sustained blood supply to the tumor and thus the cancer cell (supplying it with nutrients and oxygen, etc.).  This 5th hallmark is also known as angiogenisis.  Looking at cancers that have advanced it is clear that they have increased vascular supply than the surrounding tissues.  Finally, the 6th hallmark of cancer is that of tissue invasion.  Aggressive cancers and the cells that make them up typically run out of food supply and become more aggressive and seek out new areas of the body.  In order to do so they need to secret products that help them ‘digest’ their environment and all of the fibrotic material that accumulates.  This 6th hallmark of cancer is also referred to as metastasis.  The cancer is usually more aggressive and serious once it has moved onto and latches onto its new location.  It is also much harder to treat.

Two newly recognized and agreed upon processes occur in cancers as well (and thus the cells that make them up).  The 7th hallmark of cancer is the ability of the cancer cells to escape the immune response.  Normally, the immune response would look at mutated proteins (that are found in most cancer cells) and try to destroy them.  However, cancer cells evolve many unique ways to evade immune destruction and recognition.  Finally, the 8th hallmark of cancer cells is something called metabolic reprogramming.  This basically means that the metabolism of the cells itself no longer mirror what the normal cell has.  The genes, energy usage, and most metabolic processes have permanently changes into a more aggressive, energy hungry pro-growth state.

Thus, as you can see, cancer is not so simple.  The cells that make up the cancer have changed in so many ways.  This is partially why it is so hard to eliminate cancer once it has taken hold.  There are quite a number of pathways involved in all 8 of these processes.  Since the early 80’s we have really learned a lot about cancer; certainly we have learned how complicated they are.  We have developed drugs against every single one of these 8 hallmarks, but we have not been able to cure most cancers and permanently eliminate many tumors (especially of caught late).

Thank you for reading and i do hope that is made cancer a bit more easy to understand.
Do visit www.cancermadesimple.com for more information.

Dr. C

Oh snap, what’s a SNP?

A Single Nucleotide Polymorphism is a change o...

A Single Nucleotide Polymorphism is a change of a nucleotide at a single base-pair location on DNA. Created using Inkscape v0.45.1. (Photo credit: Wikipedia)

OK, I don’t like it either, but scientist use so many big words and then they use so many acronyms and often think that the rest of the world uses them also.  Not only does the rest of the world have little clue about what most of them talk about, they certainly don’t know/understand/recognize the acronyms and terms.  There is said it.  Let angry scientist yell at me…won’t stop it from being true.

So, today I thought I might demystify (if possible) a term we use all the time and in this case, an acronym also.  SNP.  SNPs stand for Single Nucleotide Polymorphisms.  What?  Yes, they are a single change at the nucleotide level (one of the four letter codes that represent the entirety of our DNA, an A,C, T or G) of the DNA.  You might have heard about a mutation, which can also be a result of a change at the single nucleotide at the DNA level also.  Let me explain.

We have over 3 billion nucleotides that in essence make up the entirety of our DNA makeup.  You and I are different, so we express that DNA differently, but essentially we all have quite a similar 3 billion sequence code.  The DNA is where our functional proteins come from, although the steps to get from a piece of DNA to a protein is quite complex.  You get your DNA from your mom and dad (a combination of them) as your parents did from their parents.  So, you see, the DNA is going to be different in all of us as the mix we get from our parents is unique.  But, in general all of us who get blue eyes (let’s keep blue simple..but we know there might be many shades of blue) essentially have the same blue pigment at the DNA level and thus code for a blue protein (pigment).  Now, let’s say there is a random mutation that changes one nucleotide (again the building blocks of the DNA itself) in the blue gene.  That mutation might result in no color being made, or a different color, or even the same color if the mutation is in an unimportant part of the gene.   The point is that this mutation is random.  And it might not even occur in the cells of the eye or not even in the cells that will be given to your offspring.  It means that that mutation would only be passed down to future generations if it was in the sex cells (sperm or eggs).  If not, than it is random and a single incident mutation.

A SNP on the other hand is handed down.  It is a single nucleotide change that sticks in the chromosome (the way the DNA is bundled together….the structural unit of DNA) that is passed down through subsequent generations.  So, a SNP is a change that is maintained at the genomic level.  Have you ever heard that you can not simply give your organ to someone else, as their body may very well reject it.  Well, that is due to the presence of SNPs in the genes of the body that are known as transplant antigens.  So, your mom and dad gave you a mix of their own SNPs in their transplant antigens and you will give your future offspring a unique mix as well.  However, overall in a population, a certain number of SNPs will be present.  In other population, let’s say Asia, another set of SNPS are more frequent.  A SNPs is not a random mutation.  It is a difference in the nucleotide level (a single one) in the population due to mixing of that population over time.

So for transplants (giving someone your liver for example) you can only give the organ to a person who has the exact same set of polymorphisms in your transplant antigens.  If you have different ones that the recipient, then they will likely reject your liver (or rather their own immune system will try to remove it).

SPS are found all over the genome.  The one’s I was referring to above are functional, they actually have a known consequence.  There are many other SNPS that lie in regions where there is no known function (for example that do not code for protein).  However, if you read my post last week, you will note that those regions may not be junk at all and may be functional…in ways we don’t fully understand yet.

In summary, SNPs are single nucleotide changes that are in the DNA that are acquired by hereditary properties and exist in groups of people in a population.  Some may be functional and some non functional.  They are not mutations in that they are not random and must be inherited.  Over millions of years, some SNPS can be lost, but usually the whole set of SNPs in the genome are thought to be kept in the population (as long as the population does not die-off of course)!

I hope that was helpful and the next time you see SNP will you feel a tad bit more enlightened.

Dr. C

 

The new human genome!

A slight mutation in the matched nucleotides c...

A slight mutation in the matched nucleotides can lead to chromosomal aberrations and unintentional genetic rearrangement. (Photo credit: Wikipedia)

So this week, in over 30 different journals, a detailed study was reported on the nature of the over 3 billion nucleotides (the fundamental building blocks of genes and thus of DNA) that make up the human genome.  In the turn of this century, the human genome was completely sequenced (identified at the nucleotide level).  At that time it was thought that only 1.5% of those 3 billion plus nucleotides were functional and directly coded for proteins.  Much of the remaining 98.5% of the human DNA material in all of our chromosomes where thought to be junk DNA, thus serving little to no function.

However, this has been challenged greatly by new studies published this week suggested that as much as 80% of all the DNA in our cells are functional.  They define functional as the following: nucleotides that do not code for proteins but that does for RNA that is not translated in proteins (but can be regulatory in nature), nucleotides that themselves bind proteins, or nucleotides that affect the shape of the DNA in one way or another.  Thus is a far cry from the thought that most of the genome in our bodies is junk.

What does this mean in the real world and will it revolutionize medicine and science. It certainly means that labs all around the world working on their favorite gene or gene location will pay a lot more attention to sequences outside of the traditional gene unit (usually includes, enhancer, promoters and the introns and exons of the genes themselves).  More and more data will probably come out from labs on novel regulatory mechanisms from far away gene sequences and so on.  However, clinically t is doubtful that this new finding will bear any direct relevance to treatment and disease.  Just as the impact of the human genome was rather weak after the initial wave of euphoria, this too will pass.

Human genome

Human genome (Photo credit: Wikipedia)

Why medical community still doubts herbal remedies

English: Herbal remedies for sale in San Juan ...

English: Herbal remedies for sale in San Juan de los Lagos, Mexico (Photo credit: Wikipedia)

We have all heard it:  herbal remedies can’t be wrong, they have been used for thousands of years.  In fact, it’s true…many cultures, tribes, medicine men, etc. have been using and in essence prescribing natural plant based herbal remedies for many many years….in fact, much longer than that of modern medicine/pharmaceuticals.
So why then is the medical community reluctant to embrace herbal medicines and remedies.  Although it’s fun to poke fun of doctors, medical administrators, insurance companies, and pharmaceutical executives, the universal distrust in these types of remedies is not unfounded.  Here is a small list of reasons: 1) Many herbal remedies were found to have good affects on one particular ailment (such as stomach discomfort) and then prescribed and suggested to work in other organ system (the liver, lungs, etc.) with little or no evidence.  2) Many herbal remedies have been linked to visual cues in how they were assigned to work.  For example, it is common to find that red fruits or seed products are often given to women for bleeding conditions as blood is red and so is the remedy.  3) Many herbal remedies over the years are assigned to work on various parts of the bodies as they were harvested in certain ways- functional links.  For example, the Cantonese believe that eating pig brain will make you smart, or if you have impotency- eating of dried and ground up ox testicles will help.  Although these are not plant remedies, these types of functional or anatomical links have dominated traditional remedies.  4) The vast majority of remedies, even though many have commonalities from independent groups around the world and have been used by millions, have no properly controlled studies to show that they actually work. 5) They are prescribed and administered in widely varying fashion. The list goes on and on and these objections are fair.  That does not mean that herbal remedies don’t work, it just means we have a long way to go before modern practitioners will embrace them.

The last time that a medical compound was successfully derived from a plant and used in clinical medicine was in 1967.  That agent/drug was Taxol.  That was a long time ago?  For a while people just stopped looking for them.  However, many are now pursuing this newly popular science; namely plant medicinal chemistry with newer techniques.  Who knows, maybe one of our next blockbusters will come from a herb, plant or natural product.   It might not only save lives but also teach us identify the chemical component that works in the plant itself.