Book Club – The Coming Plague

I think we’ve all heard a lot about Zika in the past few months.  Hardly a single story about the Olympics is written without the mention of this virus. Major discussion surrounds who’s going or not based on Zika. For the Center for Disease Control’s take, read here. In fact, I was planning on going to the Olympics with my girlfriends until I decided to get pregnant earlier this year.  I do not want to contract Zika and the possible debilitating birth defects associated with it.  But, I’ll also be late in my third trimester and unable to travel. Definitely a bummer, but better than microcephaly.

comingplagueWith all this talk of disease, it reminded me of a fascinating book I read nearly 20 years ago: “The Coming Plague: Newly Emerging Diseases in a World Out of Balance” written by the brilliant Laurie Garrett. This tome tracks over the history, outbreaks and social outcomes of diseases including HIV/AIDS, Ebola, Lassa Fever, and influenza. I was a much younger scientist when I read this book. I hadn’t considered the social and economic effects of disease.  In particular, I remember the stories about how HIV/AIDS in Africa. This virus has devastated families who often had both mother and father die from the disease leaving millions of orphans. But not only that, AIDS eliminated much of the workforce in certain parts of Africa, decimating the economy.

My thoughts on “The Coming Plague”

After reading this book, I insisted that my Mom, who was  substituting teaching at the time, read it too. She called one day to let me know that she told all the teachers in the break room that some deadly disease (likely a version of the Spanish Flu) was going to re-emerge and likely kill millions of people.

I think even just 20 years ago, this fear would be extremely well founded.  Today, I have high hopes that modern science has the funding, political support, and skill to quickly diagnose and develop a treatment for a newly emerging disease.  Zika provides a modern example.  In mere months, scientists have been able to confirm that Zika is linked to birth defects (one original article using animal models here) and less than a month ago, the first clinical trial of a Zika vaccine was approved by the FDA (article here).

Is the Zika response good enough, fast enough, or certain to be effective?  Only time will tell.  Does this science mean that we don’t need to concern ourselves with emerging infectious disease?  Not at all!  In fact, it may mean that we should be even more vigilant so that scientists will have the funding to study, understand, and help treat these diseases as quickly as possible.

The best week ever – Nobel Prize week!

nobelLast week was one of my favorite weeks of the year – Nobel Prize week. Some people wait for the Emmys or the Superbowl or Christmas.  I wait for the Nobels. To be fair, I care most about the science Nobels – Physics, Chemistry and Physiology or Medicine, though one cannot ignore the amazing accomplishments of the winners in Literature, Peace, and Economics. Every year, I try to guess who may win – though Thomson Reuters and others are far more scientific about their guesses than I am.  And each morning of Nobel Week, first thing I do is check the news on my phone to see who won, what for and whether or not I know them (this year – no).  Let’s talk about who won the science awards this year and what amazing discoveries they won for.

Physiology or Medicine. A lot of attention has been given to infectious diseases this year with the huge Ebola outbreak in western Africa.  Although tens of thousands of people were infected and died, other infectious diseases are even more widespread and affect millions of people a year. Malaria is a parasitic disease transmitted by mosquitoes that 3.4 billion people are at risk of contracting and that kills over 450,000 people per year. Parasitic worms are also rampant in the third world, can affect up to a third of the human population, and cause such diseases as river blindness.  This is the second most common cause of blindness by infection, with 17 million people infected and 0.8 million blinded by the disease.  The three winners of the Nobel for Physiology or Medicine this year discovered novel treatments for these parasitic diseases.  William C. Campbell and Satoshi Ōmura for roundworm parasites and Youyou Tu for malaria, saving hundreds of thousands of lives each year.

Chemistry. This is by far my favorite award this year because it is directly related to how humans safeguard their DNA, but also why when this safeguard does work, that we get cancer.  Awarded to Tomas Lindahl (UK), Paul Modrich (USA), and Aziz Sancar (USA), this Nobel celebrates the discovery of the mechanism of DNA repair. I’ve discussed in this blog how UV and other environmental factors can cause mutations in DNA, and with too many mutations, people can develop cancer or other diseases.  However, the genome doesn’t mutate out of control because cell contain the machinery that is always working to fix any DNA damage using DNA repair mechanisms. It’s like a NASCAR race, where the car is always being monitored, wheels replaced, and minor problems fixed by the pit crew.  DNA repair is the genome’s pit crew and these three scientists figured out three different ways that the cells monitors and fixes the DNA depending on the type of damage that has occurred.

Physics. We all know I’m not a physicist, but I’ll try my best. The Physics Nobel was awarded to Takaaki Kajita of Japan and Arthur B. McDonald of Canada for discovering that neutrinos have mass.  You may remember from high school that atoms are made up of protons, neutrons and electrons. However, scientists now know that there are even tinier parts of an atom called subatomic particles that include the neutrino, fermions and bosons (and others). Other than photons, which are the particles of light, neutrinos are the most numerous subatomic particle in the entire cosmos, so understanding how they work is incredibly important.  These researchers found that the three different types of neutrinos can convert from one to the other. It was predicted by the Standard Model of Physics that these neutrinos wouldn’t have mass, but these scientists also proved that they did. Their studies help to better understand matter and the universe. My favorite reporting of this award was by NPR.

So until next year Nobel Prizes.  I will be waiting with baited breath!

 

What is Personalized Medicine?

bullseyeA few years ago I was asked to teach a course to adults at the ASU Osher School of Lifelong Learning about the Emerging Era of Personalized Medicine. This was exciting because it would give me the opportunity to help empower these adults to better understand their health, the science behind what make them sick, and what scientists and doctors are doing to cure them.  This was also a challenging course to develop because only a few years ago personalized medicine wasn’t the common buzzword like it is today. In fact, in early 2014, the Personalized Medicine Coalition contracted a research survey that found that 6 in 10 of people surveyed hadn’t heard of the term “personalized medicine” (see all results of the survey here). Despite the public being unaware of this huge advance, in the past few years, scientists and doctors continue to evolve this concept and medicine isn’t just “personalized” but now it can also be described as “precision,” predictive,” “individualized,” “stratified,” “evidence-based,” “genomic” and much, much more.

So what is new about this type of medicine?  Of course since the days of Hippocrates, doctors have provided care to patients that take their “personalized” needs in mind. Based on the patient’s symptoms and their experiences, the doctor provides treatment. But what if two patients have the same symptoms but different underlying diseases?  A fever and a headache could be the flu or malaria. Or two people could have the same disease, like breast cancer, but the underlying genetic changes are different so that the cancer should be treated differently for each patient.

The current concept of personalized/precision medicine uses each person’s individual traits (genetic, proteomic, metabolomic, all the -omics) and harnesses our molecular understanding of disease for the prevention, diagnosis, and treatment of disease.

personalized-med2The ultimate goal of personalized medicine is to improve patient health and disease outcomes. The graph above shows how better understanding the genetic and molecular causes of disease can improve health at all phases of disease progression.

  1. Knowing the risk factors that cause of disease (either environmental, like smoking, or genetic, like the BRCA gene mutation) can help to prevent disease before it starts by eliminating the risk factors or providing additional screening to catch the disease early.
  2. Biomarkers that detect disease before major symptoms can be used to treat the disease early, which usually has a better outcome than treating a disease that has progressed further (think stage 1 versus stage 4 metastatic cancer).
  3. Once a disease has been diagnosed, the molecular understanding of the disease can help determine what treatment the patient should receive (see below for an example).
  4. Biomarkers can also be used to predict whether the disease will progress slowly or quickly or whether or not a selected treatment is working.

For all aspects of personalized medicine, there lies the promise to make an enormous impact both on public health but also on decreasing the cost of healthcare.

breast_cancerLet’s use breast cancer as an example of how personalized medicine plays out in real life, right now. For breast cancer detection, breast self-exams and mammograms are typically used.  With personalized medicine, we now have an understanding of one of the genetic risk factors of breast cancer – mutations in the BRCA genes.  Patients at higher risk for developing breast cancer because of these mutations can be monitored more closely or preventative action can be taken. In the past, breast cancer treatment focused on treated with non-specific chemotherapy and surgery. Although both of these treatments are still of value, now doctors also test for the presence of certain breast cancer genes like Her2.  If Her2 is present in breast cancer cell, the drug Herceptin that specifically targets this Her2 gene can be used to specifically kill those cancer cells. If Her2 isn’t present, this drug isn’t effective, causes negative side effects and wastes time and money when a more effective treatment could be used.  Once breast cancer is diagnosed, a patient would be interested in knowing how quickly their cancer will progress. This used to be primarily based on the stage of the cancer, where stage 4 cancers have spread to other locations in the body so the prognosis isn’t great. Based on molecular markers, scientists have now created panels of biomarkers (Oncotype DX and MammaPrint) that predict breast cancer recurrence after treatment.

These personalized medicine-based tests and drugs are incredible. However, this is a field that both holds considerable promise and requires lots of work to be done.  For every incredible targeted therapy developed, there are patients that are still waiting for the treatment for their disease or the genetic variant of their disease.  In future posts, I’ll talk a lot about both the promise and the pitfalls of personalized medicine.

If you want to learn more about personalized medicine, check out this YouTube video with a cartoon comparing treatment with and without the concept of personalized medicine.

What are vaccines and how do they work?

Vaccines are a hot topic. Vaccines bring up lots of discussion, lots of false information, and a vitriolic passion rarely seen in matters of science and pseudoscience. I’m going to start my discussion about vaccines by explaining what they are and what they do. My second post will address some of the false information and controversy (with an added bonus of bringing in my lovely sister’s fabulous point of view as a mom of two!) My final post will answer a question I was asked about whether or not vaccinations are needed after a stem cell transplant.

Let’s talk about what immunizations do and how they do it.  Vaccines (aka immunizations) use biological agents to induce an immune response that protects you from that disease. The immunization itself could contain a weakened version of the disease-causing agent (like an inactivated poliovirus to vaccinate against polio), a non-human version of the disease (such as the cowpox virus to vaccinate against smallpox) or a small part of the disease-causing agent (for example, the toxin or a protein on the surface of the disease-causing agent).  The vaccine is injected into the body, but it isn’t strong enough or functional so it doesn’t cause the disease, but the body attacks the vaccine’s biological agent using immune cells and develops a “memory” of this infection.  This memory is made up of both antibodies and immune cells.  Antibodies are shaped like the letter Y and the top part of the Y functions like a puzzle piece that fits together with a complementary piece on the infectious agent (called an antigen).  When the anitbody encounters a matching puzzle piece it will bind to the infectious agent and kill it quickly before it can cause disease. Therefore, the effectiveness of a vaccines depends on how good the vaccine is at making a puzzle piece fits the antigen puzzle piece on the infectious agent.
antibodySo let’s have an example.  The flu vaccine contains small proteins from several flu strains that, when injected, stimulate the immune system to create antibodies against those flu strains.  When a person encounters the flu,for example because their neighbor has the flu and sneezed on them, the antibodies and immune memory that were created by the vaccination will attack and neutralize the flu virus before it can infect the cells and make you sick.  If the flu vaccine didn’t contain proteins that create puzzle piece antigens that bind to the most common flu strain in a particular year, the flu shot is less effective and more people will get the flu.

Vaccines have done amazing things.  They have eradicated smallpox, a deadly disease that had been around for over 12,000 years and killed 30-35% of people who were infected.  Eradicating this disease saves the lives of over 5 million people each year who would have been infected and died otherwise.  Polio, another crippling disease, has nearly been eradicated with only a few hundred cases in 2012 compared to over 350,000 in 1988. Common childhood diseases like measles and whooping cough have also been decreased considerable, saving millions of lives each year through vaccines.  They are truly a modern medical miracle!

What are examples of diseases caused by one gene?

Mutations. We know what they are.  Mutations change a gene, which can change the protein.  And this change in the protein can be either neutral, good or bad.  Let’s finally talk about how these mutations can be bad.

There are over 4,000 diseases that are caused by mutations in just one gene.  This means that if there is a mutation in one copy of the gene (if dominant) or both copies of the gene (if recessive), there is nearly 100% likelihood that you will get the disease.  Let’s look at some common examples.

Cystic Fibrosis

cfThis is a genetic disease of the lung that is caused by a recessive gene called the cystic fibrosis transmembrane conductance regulator (or CFTR for short). This gene makes a protein that transports chloride across the cell membrane.  The most common mutation in this gene is a deletion that causes a frameshift, which makes a much shorter protein.  This shorter protein doesn’t work properly at transporting chloride and results in fluid build up in the lungs and other organs that leads to cystic fibrosis (also known as CF).

Since this is a recessive disease, what this means is that you need TWO copies of the mutated CFTR gene to get cystic fibrosis. Remember those genetic squares we used to figure out what the possibility of a child inheriting a particular allele of a gene?  Let’s look at one for CFTR.  If you imagine that the normal CFTR gene (the one that isn’t mutated) is “C” (shown in blue) and the mutated CFTR gene is “c” (shown in orange).  If each parent has one copy of the non-mutated and one copy of the mutated CFTR gene Cc, then they have a 25% chance of having a child with CFTR.  Why?  Because only a child with two copies of the recessive trait (which in this case is the mutated CFTR gene) will have cystic fibrosis.

Huntington Disease

This is an example of a dominant mutation that causes a disease.  The huntingtin genehuntingtin
has a region that has lots of repeats of one codon CAG. Most people have less than 36 repeats of CAG.  However, if a person has more than 36 repeats, it creates a protein that is toxic to brain cells – exactly how and why it is toxic isn’t really well understood.  Since this is a dominant mutation, you only need one copy of this mutated gene to get Huntington’s disease.  So if you have one parent with the Huntingtin mutation (shown as H*), which means they have one copy of the Huntingtin gene with >36 CAGs, then a child has a 50% chance of also inheriting Huntington’s disease (HH*)

Now you may be wondering, how do we know if the mutation will be dominant or recessive?  That’s a complicated question.  In part, you may know if you look at the family history.  A disease caused by a dominant mutation will be inherited by more often by the children of an affected parent whereas a recessive mutation is less likely to be inherited because it is only inherited when both parents have one copy of the recessive gene.  Another option is to study the function of the mutation protein and see how the mutation in the gene affects the function of the protein.  Since there are two copies of every gene, if one copy is mutated, the second copy of the gene could compensate for this mutation (in the case of cystic fibrosis).  In other cases, the mutation could cause such dysfunction that even with the normal protein around, it still causes disease (like Huntingtin’s).

Book Club – The Genome

genomeOur second book club book is The Genome The Autobiography of a Species in 23 Chapters written by the fabulous popular science author Matt Ridley.  So why do you think there are 23 chapters to this book? Do you remember how many pairs of chromosomes humans have?  Have 23 chromosomes, and Ridley devotes one chapter to each chromosome. The chapters weave stories about genes that are found on each of the chromosomes and how they affect our life (e.g., blood groups) or disease (e.g., Huntington’s disease). He also takes the time to provide information about the history of human evolution, genetics and biology, bringing the biology and its implications all together. What’s interesting about this book is that it was published 2 years before the first draft of the human genome sequence was complete in 2001.  It would be interesting to see how different this book would be if written today, 16 years later with the added knowledge and technology.

Besides really enjoying Ridley’s books, he was a visiting scientist at Cold Spring Harbor Laboratory, where I attended graduate school.  He presented to graduate class (which only had 6 people in it) in my first year Scientific Exposition and Ethics class two years after this book was written.  He also received an honorary doctorate from my graduate school the year before I received my PhD.  Although we met only briefly, his insight and ability to describe science is impressive and all of his books are worth a read.

For more Book Club books, click here.

What is a gene and what does it do?

Genome – it has the word “gene” built into it. But what exactly is a gene? You may remember that the genome is made up of DNA, long strings of bases called A, T, C, and G.  There are certain strings of bases, called a genes, that code for proteins, and proteins are the molecules that do all the stuff in your cells.

Perfectly clear, right?  Of course not, so let’s start with an analogy.  Let’s imagine that one chromosome is a chapter of a book, but the book is written in such a way that the sentences with meaning are mixed in with random letters.  All of the letters are part of the English alphabet, but some of them are written in such a way that they make sense and have meaning – like the sentences written in red below. This is just like your DNA.  Some of the DNA makes readable sentences (genes) and other DNA in between these genes doesn’t (this used to be called junk DNA, but now we know better – more on that later!).
gene_analogy

Each of these genes makes a protein (the how of this is a topic for another post).  Let’s give a few examples of genes and proteins that you may be familiar with.  Insulin is a protein that is coded for by the insulin gene. Insulin is important in regulating blood sugar, and people with diabetes often need to inject the insulin protein to help regulate blood sugar.  Another example is the lactase gene.  This gene codes for a protein that makes the enzyme that breaks down lactose.  A decrease in the amount (also known as the “expression”) of the lactase gene is what causes lactose intolerance in adults.

An analogy that is used all of the time is to think of DNA as a blueprint for something – let’s say a car.  Each gene is a blueprint for a different part of the car – a steering wheel, a brake, or a headlight and the protein that each of these individual blueprints make is the steering wheel, brake or headlight itself.  The genome is all of the blueprints put together to make the entire car.  So what does this mean to you?  Imagine if the blueprint for the brake was a little wrong and the brake on your car didn’t work quite right…the car won’t exactly function as intended. It’s the same with genes.  If the gene isn’t quite right, it can make a protein that isn’t quite right, and this can cause the body to not function quite right (causing disease).

gene_protein

And just in case you’re sitting there and still thinking about blueprints and steering wheels and book chapters and codes, let’s summarize how the Genome, DNA, genes, and proteins are all connected in this image here:
dna_and_genes