Growing tumors outside the body to kill the tumor still inside

To understand how to kill a tumor, you have to study the tumor. Historically, much of how scientists understand tumors comes from removing a tumor from a patient’s body, putting Cell_Cultureit in a plastic dish (called a petri dish), and studying whatever cells are grown in this dish. You may be familiar with the book “The Immortal Life of Henrietta Lacks” by Rebecca Skloot. This book talks about HeLa cells, which are cells that were taken from Henrietta’s cervical cancer, grown in a dish, and propagated for the past 60+ years as what is called a “cell line“.  These cells grow and divide indefinitely, and have been propagated and transferred from lab to lab to be studied.  HeLa cells are one of the most famous and most-researched cells that have helped scientists better understand cancer. HeLa cells are not the only cell line that exists or has been used to study cancer.  There are cell lines from lung cancer tumors, prostate cancer, brain cancer, and most other major cancers. However, there are a few problem with using cell lines to understand and treat cancer.

  1. Cell lines are EXTREMELY hard to create.  As you may imagine, a plastic dish is nothing like the environment inside the body that the tumor was removed from.  In the petri dish the cells are put into “media,”t he liquid that is used to feed the cells in the petri dish, and this media is also nothing like the nutrients and other growth factors feeding the tumor inside the body. Because of this unnatural environment, some of the tumor cells die – and in many cases mostor all of the tumor cells die.
  2. The cells that are left in the petri dish do not accurately represent the tumor anymore. A tumor isn’t a whole bunch of identical cells, but rather a tumor contains a lot of genetically different cells.  Scientists call this tumor heterogeneity. This is one of the reasons why drug resistant cells emerge after treating a tumor with drugs (like in the case of melanomadescribed in a previous post).  There are already drug resistant cells inside the tumor that don’t die when treated with drug.  Unfortunately, not all of these different cells in the tumor will live in a petri dish, so only a selected type or types of cells will live and can be studied.
  3. Even though cell lines had been the most useful tool in the past to understand cancer biology, they are not at all useful in understanding the EXACT tumor from a particular person. What does this mean? For example, drugs that kill HeLa cells in a petri dish might not work to kill another person’s cervical cancer because the genetic cause of that cervical cancer is different. In personalized medicine, the goal is to identify the drugs that will work to kill a particular patient’s tumor. Because of this, cell lines just aren’t good enough.

Scientists have been working on a number of solutions, and I’ll talk about four:

  1. Biobanking. A biobank collects excess tumor tissue from patients who are having a

    Where tumor tissue is stored in a biobank before researchers use it

    tumor removed as part of a surgery.  This tissue is immediately preserved by freezing and can then be used by researchers to study that particular tumor or many tumors of a particular type (e.g., lung cancer).  The disadvantage to this is that the tumor sample isn’t an unlimited resource. Once the tissue has been used up – it’s gone. The remaining examples all focus on growing the tumor tissue so that it can be propagated and used for many experiments.

  2. Modified cell line growth. HeLa cells were not grown in any special way, but researchers at Georgetown Universityhave found ways to grow tumor cells in a petri dish  that are identical to the tumor and nearly all tumors can grow under these conditions. So what are these conditions?  The researchers grow cells on top of a layer of mouse cells called feeder cells because they provide the cell-based nutrients to “feed” the tumor and allow it to grow.  They also use a particular inhibitor that allows the cells to grow indefinitely. They have created these modified cell lines from different types of tumors, from frozen biobanked tumors, and from as few as 4 live cells.  Even though this system, is better, it still doesn’t replicate the 3D architecture of a tumor…
  3. cancer organoids

    Cancer organoids. Notice the 3D clumps of cells after 217 days of growth. Thanks to the Kuo lab for the image

    Organoids. As you would expect the word to mean, an organoid is a mini 3D organ bud grown in a dish. Don’t imagine a teeny tiny beating heart.  These organoids are just clumps of cells, but an organized clump of cells that can help better understand cells and organs. The discovery of how to create organoids was so interesting that it was a 2013 Big Advance of the Year by The Scientists magazine. Scientist have also found a way to grow cancer cells into these 3D organoid structures. With tumor organoids, researchers can both study the genetics of the tumor (like you can with cell lines) as well as how the tumor behaved in a 3D environment that is more similar to what the tumor encounters in the body.  But what if we could do even better?

  4. Patient-derived xenograftsare when tumor tissue is taken directly from a patient’s tumor and put directly into a mouse.  Why would this be so awesome? The environment inside a mouse is more similar to the environment that the tumor is used to inside a person’s body.  The cells are less likely to die because they aren’t living in unnatural plastic. Also, a whole piece of tumor can be implanted into the mouse, maintaining the tumor cells connections to neighboring cells, which are critical for the tumor cells to communicate with one another for survival.

With all of these systems available to study tumors from a specific patient, what are scientists actually doing with these cells? In some cases, they are being used to sequence the genomes of the tumors to identify mutations that may be causing the tumor. If a tumor can be grown so that there is a lot of it, the tumor cells themselves can also be used to test treatments either in a dish or inside of a mouse. Imagine a cancer patient getting their tumor removed, part of the tumor is grown in one of the ways described above. Then the tumor is exposed to the top 10, or 50 or 100 anti-tumor drugs or combination of drugs to see what kills the tumor. This drug or combo of drugs can then be used to treat the patient. There are companies that are currently working on doing exactly this (check out Champions Oncology) so this “big dream” may soon become a cancer patient’s more promising reality.


Journal Club: The Microbiome Autism Connection

As I’ve mentioned in other posts, scientists have to read about and understand the current scientific literature. Lots of the time this is done alone, at your desk in the office or the lab, for hours and hours so that you can really understand whatever topic it is that you’re studying. But one of my favorite ways to share scientific papers is through a weekly meeting with the whole lab called a Journal Club. Although my husband laughs about this kind of nerdy science “club” (akin to his amusement about scientific societies), it’s a great way to discuss a particular topic and dive deep into a discussion about how the researchers got their results and came to their conclusions. This is the first of many Journal Clubs where we will do an abbreviated version of what we would discuss in a typical journal club in the lab. 

Paper TItle:  Reduced Incidence of Prevotella and Other Fermenters in Intestinal Microflora of Autistic Children

Authors: Dae-Wook Kang , Jin Gyoon Park ,Zehra Esra Ilhan, Garrick Wallstrom, Joshua LaBaer, James B. Adams, Rosa Krajmalnik-Brown
Full disclosure, Dr. LaBaer is the Director of the center I previously worked in at the Biodesign Institute at ASU. Drs. Park and Wallstrom worked in offices down the hall from me and Dr. Krajmalnik-Brown was in another center at the Biodesign Institute.

Journal: PLOS One (PLOS stands for “Public Library of Science”). In case you want to read the whole article, it can be downloaded (for free) here

Background/Introduction: Before this paper was published, scientists knew that many children with autism also had gastrointestinal (GI) issues suggesting that there may be a connection between the two. There have been some studies looking at antibiotic treatment (which could change the gut microbiome) before 3 years of age and how this might be connected with autism.  There have also been studies connecting the gut microbiome and the brain. So there was evidence that the gut microbiome and autism may be related in some way.

When this paper was written, scientists also knew about the microbiome and how changes in the bacteria (all 1,000,000,000,000,000 of them) that are in the gut are found in patients with many different diseases – from C. diff infection to obesity to depression.

Goal of this paper: Look closely at the changes in the gut microbiome of children with autism to better understand how these two might be related.

Methods/what did they do?: Bacteria in fecal samples is considered representative of bacteria in the gut microbiome. Therefore, the researchers collected fecal samples from children both with (20 children) and without (20 children) autism.  The samples from patients without autism were used as a “control” to compare to the autistic samples. The researchers also asked the children (or their parents) questions to help determine the level of GI issues, the severity of their autism, and their environmental factors like their diet. The researchers isolated bacterial DNA from each of these fecal samples and then sequenced the DNA to determine what types of bacteria are in the gut.

autism microbiome diversity

A figure from the paper comparing the phylogenetic diversity (PD) of the bacteria in autistic versus non-autistic children. you can see that the red boxes (for autistic children) are lower than the blue boxes (for non-autistic children) indicating a lower microbiome diversity.

Results: Through sequence analysis and other statistical methods, the authors found that children who did not have autism have a more diverse microbiome compared to autistic children.  If there is higher diversity, it means that the gut contains more different types of bacteria, and lower diversity means a smaller variety of bacteria in the gut. They also found that in the autistic patients with a greater diversity in their microbiome, their autism was generally less severe. They also did not find any correlation between age, gender or diet with these microbiome changes.

The scientists also looked at what specific genus and species of bacteria were more represented in non-autistic versus autistic children. Specifically the bacteria from genus Veillonellacaea, Provetella, and Coprococcus  are less abundant in autistic children.

Discussion/Significance: What does this all mean?  The researchers did find a correlation between decreased gut microbiome diversity and autism. It should be clarified that just because GI problems are often found in autistic children and the severity of the GI issues correlates with the severity of autism, this does not necessary mean that GI issues cause autism or vice versa.  That still needs to be determined. Also because the diversity of bacteria in autistic children is low, it is not clear if this is a cause of autism or an effect of a child having autism.  However, this paper does provide a “stepping stone” to better understand what is happening in the gut of autistic children and may help define a target for diagnosing autism (by looking at the decreased diversity in the gut as a diagnostic test) or treatment (perhaps through fecal transplant).

What has been done since? This paper was published in 2013.  So what has changed since the paper was published?  Do we know whether or not changes in the gut microbiome cause autism or not?  Unfortunately, this is still unclear.  However, if these microbiome changes are a cause of the neurological changes in autism, then one would want to do a clinical trial to test what happens to autism symptoms when the microbiome has been altered.  This could be done in a number ways including diet modulations, prebiotics, probiotics, synbiotics, postbiotics, antibiotics, fecal transplantation, and activated charcoal.  Researchers have started this process by holding a meeting that included patients and their families to figure out how this type of trial could be designed (for more details, check out this journal article).

For more information about the microbiome/autism connection, check out Autism Speaks. To read more Journal Clubs, visit the archives here.

Five Ways for You to Participate in Science – Citizen Science


The Bunsen burner I didn’t have. Thanks Wikipedia for the image

I had a chemistry set growing up.  It was small with tiny white bottles holding dry chemicals that sat perfectly on the four tiny shelves of an orange plastic rack.  My dad would let me use the workbench in the basement to do experiments – entirely unsupervised!! You might expect that I did really interesting chemical reactions, and this formative experience helped me to develop into the curious scientist that I am today. Completely wrong.  I remember following the instructions, mixing the chemicals, and then getting stuck because I didn’t have a Bunsen burner.  So many chemical reactions rely on heat, and the green candle stuck to the white plastic top of an aerosol hairspray can wasn’t going to cut it.

My main options for doing science as a kid revolved my failed chemistry experiments, my tiny microscope and slides, and a butterfly net that never netted a single butterfly (not for lack for trying).  However, today with computers (that’s right – no computer growing up – that’s how old I am!) there are hundreds if not thousands of ways for people to get involved in science, without having to invest in a Bunsen burner. This citizen science movement, relies on amateur or nonprofessional scientists crowd-sourcing scientific experiments. I’m talking large scale experiments run by grant-funded university-based scientists that have the possibility of really affecting how we understand the world around us. One example you may have heard about is the now defunct Search for Extraterrestrial Intelligence (SETI) which used people sitting at their computers to analyze radio waves looking for patterns that may be signed of extraterrestrial intelligence. They didn’t find anything, but it doesn’t mean that they wouldn’t have if the program had continued!

Here are five ways that you can become involved in science from where you’re sitting right now!

americangut1. American Gut: Learn about yours (or your dog’s) microbiome

For $99 and a sample of your poop, you will become a participant in the American Gut project. After providing a sample, the scientists will sequence the bacterial DNA to identify all of the bacterial genomes that are present in your gut.  This study already has over 4,000 participants and aims to better understand all of the bacteria that covers and is inside your body – called your microbiome – and to see how the microbiome differs or is similar between different people or between healthy people versus those who may be sick. The famous food writer Michael Pollan wrote about his experience participating this the American Gut project in the New York Times.  They are also looking at dogs and how microbiota are shared with family members, including our pets!

2. Foldit: solve puzzles for sciencefoldit

Puzzles can be infuriating, but at least they have a point to them when you get involved in the Foldit project.  Proteins are the building blocks of life.  Made out of long strings of amino acids, these strings are intricately folded in your cells to make specific 3D shapes that allow them to do their job (like break down glucose to make energy for the cell).  Foldit has you fold structures of selected proteins using tools provided in the game or ones that you create yourself.  These solutions help scientists to better predict how proteins may fold and work in nature.  Over 240,000 people have registered and 57,000 participants were credited in a 2010 publication in Nature for their help in understanding protein structure.  Read more about some of the results here.

3. EyeWire: Mapping the BrainEyeWire-Logo

The FAQs on the EyeWire website are fascinating because as they tell you that there are an estimated 84 billion neurons in the brain, they also insist that we can help map them and their connections. After a brief, easy training, you’re off the the races, working with other people to map the 3D images of neurons in the rat retina.  You win points, there are competitions, and a “happy hour” every Friday night. The goal is to help neuroscientists better understand how neurons connect to one another (the connectome).

4. Personal Genome Project: Understanding pgpyour DNA

The goal of the Personal Genome Project is to create a public database of health, genome and trait data that researchers can then use to better understand how your DNA affects your traits and your health. This project recruits subjects through their website and asks detailed medical and health questions.  Although they aren’t currently collecting samples for DNA sequencing because of lack of funding, they have already sequenced the genomes of over 3,500 participants. The ultimate goal is having public information on over 100,000 people for scientists to use.

mindcrowd5. MindCrowd: Studying memory to understand Alzheimer’s Disease

Alzheimer’s Disease is a disease of the brain and one of the first and most apparently symptoms is memory loss.  MindCrowd wants to start understanding Alzheimer’s disease by first understanding the differences in memory in the normal human brain.  It’s a quick 10 minute test – I took it and it was fun!  They are recruiting an ambitious 1 million people to take this test so that they have a huge set of data to understand normal memory.

This is a randomly selected list based on what I’m interested in and things that I’ve participate in, but you can find a much longer list of projects you can participate in on the Scientific American website or through Wikipedia.  Also, if you’re interested in learning more about the kind of science that people are doing in their own homes, the NY Times wrote an interesting article: Home Labs on the Rise for the Fun of Science.  If decide to try one out, share which one in the comments and what you think!

Can your body contain DNA that isn’t yours? Yes! Chimerism

There was a House episode (Season 3 Episode 2 Cane an Abel) about a young boy who was convinced that he was being probed by aliens.  Though a series of very House-like (aka “unrealistic”) medical twists and turns, House’s team finds cells clumped together in different parts of this boy’s body, including his brain, that are functioning abnormally and causing his various systems.  From sequencing the DNA from those cells, House’s team finds that those cells have different DNA than the boy’s.  In the fictional world of House, the doctors were able to quickly create a probe for the foreign DNA, find all the cells that were different and remove them (House does brain surgery!!) also removing the symptoms including the alien hallucinations. This episode is so wildly out of the realm of current medical ability and practice – so much so that I participated in a “Science Fiction TV Dinner”  all about the science and “science” found in this episode. You can watch highlight from this discussion, which included Dr. Kenneth Ramos from University of Arizona Center for Precision Medicine, below or listen to the whole podcast here.

Science Fiction TV Dinner: House M.D. from Science & the Imagination on Vimeo.

However, what I found most interesting about this episode was the fact that the boy had TWO DIFFERENT genomes in his body. Can this actually happen in real life?  If so, how??


“Chimera d’arezzo, fi, 04” by I, Sailko. Licensed under CC BY-SA 3.0 via Wikimedia Commons

The answer is yes, and it’s called a chimera or chimerism. In mythology, a chimera is a terrifying hybrid animal that’s a lion, with a goat head coming out of it’s back and a tail with a snakes head on the end. It may be clear that I’m a scientist since I’m sitting here wondering whether all three heads eat and if so, do they all connect to the same or different stomachs. But I digress…  In genetics, a chimera is an organism composed of two distinct sets of cells with two different sets of DNA. As you may remember from other discussions on this blog, DNA is the genetic material that provides the blueprint to make an organism.  DNA is also what is passed along to offspring, so that a child has 50% of the DNA from one parent and 50% of the DNA from the other (more about hereditary here). This is also why paternity tests work – if the child has 0% of DNA from the father, it’s clear that he isn’t the father,

So how in the world can a person have two different sets of DNA?  Especially since all people start off as one fertilized egg with one set of DNA instructions?  There are a few ways:

  • Organ transplants or stem cell transplants.  That organ or cells (more about stem cell transplants here) come from another person who has entirely different DNA from the transplant recipient.  So when a person gets an organ transplant, they become a chimera.  This is also true, at least temporarily, for people who have blood transfusions.
  • Are you a mother or a person who a mother gave birth to?  In that case, you might also be a chimera.  This is called fetomaternal microchimerism.  Mothers usually have a few cells identical to their children that stay in their body long term. This is often caused by immune cells being transferred back and forth between the mother and the placenta during development.   Even 22% of adults were found to still have blood cells from their mother! These cells are really difficult to find – in part because there usually isn’t any reason to look for them – but easier if the mother has a boy because then the chimeric cells contain a Y chromosome whereas the mother’s cells do not.
  • In vitro fertilization (IVF) also has the possibility of resulting in chimeric adults.  Since IVF often implants multiple fertilized eggs into the mother, there is an increased possibility of two fertilized eggs fusing – resulting in one developing human developing into an adult with two sets of DNA.

Illustration of a chimeric person from and awesome article about chimeras from the EMBO journal

Let’s talk about this last option a bit more because this is what House and Co. blamed as the cause of the child’s chimerism, but also because this is really interesting medically and socially.  There have been several noteworthy stories about  women who, for different reasons, were found to be chimeras.  Lydia Fairchild was looking for child support after a divorce, but when DNA tests to prove paternity were requested, it was found that the father was the father, but Lydia wasn’t the mother.  After numerous traumatic events, including being accusing of trying to commit fraud to obtain benefits and having the birth of her third child observed (to prove that she was that child’s mother, even though genetically it didn’t appear that the child was), Lydia was lucky.  Her lawyer heard about Karen Keegan, a women in need of a kidney transplant several years earlier, but when testing her three sons for compatibility, the tests indicated that only one was hers.  Only by looking at other cells in her body were doctors able to determine that her body contained two sets of DNA – one set was passed on to two of her boys and the other set was passed on the other.  Fortunately for Lydia, this discovery prompted DNA testing of members of Lydia’s extended family as well as other parts of Lydia’s body.  This testing showed that Lydia’s cervical cells matched her childrens’ and she was able to obtain child support. The media LOVED this. Just an example of the titles for news articles about Lydia and Karen:

However, besides the obvious media hype, chimerism has practical and legal implications. For example, in 2005, a cyclist Tyler Hamilton was charged with blood doping because they found another person’s blood mixed with his own.  He blamed this on chimerism (New York Times article here) where he had chimeric blood cells that had different DNA than the rest of his body.  He lost his case 2-1, but it brings up an interesting idea.  If everyone knows about chimerism – either through the popular media or TV shows like House – then this could lead to the “reverse CSI effect” where the jury is so aware of the possibility of chimerism that they discard all mismatched DNA evidence blaming it on chimerism.

Besides how strange this all seems, what’s even stranger is that more people are probably chimeras that scientists even realize. The only reason we know that Karen Keegan and Lydia Fairchild are chimeras is because scientists were forced to look at them more closely.  For the rest of us, we likely won’t need a transplant or have alien-probing hallucinations that induce scientists to look at many different parts in our body to see if the DNA is different.  And if more of us are chimeras, what does that mean? This is still something scientists will have to figure out.

Want to hear more about this amazing phenonemon? Check out  or this great article from the EMBO journalNPR’s RadioLab story Mix and Match featuring Karen Keegan’s story.

How do you find a biomarker? A needle in the haystack.

biomarker_useBiomarkers are biological substances that can be measured to indicate some state of disease.  They can be used to detect a disease early, diagnose a disease, track the progression of the disease, predict how quickly a disease will progress, determine what the best treatment is for the disease, or monitor whether or not a treatment is working. Biomarkers have the potential to do so much, and identifying biomarkers for different steps in the health/disease continuum would help doctors to provide each individual with targeted, precision healthcare.  Biomarkers have the potential to save billions of healthcare dollars by helping prevent disease, by treating disease early (when it’s usually less expensive to treat), or by targeting treatments and avoid giving a treatment that won’t be effective.

spotthedifferencesWith all this potential, you would expect doctors to be using data from biomarkers to guide every single healthcare decision – but this isn’t the case quite yet.  First scientists have to find these biomarkers – a process often referred to as biomarker discovery.  I like to compare finding a biomaker to those “spot the differences” games where you have to look at two images and circle what is different in one picture compared to the other.  This is exactly what scientists do when finding a biomarker, except instead of comparing pictures, they are comparing patients.  And it’s not an easy game of “spot the differences” it’s complicated: the pictures are small and there are tons of details.

Let’s imagine a scenario that a scientist might face when wanting to find a biomarker for the early detection of pancreatic cancer.   Cancer is caused by mutations in the DNA, so you decide to look for DNA mutations as your biomarker for pancreatic cancer. So how do you “spot the differences” to find DNA biomarkers for pancreatic cancer?  First, you will need patient samples – maybe tissue or blood samples from a biobank that already has samples from patients with pancreatic cancer.  If samples aren’t already available, you will have to initiate a study partnering with doctors to collect samples from pancreatic cancer patients for you.  You will also need the second “picture” to compare the pancreatic cancer “picture” to.  This second picture will be samples from people who don’t have pancreatic cancer (scientists usually call this group the “control” group).  Then you have to “look” at the two groups’ DNA so you can find those differences.  This “looking” is often done by some genomics method like sequencing the DNA. This is where a lot of the complication comes in because if you look at all of the DNA, you will be comparing 3 billion individual nucleotides (the A, T, G, and Cs we’ve discussed in earlier posts) from each patient to each of the controls.  Even if you just look at the DNA that makes proteins, you’re still comparing 30 million nucleotides per patient.  And you can’t just compare one patient to one control!  Each of us is genetically different by ~1%, so you need to compare many patients to many controls to make sure that you find DNA that is involved in the disease and not just the ~1% that is already different between individuals.  But wait, we’re not done yet!  The biomarkers that you identify have to be validated – or double checked – to make sure that these differences just weren’t found by mistake.  And before biomarkers can be used in the clinic, they need to be approved by the Food and Drug Administration (FDA)



Whew… that was a lot of work! And so many people were involved: lead scientists who directed the project and got the money to fund it, researchers who do most of the work, computer people who are experts at crunching all of the data, and maybe even engineers to help run the equipment. Finding the biomarker needle in the biological haystack is difficult and takes time, money, and lots of people.  This is one of the reasons why there are only 20 FDA approved biomarkers for cancer (data from 2014).  But just because it’s difficult, doesn’t mean it’s impossible.  Furthermore, this effort is necessary to improve healthcare and decrease healthcare costs in the future.  It just might take a bit more time than we’d all like.

If you want to read more about the challenges and some of the solutions to biomarker discovery in cancer, take a look at this scientific article.  Or read about some successes from right in our backyard at Arizona State University on identifying biomarkers for the early detection of ovarian cancer and breast cancer.


What does it mean when I have genes that increase my “risk” of disease? Like Alzheimer’s?

The last few posts (here and here) have been about people who have carrier mutations.  These people have one recessive gene mutation that they could pass on to their child.  If the child inherits two recessive genes (one from each parent), they will get the disease.  That’s how it works with recessive diseases that are caused by one gene.  About 4,000 diseases are caused by mutations in one gene (either in dominant or recessive genes).  But that leaves all of the other diseases…

Since we’re still talking about genetics, let’s stick to diseases that are caused at least in
part by gene mutations as compared to diseases caused by infection, for example.  There are many diseases that are caused by mutations in multiple genes (the technical word for this is polygenic). In these cases, no one gene can be identified as the single cause of the disease.  The genes that are involved in causing the disease can be on many different chromosomes in many different locations on these chromosomes and only if mutated in combination will someone get the disease.  And these mutations may only cause the disease if exposed to a certain environmental factor (like cigarette smoke).


If this sounds confusing and complicated to you – it is.  Scientists find it confusing and complicated too. It’s much more difficult to pinpoint the exact genes that cause a  disease if there is more than one mutation in more than one gene.  It’s like a puzzle, but you don’t know the number of pieces in advance or what the puzzle looks like.  So if you fit two pieces together (or identify two genes that are mutated), you don’t know if you have completed the puzzle and figured out what is causing a disease or if you need to look deeper.

Scientifically, this is a complicated question, but for the patient who doesn’t care how many genes cause the disease, what does it mean to them? What does this mean for risk?  If a gene is found to be associated with a polygenic disease, mutations in this gene may increase or decrease your risk of that disease.  But unlike genes cause by dominant or recessive genes, no one can say for sure 100% either way if you have a particular gene mutation that you will or won’t get a disease.

A great example of this is Alzheimer’s disease.  Only in early onset Alzheimer’s (0.1% of all cases), one dominant genetic mutation the cause of the disease. However, in 99.9% of Alzheimer’s Disease cases, more than one gene is involved (at least three genes, but probably more).  One gene that is well studied in association with Alzheimer’s Disease risk is the gene apolipoprotein E (ApoE, for short).  There are three different versions of the ApoE gene called ApoE2, ApoE3, and ApoE4 – each representing a different mutation in the ApoE gene.  The E2 version (found with 8.4% frequency in the population) is protective against Alzheimer’s Disease.  The E3 version (found with 77.9% frequency in the population) is essentially neutral (neither causing or protecting from disease).  The E4 version (found with 13.7% frequency in the general population) is the one that causes the problems and and increase the risk from 20% in a person who has zero copies of E4 to 91% risk in a person with two ApoE4 copies.  The more copied of E4 the more likely a person is to get Alzheimer’s disease at a younger age as well. And if you’re wondering, this is ABSOLUTE risk, not relative.

alzheimersAlzheimer’s disease is a particularly tricky example to use because there are few, if any, preventative treatments for the disease.  So even if you know that you have two copies of ApoE4, there isn’t much that you can do.  However, there are other diseases, where certain genes increase risk for a disease (like I described for the BRCA mutations and breast cancer risk).  In this case there are potential preventative treatments, though even after those treatments, the decrease in risk is significant but cannot be eliminated.  Overall, it’s important to understand the complexity of disease and how many factors (including unknown factors) can contribute to disease risk and onset. For scientists, knowing the risk factors can help to detect disease early or develop targeted therapies to treat the disease. For doctors, it helps to predict disease risk and tailor treatment.  And for the patient, it helps to know that diseases are complicated and risk isn’t 0% or 100%.


What can you do if you’re a genetic carrier?

In my last post, I talked all about what is means when you are a genetic carrier of a recessive gene.  To recap, the recessive gene will not cause disease, but your partner also has that recessive gene, you may have a child with a disease. Let’s think about the options, using a capital letter (G) as the normal gene and a lower case letter (g) as the recessive mutated gene.

carrier-noncarrier youandpartnercarrierIf you are a carrier, you’re have one copy of G and one copy of g (or Gg).  What if you have a child with someone who isn’t a carrier (GG)?  If you look at the possibilities (to the left) you have a 50/50 chance of having a child who isn’t a carrier or one who is.  But you will not have a child who has the disease.  On the other hand, if both you and your partner are carriers (see the picture on the right), you have 25% chance of having a child who isn’t a carrier, 50% chance of having a child who’s a carrier, and 25% chance of having a child who has the disease.

If you’re a carrier and your partner is a carrier, you know your odds.  So what are your options?  Before I start, if you’re dealing with this personally, please discuss all of this with a trained medical professional.  I can explain the biology of why things happen, but only your doctor can give you medical advice and treatment options.  Also, these decisions are all personal to you.  There is no one answer, and what works for you may not work for someone else – and this is often what we face when making these very personal medical decisions.


  • If you know that you and your partner are both carriers for a particular disease, you can choose not to get pregnant and avoid the risk altogether
  • Alternatively, you can get pregnant and  monitor the pregnancy closely.  Go ahead and roll the dice!  There is a 25% chance of having a child with that disease and a 75% chance that they won’t.  Having the knowledge in advance, you will know the likelihood and can monitor the pregnancy accordingly
  • There are tests like chorionic villus sampling  (CVS) that can test for genetic diseases (such as Tay-Sachs disease) before birth, if both you and your partner are carriers for a recessive gene that causes disease
  • If the developing child is found to have a genetic disease, depending on the disease and severity (e.g., if they will or will not survive at birth), there is the option to terminate the pregnancy. There also may be options for treatments while the child is developing or immediately at birth that may help decrease the severity of the disease right away.
  • You can choose instead to use a sperm or egg donor from someone who doesn’t carry that recessive gene.
  • You can use in vitro fertilization and check the genes of the embryo pre-implantation to select those that do not have two copies of the recessive genes.
  • Choose to adopt

As an aside, I asked my primary care physician about carrier testing a few years ago.peopleDNA  Without a family history of any genetic diseases, she was resistant (if not downright hostile) about me wanting to get carrier testing, and mentioned that insurance likely wouldn’t pay for the testing.  I’m hoping that my experience was not the norm, however, I don’t think that most primary care physicians have a deep understanding of genetics and genetics diseases and may be uncomfortable suggesting this type of screening because they would not know how to best interpret the results.  Interestingly, a number of companies now exist that will perform the carrier testing for you for a nominal fee, such as Pathway Genomics, Counsyl, and Natera.  I cannot recommend or discourage you from using or not using these services, however you generally need to work with your doctor to order these tests.

Again, these are all options, not medical advice, and all up to you as to what works best for you and your partner.  But with the knowledge of what may happen and why it may happen, you are at least armed with information to ask meaningful questions about yours and your non-existent child’s potential genes before or during your pregnancy,

What does it mean if I’m a “carrier”?

What does it mean when someone “carries” anything?  The definition of “carry”is to hold or support something while moving somewhere.  Often when you carry something it’s heavy, a burden.  When you’re a genetic carrier, it’s much the same.  You’re holding or supporting a recessive gene mutation as you move around in your normal everyday life.  Even though the recessive gene doesn’t affect you, it’s a genetic burden, because you could pass the trait down to your child.

cfLet’s remind ourselves what it means to have a recessive gene (or re-read the original post referencing 50 Shades of Grey).  You have two copies of every chromosome, and on each of these chromosomes is copies of each gene (called alleles – pronounced AL-eels).  These genes can be slightly different.  In some cases they are different enough that one copy doesn’t work as expected or work at all (these are the “recessive” genes we talked about in an earlier post).  Often the functional copy of the gene can compensate for the copy that doesn’t work right.  But in the case where both copies of the gene don’t work correctly, the person can end up with a disease.  The example that we used previously was cystic fibrosis.  A person will have cystic fibrosis only when the have two copies of the mutated CFTR gene.  The same is true for sickle cell anemia, which is caused by having two mutated copies of the hemoglobin gene called HbgS.  If a person only has one copy of HbgS, the other normal hemoglobin can produce enough hemoglobin to function just fine.  However, if there are two copies of HbgS, the HbgS protein structure collapses in cases where the person doesn’t have enough oxygen and this causes the red blood cells to make a sickle shape.
youandpartnercarrierThere are a number of diseases that are caused by having two copied of a mutated recessive gene (many are listed here).  But again, if you only have one copy, you’re just fine – but you carry that gene mutation. If you have children with someone else who is a carrier (meaning that they also have one copy of a recessive gene that would cause disease), then you have a 25% chance of having a child with that disease, because they have 25% chance of getting two copies of the recessive gene.

This isn’t a huge deal – only 25%, right?  Except that you would never know from looking at someone if they are a carrier.  And you wouldn’t know from living with yourself for all these years if you are a carrier.  And some populations or ethnic groups are more likely than others to be carriers for recessive genes for certain diseases. If you look at the chart below, I have listed a few ethnic groups and diseases which they are often genetic carriers.  After the name of the disease, I have listed the likelihood of someone from that ethnic group being a carrier for a recessive gene that would cause that disease. For Caucasians, if you and 28 people are sitting in a room, one person would carry a mutation in one copy of the CFTR gene that would cause cystic fibrosis. It is estimated that at least one in five Eastern European Ashkenazi Jewish individuals is a carrier of one gene that would cause a genetic disorder.

carrierSo what should you do now that you know that you could be a carrier for gene that could cause a disease.  There are options – the first one being doing nothing at all.  You could also look at your family history.  Are there people in your family or your partners family with a recessive genetic disease like Wilson Disease or Tay-Sachs?  If so, you may want to get tested for common recessive genes. On the other hand even without family history, if you are from a particular ethnic group such as Ashkenazi Jew, you may be encouraged to get tested no matter what (see an interesting guidance about this here) before or during pregnancy.  There is also the possibility that you want to be prepared, and before you and your partner get pregnant that both of you are tested for common carriers. Next post, we’ll talk more about what you can do if you are a carrier.





What is risk? Absolute versus Relative

riskMy mom and I were talking this afternoon – we talk every day on my drive home from work (I celebrated the day I got Bluetooth in my car) – about Angelina Jolie.  It was difficult to miss the news this past week about her New York Times opinion piece describing why she decided to remove her ovaries and Fallopian tubes.  There have been a number of interesting articles both praising (here or here or here) or criticizing or clarifying her choice.  That’s not what I want to talk about and it’s not what my mom and I talked about.  What we talked about was risk.  Most stories talking about Angelina Jolie mention that because of the gene mutation she had, there was an 87% risk of her developing breast cancer.  Despite the fact that 87% is awfully specific (and based on limited data from a certain number of women with this mutation that were studied over time), what I want to focus on isn’t the number, but what the number refers to.  In particular, I want to point out that there are different ways of talking about risk – and this is important when reading about any scientific information in the news.

coin_flipLet’s start with a quick definition – risk is the chance that something will happen.  These are usually percentages.  There is a 50% chance when you flip a coin that it will land on heads.  The risk is 50%.  Of course, when applied to the chance of developing a disease, or having a particular treatment outcome, or surviving an accident, the numbers are a lot more difficult to calculate than a coin flip.  But they are also more confusing when describing the risk as well.


rosk_tableI’m sure you’ve read news stories that say something like “Drinking more than 3 caffeinated drinks a day increases your risk of a heart attack by 50%” (this is a completely fictional example!!!) Fifty percent. What a HUGE risk.  Except what they don’t tell you is that without drinking caffeinated drinks, your risk of having a heart attach is only 1%.  So a 50% increase means your risk only increases to 2%.  This is the difference between relative versus absolute risk.  50% is the risk relative to what the actual baseline risk, whereas the absolute risk tells you the actual chance of something happening.

Let’s look at another example.  “This new drug decreases the risk of blindness in diabetic patients by 50% over 5 years”.  This is promising news!  Except, again, the 50% is relative risk – what you want to know is what the chance of a diabetic patient going blind?  If the chance that a diabetic patient goes blind is 60%, then a decrease of 50% is huge. There is only a 30% chance of blindness now.  Ont he other hand, if like the previous example, the actual chance of going blind is 2%, the 50% decrease is less impressive.  This makes the decrease in risk no less important to the patients who take the drug and don’t go blind – but it does affect how you read a news story describing the effect of the drug and whether or not you may want to take an expensive drug.

Now let’s get back to Angelina Jolie. The actual risk for breast cancer in the general population over a lifetime is ~12%.  If you have the mutations in the genes (called BRCA1/BRCA2) that Angelina Jolie has, it increases the risk to 40-80%. This is the absolute increase in the chance of getting breast cancer.  And as you may notice – the risk has a range (based on a number of factors – family history, health history, etc that we’ll get into in another post).

So how can you be a more savvy reader? You can be tipped off to relative risk by phrases like “increased by”, “decreased by”, “more than” or “less than”.  This only tells us the difference compared to baseline, but gives NO indication of what that baseline risk is. Absolute risk, on the other hand, provides the best estimate of what the overall likelihood of something happening will be.


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).