Tag Archives: science writing

Treating Cancer in the Genomic Era

Revolutionizing Cancer Treatment

by DeeAnn Visk

We have all had “ah-ha” moments. I had one on October 15, 2013 listening to Dr. Razelle Kurzrock illustrate a new way of thinking about cancer and cancer drug development. Historically, cancers are categorized by the organ in which they originate. With the advent of genomic sequencing, cancers can now be grouped by the mutations they contain. Thinking about cancer in this way will revolutionize how this disease is treated therapeutically, researched in academia, targeted by drug companies, and conceptualized in clinical trial design.

This epiphany occurred at the recent meeting of the Southern California Chapter of Women In Bio at Janssen Labs, while listening to Dr. Kurzrock, one of three excellent speakers at the meeting.

Director of Clinical Trials, Moores Cancer Research Center

Dr. Razelle Kurzrock, Director, Center for Personalized Cancer Therapy

Dr. Kurzrock pointed out that, while the light microscope was invented in 1590, it is still used today to diagnose cancer. While current cancer therapies are not quite as ancient, treatment for many cancers has not changed for up to 20 years. This is shocking, given the enormous strides in technology that have occurred in the last two decades. Most importantly, we need to change the paradigm of thinking of cancer as an organ-centric disease. Molecular abnormalities in cancer are not associated with the cancer’s organ of origin. Hence, we should treat cancers based on their molecular profile, not on where they originated in the body.

Now that the genomic era is upon us…

we can analyze the molecular signature of each cancer. Clinical trials need to be redesigned to be mutation-centric, not drug-centric. Multiple genetic markers should be employed to diagnose and classify cancers.

Generally, clinicians are entrenched in their way of thinking, which presents an obstacle to this kind of fundamental change. To paraphrase Max Planck, science progresses one funeral at a time. Regrettably, medicine also seems to progress this way. Previous ways of thinking about cancer have become so ingrained that many are not even aware of their underlying assumptions.

The concept of classifying cancer by mutational profile will also impact cancer research. How many times have you heard of a laboratory studying breast cancer, or prostate cancer, or liver cancer? Several more times than you hear about a laboratory studying a particular mutation in a cancer biomarker like the epidermal growth factor receptor (EGFR), I’ll bet.

Further areas of inertia include applications for new drugs submitted to the Food and Drug Administration (FDA). No application for an investigational new drug study (IND) has ever been filed based on a treatment targeted at a mutation in a cancer (of any kind), rather than treatment of a cancer in a specific organ. This situation persists despite the fact that the FDA has indicated it would be open to INDs using this approach.

Need a new paradigm for treating cancers.

Hope for new cancer treatments–turning in a new direction.

I hope the idea of classifying cancers by the mutations that drive them, not the organ in which they originate, changes how cancers are treated. Dr. Kurzrock did an excellent job of articulating and advocating for these changes. Employing old-school approaches to cancer is so engrained that we are often unaware of these underlying assumptions. Rethinking cancer biology certainly has changed how I would respond to a loved one being diagnosed with cancer. I would seek out a forward-thinking doctor, willing to utilize this new paradigm from the onset, not waiting for last-ditch efforts once the cancer re-occurs.

Challenging the current methods for treatment, research, and drug development will not be easy, given with the institutional barriers that remain. Financial interests of the institutions involved will need to be realigned with this new paradigm. Either that or we need AIDS-activist-like protests to spur on this change in thinking. In the end, as with AIDS, it may be patient advocacy groups that can best bring about this change in thinking in the medical, pharmaceutical, research, and regulatory communities.

The views expressed here are solely those of DeeAnn Visk are not necessarily those of Women in Bio, AWIS-SD, Janssen Labs, NPR, or your local NPR station. A special thanks to Nurith Amitai for her especially helpful editing.

This article was previously published in the January/February 2014 edition of the Association for Women in Science San Diego Chapter Newsletter.

DeeAnn Visk, Ph.D., is a freelance science writer, editor, and blogger. Her passions include cell culture, molecular biology, genetics, and microscopy. DeeAnn lives in the San Diego, California area with her husband, two kids, and two spoiled hens. You are welcome to contact her at deeann.v@cox.net

The human microbiome: a new approach to treating non-infectious diseases

The fault lies not in our genes, but in our microbiome

Conceptualizing humans as an organism, the microbes living within and on our bodies are often neglected. A recent trend in academia has been the research into the wide variety of micro-organisms living within and upon humans. Overlooked until recently, differences in the human microbiome are implicated in many disease states from auto-immune disorders to obesity. Some day is may be possible to lose a few pounds just by consuming the right mix of bacteria to colonizes your gut!

plaque--bacteria in the mouth microbiome

Many different bacteria from the mouth microbiome

Given the advent of low-cost, high-throughput sequencing and the relatively smaller genomes of micro-organisms, a plethora of studies have been done comparing microbiomes of healthy and sick patients. First academia must answer the chicken-or-the-egg-question: do people have these diseases because of the combination of bacteria they have (or don’t have) or does having the condition lead to the combination of bacteria? Does the microbiome of a sick patient arise from having a specific microbiome or does being sick lead to the presence of the specific microbiome?

To test this question, sickened laboratory animals have been inoculated with the microbiome of healthy animals. Generally, the answers point to the idea that the right combination of microbes can alleviate the symptoms of a disease. The list of non-infectious diseases (allergies, asthma, diabetes, and obesity) that have been effectively treated by reconstituting the microbiome in laboratory animals is growing. While academic research on this area is booming, what practical progress has been made on this front?

Compare the number of clinical trials using fecal transplants (46) to those using a cell therapy (29,268). Clearly there is much room for growth in the practical application of the human biome to disease states.

Additionally, these initial clinical studies are looking only at the microbiome of the lower gut. This leaves many areas of the human anatomy unstudied. What about the skin, upper gastrointestinal tract, hair, eyes, nose and other mucus membranes? While academia is well on the way to working on these issues, little has yet been seen in the way of practical application of this as evidenced by the lack of clinical trials.

Risk-based clinical trial monitoring

3 Replies

Increasing efficiency in clinical trials

While it sounds intimidating, risk based management is simply applying common sense in a systematic way. Defining, evaluating, and managing risk is easily accomplished by using a documented approach to evaluate the risks. Which needs closer monitoring: a simple clinical trial in the United States at a reputable site previously used with much success or a complex trial in Zimbabwe at a location never utilized before?

Obviously, the trial with the greater unknowns is higher risk.

risk management for the FDA clinical trial

Evaluating risk to monitor clinical trials

Recently, the FDA came out with guidelines on risk-based management for clinical trials. “The overarching goal of this guidance is to enhance human subject protection and the quality of clinical trial data by focusing sponsor oversight on the most important aspects of study conduct and reporting.”

What this means is merely commonsense in monitoring of clinical trials based on which ones have a higher risk of problems.

Another factor to consider beyond experience with a site and the complexity of the trial are the patient outcomes. Will your trial involve life and death situations?

Quantifying this can be done using a matrix of categories such as geographical location of the study, Good Clinical Practice compliance (GCP), and the relationship of the sponsor with the investigator.

Understanding these concepts is crucial to increase efficiency and decrease costs of clinical trials. As with any change in a regulatory environment, the industry is grappling with how to implement it. Pilot programs explore the implementation and thousands are waiting anxiously for “the answer”. The challenge is that the answer—as with everything within clinical research—is that it depends.

Laurie Halloran’s presentation on this and other topics in clinical trials made them easy to grasp. She presented at the San Diego Clinical Research Network meeting last week Tuesday at the Sheppard Mullin law firm.

My mother, the Chimera

34 Replies

My mother, the Chimera

During grad school, I was amazed to hear that the color of hair on your body is controlled by only one gene. Hence, each person should only have one color of hair everywhere on their body. I wanted to ask: why does my mother have two colors of hair on her body (or as the slang goes, the carpeting does not match the drapes)? But I did not, at that time, have her permission to discuss this phenomenon. Now I have her approval. I have always wondered what the doctor doing her annual exams thought: hmmm, she seems to be a natural redhead, I wonder why she keeps dyeing her hair on top brown.

Human zygote at the 4 cell stage.

Later I stumbled across a paper discussing the ideas of chimeras in humans.¹ Here I first read how an individual can come to be made up of more than one type of DNA. The classical view is that each person is made up of one individual type of DNA which should be as unique as their fingerprint. Hypothetically, if two fertilized eggs (zygotes) fuse together while in the womb and then merged together completely, you get what appears to be a normal individual, but made up of two different DNA types.² I estimate human chimeras are born at approximately 1 in 50 live births, the same rate as for twins.

What is a chimera, anyway?

An ancient Greek plate, showing the original legendary chimera: a lion with a bonus goat head

What image does the word chimera bring up? A lion with a goat coming out of its back? The term chimera originated with the Greeks, describing a monster. Using chimera to describe a human with two different types of DNA in the same body does not imply they are monsters. Tetragametic chimerism sounds like you have cancer–human chimera just makes you sound cool.

Chimeric mouse on right, with two solid colored mice on left. Note in addition to different coat coloring, the chimeric mouse also has different colored eyes.

In the last century, the term chimera has been used to describe individual engineered mice born from a zygote derived from more than one type of mouse. Chimeric mice have two fur colors on different parts of their bodies. This is because the DNA that controls coat color is different in different parts of the mouse. So when people, who had not been manipulated as zygotes, began to be detected with different DNA in different parts of their bodies, the term human chimera was coined.

So how can you tell if you are a human chimera?

Two different colored eyes are well known to occur in dogs.

Tell-tale signs are two colors of hair on different parts of your body, two colors of skin on different places of your body, or two eyes each of a distinct color. The phenomenon of two different colored eyes is called hererochromia iridum. The definitive method to determine your status as a human-human chimera is to have tissue taken from several different areas of your body and tested to see if the DNA is all the same. The expense and risk (anyone feel like having a piece of your liver removed?) generally is prohibitive, but given the rapidly lowering price of genetics testing, it may soon be within financial reach.

Or you may be completely unable to tell that parts of your body arose from two different zygotes. You may only get the news if there is DNA testing of you and your children; or if you are trying to get an organ donation from relatives, to whom you are no longer a parent according to the DNA. Yes, this really has happened.

Any twins in your family?

Given her two different colored eyes and twins running in her family, it is likely (I’ll give you 95% odds) that Jane Seymour is a human-human chimera.

Another way to determine the probability that you are a chimera is the prevalence of twins in your family. My grandmother was the sibling of one set of twins and aunt to another. When I brought up my mom’s chimerism at a family gathering, my aunt, wanted to know if she was a chimera. Sure enough, her eyes are different shades of green/hazel. So I would conclude that she is also a human-human chimera.

Let’s look at Jane Seymour. She has two different color eyes, a sign of being a human chimera. Her most recent children are twins. Twins run in families. So, as in my mom’s situation, it is likely that her mother had two eggs available for fertilization at the same time. The twin information along with her two different colored eyes leads to the conclusion that Jane Seymour is most likely a human-human chimera.

In closing…

Mike Scherzer professional baseball pitcher

Mike Scherzer, a professional baseball pitcher for the Detroit Tigers, clearly has one light blue and one brown eye.

All the examples given so far are women who are chimeras–what about men? Questions of paternity are nothing new. But what if a man was pretty sure he was the father, but the DNA tests said no? There are certainly ways of testing to show that the father of a child in question is related to the uncle degree. But what if the father has no brothers? I leave other scientist and lawyers to explore these questions.

So now my Mom can think of herself as her own twin. Or she can make jokes about how this explains why she has the energy of two people. Or if she wants to stump her doctor, she can say that she suffers from tetragametic chimerism,

______________________

¹ “Embryogenesis of chimeras, twins and anterior midline asymmetries.” CE Boklage. Human Reproduction. 2006.

² The following paper offers a different hypothesis to explain the formation of chimeras. Read at your own risk. “Traces of embryogenesis are the same in monozygotic and dizygotic twins: not compatible with double ovulation.” Human Reproduction. 2009.

Effective Science Writing – 10 tips

2 Replies

Written by me, DeeAnn Visk, this article was originally published by the Oxbridge Biotech Roundtable (OBR) Review in April 2013–the following is an excerpt from that article, based on a science writing talk sponsored by ORT given by Lynne Friedmann.

Effective Science Writing – 10 tips

1) Use active voice

An active voice lends more simplicity, energy, and directness to prose (resume writing, anyone?). Scientists are encouraged to write in a passive voice making for clunkier, longer, and vague prose.

Examples: Steve loves Amy (active voice)

Amy is loved by Steve (passive voice)

2) Employ style guides

Style guides shepherd writers through the nuts and bolts of writing, addressing questions such as what to capitalize, where commas should go, grammar questions, etc. Individual journals may have their own style guides; be cognizant of the rules for the organization for which you are writing—even Wikipedia has a style guide.

Example: 12pm or 12am? Using midnight or noon avoids confusion

Publications/blogs may or may not care; develop good habits now. In the future, you will need to keep an editor happy; they do not want to look dumb. Editors comparing two equivalent papers choose the one with the least editing required.

3) Overcome “writer’s block”

Treat your writing time like an appointment until it becomes a habit. For those of you with difficulty starting, just begin. Fire your internal editor, ignore grammar, spelling, and punctuation—just get the ideas down on paper. Stuck on the next word? Just write “XXXXX”. Keep the flow going. Write down your first draft as fast as possible.

4) Focus on the goal

Reduce why you are writing something to one sentence: I want my manager to approve my budget. Write it on a piece of paper and hang it where you can see it. Refer to it while writing. Information without context is useless—do ideas support my goal?

5) Make writing transparent

As Mark Twain said “never use a $5 word when a 50 cent one will do.” Deliver information that can entertain people, the story behind the research, interject patient stories, trying to solve puzzles, and mysteries. Work in something about the process of science, one piece of information in a continuum. Be clear: do not overload opening sentence; go from general to specific. You want the reader to hold your hand and never let go. Allow readers to see and feel the experience by using descriptive and specific sensory language.

6) Do not use science clichés

Describe so that writer can see how it is a break through. As Friedmann stated tongue-in cheek, “The ‘missing link’ has been found so many times, how could any possibly still be lost?” Other worn clichés include: shedding light, the holy grail, the silver bullet, and paradigms shifting. Don’t these just make your eyes glaze over? Or do you find yourself grinding your teeth in irritation instead?

7) Write, revise, and edit in sequence

Compose your copy well ahead of the deadline. Don’t look at it for a day or two, then come back and eliminate the first paragraph or two. Test your copy during revision. Print it out—difficult to proof on-screen. Go to a different physical space; get up walk around, read it aloud. Are you bored? Confused? After each sentence, ask yourself “so what”? Get rid of sentences that begin with “Th” words: the, this, they. Each time you read a sentence remove one word, and see if the sentence still conveys the meaning. You are on the right track when “sentences shrivel like bacon in a pan”. Proof read copy backwards to find typos.

8) Professional organizations as valuable resources

Professional organizations offer seminars and job leads. A good resource is the National Association of Science Writers. Environmental journalists normally find themselves evolving into activist (not just merely reporters), issuing calls to action. If you are thinking about becoming one, look at the Society of Environmental Journalist. The American Medical Writers Association holds great conferences and workshops. Check out their websites for hints on the craft of writing.

9) Where to find science writing opportunities

Consider writing for various organizations such as your school’s alumni magazine, Roundtable Review (a blog hosted by ORT), MIT Technology review. Both academic and industry grants require excellent writing—volunteer to help. Many websites need content/blog writers; begin by offering to write for free.

10) Receiving feedback on your writing

Keep your inner defensive monster in the cage. Take a deep breath and relax. You must respond well to correction, if you want people to continue giving it to you. Feedback is a gift, assisting you to improve your writing. Thank whoever is taking time to give you feedback; try incorporating their suggestions into your writing.

The long and the short of your telomeres

2 Replies

page contents

The long and the short of your telomeres

A friend of mine, Bonnie, sent me an interesting site, which offers to determine the length of your telomeres (pronounced tea/low/mirrors). My initial response, given that telomeres shorten with age, was that the test would only tell you what you could already know by looking at your birth certificate: your age.

Telomeres length indicates wear and tear on your chromosomes; like the tread depth on your tires. Each time a cell divides, the end of the chromosomes (telomere) generally gets shortened. Normally, a cell can only divide so many times before the telomeres on the chromosome ends are too short to allow any more replications and the cell dies.

TeloMe, the company in question, will determine the length of your telomeres. This can be used as a starting point to monitor how healthy you are living; you can make life style choices to lengthen your telomeres such as limiting caloric intake, not smoking, eating lots of fruits and vegetables, and getting regular exercise. Hmmmm…What do peer-reviewed articles in reputable journals say? Querying the PubMed database with the word “telomere” leads to 14,000+ papers. Yikes! That’s a lot to review.

This is fluorescent microscope image of chromosomes (DNA, in blue) with the telomeres in yellow.

Fortunately, there is another company, Telome Health(TH)—no relationship with TeloMe, as per a phone call to TH’s offices—that has nicely gathered a “short” list of 155 peer-reviewed papers on telomeres. There is strong evidence for the shortening of telomeres being a bad thing. You can shorten the rate at which your telomeres are shortened. However, I am not convinced that there is way to lengthen your telomeres.

So should I get my telomere length tested?

So if you really want to go ahead and test the length of your telomeres you have my permission. Personally, I would go with the already established company, Telome Health. The company is well established and certified to do the testing as a clinical diagnostic test.

Or if you want to do it the less expensive way, take care of yourself:

1) Eat nutritious healthy meals

2) Get regular sleep

3) No smoking

4) Get regular exercise

5) Take Omega-3 fats

6) Reduce stress in your life

Basic, good living will keep you healthy. This just helps to explain why and gives you a way to track it.