October 8, 2013

Preventing Chronic Disease

The War on Cancer

How are we faring in the War on Cancer?

Read Time 9 minutes

A couple of weeks ago Tim Ferriss and I were having dinner and the topic of cancer came up. As some of you may know my background is in oncology, specifically in exploring immune-based therapies for cancer by exploiting the properties of regulator T-cells.  But that was a long time ago.  Like many of you, I expect, I’ve also been personally impacted by cancer having lost a friend to glioblastoma multiforme (GBM). I often describe GBM to people as one of the cancers that gives cancer a bad name.  When I went to medical school I planned on becoming a pediatric oncologist, and though I ultimately chose to pursue surgical oncology, my interest in helping people with cancer never wavered.

Over dinner that night, Tim asked me if I could write – in about 1,000 words! – a post on cancer that would be interesting and digestible to a broad audience.  “1,000 words?!,” I asked. “How about 30,000 words?,” I responded only half kidding. After explaining why I couldn’t possibly write such an abridged version, Tim talked me into it. And so, I plan to accept the challenge and hope to provide readers with such a post (it will be on Tim’s blog when I do so), hopefully in the next month or two.

For an introduction, however, I’d like take a step back and place this topic in a broader context. I don’t need to say much about cancer that you don’t already know.  You probably know that about one in three Americans will develop cancer in their lifetime, and you probably know that about half of them will succumb to the disease.  What you may not know, however, is that we have made virtually no progress in extending survival for patients with metastatic solid organ tumors since the “War on Cancer” was declared over 40 years ago.  In other words, when a solid organ tumor (e.g., breast, colon, pancreatic) spreads to distant sites, the likelihood of surviving today is about what it was 40 years ago with rare exceptions. We may extend survival by a few months, but not long-term (i.e., overall) survival.

We screen better today for sure, but subtracting lead-time bias, it’s not clear this extends overall survival.  We’ve had success in treating and even curing hematologic cancers (e.g., some forms of leukemia and lymphoma).  Certainly testicular cancer patients (especially seminomatous) are better off today and those with GI stromal tumors (GIST), too.  Surgical control of cancer is much better today and some local treatments (e.g., specific radiation), too.  But for the most part, when a patient has metastatic cancer today, the likelihood of living 10 more years is virtually unchanged from 40 years ago.

About a year ago, I was asked to give a talk about metabolic disease to a group of physicians. But before I spoke, a very astute and soft-spoken oncologist, Dr. Gary Abrass, gave the following introduction as a way to frame the context of my talk.  After all, I’m sure many in the audience were wondering what could a discussion of insulin resistance have to do with cancer. I have thought often of his words that night in the many months since he so eloquently and informally introduced me.

I asked Dr. Abrass if I could have a copy of his talk and share it with you, to which he kindly agreed. Below is, nearly verbatim, the talk he delivered that night.  (Dr. Abrass did give me the liberty of tweaking the text a bit, for emphasis and clarity.)

How have we fared in the War on Cancer?

On December 23, 1971, President Nixon declared war on cancer by signing the National Cancer Act. I was going to title this, “40 years in 4 minutes,” but I think this will take me a bit longer. At the time I was a third year medical student.  Two years before, Neil Armstrong had inflated our national pride by setting foot on the moon, and there seemed no scientific goal unachievable. Activist Mary Lasker published a full-page advertisement in The New York Times: “Mr. Nixon: You Can Cure Cancer.” And she went on to quote Dr. Sidney Farber, Past President of the American Cancer Society and whose name now sits atop the Harvard Cancer Center, “We are so close to a cure for cancer. We lack only the will and the kind of money and comprehensive planning that went into putting a man on the moon.”  Since then, the federal government has spent well over $105 billion on the effort.

Forty years later, Dr. Farber’s prophecy remains unfulfilled.  In 2012 cancer killed an estimated 577,190 people in the United States.  The death rate, adjusted for the size and age of the population, has decreased by only 5 percent since 1950.  And most of this decline is due to mammography screening in breast cancer and cessation of smoking, resulting in less lung cancer in men.

We have however developed a greater understanding of the biological and molecular basis of cancer.  When I was a medical student, this graphic summarized what we knew about the growth cycle of the cancer cell.

By Zephyris at en.wikipediaderivative work: Beaoderivative work: Histidine (Cell_Cycle_2.svg) [CC-BY-SA-3.0 or GFDL], from Wikimedia Commons
There was an S-phase in which DNA was synthesized, a mitotic phase when the cell divided and a G1 and G2, which to my mind stood for “gaps” in our knowledge.  We added a few dozen chemotherapy drugs on this wheel, and treatment basically amounted to carpet-bombing. And for some diseases — particularly leukemias, lymphomas, and testicular cancers — it was quite effective.

The next graphic demonstrates what we have learned, a truly overwhelming accomplishment, a dizzying array of interconnecting signaling “pathways,” and spawned a whole new field, “translational medicine.”

Roadnottaken at the English language Wikipedia [GFDL or CC-BY-SA-3.0], via Wikimedia Commons
Receptors have been identified on the surface of cells, which function as locks to be opened by various circulating substances (i.e., hormones) initiating a series of downstream events. Mutations in this cascade of on/off switches can promote tumor growth.

With the completion of the Human Genome Project, new sequencing technologies have also opened up the prospect of personal genome sequencing as an important diagnostic tool. A major step toward that goal was the completion of the sequencing of the full genome, first on James D. Watson, one of the co-discoverers of the structure of DNA.  In fact, Steve Jobs had personal genome sequencing.  The price is down to $1,000 and Mayo Clinic Proceedings recently had an article raising the concern of direct to consumer advertising for genomic sequencing. We are now able to sequence gene by gene, pathway by pathway, the genetic code of some cancers.  New “smart” drugs have been developed that target various mutations in these pathways. And currently there are over 800 “targeted agents” in clinical development.  These drugs have been described by some investigators as “The Holy Grail,” but the clinical results suggest more of a commemorative cup for a “Happy Meal.”

While there is nothing unique about this paper, it is a good example of a typical negative trial targeting the IGF-1 receptor with a monoclonal antibody.  The lack of response does not make us question the role of the IGF pathway as a prime driver of malignancy, but rather demonstrates the ability of the cancer to resist therapy.  It seems there is so much redundancy in the system that the cancer finds alternate pathways. The cancer cell continues to defend itself, to bob-and-weave like the arcade game “Whack-a-Mole.”

So the investigators combined the IGF-1 monoclonal antibody with various other therapies: standard platinum based chemotherapy regimens, the “small molecule” tyrosine kinase inhibitor gefitinib (Iressa) targeting another common pathway (EGFR), and also the mTOR inhibitor temsirolimus (Torisel) which targets the IGF-1 pathway a bit further along.  In any case, the point is, it still didn’t work. But why?

Investigators have mapped the genome of a typical lung cancer patient and found over 50,000 mutations. That’s a lot of targets! Granted they are not all ‘driver’ mutations, some are ‘passenger’ mutations. The patient whose genome was mapped was a 51-year-old man who’d reported smoking 25 cigarettes a day for 15 years. At 50,000 mutations, it works out to one mutation for every 2.7 cigarettes.

Last year the New England Journal of Medicine published a study by Gerlinger and colleagues. These investigators looked at intra-tumor heterogeneity. They performed a molecular dissection. They found diversity within the tumor itself.  Each cancer is not cancer but, indeed, it is CANCERS. In other words “all cancers are rare cancers.”  Let me repeat this point.  Each tumor is a collection of heterogeneous – not homogenous – mutated cells. This article has engendered some discussion and some controversy. Many say that the results of the study bring the idea of personalized medicine to a halt, or at least dramatically slow it down.  Are there exceptions? Yes, but they are rare.  One example of an exception to this revelation is chronic myelogenous leukemia (CML), a cancer with a known single driver mutation.

In September 2011, biologist Dr. Alasdair MacKenzie of the University of Aberdeen, speaking at the British Science Festival in Bradford, explained that researchers trying to fully understand how our DNA causes disease might not be looking in all the right parts of the genome. The past decade of genetic studies has revealed that our 3.2-billion-long-DNA-letter code is more complex than anyone could have thought.  More than 98% of the human genome does not encode protein sequences. It’s been referred to as “Junk DNA” and thought not to have a function, but maybe more correctly is that we do not know the function.  He refers to this as the “dark matter” of the genome. And it’s thought that some of these “alternate pathways”, in which our resourceful cancer cell seeks refuge, may reside here. If this was not complicated enough, the new field of Epigenetics has grown exponentially resulting in a widening of the battlefield.

These are factors that can affect the expression of genes without causing mutations, turning switches on and off.  In terms of cancer, much of this research has concentrated on what are called “Nononcogenic stress targets.”  We can stress an organism in many ways: heat, poison, starvation, suffocation or more scientifically thermal, chemical, metabolic and oxidative stress.  Organisms have an ingenious way of responding to such stress.  In the 1960s an assistant in FM Ritossa’s lab accidentally boosted the incubation temperature of Drosophila (fruit flies), and when later examining the chromosomes, Ritossa found a “puffing pattern” that indicated the elevated gene transcription of an unknown protein.

This was later described as the “Heat Shock Response” and the proteins were termed the “Heat Shock Proteins.” This same HSP increases survival under a great many pathophysiological conditions. The HSP70s are an important part of the cell’s machinery for protein folding and help to protect cells from stress. While it enhances the organism’s survival and longevity under most circumstances, HSF1 has the opposite effect in supporting the lethal phenomenon of cancer. These proteins enhance the growth of cancer cells and protect tumors from treatments. This remarkable protein affords a protective response to other proteins in the cell, acting as a “chaperone” preventing them from mis-folding or “denaturing,” like when a boiled egg white turns opaque. These heat shock proteins are expressed at high levels in many tumor types: breast, endometrial, lung, prostate, even brain tumors. HSP overexpression signals a poor prognosis in terms of survival and response to therapy. HSP’s are now on the radar as a key target in the ongoing battle. This protein folding stress response is a hot topic in current cancer research.  I have been communicating with Dr. Debu Tripathy who is currently studying epigenetic changes and protein folding stress responses associated with obesity. This protein folding stress response affords the cancer cell a survival advantage, and we share this protective mechanism with a fly, such a distant relative in our family tree, that one can only conclude that the cancer cell has hijacked this maneuver, this protective drive for immortality from the legacy of 100’s of millions of years of evolution…such a resourceful and formidable opponent.

In any case, when the Human Genome Project was near completion, President Clinton hosted a White House ceremony and announced that, “it will revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases, and that humankind is on the verge of gaining immense new power to heal.”

The hubris of it all.  It’s reminiscent of the quote of Sidney Farber.  Hopefully this is not tempting fate.  Theologians tell us the only unforgivable sin is pride. The increasing complexity of the science is affording us quite a dose of humility.  British Physicist Brian Cox said that “being at the junction of the known and the unknown is a beautiful place to be for a scientist,” but it seems the more we know, the more we don’t know.  Not unlike Winston Churchill’s characterization of Russia as “a riddle wrapped in a mystery inside an enigma.”  Not unlike modern theoretical physics, one questions whether we are capable of understanding the complexity of the science.  Hopefully it’s not like trying to teach my dog quantum theory. We are so smart, but it seems that the cancer cell is smarter. It bobs and weaves, slips our punches, and when we back it into a corner, it defends itself in remarkable ways borne of millions of years of evolutionary acumen much of it hidden in the dark matter of our genome.

Maybe we should call a truce in the War on Cancer and concentrate on prevention. Besides smoking, the most preventable cause of cancer seems to be obesity.  It is generally thought that obesity may account for about a third of many cancer types, particularly breast, colon, uterus, kidney and esophagus.  Obesity is a risk factor for type II diabetes and these patients are not only more likely to get cancer, but to have poor outcomes. Other speakers will explore the relationship of obesity and cancer, the epidemiology and the science, and see if this lends support to any practical prevention measures.

Gary Abrass, M.D.
April 19, 2012

Afterword

Just as the best way to get in shape is not to ever get out of shape, the best treatment for cancer is almost assuredly not to get cancer. And that’s clearly the theme of the introduction Dr. Abrass gave me.  But I’m sure many of you are asking a more important question — what happens if I or someone I care about has cancer? If you can be patient with me, I do plan to address this, to the best of my understanding, in the coming months.

 

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220 Comments

  1. I keep meaning to pick up George Johnson’s new book The Cancer Chronicles. Have you taken a look at it or heard through your sources whether or not it is good?

  2. Thanks for touching upon this.

    Just a few weeks ago Nature produced an issue with several review articles discussing the state of our knowledge on intratumor heterogeneity: http://www.nature.com/nature/journal/v501/n7467/full/nature12627.html

    Although there are instances in which the sheer number of mutations are overwhelming (lung cancer and melanoma being the worst) there are instances of very good (at least initial) responses to targeted therapy even with highly mutated systemic cancer. An example is vemurafenib, which targets the Braf V600E mutation in ~50% of surveyed melanoma biopsies in the TCGA dataset. Recent work by Rene Bernards and others are identifying common evolutionarily favored “escape” pathways for resistance to these drivers (http://ryongraf.com/2013/09/usha-mahajani/) that are actionable with current therapeutics. It’s not a cure, but it is progress.

    Along the lines of non-ncogenic stress targets, a recent Phase I clinical trial was conducted using a ketogenic diet as an intervention in metastatic, heavily pre-treated cancer patients: http://www.ncbi.nlm.nih.gov/pubmed/21794124 Overall, the results are favorable for a Phase I study.

    All that said, as someone actively involved in research on cancer metastasis, I acknowledge the immense challenge of treating systemic cancer in any capacity, and I am immensely interested in any measure that can be used to prevent cancer. However, the clinical trial design to test and validate prevention interventions is very difficult, but that not an excuse, and is perhaps a discussion for another time!

    Ryon

    • Ryon, thanks so much for putting additional perspective on this. I could not agree with you more that primary prevention trials will be very difficult, and money would probably be better spent at secondary prevention (i.e., adjuvant setting, but not neoadjuvant setting). I spent too much time thinking about this and discussing it others, but the right trial is still a few clock cycles away from me. I will dive into this more in subsequent posts.

      p.s. Andrew and I missed you on Fiesta this morning for some FTP sets…next time?

  3. “…a 51-year-old man who’d reported smoking 25 cigarettes a day for 15 years…”

    Wait – who starts smoking at age 36?

  4. Thank you for all you do, Peter. I love the conclusion of this article — “Maybe we should call a truce in the War on Cancer and concentrate on prevention. Besides smoking, the most preventable cause of cancer seems to be obesity.” The challenge being that we haven’t found an answer to help people with sustainable weight loss, as witnessed by the diet industry being a $2 Billion industry. What would it take for this to change? In my opinion it is to address improvements to a person’s state of health not only in terms of the physical aspects of diet and exercise, but to take a more holistic approach and delve into a person’s well-being on a mental, emotional and even spiritual level. What is driving a person to over consume foods (oftentimes less than healthy foods) rather than nourish their bodies? I’d encourage anyone reading this to find a program like we’ve developed that provides a simple and very sustainable approach to making true lifestyle changes in a way that becomes natural to them and part of a lifelong dedication to being the best they can be. In the first week of making wiser eating choices people in our program are enjoying losing weight, feeling less joint pain, sleeping better, feeling energized throughout the day and just are happier. That’s the outer, and we know that these eating choices are reversing the metabolic syndrome and insulin resistance — after 7 short days! The essential piece to sustained results, however, isn’t about adhering to some eating program, it is coaching that helps people uncover what they are stuffing emotionally or what is seeking to be expressed creatively through them… they make the connection and what once required “motivation” is now sustained through true “inspiration”. The statistic is that upwards of 90% of today’s chronic conditions can be positively impacted by better lifestyle choices. I’d invite anyone to take a 6-week journey of self-discovery to improve their health in a way that may very well improve conditions they might be facing. Be Well!

  5. This is a fantastic post. I do not think people realize that cancer really is CANCERS. Lung cancer in one patient is not the same as lung cancer in another. There may be over 100 unique mutations in each case. They cannot be treated the same and if they are, the outcome will be different. Every tumor is unique. Every metastasized tumor is not the same either. When people get frustrated at the lack of advancement, I do not believe they realize just how complex it really is. I hope numerous people read this and begin to understand the magnitude of it. There is hope though, it is just a matter of time

  6. I’ve been following your interesting experiment with ketosis and diet. Just an average joe interested in nutrition.
    I assume you aren’t sold on the PCRM storyline that says that Plant Based Diet is a great way to help avoid cancer.
    Higher protein intake promotes some types of cancer growth?
    NutritionFacts.org among others really promote plant based as a way to hopefully avoid cancer.
    Any thoughts?

    • Correct, Duke. I’m certainly familiar with the arguments for this approach, but I have never seen compelling evidence, at least compelling enough to change my behavior. The problem is two-fold: i) Ecologic studies offer no evidence (despite a compelling narrative), ii) the animal and cell experiments are highly flawed (e.g., dose, cell line, protein type).

      So until I see compelling evidence, I will continue to eat as I do.

  7. Look forward to your analysis and views. My little understanding of the subject is that only tissue that proliferate vs. those that may not, or not nearly as much are susceptible to mutation. Somehow, the the status of the oncogene and tumor suppressing factor is altered. Cancer like CAD is age driven so anything that might accelerate the aging process and early ignition of the cancer process needs to be forestalled. Very possible IR a contributing factor.
    I also understand that those with allergies seem to incur cancer at much lower rate due to an overactive immune system which in this case might be good, but in other instances not so good.
    Again, look forward to your thoughts.

  8. THANKS FOR ALL YOU DO!!!
    LOOKING FORWARD TO THE 1000 WORD POST!!!
    THAT MUST HAVE BEEN A FUN DINNER.

  9. I am a 3x breast cancer survivor and am in the ketogenic camp ….. I look forward to your commentary!!

  10. I’ll be interested to see your write-up…with your oncology background and work with NuSI, I suspect your viewpoint may be somewhat different from many in the cancer research community. I assume you’re familiar with Seyfried’s work framing cancer as a metabolic disease.

    http://www.ncbi.nlm.nih.gov/pubmed/20181022
    http://www.amazon.com/Cancer-Metabolic-Disease-Management-Prevention/dp/0470584920

    And a long but interesting (to me, as a layperson) synopsis of the history of cancer research that mentions Seyfried’s work, as well:

    http://robbwolf.com/2013/09/19/origin-cancer/

    • That Robb Wolf article is fascinating. I had already bought and read part of Seyfried’s book Cancer as a Metabolic Disease, after seeing a YouTube video of him. This article makes me want to go home and read the rest of the book immediately. Thanks for posting. I look forward to Peter’s coming take on this topic.

  11. Is that the Tim Ferriss of “The 4 Hour Work Week” and other extreme self-help books (not Timothy Ferris, author of Coming of Age in the Milky Way)? I trust your judgement, but I’d be a little concerned that your appearing in his blog would look better on his CV than it would on yours. 🙁

    Do you really believe his claim that the supplement he developed (Brain Quicken) would dramatically increase short term memory within 60 minutes?

  12. Thanks for the article. I have something of an interest in this area since my uncle died from cancer and my sister-in-law is a breast cancer survivor. There is a very interesting article posted on Robb Wolf’s blog relating to cancer. It is by Travis M Christofferson. Here is the link: http://robbwolf.com/2013/09/19/origin-cancer/. The main context of the article is sugar’s role in cancer. He also touches on some of the points mentioned here.

    • Yes, I read the earlier (much more detailed, much longer) version of Travis’ piece a few months ago when he shared it with a friend and gave that friend permission to share with me.

  13. I’ve lost more than my share of close friends and loved ones to cancer. The only one who beat the odds in a big way was the one who zealously followed the so-called Pauling protocol (megadoses of vitamin C and certain amino acids). He may be the far outlier that his oncologist claimed he was, but it has always made me wonder why, after 40 years of zero progress in long-term survival of metastatic tumors, the leading researchers have not questioned their understanding of the underlying pathogenesis? I sincerely hope you represent the leading edge of effective new thinking about this, and anxiously await reading your posts on this. I sincerely hope that you write more than just a single blog entry for Tim.

  14. Hello Dr Attia, I love your blog and site NuSI. I see others have posted ab out Thomas Seyfried, there is also Dr Dr. Dominic D’Agostino and Dr Peter Pendersen who both are working on cancer from a metabolic stand point. One very promising development is 3-BP (3-Bromopyruvate) that Dr Penersen is one of the researchers of. There is also PD-1 that is working with the immune system. Here is a cut and paste from a biochemist friend of mine had posted ” To find a tumor-generated protein that inactivates T-cells was monumental. And it was only a matter of time before scientists countered with an antibody to prevent that protein from binding to PD-1. That has been done, and in a human clinical trial, it worked”.

    REFERENCE: http://www.nejm.org/doi/full/10.1056/NEJMoa1200690

  15. Excellent blog! It is great reading “out of the box” thinking on these important topics. Do you know who I could contact about detecting and tracking algorithms that may be applicable to finding cancers? I have a new algorithm that we think shows potential in this area.

  16. Peter, Thank you so much for this post. I’ve been waiting for you to turn your attention to cancer since I started following you this past spring. I’m the father of a 6 year old boy with a mixed-grade glioma and also the co-founder of a childhood cancer nonprofit (www.maxloveproject.com) that focuses on improving nutrition for families in treatment and survivorship. Your TED Talk and blogging pushed us to take a deeper look at the keto/cancer research and eventually to help interested families find experienced ketogenic dietitians. Because of recent unfavorable MRI scans, we’ve put our son on the KD and we’ve gone with him. Although there are many amazing people doing work in this area, your writing has had a big impact on us and many of the families that we work with (in fact, I wrote a short blog post last week about your impact: http://maxloveproject.org/blog/2013/9/27/maxlove-project-gets-personal-pt-3.) I write this all in order to say thank you! Keep doing what you’re doing!

    • Justin, I’m sorry to hear about what your little boy is going through. I can’t even imagine. I wish you all the best and I’m sorry we don’t have definitive answers to what to do.

  17. Peter, do you heard about kataegis e.g. hypermutation in somatic cells, like cancer cells (http://en.wikipedia.org/wiki/Kataegis), which could explain amount of mutation found in cancers. Maybe inhibitor for APOBEC class protein, which drive kataegis, in combination of chemotherapy could improve efficiency of chemotherapy it self, because maybe cancer cells couldn’t get resistance to chemotherapy so fast. Also in theory, these class of inhibitors shouldn’t so toxic to patient .

  18. Peter, many thanks for all you do.

    While reading your latest post, the library called to say Dr. Seyfried’s book was in. Thank you, Inter-Library Loan.

    Chapter 19, page 375 offers this: “In principle, there are few chronic diseases that are more easily preventable than cancer.”

    Too bad Mom, Dad, and numerous (female) cousins didn’t get this memo before they expired.

    Several other cousins and I have faired better, if you don’t mind losing a prostate, testicle, breast or cervix along the way.

    http://www.amazon.com/Cancer-Metabolic-Disease-Management-Prevention/dp/0470584920

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}' /> <input type='hidden' class='gform_hidden' name='is_submit_5' value='1' /> <input type='hidden' class='gform_hidden' name='gform_submit' value='5' /> <input type='hidden' class='gform_hidden' name='gform_unique_id' value='' /> <input type='hidden' class='gform_hidden' name='state_5' value='WyJbXSIsIjU1MGM3MDVmNDUwOTYxNmQyYTU0NTkwMjUzZjU2NGI1Il0=' /> <input type='hidden' class='gform_hidden' name='gform_target_page_number_5' id='gform_target_page_number_5' value='0' /> <input type='hidden' class='gform_hidden' name='gform_source_page_number_5' id='gform_source_page_number_5' value='1' /> <input type='hidden' name='gform_field_values' value='' /> </div> <p style="display: none !important;"><label>&#916;<textarea name="ak_hp_textarea" cols="45" rows="8" maxlength="100"></textarea></label><input type="hidden" id="ak_js_4" name="ak_js" value="57"/><script>document.getElementById( "ak_js_4" ).setAttribute( "value", ( new Date() ).getTime() );</script></p></form> </div>
[gravityform id="1" title="false" description="false"]
<div class='gf_browser_unknown gform_wrapper form--inline_wrapper gtm--newsletter-form_wrapper gform_legacy_markup_wrapper' id='gform_wrapper_1' ><form method='post' enctype='multipart/form-data' id='gform_1' class='form--inline gtm--newsletter-form gform_legacy_markup' action='/war-cancer/comment-page-1/' novalidate> <div class='gform_body gform-body'><ul id='gform_fields_1' class='gform_fields top_label form_sublabel_below description_below'><li id="field_1_1" class="gfield gfield_contains_required field_sublabel_below field_description_below gfield_visibility_visible" data-js-reload="field_1_1"><label class='gfield_label' for='input_1_1' >Email<span class="gfield_required"><span class="gfield_required gfield_required_asterisk">*</span></span></label><div class='ginput_container ginput_container_email'> <input name='input_1' id='input_1_1' type='email' value='' class='large' placeholder='Your email address' aria-required="true" aria-invalid="false" /> </div></li><li id="field_1_11" class="gfield gfield--width-full ohnohoney field_sublabel_below field_description_below gfield_visibility_hidden" data-js-reload="field_1_11"><div class='admin-hidden-markup'><i class='gform-icon gform-icon--hidden'></i><span>Hidden</span></div><label class='gfield_label' for='input_1_11' >H-o-n-e-y-p-o-t</label><div class='ginput_container ginput_container_text'><input name='input_11' id='input_1_11' type='text' value='' class='large' aria-invalid="false" /> </div></li><li id="field_1_10" class="gfield gfield--width-full field_sublabel_below field_description_below gfield_visibility_visible" data-js-reload="field_1_10"><label class='gfield_label' for='input_1_10' >CAPTCHA</label><div id='input_1_10' class='ginput_container ginput_recaptcha' data-sitekey='6LeuYQ0dAAAAAHQqB_Z3xNQAwCRlN5ykarrLsrZw' data-theme='dark' data-tabindex='-1' data-size='invisible' data-badge='bottomleft'></div></li><li id="field_1_2" class="gfield gform_hidden field_sublabel_below field_description_below 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data-js-reload="field_1_7"><div class='ginput_container ginput_container_text'><input name='input_7' id='input_1_7' type='hidden' class='gform_hidden' aria-invalid="false" value='' /></div></li><li id="field_1_6" class="gfield gform_hidden field_sublabel_below field_description_below gfield_visibility_visible" data-js-reload="field_1_6"><div class='ginput_container ginput_container_text'><input name='input_6' id='input_1_6' type='hidden' class='gform_hidden' aria-invalid="false" value='' /></div></li><li id="field_1_12" class="gfield gform_validation_container field_sublabel_below field_description_below gfield_visibility_visible" data-js-reload="field_1_12"><label class='gfield_label' for='input_1_12' >Email</label><div class='ginput_container'><input name='input_12' id='input_1_12' type='text' value='' autocomplete='new-password'/></div><div class='gfield_description' id='gfield_description_1_12'>This field is for validation purposes and should be left 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