Lemons as Gifts, Viruses for Good, Failure for Success and College Graduation: A Well-Intended Tale

You have all heard the oft tossed-around sanguine proverbial phrase: "If life gives you lemons, make lemonade," coined by American writer Elbert G. Hubbard, who unfortunately perished, paradoxically enough, aboard the RMS Lusitania, the ship infamously sunk by a German submarine near Ireland on May 7, 1915 (influencing the U.S. to declare war in 1917 on Germany). Or perhaps, you've encountered comedian Ron White's more humorous version: "I believe when life gives you lemons, you should make lemonade...and try to find someone whose life has given them vodka, and have a party."

This week, which happens to be the dreaded finals week at Columbia University (no vodka for anyone), whilst a friend bemoaned her life and stolen library seat (it truly becomes a war zone, folks), another said: "Well you know, if life gives you lemons, just be glad it wasn't herpes!"

Making lemonade out of herpes is just what researchers at Rice University have done last week. Well, metaphorically speaking. They used a different virus, and they made something a million times cooler than lemonade. They have created a tunable virus that works like a locked box. Two keys open the box, and its contents can be released to targeted areas via a nano-delivery system to fight diseases like cancer.

Because I took my virology final exam yesterday, this is my first story for you. But why would someone use a virus to fight a disease? Aren't viruses villainous abominations? No, despite the fact that viruses can cause humans much pain and suffering, very smart people have determined that they can be remarkable tools for beneficial uses. Just as we have the ability to make viruses non-infectious in order to vaccinate against the harmful viruses, we can make non-infectious viruses to use for other purposes (PA: get vaccinated! You help yourself and others by doing so! When a critical mass of people in a population are vaccinated and immunized against a disease, other members of society such as infants, pregnant women and immunocompromized persons who are ineligible for some vaccines get protection. This is called herd immunity.)

For example, in 1952, Martha Chase and Alfred Hershey utilized viruses to prove that DNA, instead of proteins, is central to heredity. They used bacteriophages, made of DNA and protein, to infect bacteria. They illustrated that the DNA enters the host bacteria cell, but the proteins mostly do not. Hershey later shared the 1969 Nobel Prize for findings related to the genetic configuration of viruses. In addition to their research benefits, viruses have remarkable applications to genetics and gene therapy, for they have the capacity to interact closely with the genome of the host.

I will explain a little bit about viruses so you can understand the research better (don't stop reading!) Viruses are intracellular parasites with DNA or RNA genomes. Viruses typically infect a host cell, replicate its genome in the host cells, and create new virions, or virus particles. This sometimes is harmful to the host, and sometimes it is not. An archetypal virus contains a protein outer shell called the capsid, which is composed of many copies of coat proteins that are displayed symmetrically. Some viruses have a lipid envelope, but some do not. Inside the capsid is the viral genome. This genome has the genes that will replicate inside the host. Viruses differ in size, and the ability to make certain proteins themselves. Many viruses rely on the host's protein replication machinery. A typical virus has either an icosahedral (sphere-like shape) or helical (rod-like shape) structure.

Researchers are now attempting to use viruses to fix genetic mutations in people with severe and debilitating diseases. The way they plan on doing this is by editing the genome of the virus, so that instead of harmful material for the person who will receive the virus, it contains a better version of the person's faulty genes. These viruses are called viral vectors.

Viral vectorology, a field that has been around for the last 30 years, specializes in making recombinant viral vectors to provide new genes to cells in mammals without harming the host. Now, many viral vectors, including those derived from adeno-associated viruses, adenoviruses, retroviruses and herpes simplex virus-1, have been shown to facilitate the expression of transgenes in various cell types successfully. The vectors only contain the most basic elements of viruses that enable gene delivery, and therefore they cannot possibly give someone the original disease their genomes are associated with. Pavel Osten, a researcher from Northwestern University who has authored papers on this topic, believes that gene therapy like this will eventually become the go-to treatment for diseases such as many destructive and untreatable brain disorders. Virus nanoparticle systems are very useful because of their variable properties including multivalency, genetic design, geometry and self-assembly. In addition, they exhibit beautiful symmetry, homogeneity of size and shape, and established surface chemistry involved in multiple particle interactions. Viruses are truly remarkable sometimes.

Self-assembly of nanoparticles is one component that has been at the heart of recent nanotechnology and nanoscience research. This feature has allowed viral nanoparticles to be applied to applications as diverse as the design of batteries and medical imaging. For example, small lithium batteries (that can increase power without weight) or new high-powered machines such as hybrid cars that can use these batteries and require elevated rates of energy provision can benefit from materials that can satisfy those requirements. Making robust materials for the electrodes of these batteries has been challenging for engineers. Viruses may be able to help in this regard. For example, researchers at MIT have utilized a modified virus called M13 to grow manganese oxide nanowires (about the width of a red blood cell) in water. The virus helps bind molecules of metal in the water into a precise structural design that is spiky. When these are mixed with palladium, lithium batteries have augmented energy potential because the surface area of wire increases (the spiky and rough nature of the surface promotes this feature). This then enlarges the area where the electrochemical reactions take place when batteries go through charging cycles.

However, there are concerns in the use of viral vectors such as targeted specificity. That is why this new research is groundbreaking. The study, published online in the American Chemical Society ACS Nano, and conducted in the Rice University lab of bioengineer Junghae Suh, uses an adeno-associated virus (AAV) that will unlock only when two keys, in the form of specific proteases, are present. Proteases are enzymes that cleave proteins, and activate other proteases through cutting or binding. Many AAVs have been made to try to target receptors that are heighted on diseased cells. However, this paper's focus on proteases specifically has many useful applications. In breast cancer, like many cancers, tumor cells release higher numbers of extracellular proteases and immune cells that come to the rescue also release elevated levels of proteases. The viruses in the study are locked until they meet the right protease "keys" at disease sites. After they unlock, they can bind to the cell and then convey their contents to the cell. These contents could either kill the cell, if it is cancerous for example, or deliver transgenes to repair the cell. In addition to cancer, heart and neurological diseases including Parkinson's and heart attacks exhibit elevated protease levels. As our imaging techniques for the molecular level improve, specific proteases and their number will be able to identified at target disease spots. Then, in the future, viruses can be engineered for those specific variables.

The lab genetically appended proteins to the self-assembling AAVs. The proteases then cleaved these peptides, thus removing the locks and allowing the virus to bind to the target cells. Most importantly, the protease activatable viruses or PAVs that were created operate like a digital AND gate, thus requiring not one, but two, keys to unlock them. If the PAV was targeted at only one protease, it may be present at other places in the body that are inflamed, not just at the selected disease area. By requiring two proteases, delivery specificity is enhanced. Ultimately, these AAVs could include more combinatorial keys to unlock the virus, composed of a mix of enzymes and cell receptors.

Therefore, the moral of the story is: things that seem horrible, no-good, bad and ugly at first sight may offer unbelievable potential for good. This has been a recurring theme in my life, and I believe it is one of the most salient things I have truly learned during my time at Columbia. But you have to take an active role to flip negative changes or realizations or effects on their head. If these researchers can do these amazing things with viruses, which most people thought for a very long time were only bad, to actually help people, then I urge you today to try just a little bit harder to do the same, no matter what your particular problem may be. Your breakup or lost job or stolen peony plants from your porch in Texas (a serious problem my father once experienced) holds wild potential for the future. Be imaginative. Albert Einstein said: "In the middle of difficulty lies opportunity." The best opportunities for imaginative, innovative, positive change may only arise with loss. There is an opportunity cost to everything, and sometimes those costs are worth exploring. Fear, comfort and satisfaction can impede genius and progress. Henry Ford reminded us: "When everything seems to be going against you, remember that the airplane takes off against the wind, not with it." When you have no control over lost opportunities, the only direction to move is forward. And you may never take those steps unless you are forced to by your circumstances.

Rumi once wrote, "The wound is the place where the Light enters you." Pain is a gift. Not just emotional pain, but physical pain as well. Pain naturally guides us in the right direction, moving away from harm. It teaches us to do things differently. There is a rare genetic disorder called congenital insensitivity to pain. Many individuals with the disorder have a mutation in their SCN9A gene, something that was fairly recently discovered, in 2006 by geneticist Geoffrey Woods. People who have it are unable to feel pain, and often suffer from mutilation, and early death. Children with the disorder accidentally and unknowingly break their own bones and walk around on them for weeks and give themselves third-degree burns.

I graduate from college in seven days. Although I have done almost everything in my power to enact the wonderful analgesic known as denial, graduation has been on my mind. An integral part of graduation is commencement, where at Columbia, our beautiful repose of a quad transforms into a sea of light blue gowns and hats to the tune of Frank Sinatra's New York, New York. My beleaguered and hilarious friend at Georgetown University recently texted me a picture of the Wikipedia page for Guy Consolmagno: "This is the commencement speaker for Georgetown College. Sounds like a fucking joke but I assure you it is not... Bill Clinton was here yesterday, Biden and Obama have spoken here recently...Maria Shriver, Warren Buffet too. But why do something nice for commencement when you can have a Vatican astronomer!? Our school of foreign service got Robert Gates. And we got a Vatican astronomer." I do not wish to overly degrade Guy, who may very well be a very nice guy. But someone who believes that the apparently ludicrous idea in contemporary society that religion and science are competing ideologies is a "destructive myth"and that science requires religion to have a conscience, may not deliver the most agreeable speech one is forced to suffer through in 80 degree heat.

In my last story to you, I would like to recount three of the most sage and enjoyable commencement speeches I have ever heard, and explain the threads that wind them together. Very successful people, from three very disparate fields to which I am particularly partial, gave the speeches: Steve Jobs (Stanford, 2005), Conan O'Brien (Harvard, 2000), and J.K. Rowling (also Harvard, 2008). All of these speakers, not despite, but because of their success, spoke of the outlying benefits of failure and loss.

Steve Jobs spoke of three personal stories concerning connections, love, loss and death. I was astounded to first hear that he was given up for adoption initially to a lawyer and his wife that rejected him because they "wanted a girl" (imagine what they feel like now), dropped out of college, to save the working class couple that never went to college but ended up adopting him, money, lived on a dorm room floor and returned coca cola bottles for five cents to eat, and was fired from the very company he started. He says that dropping out was "one of the best decisions I ever made." He realized he could take the classes that truly fascinated him, instead of just the requirements. One of these classes was a calligraphy class. He did not believe that anything he learned would be useful for his life. But he said, "ten years later, when we were designing the first Macintosh computer, it all came back to me...It was the first computer with beautiful typography." He started Apple, the company we all love (and hate when our iPhone battery dies in forty-five minutes). The Macintosh was announced, and Jobs celebrated his thirtieth birthday. And then he got an unwelcome surprise; he was fired from the very company he started and the Board of Directors ousted him when his vision disagreed with the person he had hired to co-run Apple with him. He referred to it as "devastating." But then he said, "I didn't see it then, but it turned out that getting fired from Apple was the best thing that could have ever happened to me. The heaviness of being successful was replaced by the lightness of being a beginner again... It freed me to enter one of the most creative periods of my life." He moved on to start NeXT, Pixar (the company to create the first computer animated feature film - Toy Story - duh) and fell in love and got married. What happened next was equally surprising as his dismissal; Apple bought NeXT and he returned. The technology from NeXT formed the core of Apple's resurgence. As we know, Jobs sadly passed away from pancreatic cancer six years after his speech. In 2005, he had already been diagnosed for two years. He wisely said: "Remembering that I'll be dead soon is the most important tool I've ever encountered to help me make the big choices in life. Because almost everything -- all external expectations, all pride, all fear of embarrassment or failure - these things just fall away in the face of death." For the last half of his life, he looked at himself in the mirror in the morning and asked himself, if he were to die today, would he change what he was planning to do next? When the yes' piled up, he changed his course. "No one has ever escaped it. And that is as it should be, because Death is very likely the single best invention of Life. It is Life's change agent. It clears out the old to make way for the new."

The next speech, to lighten the mood, was delivered in a spectacular fashion by the riotous Conan O'Brien. After graduating from Harvard, a fact he perennially jokes people never let escape when he does stupid things, he moved to Los Angeles, rented a shack of an apartment and owned a car that "Isuzu only manufactured for a year because they found out that technically it's not a car." He was fired from his first job after a year and had no money. He searched for work everywhere. Finally, after a curious array of temporary jobs, he got onto a network. The reviled show was canceled after a month to the sound of resounding applause. Conan recalls, "This was what the most respected and widely read television critic, Tom Shales, wrote in the Washington Post. 'O'Brien is a living collage of annoying nervous habits... He has dark, beady little eyes like a rabbit. He is one of the whitest white men ever. Let the Late Show with Conan O'Brien become the late Late Show...' There's more, but it gets kind of mean." But he concludes with the final phrase: "My mistakes have been necessary... each time it was bruising and tumultuous. And yet every failure was freeing, and today I'm as nostalgic for the bad as I am for the good. So that's what I wish for all of you--the bad as well as the good. Fall down. Make a mess. Break something occasionally. Know that your mistakes are your own unique way of getting to where you need to be. And remember that the story is never over." He concludes with a current rave review of his comedic genius...That he wrote himself "this morning"... Delusion and comedy are always there initially when the seas get rough. But do not settle with them. Also, as every girl an Audrey Hepburn fan knows, laughter is the best prescription (yeah, I just basely used a synonym to avoid too many clichés today) to burn calories.

The last speech completes the circle perfectly. Rowling had two major themes to her speech: the "fringe benefits" of failure and the weight of imagination. I have urged you to use your imagination to turn your failures into even greater successes. To take what is commonly thought to be bad, and use it for change, for good. Rowling explains that only seven years after she was in my shoes, she was divorced, jobless, a single parent and terribly poor. She claims, "By every usual standard, I was the biggest failure I knew." She intimates that her failure taught her things about herself that she would never have learned otherwise.

The very first day of my junior year here I lost some of my best friends, my lovely apartment arrangement, my loving boyfriend, my good health, and (only briefly following) some of my sanity in one fell swoop. But during those weeks, my outlook on life changed. I immediately became, I am still not sure how to this day, a calmer, more understanding, and less irate person. I managed to change flaws in emotional reactions, perceptions and perspectives that I had always cognitively been aware of, but never had the force to alter. Although my semester, and year, were challenging, I have never been happier today, or prouder of myself. I know I am a better person because of it, and I am so grateful now for the array of things I once cursed and deplored. I also lost a lot of weight, which was really an unexpected plus. But in all seriousness, I began to get to know my professors more closely (something I encourage everyone in college to prioritize), I started to regain the intensity and creativity I had lost in my complacent happiness, and I met new beautiful friends in the most unlikely places that I will treasure for life. I also gained the best gift of all: living and breathing without the regrets I would surely have had, had my life not altered so.

Failure for J.K. Rowling entailed eliminating the inessential. She was freed. She says, "I stopped pretending to myself that I was anything other than what I was, and began to direct all my energy into finishing the only work that mattered to me." If she had been successful earlier, in a more conventional way, we never would have been graced with the magical world she created in the cavity of her skull, and the 700 page books we delightfully raced through as kids ("I read it in only seven hours." "Well, I read it in five." "No way!!").

Her next advice could not be said more impeccably: "The knowledge that you have emerged wiser and stronger from setbacks means that you are, ever after, secure in your ability to survive. You will never truly know yourself, or the strength of your relationships, until both have been tested by adversity. Such knowledge is a true gift, for all that it is painfully won, and it has been worth more than any qualification I ever earned."

She concludes with an encouragement to imagine. For "Imagination is not only the uniquely human capacity to envision that which is not, and therefore the fount of all invention and innovation. In its arguably most transformative and revelatory capacity, it is the power that enables us to empathize with humans whose experiences we have never shared."

She worked in Amnesty International's African research department in London after college. She read, saw and heard tales of horrible actions and conditions beset on people around the world. She says she was also inspired by the remarkable goodness pervading humanity. She witnessed people, out of empathetic concern, help those whose situations they could not possibly understand. Although penniless at the time, J.K. Rowling now happens to not only be the first billionaire female author, but also the first to drop off the Forbes annual list of billionaires for charitable donation, a substantial amount of which has been directed at Amnesty.

"Unlike any other creature on this planet, humans can learn and understand, without having experienced. They can think themselves into other people's places." Although, this theory of mind and empathetic concern likely does apply to other creatures, the importance of her message is undiminished.

Become a better person. Use your failures and misgivings to enact positive change that will help others. Or alter something bad into something good to do the same. Just as researchers this week found a way to create a possible novel solution for cancer treatment out of something most people avoid like the plague (pun intended), embrace your failures for the opportunities they emit. I would like to end with the same quote Rowling draws upon, from the Greek author Plutarch. "What we achieve inwardly will change outer reality." Alter your perspective about what, at first-glance, seemed nothing but bad. See the opportunity, see the freedom for change. Have you ever stood in the wind, on top of a mountain, a beach overlooking a swath of wine dark sea, a smoky city roof or even in front of your open window and closed your eyes and smiled? It's that feeling.